On June 3, 2018 Exelixis, Inc. (Nasdaq: EXEL) reported results from sub-group analyses of the CELESTIAL phase 3 pivotal trial of cabozantinib in advanced hepatocellular carcinoma (HCC) comparing outcomes by duration of sorafenib treatment in patients whose only prior treatment was sorafenib and outcomes based on age (Press release, Exelixis, JUN 3, 2018, View Source;p=RssLanding&cat=news&id=2352879 [SID1234527074]). The findings, presented in two posters at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting during the Gastrointestinal (Noncolorectal) Cancer Poster Session from 8:00 – 11:00 a.m. CDT in Hall A, showed that cabozantinib improved overall survival (OS) and progression-free survival (PFS) compared with placebo irrespective of duration of prior sorafenib treatment or age category.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We’re pleased with the encouraging CELESTIAL subgroup data presented at ASCO (Free ASCO Whitepaper), which showed that cabozantinib provided benefits to patients regardless of duration of prior sorafenib treatment or age," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "We continue to work closely with the U.S. FDA as they review the filing application for cabozantinib for previously treated advanced hepatocellular carcinoma and hope it may soon provide a new option for patients with this difficult-to-treat cancer who have few alternatives."

Outcomes in Patients who had Received Sorafenib [abstract 4088]

The sub-analysis of patients in CELESTIAL who received sorafenib as their only prior systemic therapy was presented by Robin Kate Kelley, M.D., University of California San Francisco. In this subgroup-analysis, patients were grouped by the length of time they had been treated with sorafenib (less than three months; three to six months; more than six months) to assess the effect of cabozantinib in patients with varying benefit from prior sorafenib. In all three groups, cabozantinib improved OS and PFS versus placebo:

Treatment-related grade 3 or 4 adverse events (AEs) that occurred in at least 5 percent of any patient group were palmar-plantar erythrodysesthesia, aspartate aminotransferase increased, hypertension, fatigue, decreased appetite, diarrhea, asthenia and anemia.

Outcomes in Patients Based on Age [abstract 4090]

The sub-analysis evaluating patients in the CELESTIAL trial based on age was presented by Lorenza Rimassa, M.D., Humanitas Clinical and Research Center. In this sub-analysis, patients were grouped as younger than 65 years of age and 65 years of age and older. The findings showed OS and PFS were consistently improved with cabozantinib versus placebo in each age category:

Treatment-related grade 3 or 4 AEs occurred in at least 5 percent of either age group and were similar in nature and frequency to the AEs that occurred in patients who received sorafenib as their only prior systemic therapy.

An encore of the CELESTIAL trial data originally presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO-GI) will be presented by Dr. Ghassan K. Abou-Alfa, Memorial Sloan Kettering Cancer Center, during the Gastrointestinal (Noncolorectal) Cancer Poster Discussion Session today from 4:45 – 6:00 p.m. CDT in Hall D2 [abstract 4019].

The CELESTIAL trial was the basis for Exelixis’ supplemental New Drug Application filed with the U.S. Food and Drug Administration (FDA) for CABOMETYX (cabozantinib) tablets as a treatment for patients with previously treated advanced HCC. The Prescription Drug User Fee Act action date for this application is January 14, 2019. On March 28, 2018, our partner Ipsen announced that they received validation of the application for variation to the CABOMETYX marketing authorization from the European Medicines Agency, the European regulatory authority, for the addition of a new indication for patients with previously treated advanced HCC.

About the CELESTIAL Study

CELESTIAL is a phase 3 randomized, double-blind, placebo-controlled study of cabozantinib in patients with advanced HCC conducted at more than 100 sites globally in 19 countries. The trial was designed to enroll 760 patients with advanced HCC who received prior sorafenib and may have received up to two prior systemic cancer therapies for HCC and had adequate liver function. Enrollment of the trial was completed in September 2017. Patients were randomized 2:1 to receive 60 mg of cabozantinib once daily or placebo and were stratified based on etiology of the disease (hepatitis C, hepatitis B or other), geographic region (Asia versus other regions) and presence of extrahepatic spread and/or macrovascular invasion (yes or no). No cross-over was allowed between the study arms during the blinded treatment phase of the trial. The primary endpoint for the trial is overall survival, and secondary endpoints include objective response rate and progression-free survival. Exploratory endpoints include patient-reported outcomes, biomarkers and safety.

