On May 16, 2019 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that four abstracts featuring data for Rubraca (rucaparib) and ongoing studies in multiple tumor types will be presented at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place May 31 – June 4 in Chicago (Press release, Clovis Oncology, MAY 16, 2019, View Source [SID1234536406]).

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The accepted abstracts summarize clinical trials in which Rubraca is being evaluated as a single agent and as combination therapy with nivolumab in a variety of solid tumor types including ovarian, prostate, biliary tract and endometrial cancers. These include additional genomic profiling data from TRITON2, and new data from extended follow up of patients in ARIEL3.

"Increased understanding about the role of genomic mutations, as well as the growing number and type of oncology therapies, offer tremendous potential for us to more precisely target and improve treatment of the most challenging cancers," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "In our own clinical development program and in investigator-led studies, we are evaluating the utility of Rubraca in multiple solid tumor types where there is genomic rationale, including among patients with BRCA1/2 mutations as well as mutations in other genes that play a role in DNA repair."

The two Clovis Oncology-sponsored abstracts accepted for presentation at the 2019 ASCO (Free ASCO Whitepaper) Annual Meeting comprise:

Abstract 5031 (Poster Board #143) – Genomic characteristics of deleterious BRCA1 and BRCA2 alterations and associations with baseline clinical factors in patients with metastatic castration-resistant prostate cancer enrolled in TRITON2

Presenter: Wassim Abida, MD, PhD
Session: Genitourinary (Prostate) Cancer
Date/Time: Saturday, June 1, 1:15-4:15 p.m. Central Daylight Time (CDT)
Location: Hall A
Abstract 5522 (Poster Board #345) – Exploratory analysis of the effect of maintenance rucaparib on post-progression outcomes in patients with platinum-sensitive recurrent ovarian carcinoma and updated safety data from the phase 3 study ARIEL3

Presenter: Robert L. Coleman, MD, FACOG, FACS
Session: Gynecologic Cancer
Date/Time: Saturday, June 1, 1:15-4:15 p.m. CDT
Location: Hall A
This poster (abstract #5522) will be discussed at the associated poster discussion session on Saturday, June 1, 4:30-6:00 p.m. CDT in Room S406.

The two Clovis-sponsored posters will be available online at View Source once they are presented at the meeting.

Additionally, two investigator-sponsored abstracts describing combination studies of Rubraca and nivolumab trials in progress are also being presented:

Abstract TPS2663 (Poster Board #297b) – A phase Ib/IIa study of rucaparib (PARP inhibitor) combined with nivolumab in metastatic castrate-resistant prostate cancer and advanced/recurrent endometrial cancer

Presenter: Raanan Alter, MD
Session: Developmental Immunotherapy and Tumor Immunobiology
Date/Time: Saturday, June 1, 8:00-11:00 a.m. CDT
Location: Hall A
Abstract TPS4153 (Poster Board #252a) – A multi-center phase II trial of rucaparib in combination with nivolumab as maintenance therapy for patients with advanced biliary tract cancer

Presenter: Vaibhav Sahai, MD
Session: Gastrointestinal (Noncolorectal) Cancer
Date/Time: Monday, June 3, 8:00-11:00 a.m. CDT
Location: Hall A
About Rubraca (rucaparib)

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian and metastatic castration-resistant prostate cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway.

Rubraca U.S. FDA Approved Indications

Rubraca is indicated as monotherapy for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Rubraca is indicated as monotherapy for the treatment of adult patients with deleterious BRCA mutations (germline and/or somatic) associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies and selected for therapy based on an FDA-approved companion diagnostic for Rubraca.

Select Important Safety Information

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur uncommonly in patients treated with Rubraca, and are potentially fatal adverse reactions. In approximately 1100 treated patients, MDS/AML occurred in 12 patients (1.1%), including those in long-term follow-up. Of these, five occurred during treatment or during the 28-day safety follow-up (0.5%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 28 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA-damaging agents. Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1).

Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose (see Dosage and Administration [2.2] in full Prescribing Information) and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample cytogenetic analysis. If MDS/AML is confirmed, discontinue Rubraca.

Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca.

Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1–4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%) and neutropenia (20%).

Most common laboratory abnormalities in ARIEL3 (≥ 25%; Grade 1–4) were increase in creatinine (98%), decrease in hemoglobin (88%), increase in cholesterol (84%), increase in alanine aminotransferase (ALT) (73%), increase in aspartate aminotransferase (AST) (61%), decrease in platelets (44%), decrease in leukocytes (44%), decrease in neutrophils (38%), increase in alkaline phosphatase (37%) and decrease in lymphocytes (29%).

Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%; Grade 1–4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%) and thrombocytopenia (21%).

Most common laboratory abnormalities in Study 10 and ARIEL2 (≥ 35%; Grade 1–4) were increase in creatinine (92%), increase in alanine aminotransferase (ALT) (74%), increase in aspartate aminotransferase (AST) (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%) and decrease in absolute neutrophil count (35%).

Co-administration of Rubraca can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring. Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose. You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Clovis Oncology, Inc. at 1-844-258-7662.

Click here or full Prescribing Information and additional Important Safety Information.

Rubraca ▼ (rucaparib) EU Authorized Use and Important Safety Information

Rucaparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.

Rucaparib is indicated as monotherapy treatment of adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with two or more prior lines of platinum-based chemotherapy, and who are unable to tolerate further platinum-based chemotherapy.

Summary warnings and precautions: Haematological toxicity: Patients should not start Rubraca until they have recovered from haematological toxicities caused by previous chemotherapy (≤ CTCAE Grade 1). Complete blood count testing prior to starting treatment with Rubraca and monthly thereafter is advised. Rubraca should be interrupted or dose reduced and blood counts monitored weekly until recovery for the management of low blood counts. Myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML): If MDS/AML is suspected, the patient should be referred to a haematologist for further investigation. If MDS/AML is confirmed, Rubraca should be discontinued. Photosensitivity: Patients should avoid spending time in direct sunlight as they may burn more easily. When outdoors, patients should wear protective clothing and sunscreen with SPF of 50 or greater. Gastrointestinal toxicities: Low grade (CTCAE Grade 1 or 2) nausea and vomiting may be managed with dose reduction or interruption. Additionally, antiemetics may be considered for treatment or prophylaxis.

Click here to access the current Summary of Product Characteristics. Healthcare professionals should report any suspected adverse reactions via their national reporting systems.

On May 16, 2019 Cellectar Biosciences, Inc. (NASDAQ: CLRB), a clinical stage biopharmaceutical company focused on the discovery, development and commercialization of drugs for the treatment of cancer, reported that it has entered into definitive agreements with institutional investors to purchase approximately $5.0 million in a registered direct offering of 1,982,000 common shares and approximately $5.0 million in a concurrent private placement of 2,018,000 common shares (Press release, Cellectar Biosciences, MAY 16, 2019, View Source [SID1234536405]). In conjunction with the offerings the company issued 4,000,000 unregistered warrants to purchase common stock.

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The offerings are expected to result in total gross proceeds of $10.0 million before deducting estimated offering expenses. The company intends to use the net proceeds from the offering for research and development, funding clinical studies, working capital and general corporate purposes. The shares of common stock and warrants were priced at $2.50 per fixed combination. The warrants sold in the private placement will be exercisable immediately, expire five years after the date of issuance, and have an exercise price of $2.40.

Roth Capital Partners served as sole placement agent for the transaction. The offering is expected to close on May 20, 2019, subject to customary closing conditions.

The registered offering described above is being made pursuant to a Registration Statement previously filed with and subsequently declared effective by the Securities and Exchange Commission ("SEC"). Copies of the prospectus supplement and accompanying base prospectus relating to the registered offering may be obtained, when available, from Roth Capital Partners, 888 San Clemente Drive, Suite 400, Newport Beach, CA 92660, (800) 678-9147 or by accessing the SEC’s website, www.sec.gov.

The unregistered common shares and warrants were offered pursuant to the exemption from registration afforded by Section 4(a)(2) under the Securities Act of 1933, as amended (the "Act"), and Regulation D promulgated thereunder. Such common shares, warrants and common shares issuable upon exercise of such warrants have not been registered under the Act, and may not be offered or sold in the United States absent registration with the SEC or an applicable exemption from such registration requirements. The Company has agreed to file a registration statement registering for resale the unregistered common shares and common shares issuable upon exercise of the warrants within fifteen days of today’s date.

This press release shall not constitute an offer to sell or the solicitation of an offer to buy any of the securities described herein, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On May 16, 2019 Celgene Corporation (NASDAQ:CELG), reported that the European Commission (EC) has approved two new triplet regimens based on Celgene’s proprietary IMiD treatments, REVLIMID (lenalidomide) and IMNOVID (pomalidomide) (Press release, Celgene, MAY 16, 2019, View Source [SID1234536404]).

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REVLIMID in combination with bortezomib and dexamethasone (RVd), is now indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for transplant. In addition, IMNOVID, in combination with bortezomib and dexamethasone (PVd), is now indicated for the treatment of adult patients with multiple myeloma who have received at least one prior treatment regimen including lenalidomide.

"The approval of these combination therapies marks a significant milestone for patients with multiple myeloma in Europe," said Nadim Ahmed, President of Hematology/Oncology for Celgene. "With these new triplet regimens we hope to improve outcomes for both newly diagnosed patients as well as those who have relapsed or become refractory to first-line therapy. IMiD agents have brought significant benefit to multiple myeloma patients and we are committed to advancing our pipeline of novel myeloma treatments in order to ensure physicians and patients continue to have new treatment options available to fight this disease."

The choice of treatment in a first-line therapy setting is important1 as patients progressively become less responsive to therapy, and experience shorter periods of remission at later lines of treatment.2 Studies have shown that RVd can provide newly diagnosed patients that are not eligible for a transplant with a treatment option that significantly prolongs the first remission.3

"Determining first-line therapy is an important consideration in the overall treatment plan for patients with multiple myeloma," said Prof. Thierry Facon, Professor of Haematology in the Department of Haematology, Lille University Hospital, France. "Since REVLIMID in combination with dexamethasone is already a standard of care in multiple myeloma, we’re excited by the prospect of a new REVLIMID-based triplet option for previously untreated patients who are not eligible for transplant."

The approval for the REVLIMID triplet (RVd) was supported by data from SWOG S07773, a phase 3 trial evaluating the triplet combination, RVd, in adult patients with previously untreated multiple myeloma.

"Today’s approval for use of the IMNOVID-containing triplet, PVd, as early as first relapse, underscores the potential clinical benefit this regimen can provide to patients following a prior treatment including REVLIMID," said Prof. Meletios Dimopoulos, Professor and Chairman of the Department of Clinical Therapeutics at the University Athens School of Medicine, Athens, Greece. "REVLIMID-based regimens are often used as a standard of care in newly diagnosed multiple myeloma patients, and there is a growing patient population who become refractory to REVLIMID and need proven treatment options."

The approval of the IMNOVID triplet (PVd) was supported by data from OPTIMISMM4, the first prospective phase 3 trial to evaluate an IMNOVID-based triplet regimen in patients who were all previously treated with REVLIMID, and the majority (70%) of patients were REVLIMID refractory. Results from OPTIMISMM were recently published in TheLancet Oncology.

Pomalidomide in combination with bortezomib and dexamethasone (PVd) is not approved for any use in the United States

Lenalidomide in combination with bortezomib and dexamethasone (RVd) is not approved for any use in the United States.

About Multiple Myeloma

Multiple myeloma is a life-threatening blood cancer that is characterized by tumor proliferation and suppression of the immune system.5,6 It is a rare but deadly disease – around 42,000 people are diagnosed with multiple myeloma in Europe, and approximately 26,000 people die from the disease each year.7 The typical multiple myeloma disease course includes periods of symptomatic myeloma followed by periods of remission, and eventually, the disease becomes refractory (nonresponsive).8

About SWOG S0777

SWOG S0777 is a randomized, open-label, multicentre, phase 3 study aiming to evaluate the efficacy and safety of RVd compared to Rd in treating patients with newly diagnosed multiple myeloma (ndMM) who were not intending on immediately receiving ASCT.3

SWOG S0777 recruited 525 patients with symptomatic and measurable ndMM aged 18 years and older. Patients were randomly assigned (1:1) to receive either an initial treatment of lenalidomide with bortezomib and dexamethasone (RVd group) or lenalidomide and dexamethasone alone (Rd group) both followed by standard Rd until disease progression. Randomization was stratified based on International Staging System stage (I, II, or III) and intent to transplant (yes versus no). The RVd regimen was given as eight 21-day cycles. Bortezomib was given at 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, combined with oral lenalidomide 25 mg daily on days 1-14 plus oral dexamethasone 20 mg daily on days 1, 2, 4, 5, 8, 9, 11, and 12. The Rd regimen was given as six 28-day cycles. The standard Rd regimen consisted of 25 mg oral lenalidomide once a day for days 1-21 plus 40 mg oral dexamethasone once a day on days 1, 8, 15, and 22.3

Results from SWOG S07773 showed that median progression-free survival (PFS) was significantly improved in patients receiving RVd compared to those receiving REVLIMID and dexamethasone (Rd) alone (42 months versus 30 months; HR 0.76, 95% CI 0.62-0.94; P=0.01). Median overall survival was also significantly improved in patients receiving RVd compared to those receiving Rd (89 months versus 67 months; HR 0.72, 95% CI 0.56–0.94; P=0.013). The rates of overall and complete response were higher in those receiving RVd compared to Rd (overall response: 82% RVd vs 72% Rd; complete response: 16% RVd vs 8% Rd) the duration of response was also significantly longer in those receiving RVd compared to Rd (52 months vs 38 months, respectively).3 The safety of RVd was also consistent with the well-established safety profiles of each drug in the triplet regimen.3

Upon completion of induction, all patients received ongoing maintenance with 25 mg oral lenalidomide once a day for 21 days plus 40 mg oral dexamethasone once a day for days 1, 8, 15, and 22 of each 28-day cycle.3

About OPTIMISMM

OPTIMISMM is the first phase 3 trial designed to compare the safety and efficacy of PVd versus Vd, as an early line of therapy in patients with relapsed and refractory multiple myeloma (with 1-3 prior regimens of therapy) and prior REVLIMID-exposure, including REVLIMID-refractory patients.4

The multi-center, international, open-label, randomized phase 3 clinical trial included 559 patients (281 patients in the PVd arm and 278 in the Vd arm). Demographic, baseline, and prior disease characteristics were generally well balanced between the two treatment arms. The median number of prior lines of therapy was two, while more than one third had one prior line of treatment (40% across both treatment arms). All patients had prior treatment with REVLIMID with the majority being REVLIMID refractory (71%in the PVd arm vs 69% in the Vd arm) and 70% vs 66%, respectively, were refractory to their last treatment. Median follow-up was 16 months.4

Patients were stratified based on age, number of prior anti-myeloma regimens, and β2-microglobulin levels. Patients were randomized 1:1 to receive PVd or Vd until disease progression. In 21-day cycles, patients received IMNOVID 4 mg/d on days 1-14 (PVd arm only); bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of cycles 1-8 and on days 1 and 8 of cycles 9 and beyond; and dexamethasone 20 mg/d (10 mg if aged > 75 years) on the days of and after receiving bortezomib treatment.4

Results from OPTIMISMM4 showed that patients receiving PVd achieved a significantly longer PFS than those in the Vd treatment arm (median PFS 11.2 months vs. 7.1 months, respectively [P= < .0001, HR 0.61; 95% CI: (0.49-0.77)]), reducing the risk of disease progression or death by 39% in the PVd arm. In an exploratory sub-group analysis of patients with one prior line of therapy, median progression-free survival with PVd was 20.7 months vs 11.6 months with Vd (95% CI: 7.52, 15.74). In these patients, the benefit of PVd was observed independent of whether they were refractory or non-refractory to prior therapy with lenalidomide.

Neutropenia (PVd 42% vs Vd 9%), infections (PVd 31% vs Vd 18%), and thrombocytopenia (PVd 27% vs Vd 29%) were among the most frequently reported grade 3/4 treatment-emergent adverse events. Rates of grade 3/4 deep vein thrombosis (PVd: 0.7% versus Vd: 0.4%) and pulmonary embolism (PVd: 4.0% versus Vd: 0.4%) were low, and no events were fatal. Second primary malignancies occurred in 3.2% of patients treated with PVd and 1.5% of patients treated with Vd. The most common reason for treatment discontinuation was progressive disease. Patients discontinuing treatment due to adverse events were 10.7% for PVd versus 17.6% for Vd. The safety of PVd was consistent with the well-established safety profiles of each drug in the triplet therapy.4

About Celgene’s Immunomodulatory Drugs

IMiD agents are Celgene’s proprietary small molecule, orally available compounds for the treatment of some blood cancers. IMiD agents are hypothesized to have multiple mechanisms of action. They have been found to increase activation and proliferation of T cells, and proliferation of the IL-2 protein and activity of CD8+ effector T cells. IMiD agents have also been found to affect the stimulation and expression of natural killer (NK) cells, working within the environment of the cell to stimulate the immune system to attack the cancer cells, as well as attack the cancer cells directly. In addition to immunomodulatory properties, IMiD agents are hypothesized to have tumoricidal and antiangiogenic activity. Celgene’s portfolio of IMiD agents have become a foundation of multiple myeloma research, with a growing number of studies exploring these compounds as combination partners across a range of settings of the disease.