Results of the trial were first presented by Dr. Abou-Alfa at 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium in January 2018.

About HCC

Liver cancer is the second-leading cause of cancer death worldwide, accounting for more than 700,000 deaths and nearly 800,000 new cases each year.1 In the U.S., the incidence of liver cancer has more than tripled since 1980.2 HCC is the most common form of liver cancer, making up about three-fourths of the estimated nearly 42,000 new cases in the U.S. in 2018. HCC is the fastest-rising cause of cancer-related death in U.S.3 Without treatment, patients with advanced HCC usually survive less than 6 months.4

About CABOMETYX (cabozantinib)

CABOMETYX tablets are approved in the United States for the treatment of patients with advanced RCC. CABOMETYX tablets are also approved in the European Union, Norway, Iceland, Australia, Switzerland and South Korea for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy, and in the European Union for previously untreated intermediate- or poor-risk advanced RCC. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan, including RCC and HCC.

Please see Important Safety Information below and full U.S. prescribing information at View Source

U.S. Important Safety Information

Hemorrhage: Severe and fatal hemorrhages have occurred with CABOMETYX. In two RCC studies, the incidence of Grade ≥ 3 hemorrhagic events was 3% in CABOMETYX-treated patients. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.
Gastrointestinal (GI) Perforations and Fistulas: In RCC studies, fistulas were reported in 1% of CABOMETYX-treated patients. Fatal perforations occurred in patients treated with CABOMETYX. In RCC studies, gastrointestinal (GI) perforations were reported in 1% of CABOMETYX-treated patients. Monitor patients for symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula which cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. In RCC studies, venous thromboembolism occurred in 9% (including 5% pulmonary embolism) and arterial thromboembolism occurred in 1% of CABOMETYX-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.
Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension, including hypertensive crisis. In RCC studies, hypertension was reported in 44% (18% Grade ≥ 3) of CABOMETYX-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.
Diarrhea: In RCC studies, diarrhea occurred in 74% of patients treated with CABOMETYX. Grade 3 diarrhea occurred in 11% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose.
Palmar-Plantar Erythrodysesthesia (PPE): In RCC studies, palmar-plantar erythrodysesthesia (PPE) occurred in 42% of patients treated with CABOMETYX. Grade 3 PPE occurred in 8% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade 3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced dose.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-fetal Toxicity may be associated with CABOMETYX. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during CABOMETYX treatment and for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, hypertension, PPE, weight decreased, vomiting, dysgeusia, and stomatitis.
Strong CYP3A4 Inhibitors: If concomitant use with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage.
Strong CYP3A4 Inducers: If concomitant use with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.
Lactation: Advise women not to breastfeed while taking CABOMETYX and for 4 months after the final dose.
Hepatic Impairment: In patients with mild to moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

On June 3, 2018 Celgene Corporation (NASDAQ:CELG) reported additional results from RELEVANCE, a phase III, randomized, open-label, international clinical study conducted in partnership with the Lymphoma Academic Research Organisation (LYSARC), were presented at the 54th Annual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Scientific Sessions (ASCO) (Free ASCO Whitepaper) in Chicago, Illinois on June 1-5, 2018 (Press release, Celgene, JUN 3, 2018, View Source [SID1234527064]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

This investigational study evaluated REVLIMID (lenalidomide) plus rituximab (R2), followed by R2 maintenance, an investigational regimen, compared to the standard of care treatment of rituximab plus chemotherapy (R-chemo: R-CHOP, R-bendamustine or R-CVP) followed by rituximab maintenance in patients with previously untreated follicular lymphoma. Investigators found that treatment with a chemotherapy-free R2 regimen offered numerically similar efficacy results for the primary endpoints of progression free survival (PFS) and complete response or unconfirmed complete response (CR/CRu) at 120 weeks with a different safety profile than treatment with the conventional R-chemo standard. As previously disclosed, the study did not achieve the primary endpoints of superior PFS and CR/CRu.