U.S. Safety Information

ABOUT POMALYST/IMNOVID

Indication

POMALYST (pomalidomide) is a thalidomide analogue indicated, in combination with dexamethasone, for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM
Embryo-Fetal Toxicity

POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment.
Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment.
POMALYST is only available through a restricted distribution program called POMALYST REMS .

Venous and Arterial Thromboembolism

Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Prophylactic antithrombotic measures were employed in clinical trials. Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.

CONTRAINDICATIONS

Pregnancy : POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If POMALYST is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus.
WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity & Females of Reproductive Potential: See Boxed WARNINGS
Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm.
Blood Donation: Patients must not donate blood during treatment with POMALYST and for 4 weeks following discontinuation of POMALYST therapy because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST.
POMALYST REMS Program: See Boxed WARNINGS
Prescribers and pharmacies must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive POMALYST. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements.
Further information about the POMALYST REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436.
Venous and Arterial Thromboembolism: See Boxed WARNINGS. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.
Increased Mortality with Pembrolizumab : In clinical trials in patients with multiple myeloma, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.
Hematologic Toxicity : Neutropenia (46%) was the most frequently reported Grade 3/4 adverse reaction in patients taking POMALYST in clinical trials, followed by anemia and thrombocytopenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification.
Hepatotoxicity : Hepatic failure, including fatal cases, has occurred in patients treated with POMALYST. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST. Monitor liver function tests monthly. Stop POMALYST upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.
Severe Cutaneous Reactions Including Hypersensitivity Reactions : Angioedema and severe cutaneous reactions including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe cutaneous reactions such as SJS, TEN or DRESS, and do not resume therapy.
Dizziness and Confusional State : In patients taking POMALYST in clinical trials, 14% experienced dizziness (1% Grade 3 or 4) and 7% a confusional state (3% Grade 3 or 4). Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.
Neuropathy : In patients taking POMALYST in clinical trials, 18% experienced neuropathy (2% Grade 3 in one trial) and 12% peripheral neuropathy.
Second Primary Malignancies : Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.
Tumor Lysis Syndrome (TLS) : TLS may occur in patients treated with POMALYST. Patients at risk are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
ADVERSE REACTIONS

The most common adverse reactions for POMALYST (≥30%) included fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper-respiratory tract infections, back pain, and pyrexia.

In the phase III trial, nearly all patients treated with POMALYST + low-dose dex experienced at least one adverse reaction (99%). Adverse reactions (≥15% in the POMALYST + low-dose dex arm and ≥2% higher than control) included neutropenia (51.3%), fatigue and asthenia (46.7%), upper respiratory tract infection (31%), thrombocytopenia (29.7%), pyrexia (26.7%), dyspnea (25.3%), diarrhea (22%), constipation (21.7%), back pain (19.7%), cough (20%), pneumonia (19.3%), bone pain (18%), edema peripheral (17.3%), peripheral neuropathy (17.3%), muscle spasms (15.3%), and nausea (15%). Grade 3 or 4 adverse reactions (≥15% in the POMALYST + low-dose dex arm and ≥1% higher than control) included neutropenia (48.3%), thrombocytopenia (22%), and pneumonia (15.7%).

DRUG INTERACTIONS

Avoid concomitant use of POMALYST with strong inhibitors of CYP1A2. Consider alternative treatments. If a strong CYP1A2 inhibitor must be used, reduce POMALYST dose by 50%.

USE IN SPECIFIC POPULATIONS

Pregnancy: See Boxed WARNINGS. If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. There is a POMALYST pregnancy exposure registry that monitors pregnancy outcomes in females exposed to POMALYST during pregnancy as well as female partners of male patients who are exposed to POMALYST. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
Lactation : There is no information regarding the presence of pomalidomide in human milk, the effects of POMALYST on the breastfed child, or the effects of POMALYST on milk production. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child from POMALYST, advise women not to breastfeed during treatment with POMALYST.
Pediatric Use : Safety and effectiveness have not been established in pediatric patients.
Geriatric Use : No dosage adjustment is required for POMALYST based on age. Patients >65 years of age were more likely than patients ≤65 years of age to experience pneumonia.
Renal Impairment : Reduce POMALYST dose by 25% in patients with severe renal impairment requiring dialysis. Take dose of POMALYST following hemodialysis on hemodialysis days.
Hepatic Impairment : Reduce POMALYST dose by 25% in patients with mild to moderate hepatic impairment and 50% in patients with severe hepatic impairment.
Smoking Tobacco : Advise patients that smoking may reduce the efficacy of POMALYST. Cigarette smoking reduces the AUC of pomalidomide by 32% by CYP1A2 induction.
Please see full Prescribing Information , including Boxed WARNINGS.

Please see full SmPC for more information.

About REVLIMID

REVLIMID (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM)

REVLIMID is indicated as maintenance therapy in patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT)

REVLIMID is indicated for the treatment of patients with transfusion-dependent anemia due to low-or intermediate-1–risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities

REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib

REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity

Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS program.

Information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)

REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism

REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus

Severe Hypersensitivity Reactions: REVLIMID is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: See Boxed WARNINGS

Females of Reproductive Potential: See Boxed WARNINGS
Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm
Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID
REVLIMID REMS Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the REVLIMID REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements

Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia.Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex or REVLIMID as maintenance therapy should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. MDS: Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or dose reduction. Please see the Black Box WARNINGS for further information. MCL: Patients taking REVLIMID for MCL should have their CBCs monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction

Venous and Arterial Thromboembolism: See Boxed WARNINGS: Venous thromboembolic events (DVT and PE) and arterial thromboses (MI and CVA) are increased in patients treated with REVLIMID. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended and the regimen should be based on patient’s underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision

Increased Mortality in Patients with CLL: In a clinical trial in the first-line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving REVLIMID, an increase of hematologic plus solid tumor SPM, notably AML and MDS, have been observed. Monitor patients for the development of SPM. Take into account both the potential benefit of REVLIMID and risk of SPM when considering treatment

Increased Mortality with Pembrolizumab: In clinical trials in patients with multiple myeloma, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID/dex. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered

Severe Cutaneous Reactions Including Hypersensitivity Reactions: Angioedema and severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash, or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS, TEN, or DRESS is suspected and should not be resumed following discontinuation for these reactions

Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken

Tumor Flare Reaction (TFR): TFR has occurred during investigational use of lenalidomide for CLL and lymphoma. Monitoring and evaluation for TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤Grade 1. REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment (>4 cycles) with REVLIMID has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection

Thyroid Disorders: Both hypothyroidism and hyperthyroidism have been reported. Measure thyroid function before start of REVLIMID treatment and during therapy

Early Mortality in Patients with MCL: In another MCL study, there was an increase in early deaths (within 20 weeks), 12.9% in the REVLIMID arm versus 7.1% in the control arm. Risk factors for early deaths include high tumor burden, MIPI score at diagnosis, and high WBC at baseline (≥10 x 109/L)

ADVERSE REACTIONS

Multiple Myeloma

In newly diagnosed: The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more Grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18
The most common adverse reactions reported in ≥20% (Arm Rd Continuous): diarrhea (46%), anemia (44%), neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash (26%), decreased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%), abdominal pain (21%), muscle spasms (20%), and thrombocytopenia (20%)
Maintenance Therapy Post Auto-HSCT: The most frequently reported Grade 3 or 4 reactions in ≥20% (REVLIMID arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions of lung infection and neutropenia (more than 4.5%) occurred in the REVLIMID arm
The most frequently reported adverse reactions in ≥20% (REVLIMID arm) across both maintenance studies (Study 1, Study 2) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%)
After at least one prior therapy: The most common adverse reactions reported in ≥20% (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), and weight decreased (20% vs 15%)
Myelodysplastic Syndromes

Grade 3 and 4 adverse events reported in ≥ 5% of patients with del 5q MDS were neutropenia (53%), thrombocytopenia (50%), pneumonia (7%), rash (7%), anemia (6%), leukopenia (5%), fatigue (5%), dyspnea (5%), and back pain (5%)
Adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): thrombocytopenia (61.5%), neutropenia (58.8%), diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)
Mantle Cell Lymphoma

Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%)
Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%)
DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels is recommended due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant warfarin

USE IN SPECIFIC POPULATIONS

PREGNANCY: See Boxed WARNINGS: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. There is a REVLIMID pregnancy exposure registry that monitors pregnancy outcomes in females exposed to REVLIMID during pregnancy as well as female partners of male patients who are exposed to REVLIMID. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to REVLIMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436
LACTATION: There is no information regarding the presence of lenalidomide in human milk, the effects of REVLIMID on the breastfed infant, or the effects of REVLIMID on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants from REVLIMID, advise female patients not to breastfeed during treatment with REVLIMID
PEDIATRIC USE: Safety and effectiveness have not been established in pediatric patients
RENAL IMPAIRMENT: Adjust the starting dose of REVLIMID based on the creatinine clearance value and in patients on dialysis
Please see full Prescribing Information , including Boxed WARNINGS.

Please see full SmPC for further information.

On May 16, 2019 Bristol-Myers Squibb Company (NYSE:BMY) reported the presentation of data from across the company’s oncology portfolio at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2019 in Chicago, May 31-June 4, and the 24th Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Amsterdam, June 13-16 (Press release, Bristol-Myers Squibb, MAY 16, 2019, View Source [SID1234536403]). Data from over 90 Company-sponsored studies, investigator-sponsored studies and collaborations evaluating oncology compounds and early translational medicine across 20 types of cancer will be featured at the two meetings. Presentations will highlight the role of Immuno-Oncology (I-O) monotherapy and combination approaches in improving survival and quality of life outcomes, as well as translational research investigating novel biomarkers and diagnostics to aid in the selection of tailored treatments for each patient based on their unique disease biology.

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                  Schedule Your 30 min Free Demo!

2019 ASCO (Free ASCO Whitepaper) Annual Meeting – Highlights of Bristol-Myers Squibb data include:
*All times noted are Central Daylight Time

Hepatocellular Carcinoma

Primary efficacy and safety results from the Phase 1/2 CheckMate -040 study evaluating the combination of Opdivo (nivolumab) plus Yervoy (ipilimumab) in patients with advanced hepatocellular carcinoma, the most common type of liver cancer, will be presented. These data (Abstract #4012), including objective response rate and overall survival, will be featured in a poster display on Monday, June 3 from 8-11 AM CDT, and in a poster discussion from 3-4:30 PM CDT.
Melanoma

Safety and efficacy of Opdivo in combination with Yervoy in patients with symptomatic melanoma brain metastases (Abstract #9501) will be featured in an oral session on Tuesday, June 4, from 9:45 AM-12:45 PM CDT.
New long-term survival data and health outcomes research evaluating Opdivo in combination with Yervoy in advanced melanoma—in terms of survival outcomes (CA209-004, Abstract #9533), quality of life after four years and during the treatment-free interval following discontinuation of therapy (CheckMate -067, Abstracts #9551 and #9568), and treatment-free survival (pooled data from CheckMate -067 and -069, Abstract # 9550) – will be featured in a poster display on Monday, June 3 from 1:15-4:15 PM CDT.
Renal Cell Carcinoma

Safety and efficacy of Opdivo in combination with Yervoy in patients with asymptomatic advanced renal cell carcinoma brain metastases (Abstract #4517) will be featured in a poster display on Monday, June 3 from 1:15-4:15 PM CDT, and in a poster discussion from 4:30-6 PM CDT.
Translational Medicine and Tumor Biology

Translational data to identify potentially predictive biomarkers and expand translational research capabilities will be presented. Through the use of gene expression profiling (GEP) and machine-learning modeling, a novel, tumor-associated inflammation gene signature was identified through correlative, immunohistochemistry assessment of CD8 expression on T cells. This CD8-derived signature was then used to assess inflammation of the tumor microenvironment across 12 tumor types (Abstract #2593). Additionally, using an innovative artificial intelligence-based approach, combined with T-cell localization gene signatures by GEP, researchers quantified the abundance of immune cells and their spatial location within the tumor microenvironment (Abstract #2594). Both abstracts will be featured in a poster session on Saturday, June 1 from 8-11 AM CDT.
24 th Annual Congress of the EHA (Free EHA Whitepaper) – Highlights of Bristol-Myers Squibb data include:
*All times noted are Central European Standard Time

Multiple Myeloma

Extended 18-month follow-up data from the Phase 2 ELOQUENT-3 trial (Abstract #PS1370) evaluating the addition of Empliciti (elotuzumab) to pomalidomide and low-dose dexamethasone in relapsed/refractory (R/R) multiple myeloma, including a descriptive overall survival analysis for the combination, will be featured in a poster session on Saturday, June 15 from 5:30-7 PM CEST.
Classical Hodgkin and Non-Hodgkin Lymphoma

Updated safety and efficacy results in two patient subgroups from the Phase 2 CheckMate -744 study, the first risk-stratified, response-adapted study of Opdivo and ADCETRIS (brentuximab vedotin), followed by ADCETRIS and bendamustine for suboptimal response, in children, adolescents and young adults with R/R classical Hodgkin lymphoma (cHL), prior to autologous stem cell transplantation (Abstract #S822) will be presented in an oral presentation on Saturday, June 15 from 12:30-12:45 PM CEST.
Two-year results from cohort D of the Phase 2 CheckMate -205 study, evaluating Opdivo plus doxorubicin, vinblastine and dacarbazine in patients with newly diagnosed advanced-stage cHL (Abstract #S821), will be presented in an oral presentation on Saturday, June 15 from 12:15-12:30 PM CEST.
A full analysis of the Phase 1/2 CheckMate -436 study, evaluating Opdivo and ADCETRIS in patients with R/R primary mediastinal large B-cell lymphoma (Abstract #S1601), will be presented in an oral presentation on Sunday, June 16 from 9-9:15 AM CEST.
2019 ASCO (Free ASCO Whitepaper) Annual Meeting – Company-sponsored and collaborative data include:
*All times noted are Central Daylight Time

Gastrointestinal Malignancies

Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040
Author: Yau
Abstract: #4012
Poster Discussion Session: Gastrointestinal (Noncolorectal) Cancer
Monday, June 3, Poster Display: 8-11 AM, Hall A
Discussion: 3-4:30 PM, Arie Crown Theater
Nivolumab (NIVO) + low-dose ipilimumab (IPI) as first-line (1L) therapy in microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Clinical update
Author: Lenz
Abstract: #3521
Poster Session: Gastrointestinal (Colorectal) Cancer
Monday, June 3, Poster Display: 8-11 AM, Hall A
Melanoma

Long-term follow-up of CA209-004: A phase I dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma
Author: Atkins
Abstract: #9533
Poster Session: Melanoma/Skin Cancers
Monday, June 3, Poster Display: 1:15-4:15 PM, Hall A
Sensitivity of treatment-free survival (TFS), a novel outcome, to subgroup analyses of patients (pts) with advanced melanoma (MEL) treated with immune checkpoint inhibitors (ICI)
Author: Mantia
Abstract: #9550
Poster Session: Melanoma/Skin Cancers
Monday, June 3, Poster Display: 1:15-4:15 PM, Hall A
Patient-reported quality of life (QoL) of advanced melanoma patients in a Phase 3 study of nivolumab (NIVO) with or without ipilimumab (IPI) versus IPI: CheckMate 067 4-year data
Author: Schadendorf
Abstract: #9551
Poster Session: Melanoma/Skin Cancers
Monday, June 3, Poster Display: 1:15-4:15 PM, Hall A
Quality of life (QoL) and symptom burden in patients (pts) with advanced melanoma during the treatment-free interval (TFI) after discontinuation of nivolumab (NIVO) or NIVO plus ipilimumab (IPI)
Author: Taylor
Abstract: #9568
Poster Session: Melanoma/Skin Cancers
Monday, June 3, Poster Display: 1:15-4:15 PM, Hall A
An analysis of nivolumab-mediated adverse events and association with clinical efficacy in resected stage III or IV melanoma (CheckMate 238)
Author: Mandala
Abstract: #9584
Poster Session: Melanoma/Skin Cancers
Monday, June 3, Poster Display: 1:15-4:15 PM, Hall A
Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab (IPI) in patients with symptomatic melanoma brain metastases (CheckMate 204)
Author: Tawbi
Abstract: #9501
Oral Session: Melanoma/Skin Cancers
Tuesday, June 4, 9:45 AM-12:45 PM, S406
Presentation: 9:57-10:09 AM, S406
Genitourinary Malignancies

CheckMate 214 post-hoc analyses of nivolumab plus ipilimumab or sunitinib in IMDC intermediate/poor-risk patients with previously untreated advanced renal cell carcinoma with sarcomatoid features
Author: McDermott
Abstract: #4513
Poster Discussion Session: Genitourinary (Nonprostate) Cancer
Monday, June 3, Poster Display: 1:15-4:15 PM, Hall A
Discussion: 4:30-6 PM, Hall D2
Safety and efficacy of nivolumab plus ipilimumab (NIVO+IPI) in patients with advanced renal cell carcinoma (aRCC) with brain metastases: Interim analysis of CheckMate 920
Author: Emamekhoo
Abstract: #4517
Poster Discussion Session: Genitourinary (Nonprostate) Cancer
Monday, June 3, Poster Display: 1:15-4:15 PM, Hall A
Discussion: 4:30-6 PM, Hall D2
Consistent efficacy of nivolumab plus ipilimumab across number of International Metastatic Database Consortium (IMDC) risk factors in CheckMate 214
Author: Escudier
Abstract: #4575
Poster Session: Genitourinary (Nonprostate) Cancer
Monday, June 3, Poster Display: 1:15-4:15 PM, Hall A
Clinical and economic outcomes associated with sequential treatment in patients with advanced renal cell carcinoma (aRCC)
Author: Regan
Abstract: #4566
Poster Session: Genitourinary (Nonprostate) Cancer
Monday, June 3, Poster Display: 1:15-4:15 PM, Hall A
Nivolumab monotherapy in patients with advanced platinum-resistant urothelial carcinoma: Efficacy and safety update from CheckMate 275
Author: Siefker-Radtke
Abstract: #4524
Poster Session: Genitourinary (Nonprostate) Cancer
Monday, June 3, Poster Display: 1:15-4:15 PM, Hall A
Real-world outcomes with IO therapies: A prospective observational cohort study in patients (pts) with advanced melanoma (OPTIMIzE)
Author: Kirkwood
Abstract: #e14144
Online Only
Translational Medicine and Biomarkers