"These findings provide important insight into the efficacy and safety of a chemotherapy-free regimen in patients with previously untreated follicular lymphoma and represent an important step forward in understanding possible treatment options for these patients," said Nathan Fowler, MD, Associate Professor, Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center.

The co-primary efficacy endpoints of the study were CR and CRu at 120 weeks and PFS during the pre-planned analysis (final analysis of CR/CRu and interim analysis of PFS). An analysis of the findings found that 48% of patients in the R2 arm and 53% of those receiving R-chemo maintained CR/Cru 120 weeks after randomization, with a 3-year estimated interim PFS rate of 77% and 78% respectively (P=0.48, HR (95% CI) 1.10 (0.85-1.43)). Preliminary overall survival, one of the study’s secondary endpoints, showed a 3-year survival rate of 94% in both treatment arms. Other secondary endpoints included number of patients with adverse events, time to treatment failure, event-free survival, time to next anti-lymphoma treatment, time to next chemotherapy treatment, overall response rate at 120 weeks based on International Working Group (IWG) 1999 criteria, and health-related quality of life as measured by the EORTC QLQ-C30.

The majority of patients in both arms completed treatment (69% R2 and 71% R-chemo). The most common Grade 3/4 TEAEs in both arms were neutropenia (32% R2 vs. 50% R-chemo), febrile neutropenia (2% R2 vs. 7% R-chemo) and cutaneous events (7% R2 vs. 1% R-chemo). SPMs were reported in 7% R2 and 10% R-chemo patients, and Grade 5 AEs were 1% in both treatment arms.

"We believe the findings of the RELEVANCE trial add further to the understanding of the R2 regimen in patients with follicular lymphoma," said Nadim Ahmed, President of Hematology and Oncology for Celgene. "We now look forward to the results of our AUGMENT study, which is evaluating this important regimen in previously treated patients with indolent lymphomas. These studies support our ongoing efforts to develop a portfolio of novel treatments for lymphoma."

REVLIMID alone or in combination with rituximab is not approved for use in follicular lymphoma in any country.

ABOUT RELEVANCE

RELEVANCE is the first multi-center, international, open-label, randomized phase III clinical trial of the chemotherapy-free combination immunotherapy R2 vs. R-chemo followed by rituximab maintenance in previously untreated, advanced follicular lymphoma patients. The study was conducted by Celgene in the US and Japan and by LYSARC in the rest of the world at 136 centers in 10 countries and evaluated the safety and efficacy of REVLIMID plus rituximab (R2) followed by R2 maintenance compared to the standard of care treatment of rituximab plus chemotherapy (R-CHOP, R-bendamustine or R-CVP) followed by rituximab maintenance.

The trial evaluated 1030 patients with advanced follicular lymphoma who had not received prior treatment and were deemed to require treatment per Groupe d’Etude des Lymphomes Folliculaires (GELF) Criteria. Patients received treatment for 120 weeks and were randomized to receive either R2 or R-chemo treatment. The median age of the patients was 59 years.

The R2 arm received REVLIMID + Rituximab on the following dosing schedules: REVLIMID 20-mg on days 2-22 every 28 days for up to 6 cycles. Patients with a complete response after 6 cycles then received REVLIMID 10-mg on days 2-22 every 28 days for 12 cycles. Patients with a partial response after 6 cycles continued to receive REVLIMID 20 mg for 3-6 cycles until they achieved a CR/CRu, at which time they then received REVLIMID 10 mg on days 2-22 of every 28-day cycle for up to 9 or 6 cycles, respectively. Patients who remained in partial response after the additional 6 cycles received REVLIMID 10 mg for a total of 18 cycles. Rituximab 375 mg/m2 was administered on days 1, 8, 15 and 22 of cycle 1, day 1 of cycles 2 to 6; 8 weeks later responding patients continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles.