Serum IL-6 and CRP as prognostic factors in melanoma patients receiving single agent and combination checkpoint inhibition
Author: Weber
Abstract: #100
Clinical Science Symposium: Fine-Tuning Checkpoint Inhibition: Biomarkers of Response and Resistance
Saturday, June 1, Clinical Science Symposium: 8-9:30 AM, Hall D1
Presentation: 8-8:12 AM, Hall D1
Development of a baseline prognostic cytokine signature that correlates with nivolumab (NIVO) clearance (CL): Translational pharmacokinetic/pharmacodynamic (PK/PD) analysis in patients with renal cell carcinoma (RCC)
Author: Wang
Abstract: #2544
Poster Session: Developmental Immunotherapy and Tumor Immunobiology
Saturday, June 1, Poster Display: 8-11 AM, Hall A
Association of an inflammatory gene signature with CD8 expression by immunohistochemistry (IHC) in multiple tumor types
Author: Szabo
Abstract: #2593
Poster Session: Developmental Immunotherapy and Tumor Immunobiology
Saturday, June 1, Poster Display: 8-11 AM, Hall A
CD8+ T cells in tumor parenchyma and stroma by image analysis (IA) and gene expression profiling (GEP): Potential biomarkers for immuno-oncology (I-O) therapy
Author: Szabo
Abstract: #2594
Poster Session: Developmental Immunotherapy and Tumor Immunobiology
Saturday, June 1, Poster Display: 8-11 AM, Hall A
Association of human endogenous retrovirus (hERV) expression with clinical efficacy of PD-1 blockade in metastatic clear cell renal cell carcinoma (mccRCC)
Author: Pignon
Abstract: #4568
Poster Session: Genitourinary (Nonprostate) Cancer
Monday, June 3, Poster Display: 1:15-4:15 PM, Hall A
New and Early Assets

Baseline tumor-immune signatures associated with response to bempegaldesleukin (NKTR-214) and nivolumab
Author: Hurwitz
Abstract: #2623
Poster Session: Developmental Immunotherapy and Tumor Immunobiology
Saturday, June 1, Poster Display: 8-11 AM, Hall A
CA224-060: A randomized, open label, phase II trial of relatlimab (anti-LAG-3) and nivolumab with chemotherapy versus nivolumab with chemotherapy as first-line treatment in patients with gastric or gastroesophageal junction adenocarcinoma
Author: Feeney
Abstract: #TPS4143
Poster Session: Gastrointestinal (Noncolorectal) Cancer
Monday, June 3, Poster Display: 8-11 AM, Hall A
CA045-001: A phase III, randomized, open label study of bempegaldesleukin (NKTR-214) plus nivolumab (NIVO) versus NIVO monotherapy in patients (pts) with previously untreated, unresectable or metastatic melanoma (MEL)
Author: Khushalani
Abstract: #TPS9601
Poster Session: Melanoma/Skin Cancers
Monday, June 3, Poster Display: 1:15-4:15 PM, Hall A
A phase III randomized open label study comparing bempegaldesleukin (NKTR-214) plus nivolumab to sunitinib or cabozantinib (investigator’s choice) in patients with previously untreated advanced renal cell carcinoma
Author: Tannir
Abstract: #TPS4595
Poster Session: Genitourinary (Nonprostate) Cancer
Monday, June 3, Poster Display: 1:15-4:15 PM, Hall A
A phase 3 randomized study of neoadjuvant chemotherapy (NAC) alone or in combination with nivolumab (NIVO) ± BMS-986205 in cisplatin-eligible muscle invasive bladder cancer (MIBC)
Author: Sonpavde
Abstract: #TPS4587
Poster Session: Genitourinary (Nonprostate) Cancer
Monday, June 3, Poster Display: 1:15-4:15 PM, Hall A
Clinical Collaborations

Preliminary immunogenicity, safety, and efficacy of JNJ-64041757 (JNJ-757) in non-small cell lung cancer (NSCLC): Results from two phase 1 studies
Author: Brahmer
Abstract: #9093
Poster Session: Lung Cancer-Non-Small Cell Metastatic
Sunday, June 2, Poster Display: 8-11 AM, Hall A
An open label, multicenter, phase I/II study of RP1 as a single agent and in combination with PD1 blockade in patients with solid tumors
Author: Middleton
Abstract: #TPS2671
Poster Session: Developmental Immunotherapy and Tumor Immunobiology
Saturday, June 1, Poster Display: 8-11 AM, Hall A
Ph1/2 study of Rova-T in combination with nivolumab (Nivo) ± ipilimumab (Ipi) for patients (pts) with 2L+ extensive-stage (ED) SCLC
Author: Malhotra
Abstract: #8516
Poster Session: Lung Cancer-Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers
Sunday, June 2, Poster Display: 8-11 AM; Hall A
Discussion: 11:15 AM–12:45 PM, S406
24 th Congress of the EHA (Free EHA Whitepaper) – Company-sponsored and collaborative data include:
*All times noted are Central European Summer Time

Lymphoma

Nivolumab Plus Doxorubicin, Vinblastine and Dacarbazine for Newly Diagnosed Advanced-Stage Classical Hodgkin Lymphoma: 2-Year Extended Follow-Up From Cohort D of the Phase 2 CheckMate 205 Study
Author: Domingo-Domènech
Abstract: #S821
Oral Session: Hodgkin lymphoma – Clinical
Saturday, June 15, 11:30 AM-12:45 PM, Hall 5
Presentation: 12:15-12:30 PM, Hall 5
Nivolumab and Brentuximab Vedotin-Based, Response-Adapted Treatment in Primary Refractory and in Pediatric Patients with Relapsed/Refractory Classical Hodgkin Lymphoma in CheckMate 744
Author: LeBlanc
Abstract: #S822
Oral Session: Hodgkin lymphoma – Clinical
Saturday, June 15, 11:30 AM-12:45 PM, Hall 5
Presentation: 12:30-12:45 PM, Hall 5
Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-cell Lymphoma: Efficacy and Safety Results from the Phase 2 CheckMate 436 Study
Author: Zinzani
Abstract: #S1601
Oral Session: Aggressive lymphomas – First line, combination therapy and real-life data
Sunday, June 16, 8-9:15 AM, Hall 5
Presentation: 9-9:15 AM, Hall 5
Multiple Myeloma

Elotuzumab Plus Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Efficacy Results After Additional Follow-Up of the Phase 2, Randomized ELOQUENT-3 Study
Author: Dimopoulos
Abstract: #PS1370
Poster Session: Myeloma and other monoclonal gammopathies – Clinical
Saturday, June 15, 5:30-7 PM, Poster Area
Investigating Mechanisms of Elotuzumab and Lenalidomide in Multiple Myeloma
Author: Richardson
Abstract: #PF568
Poster Session: Myeloma and other monoclonal gammopathies – Biology & Translational Research
Friday, June 14, 5:30-7 PM, Poster Area
Use of Pomalidomide-Based Regimens in Relapsed/Refractory Multiple Myeloma in Four European Countries – Findings From PREAMBLE
Author: Moreau
Abstract: #PS1405
Poster Session: Myeloma and other monoclonal gammopathies – Clinical
Saturday, June 15, 5:30-7 PM, Poster Area
Leukemia

DASCERN 2-Year Extended Follow-Up of Dasatinib Efficacy and Safety in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Who Have Suboptimal Responses to 3 Months of Imatinib
Author: Saglio
Abstract: #PF405
Poster Session: Chronic myeloid leukemia – Clinical
Friday, June 14, 5:30-7 PM, Poster Area
DASFREE: 2-Year Update: Dasatinib Discontinuation in Patients (pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Deep Molecular Response (DMR)
Author: Shah
Abstract: #PF408
Poster Session: Chronic myeloid leukemia – Clinical
Friday, June 14, 5:30-7 PM, Poster Area
Growth Rate and Endocrine Effects of Dasatinib Therapy Observed in Retrospective Analysis of a Phase II Clinical Trial for Pediatric Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)
Author: Patterson
Abstract: #PF416
Poster Session: Chronic myeloid leukemia – Clinical
Friday, June 14, 5:30-7 PM, Poster Area
Dosing Patterns of Dasatinib and Nilotinib Use in SIMPLICITY, an Observational Study in Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Patients (pts) in Routine Clinical Practice
Author: Cortes
Abstract: #PS1181
Poster Session: Chronic myeloid leukemia – Clinical
Saturday, June 15, 5:30-7 PM, Poster Area
Bristol-Myers Squibb: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. The focus of our research is to increase quality, long-term survival for patients and make cure a possibility. Through a unique multidisciplinary approach powered by translational science, we harness our deep scientific experience in oncology and Immuno-Oncology (I-O) research to identify novel treatments tailored to individual patient needs. Our researchers are developing a diverse, purposefully built pipeline designed to target different immune system pathways and address the complex and specific interactions between the tumor, its microenvironment and the immune system. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines, like I-O, a reality for patients.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology, and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has treated more than 35,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with progression after platinum-based chemotherapy and at least one other line of therapy. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy, and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests, at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 6% (25/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4% (24/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 1.7% (2/119) of patients.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10% (52/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 7% (8/119) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. For patients without HCC, withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT is within normal limits at baseline and increases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times the ULN. Permanently discontinue OPDIVO and administer corticosteroids if AST or ALT increases to >10 times the ULN or total bilirubin increases >3 times the ULN. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 13% (51/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 8% (10/119) of patients.

In Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hypophysitis occurred in 3.4% (4/119) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred in 5% (21/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 5.9% (7/119) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving this dose of OPDIVO with YERVOY. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of patients receiving this dose of OPDIVO with YERVOY. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 15% (18/119) of patients. Hyperthyroidism occurred in 12% (14/119) of patients. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 1.7% (2/119) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16.6% (91/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 14% (17/119) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7 months of exposure. Encephalitis occurred in one RCC patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 months of exposure. Encephalitis occurred in one MSI-H/dMMR mCRC patient (0.8%) receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg after 15 days of exposure.

Other Immune-Mediated Adverse Reactions

Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome.

If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate study in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 4.2% (5/119) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue breastfeeding during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 032, serious adverse reactions occurred in 45% of patients receiving OPDIVO (n=245). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, pneumonitis, pleural effusions, and dehydration. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY and in 43% of patients receiving sunitinib. The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 49% of patients (n=154). The most frequent serious adverse reactions reported in ≥2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia. In Checkmate 238, Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. Serious adverse reactions occurred in 18% of OPDIVO-treated patients.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 032, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=245) were fatigue (45%), decreased appetite (27%), musculoskeletal pain (25%), dyspnea (22%), nausea (22%), diarrhea (21%), constipation (20%), and cough (20%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) vs sunitinib (n=535) were fatigue (58% vs 69%), rash (39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs 40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs 25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), decreased appetite (21% vs 29%), dyspnea (20% vs 21%), and vomiting (20% vs 28%). In Checkmate 205 and 039, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO (n=236) were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent, the most common adverse reactions (≥20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, the most common adverse reactions (≥20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 238, the most common adverse reactions (≥20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.

Checkmate Trials and Patient Populations

Checkmate 037–previously treated metastatic melanoma; Checkmate 066–previously untreated metastatic melanoma; Checkmate 067–previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 017–second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057–second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 032–small cell lung cancer; Checkmate 025–previously treated renal cell carcinoma; Checkmate 214–previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 205/039–classical Hodgkin lymphoma; Checkmate 141–recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 275–urothelial carcinoma; Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 040–hepatocellular carcinoma; Checkmate 238–adjuvant treatment of melanoma.

About Empliciti

Empliciti is an immunostimulatory antibody that specifically targets Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7), a cell-surface glycoprotein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 also is expressed on Natural Killer cells, plasma cells and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage.

Empliciti has a dual mechanism-of-action. It directly activates the immune system through Natural Killer cells via the SLAMF7 pathway. Empliciti also targets SLAMF7 on myeloma cells, tagging these malignant cells for Natural Killer cell-mediated destruction via antibody-dependent cellular toxicity.

Empliciti was initially approved by the FDA in 2015 in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies.

U.S. FDA-APPROVED INDICATIONS FOR EMPLICITI

EMPLICITI (elotuzumab) is indicated in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received one to three prior therapies.

EMPLICITI (elotuzumab) is indicated in combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

IMPORTANT SAFETY INFORMATION

Infusion Reactions

Infusion reactions were reported in 10% of patients treated with EMPLICITI in the ELOQUENT-2 trial [EMPLICITI + lenalidomide + dexamethasone (ERd) vs lenalidomide + dexamethasone (Rd)] and 3.3% in the ELOQUENT-3 trial [EMPLICITI + pomalidomide + dexamethasone (EPd) vs pomalidomide + dexamethasone (Pd)].

In the ELOQUENT-2 trial, all infusion reactions were Grade 3 or lower, with Grade 3 infusion reactions occurring in 1% of patients. The most common symptoms included fever, chills, and hypertension. Bradycardia and hypotension also developed during infusions. In the trial, 5% of patients required interruption of the administration of EMPLICITI for a median of 25 minutes due to infusion reactions, and 1% of patients discontinued due to infusion reactions. Of the patients who experienced an infusion reaction, 70% (23/33) had them during the first dose.

In the ELOQUENT-3 trial, the only infusion reaction symptom was chest discomfort (2%), which was Grade 1. All the patients who experienced an infusion reaction had them during the first treatment cycle.

If a Grade 2 or higher infusion reaction occurs, interrupt the EMPLICITI infusion and institute appropriate medical and supportive measures. If the infusion reaction recurs, stop the EMPLICITI infusion and do not restart it on that day. Severe infusion reactions may require permanent discontinuation of EMPLICITI therapy and emergency treatment.

Premedicate with dexamethasone, H1 blocker, H2 blocker, and acetaminophen prior to EMPLICITI infusion.

Infections

In the ELOQUENT-2 trial (N=635), infections were reported in 81% of patients in the ERd arm and 74% in the Rd arm. Grade 3-4 infections were 28% (ERd) and 24% (Rd). Discontinuations due to infections were 3.5% (ERd) and 4.1% (Rd). Fatal infections were 2.5% (ERd) and 2.2% (Rd). Opportunistic infections were reported in 22% (ERd) and 13% (Rd). Fungal infections were 10% (ERd) and 5% (Rd). Herpes zoster was 14% (ERd) and 7% (Rd).

In the ELOQUENT-3 trial (N=115), infections were reported in 65% of patients in both the EPd arm and the Pd arm. Grade 3-4 infections were reported in 13% (EPd) and 22% (Pd). Discontinuations due to infections were 7% (EPd) and 5% (Pd). Fatal infections were 5% (EPd) and 3.6% (Pd). Opportunistic infections were reported in 10% (EPd) and 9% (Pd). Herpes zoster was reported in 5% (EPd) and 1.8% (Pd).

Monitor patients for development of infections and treat promptly.

Second Primary Malignancies

In the ELOQUENT-2 trial (N=635), invasive second primary malignancies (SPM) were 9% (ERd) and 6% (Rd). The rate of hematologic malignancies was the same between ERd and Rd treatment arms (1.6%). Solid tumors were reported in 3.5% (ERd) and 2.2% (Rd). Skin cancer was reported in 4.4% (ERd) and 2.8% (Rd).

In the ELOQUENT-3 trial (N=115), invasive SPMs were 0% (EPd) and 1.8% (Pd).

Monitor patients for the development of SPMs.

Hepatotoxicity

In the ELOQUENT-2 trial (N=635), AST/ALT >3X the upper limit, total bilirubin >2X the upper limit, and alkaline phosphatase <2X the upper limit were 2.5% (ERd) vs 0.6% (Rd). Of 8 patients experiencing hepatotoxicity, 2 patients discontinued treatment while 6 patients had resolution and continued. Monitor liver enzymes periodically. Stop EMPLICITI upon ≥Grade 3 elevation of liver enzymes. Continuation of treatment may be considered after return to baseline values.

Interference with Determination of Complete Response

EMPLICITI is a humanized IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein.

Pregnancy/Females and Males of Reproductive Potential

There are no available data on EMPLICITI use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage.

There is a risk of fetal harm, including severe life-threatening human birth defects, associated with lenalidomide and pomalidomide, and they are contraindicated for use in pregnancy. Refer to the respective product full prescribing information for requirements regarding contraception and the prohibitions against blood and/or sperm donation due to presence and transmission in blood and/or sesemen and for additional information.