The R-chemo arm received ONE of the following: Rituximab – CHOP (72%), Rituximab – CVP (5%), or Rituximab – Bendamustine (23%). Seven to 8 weeks later, responding patients continued with 375 mg/m2 rituximab every 8 weeks for 12 cycles.

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

On June 3, 2018 Celgene Corporation (NASDAQ:CELG) reported updated six-month safety and efficacy data from the TRANSCEND (NHL-001) study of lisocabtagene maraleucel (liso-cel; JCAR017), an investigational CD19-directed CAR T cell therapy, in patients with relapsed/refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (NHL) in a presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL (Press release, Celgene, JUN 3, 2018, View Source [SID1234527063]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"As liso-cel data mature, the durable response rates continue to demonstrate the potential of CAR T cell therapy in patients with DLBCL who have relapsed or are refractory to prior treatments," said principal investigator Jeremy Abramson, M.D., of Massachusetts General Hospital. "Added to the emerging side effect profile with liso-cel, this therapy has encouraging potential in diffuse large B-cell lymphoma."

The update provided today was based on a cutoff date of May 4, 2018 and included data from 114 liso-cel treated and 102 safety evaluable patients, of which 51 patients were treated at the pivotal dose of 100 million cells. Abramson highlighted 37 patients who meet the criteria for the planned pivotal patient population in TRANSCEND NHL-001 (including r/r DLBCL, transformed from follicular lymphoma (tFL), and poor-risk high-grade double/triple-hit lymphoma), and were treated with the pivotal cell dose. The new long-term follow up data add to those disclosed on May 16, 2018 in ASCO (Free ASCO Whitepaper) Abstract #7505.

At six months, 49% of patients remained in remission, with 46% maintaining a complete response (CR) in this cohort (n=37). When durability of response beyond six months was evaluated across all dosing levels ranging from 5 x 107 to 1 x 108 CAR T cells, 93% of patients in CR remained in CR at data cut off. Liso-cel therapy was available for 99% (132/134) of patients apheresed.

The most common treatment-emergent adverse events that occurred at ≥25% incidence included neutropenia (63%), anemia (53%), fatigue (46%), thrombocytopenia (34%), decreased appetite (29%), nausea (28%), hypotension (26%), cough (26%), headache (25%), dizziness (25%), constipation (25%), and diarrhea (25%). Cytokine release syndrome and neurotoxicity were observed at a rate of 37% and 23% for all grades, and 1% and 13% for grades 3 and 4, respectively (n=102). Based on this emerging safety profile, outpatient administration is being evaluated in the TRANSCEND trial.

"The updated efficacy and tolerability data for liso-cel continue to support a potential best-in-class CD19 CAR T profile," said Nadim Ahmed, President, Hematology and Oncology for Celgene. "With the TRANSCEND pivotal cohort now fully enrolled, we look forward to further progressing this critical program for poor-prognosis patients with relapsed or refractory aggressive NHL and investigating the clinical utility of liso-cel in earlier lines of therapy."

About Liso-cel and TRANSCEND

Liso-cel is an investigational defined composition CD19-directed CAR T cell product candidate using a 4-1BB costimulatory domain. TRANSCEND is an open-label, multicenter phase I study to determine the safety, pharmacokinetics, and antitumor activity of liso-cel in adult patients with relapsed or refractory diffuse large B cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma Grade 3B, and mantle cell lymphoma.