Adverse Reactions

ELOQUENT-2 trial:

Serious adverse reactions were 65% (ERd) and 57% (Rd). The most frequent serious adverse reactions in the ERd arm compared to the Rd arm were: pneumonia (15%, 11%), pyrexia (7%, 5%), respiratory tract infection (3.1%, 1.3%), anemia (2.8%, 1.9%), pulmonary embolism (3.1%, 2.5%), and acute renal failure (2.5%, 1.9%).
The most common adverse reactions in ERd and Rd, respectively (≥20%) were fatigue (62%, 52%), diarrhea (47%, 36%), pyrexia (37%, 25%), constipation (36%, 27%), cough (34%, 19%), peripheral neuropathy (27%, 21%), nasopharyngitis (25%, 19%), upper respiratory tract infection (23%, 17%), decreased appetite (21%, 13%), and pneumonia (20%, 14%).
ELOQUENT-3 trial:

Serious adverse reactions were 22% (EPd) and 15% (Pd). The most frequent serious adverse reactions in the EPd arm compared to the Pd arm were: pneumonia (13%, 11%) and respiratory tract infection (7%, 3.6%).
The most common adverse reactions in EPd arm (≥20% EPd) and Pd, respectively, were constipation (22%, 11%) and hyperglycemia (20%, 15%).
Please see the full Prescribing Information .

About Sprycel

Sprycel is a second-generation tyrosine kinase inhibitor (TKI) designed to help inhibit BCR-ABL, an abnormal protein found on the mutated Philadelphia chromosome in most patients with chronic myeloid leukemia (CML) and some patients with ALL, which can trigger the overproduction of damaged or immature white blood cells. By targeting the BCR-ABL protein, Sprycel can reduce the number of damaged white blood cells in the body, allowing for the production of more normal cells.

Sprycel is currently approved in more than 60 countries for the treatment of adults with Ph+ ALL or Ph+ CML in chronic phase (CP-CML) who are resistant or intolerant to prior therapy, and in more than 50 countries for the treatment of adults with newly diagnosed Ph+ CP-CML. In 2017, Sprycel received its first pediatric indication when it became the first second-generation TKI approved for the treatment of patients one year of age and older with Ph+ CP-CML. Sprycel is also approved in combination with chemotherapy for the treatment of pediatric patients with newly diagnosed Ph+ ALL.

In Europe, both pediatric indications for Sprycel include the PFOS formulation, the approvals of which made Sprycel the first TKI with an approved powder formulation for administration in pediatric patients with Ph+ CP-CML and Ph+ ALL. The PFOS formulation is also approved for adult patients with Ph+ CP-CML who cannot swallow tablets.

U.S. FDA-APPROVED INDICATIONS FOR SPRYCEL

SPRYCEL (dasatinib) is indicated for the treatment of adult patients with:

Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase
Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy
SPRYCEL is indicated for the treatment of pediatric patients 1 year of age and older with:

Ph+ CML in chronic phase
Newly diagnosed Ph+ ALL in combination with chemotherapy
IMPORTANT SAFETY INFORMATION

Myelosuppression:

Treatment with SPRYCEL is associated with severe (NCI CTCAE Grade 3/4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML.

Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.

In patients with chronic phase CML, perform complete blood counts (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated
In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated
In pediatric patients with Ph+ ALL treated with SPRYCEL in combination with chemotherapy, perform CBCs prior to the start of each block of chemotherapy and as clinically indicated. During the consolidation blocks of chemotherapy, perform CBCs every 2 days until recovery
Myelosuppression is generally reversible and usually managed by withholding SPRYCEL temporarily and/or dose reduction
In clinical studies, myelosuppression may have also been managed by discontinuation of study therapy
Hematopoietic growth factor has been used in patients with resistant myelosuppression
Bleeding-Related Events:

SPRYCEL can cause serious and fatal bleeding. In all CML or Ph+ ALL clinical studies, Grade ≥3 central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving SPRYCEL. The incidence of Grade 3/4 hemorrhage occurred in 5.8% of adult patients and generally required treatment interruptions and transfusions. The incidence of Grade 5 hemorrhage occurred in 0.4% of adult patients. The most frequent site of hemorrhage was gastrointestinal.

Most bleeding events in clinical studies were associated with severe thrombocytopenia
In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro
Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhage
Fluid Retention:

SPRYCEL may cause fluid retention. After 5 years of follow-up in the adult randomized newly diagnosed chronic phase CML study (n=258), grade 3/4 fluid retention was reported in 5% of patients, including 3% of patients with grade 3/4 pleural effusion. In adult patients with newly diagnosed or imatinib-resistant or -intolerant chronic phase CML, grade 3/4 fluid retention occurred in 6% of patients treated with SPRYCEL at the recommended dose (n=548). In adult patients with advanced phase CML or Ph+ ALL treated with SPRYCEL at the recommended dose (n=304), grade 3/4 fluid retention was reported in 8% of patients, including grade 3/4 pleural effusion reported in 7% of patients. In pediatric patients with chronic phase CML, cases of Grade 1 or 2 fluid retention were reported in 10.3% of patients.

Patients who develop symptoms of pleural effusion or other fluid retention, such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough should be evaluated promptly with a chest x-ray or additional diagnostic imaging as appropriate
Fluid retention events were typically managed by supportive care measures that may include diuretics or short courses of steroids
Severe pleural effusion may require thoracentesis and oxygen therapy
Consider dose reduction or treatment interruption
Cardiovascular Events:

SPRYCEL can cause cardiac dysfunction. After 5 years of follow-up in the randomized, newly diagnosed chronic phase CML trial in adults (n=258), the following cardiac adverse reactions occurred:

Cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac-related fluid retention (8.5% dasatinib vs 3.9% imatinib), and conduction system abnormalities, most commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0% imatinib). Two cases (0.8%) of peripheral arterial occlusive disease occurred with imatinib and 2 (0.8%) transient ischemic attacks occurred with dasatinib
Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.

Pulmonary Arterial Hypertension (PAH):

SPRYCEL may increase the risk of developing PAH in adult and pediatric patients, which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL.

Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should be permanently discontinued
QT Prolongation:

SPRYCEL may increase the risk of prolongation of QTc in patients including those with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy.

Correct hypokalemia or hypomagnesemia prior to and during SPRYCEL administration
Severe Dermatologic Reactions:

Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients treated with SPRYCEL.

Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified
Tumor Lysis Syndrome (TLS):

TLS has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease.

Due to potential for TLS, maintain adequate hydration, correct uric acid levels prior to initiating therapy with SPRYCEL, and monitor electrolyte levels
Patients with advanced stage disease and/or high tumor burden may be at increased risk and should be monitored more frequently
Embryo-Fetal Toxicity:

Based on limited human data, SPRYCEL can cause fetal harm when administered to a pregnant woman. Hydrops fetalis, fetal leukopenia and fetal thrombocytopenia have been reported with maternal exposure to SPRYCEL. Transplacental transfer of dasatinib has been measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma.

Advise females of reproductive potential to avoid pregnancy, which may include the use of effective contraception, during treatment with SPRYCEL and for 30 days after the final dose
Effects on Growth and Development in Pediatric Patients:

In pediatric trials of SPRYCEL in chronic phase CML after at least 2 years of treatment, adverse reactions associated with bone growth and development were reported in 5 (5.2%) patients, one of which was severe in intensity (Growth Retardation Grade 3). These 5 cases included cases of epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia. Of these 5 cases, 1 case of osteopenia and 1 case of gynecomastia resolved during treatment.

Monitor bone growth and development in pediatric patients.

Lactation:

No data are available regarding the presence of dasatinib in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. However, dasatinib is present in the milk of lactating rats.

Because of the potential for serious adverse reactions in nursing children from SPRYCEL, breastfeeding is not recommended during treatment with SPRYCEL and for 2 weeks after the final dose
Drug Interactions:

Effect of Other Drugs on Dasatinib

Strong CYP3A4 inhibitors: The coadministration with strong CYP3A inhibitors may increase dasatinib concentrations. Increased dasatinib concentrations may increase the risk of toxicity. Avoid concomitant use of strong CYP3A4 inhibitors. If concomitant administration of a strong CYP3A4 inhibitor cannot be avoided, consider a SPRYCEL dose reduction
Grapefruit juice may increase plasma concentrations of SPRYCEL and should be avoided
Strong CYP3A4 inducers: The coadministration of SPRYCEL with strong CYP3A inducers may decrease dasatinib concentrations. Decreased dasatinib concentrations may reduce efficacy. Consider alternative drugs with less enzyme induction potential. If concomitant administration of a strong CYP3A4 inducer cannot be avoided, consider a SPRYCEL dose increase
St. John’s wort may decrease plasma concentrations of SPRYCEL and should be avoided
Gastric Acid Reducing Agents: The coadministration of SPRYCEL with a gastric acid reducing agent may decrease the concentrations of dasatinib. Decreased dasatinib concentrations may reduce efficacy
Do not administer H2 antagonists or proton pump inhibitors with SPRYCEL. Consider the use of antacids in place of H2 antagonists or proton pump inhibitors. Administer the antacid at least 2 hours prior to or 2 hours after the dose of SPRYCEL. Avoid simultaneous administration of SPRYCEL with antacids.