The pivotal cohort includes patients with DLBCL (NOS and transformed from follicular lymphoma) who are ECOG Performance Status 0-1. These patients represent a high-risk patient population, with approximately 90% of treated patients having one or more predictors of poor survival, including double or triple hit lymphoma, being chemorefractory to front-line or subsequent therapies, never reaching a complete remission with prior treatments, or never having undergone an autologous transplant.

On June 3, 2018 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seattle Genetics, Inc. (Nasdaq: SGEN) reported the presentation of updated phase 1 data of enfortumab vedotin, an investigational antibody-drug conjugate (ADC), at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting in Chicago (Press release, Astellas, JUN 3, 2018, View Source [SID1234527059]). In this phase 1 study (EV-101), enfortumab vedotin was evaluated as monotherapy for patients with metastatic urothelial cancer including patients who previously received a checkpoint inhibitor.i This phase 1 study is part of a broader program focused on investigating enfortumab vedotin in both monotherapy and in combination with a checkpoint inhibitor for locally advanced or metastatic urothelial cancer.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

(PRNewsfoto/Astellas Pharma Inc.)

"Many patients with locally advanced or metastatic urothelial cancer previously treated with checkpoint inhibitors have a poor prognosis and limited subsequent treatment options," said Jonathan E. Rosenberg, M.D., medical oncologist at Memorial Sloan Kettering Cancer Center and presenter of the updated phase 1 data at ASCO (Free ASCO Whitepaper). "Data from the ongoing study support the potential of enfortumab vedotin in locally advanced or metastatic urothelial cancer, based on the objective response rate and preliminary estimates of survival."

"We are encouraged by these updated data for enfortumab vedotin, which further support the rapid expansion of a comprehensive clinical trial program and the registrational study that is already underway in metastatic urothelial cancer," said Steven Benner, M.D., Senior Vice President and Global Therapeutic Area Head, Oncology Development, Astellas. "We look forward to working closely with our partner, Seattle Genetics, as we continue to evaluate enfortumab vedotin for patients with metastatic urothelial cancer."

Robert Lechleider, M.D., Senior Vice President, Clinical Development at Seattle Genetics added, "These ASCO (Free ASCO Whitepaper) data from the phase 1 study of enfortumab vedotin further support its Breakthrough Therapy Designation from the FDA, and the rationale for our ongoing pivotal trial, EV-201. We look forward to completing enrollment of the EV-201 pivotal trial for patients with metastatic urothelial cancer who have received both a platinum-based therapy and a checkpoint inhibitor. Positive data in this patient subgroup may represent a potential expedited registration pathway."

The following updated results were presented by Dr. Rosenberg:

Updated Results from the Enfortumab Vedotin Phase 1 (EV-101) Study in Patients with Metastatic Urothelial Cancer: (Abstract #4504, oral abstract session on Sunday, June 3 from 9:12-9:24 a.m. CT)1

Study Design

A total of 112 patients with metastatic urothelial cancer treated with 1 or more prior chemotherapy or who were ineligible for cisplatin received a 30-minute infusion of enfortumab vedotin at 1.25 mg/kg on day 1, 8 and 15 of each 28-day cycle.ii
Sixty-three percent of patients had received 2 or more prior therapies in the metastatic setting.1
The primary objective of the study was tolerability. A secondary objective was antitumor activity, which was assessed by investigators every 8 weeks.2
Study Results

Of 112 evaluable patients, confirmed complete responses were observed in 4 patients and confirmed partial responses were observed in 41 patients, with an overall response rate of 41 percent.1
The most commonly reported treatment-related adverse event was All Grade fatigue (54 percent). Anemia (8 percent), hyponatremia (7 percent), urinary tract infection (7 percent) and hyperglycemia (6 percent) were the most common ≥ Grade 3 AEs.1 Four patients experienced a fatal treatment-related adverse event (respiratory failure, urinary tract obstruction, diabetic ketoacidosis, multi-organ failure).2
Additionally, the ORR in the 89 patients with prior checkpoint inhibitor therapy was 40 percent, 44 percent in the 23 patients who had not been treated with a checkpoint inhibitor, and 39 percent in the 33 patients with liver metastases.1
For all enrolled patients, the interim median overall survival was 13.6 months, the overall median duration of response was 5.75 months and the median progression-free survival was 5.4 months.1
EV-201 Study: A Single-Arm, Open-Label, Multicenter Study of Enfortumab Vedotin for Treatment of Patients with Locally Advanced or Metastatic Urothelial Cancer Who Previously Received Immune Checkpoint Inhibitor Therapy (Abstract #TPS4590, poster session on Saturday, June 2 from 8:00-11:30 a.m. CT)iii