Adverse Reactions:

The safety data reflects exposure to SPRYCEL administered as single-agent therapy at all doses tested in clinical studies (n=2809) including 324 adult patients with newly diagnosed chronic phase CML, 2388 adult patients with imatinib-resistant or -intolerant chronic or advanced phase CML or Ph+ ALL, and 97 pediatric patients with chronic phase CML.

The median duration of therapy in all 2712 SPRYCEL-treated adult patients was 19.2 months (range 0–93.2 months). Median duration of therapy in:

1618 adult patients with chronic phase CML was 29 months (range 0–92.9 months)
Median duration for 324 adult patients in the newly diagnosed chronic phase CML trial was approximately 60 months
1094 adult patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0–93.2 months)
In two non-randomized trials in 97 pediatric patients with chronic phase CML (51 patients newly diagnosed and 46 patients resistant or intolerant to previous treatment with imatinib), the median duration of therapy was 51.1 months (range 1.9 to 99.6 months).

In a multicohort study of SPRYCEL administered continuously in combination with multiagent chemotherapy in 81 pediatric patients with newly diagnosed Ph+ ALL, the median duration of therapy was 24 months (range 2 to 27 months).

In the newly diagnosed adult chronic phase CML trial, after a minimum of 60 months of follow-up, the cumulative discontinuation rate for 258 patients was 39%.

In the overall population of 2712 adult patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse reactions leading to treatment discontinuation.

Among the 1618 adult patients with chronic phase CML, drug-related adverse reactions leading to discontinuation were reported in 329 (20.3%) patients.

In the adult newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 16% of SPRYCEL-treated patients with a minimum of 60 months of follow-up
Among the 1094 adult patients with advanced phase CML or Ph+ ALL, drug-related adverse reactions leading to discontinuation were reported in 191 (17.5%) patients.

Among the 97 CML pediatric subjects, drug-related adverse reactions leading to discontinuation were reported in 1 patient (1%).

Patients ≥65 years are more likely to experience the commonly reported adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance, and more likely to experience the less frequently reported adverse reactions of abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema and weight decrease, and should be monitored closely.

In adult newly diagnosed chronic phase CML patients:
Drug-related serious adverse reactions (SARs) were reported for 16.7% of patients. Serious adverse reactions reported in ≥5% of patients included pleural effusion (5%)
Grade 3/4 laboratory abnormalities included neutropenia (29%), thrombocytopenia (22%), anemia (13%), hypophosphatemia (7%), hypocalcemia (4%), elevated bilirubin (1%), and elevated creatinine (1%)
In adult patients resistant or intolerant to prior imatinib therapy:
Drug-related SARs were reported for 26.1% of SPRYCEL-treated patients treated at the recommended dose of 100 mg once daily in the randomized dose-optimization trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy. Serious adverse reactions reported in ≥5% of patients included pleural effusion (10%)
Grade 3/4 hematologic laboratory abnormalities in chronic phase CML patients resistant or intolerant to prior imatinib therapy who received SPRYCEL 100 mg once daily with a minimum follow up of 60 months included neutropenia (36%), thrombocytopenia (24%), and anemia (13%). Other grade 3/4 laboratory abnormalities included: hypophosphatemia (10%), and hypokalemia (2%)
Among chronic phase CML patients with resistance or intolerance to prior imatinib therapy, cumulative grade 3/4 cytopenias were similar at 2 and 5 years including: neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%) and anemia (13% vs 13%)
Grade 3/4 elevations of transaminases or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML
Elevations in transaminases or bilirubin were usually managed with dose reduction or interruption
Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation
In pediatric subjects with Ph+ CML in chronic phase
Drug-related SARs were reported for 14.4% of pediatric patients
Adverse reactions associated with bone growth and development were reported in 5 (5.2%) pediatric patients with chronic phase CML
In the pediatric studies, the rates of laboratory abnormalities were consistent with the known profile for laboratory parameters in adults
In pediatric subjects with Ph+ ALL who were administered SPRYCEL in combination with multiagent chemotherapy
Fatal adverse reactions occurred in 3 patients (4%), all of which were due to infections
Eight patients (10%) experienced adverse reactions leading to treatment discontinuation
The most common serious adverse reactions (incidence ≥10%) were pyrexia, febrile neutropenia, mucositis, diarrhea, sepsis, hypotension, infections (bacterial, viral and fungal), hypersensitivity, vomiting, renal insufficiency, abdominal pain, and musculoskeletal pain
Grade 3/4 laboratory abnormalities (≥10%) included neutropenia (96%), thrombocytopenia (88%), anemia (82%), elevated SGPT (ALT) (47%), hypokalemia (40%), elevated SGOT (AST) (26%), hypocalcemia (19%), hyponatremia (19%), elevated bilirubin (11%), and hypophosphatemia (11%)
Most common adverse reactions (≥15%) in patients receiving SPRYCEL as single-agent therapy included myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain.

Most common adverse reactions (≥30%) in pediatric patients receiving SPRYCEL in combination with chemotherapy included mucositis, febrile neutropenia, pyrexia, diarrhea, nausea, vomiting, musculoskeletal pain, abdominal pain, cough, headache, rash, fatigue, constipation, arrhythmia, hypertension, edema, infections (bacterial, viral and fungal), hypotension, decreased appetite, hypersensitivity, dyspnea, epistaxis, peripheral neuropathy, and altered state of consciousness.

Please see full Prescribing Information .

About the Bristol-Myers Squibb and Ono Pharmaceutical Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally, except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol-Myers Squibb further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

On May 16, 2019 Bio-Path Holdings, Inc., (NASDAQ:BPTH), a biotechnology company leveraging its proprietary DNAbilize antisense RNAi nanoparticle technology to develop a portfolio of targeted nucleic acid cancer drugs, reported its financial results for the first quarter ended March 31, 2019 and provided an update on recent corporate developments (Press release, Bio-Path Holdings, MAY 16, 2019, View Source [SID1234536402]).

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"During the first quarter, we continued to execute on our strategic initiatives to build our DNAbilize technology and advance our clinical development programs. We were delighted to present data from preclinical studies supporting the potential of BP1003, a novel liposome-incorporated STAT3 oligodeoxynucleotide inhibitor for the treatment of pancreatic cancer, non-small cell lung cancer (NSCLC) and acute myelogenous leukemia (AML) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting before an audience of world-leading oncologists," said Peter Nielsen, President and Chief Executive Officer of Bio-Path Holdings. "We look forward to completing Investigational New Drug (IND) enabling studies in 2019 through early 2020, and to file an IND application for a Phase 1 study of BP1003 for the treatment of pancreatic cancer in 2020."

Recent Corporate Highlights

·Presented Preclinical Data at American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019. In April 2019, Bio-Path presented data from preclinical studies supporting the potential of BP1003, a novel liposome-incorporated STAT3 oligodeoxynucleotide inhibitor, for the treatment of pancreatic cancer, non-small cell lung cancer (NSCLC) and acute myelogenous leukemia (AML). These data were presented in a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 in Atlanta, GA.
·Raised $21.3 Million During the First Quarter. In March 2019, Bio-Path issued 712,910 shares of its common stock at a price of $25.95 per share, for gross proceeds of approximately $18.5 million in one transaction. In addition, Bio-Path completed two smaller offerings during the first quarter.

Financial Results for the First Quarter Ended March 31, 2019

·The Company reported a net loss of $1.5 million, or $0.89 per share, for the three months ended March 31, 2019, compared to a net loss of $1.9 million, or $3.38 per share, for the three months ended March 31, 2018.

·Research and development expenses for the three months ended March 31, 2019 decreased to $0.4 million, compared to $0.9 million for the three months ended March 31, 2018 primarily due to decreased clinical trial expenses as we modified operations between Stage 1 and Stage 2 of our Phase 2 clinical trial in AML to include venetoclax combination treatment with prexigebersen.

·General and administrative expenses for the three months ended March 31, 2019 increased to $1.1 million, compared to $1.0 million for the three months ended March 31, 2018 primarily due to increased legal fees and insurance costs.

·As of March 31, 2019, the Company had cash of $19.3 million, compared to $1.0 million at December 31, 2018. Net cash used in operating activities for the three months ended March 31, 2019 was $2.0 million compared to $1.7 million for the comparable period in 2018. Net cash provided by financing activities for the three months ended March 31, 2019 was $20.3 million.

Conference Call and Webcast Information

Bio-Path Holdings will host a conference call and webcast today at 8:30 a.m. ET to review these first quarter 2019 financial results and to provide a general update on the Company. To access the conference call please dial (844) 815-4963 (domestic) or (210) 229-8838 (international) and refer to the conference ID 4956638. A live audio webcast of the call and the archived webcast will be available in the Media section of the Company’s website at www.biopathholdings.com.