In addition, the EV-201 trial in progress poster was presented at the meeting. EV-201 is an ongoing single-arm, single-agent pivotal phase 2 clinical trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with checkpoint inhibitor therapy, including those who had also been treated with a platinum chemotherapy and those who were platinum naive.3

More information about the enfortumab vedotin clinical trials can be found at View Source

About Urothelial Cancer
According to the American Cancer Society, urothelial cancer, also known as transitional cell carcinoma (TCC), is the most common type of bladder canceriv (90 percent of casesv). Approximately 81,000 people in the U.S. are anticipated to be diagnosed with bladder cancer during 2018.vi Bladder cancer is the fourth most common cancer in men, but is less common in women.6 Outcomes are poor for people diagnosed with metastatic disease, with a five-year survival rate of 4.8 percent.vii

About Enfortumab Vedotin
Enfortumab vedotin is an investigational ADC composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent, MMAE, using Seattle Genetics’ proprietary, linker technology. Enfortumab vedotin targets Nectin-4, a cell adhesion molecule identified as an ADC target by Astellas, which is expressed on many solid tumors.

On June 3, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported positive data from the Phase 2 CAPTIVATE (PCYC-1142) study evaluating IMBRUVICA (ibrutinib) in combination with VENCLEXTA (venetoclax) in previously-untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients (Press release, AbbVie, JUN 3, 2018, View Source [SID1234527050]). Early results of the combination oral regimen suggest promising activity in treatment-naïve CLL/SLL with 77 percent of the first 30 patients achieving responses with no detectable minimal residual disease (MRD) after six cycles of the combination therapy. MRD is determined by measuring the number of cancer cells remaining and helps confirm depth of remission. The first 14 CLL/SLL patients to complete the clinical trial combination therapy of 12 cycles (15 cycles of ibrutinib) achieved responses with no detectable MRD in approximately nine out of 10 patients, with 93 percent achieving MRD negativity when measuring in peripheral blood and 86 percent with MRD negativity when measuring in the bone marrow.1

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

These data will be presented today as an oral presentation at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (abstract #7502).1 The results were also selected for the 2018 Best of ASCO (Free ASCO Whitepaper) Meetings. IMBRUVICA is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"The findings underscore prior data sets that have been reported by external investigators and support the potential benefit of combining these two agents with complementary mechanisms of action, IMBRUVICA and venetoclax, which may work together to deliver deep responses in chronic lymphocytic leukemia," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "The Phase 2 results from the CAPTIVATE study suggest we could be one step closer to advancing treatment without the use of chemotherapy for patients with CLL and SLL."

CLL is the most common form of leukemia in adults and is a type of cancer that can develop from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes). These cancer cells start in the bone marrow and later spread to the blood. The prevalence of CLL is approximately 115,000 patients in the U.S. with approximately 19,000 newly diagnosed patients every year.2,3 SLL is a slow-growing lymphoma biologically similar to CLL in which too many immature white blood cells cause lymph nodes to become larger than normal.4 CLL/SLL are predominantly diseases of the elderly, with an average age of 70 at diagnosis.3 Treatment options for CLL vary greatly, depending on the person’s age, the disease risk group, and symptoms. Many people live a long time with CLL, but in general it is very difficult to cure, and early treatment hasn’t been shown to help people live longer.5

"IMBRUVICA demonstrates the progress made in evaluating non-chemotherapy treatments for CLL and the potential for improved outcomes," said William G. Wierda, M.D., Ph.D., D.B. Lane Cancer Research Distinguished Professor, Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston, TX, and lead investigator of the
CAPTIVATE study.* "We are now working with IMBRUVICA on treatments directed at potentially achieving deep remission with undetectable minimal residual disease and anticipate long treatment-free remissions. Early results from the CAPTIVATE study suggest that IMBRUVICA, when used in combination with venetoclax, may be able drive this much-desired outcome – deep undetectable MRD remission."

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASCO (Free ASCO Whitepaper) 2018, please visit: View Source

Abstract #7502: Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL)
Oral presentation: Sunday, June 3 at 10:09 – 10:21 a.m. CDT

In the Phase 2 CAPTIVATE (PCYC-1142) study, treatment-naïve CLL/SLL patients received single-agent ibrutinib (420 mg/day) alone for three 28-day cycles before initiating venetoclax ramp-up (standard ramp-up to 400 mg/day). Early data suggest promising activity for the combination oral regimen with undetectable MRD achieved in 77% of the first 30 patients after six cycles of therapy and undetectable MRD in 86% of the first 14 patients after 12 cycles of therapy in both the bone marrow and blood.

CAPTIVATE is a multicenter study that has enrolled 164 treatment-naïve CLL/SLL patients as defined by the International Workshop on Chronic Lymphocytic Leukemia criteria (median age: 58); 15% had del17p, 18% had del11q, and 32% had longest lymph node diameter (LDi) of 5 or more centimeters (cm). The trial was designed to evaluate if remission with undetectable MRD can provide treatment-naïve CLL/SLL patients with treatment holidays (a period of time when a patient is able to stop therapy).

The first 30 patients enrolled for safety run-in completed six or more cycles of ibrutinib and venetoclax (median treatment duration: 10.4 months ibrutinib, 7.6 months venetoclax). In the safety run-in of the first 14 patients who completed 12 cycles of ibrutinib and venetoclax, no dose-limiting toxicities occurred, with an overall response rate of 100% in the 11 patients assessed (6 complete responses, 5 partial responses). Bone marrow was MRD-negative in 12 of 14 assessed patients after 12 cycles of ibrutinib and venetoclax.

The most common AEs (occurring in ≥ 20% patients) were diarrhea (63%), fatigue (27%), nausea (35%), headache (24%), upper respiratory tract infection (24%) and arthralgia (29%). Grade 3 or higher AEs (occurring in ≥ 3% patients) were neutropenia (27%), hypertension (6%), diarrhea (4%) and thrombocytopenia (6%). No clinical tumor lysis syndrome (TLS) occurred and lab TLS was seen in 1 of 164 patients. In treated patients with baseline LDi 5 cm or greater, LDi decreased to less than 5 cm in 43 of 53 patients (81%) after ibrutinib lead-in. TLS risk shifted from high to medium/low in 36 of 40 patients (90%), and overall, the proportion of high-risk TLS decreased from 24% at baseline to 3% after ibrutinib lead-in.

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by blocking a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells as well as other serious, debilitating conditions.6 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host disease (cGVHD).7

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was initially approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for adult patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with previously treated CLL/SLL.
In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.
Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases.8 IMBRUVICA was one of the first medicines to receive FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. To date, 100,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0 to 1% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 0 to 6% of patients. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA.

Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (range, 3 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 2 to 13%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. 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 hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (62%)*, neutropenia (61%)*, diarrhea (43%), anemia (41%)*, musculoskeletal pain (30%), bruising (30%), rash (30%), fatigue (29%), nausea (29%), hemorrhage (22%), and pyrexia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%)*, thrombocytopenia (16%)*, and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9 % (WM [6%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%)*, pneumonia (10%), sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements and adverse reactions.

DRUG INTERACTIONS

CYP3A Inhibitors: Dose adjustment may be recommended.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS
Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.