On May 19, 2021 Aileron Therapeutics (NASDAQ:ALRN), a chemoprotection oncology company focused on fundamentally transforming the experience of chemotherapy for cancer patients, reported that it will host a key opinion leader (KOL) investor event focused on the topic of protecting cancer patients from chemotherapy-induced toxicities on Wednesday, May 26, 2021 at 11:00 am ET (Press release, Aileron Therapeutics, MAY 19, 2021, View Source [SID1234580291]).

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!

The fireside chat, moderated by Soumit Roy, Ph.D., Managing Director at JonesTrading, will feature Alan List, M.D. and Lodovico Balducci, M.D., discussing the unmet need in addressing chemotherapy-induced toxicities, the resulting medical impact and quality-of-life burden on cancer patients, as well as the opportunity for a new paradigm known as chemoprotection that focuses on proactive prevention.

Dr. List is a hematologist and physician scientist who is internationally recognized for his many contributions in the development of more effective treatment strategies for myeloid and other malignancies. He is the author of more than 450 peer-reviewed manuscripts, chapters and books, and is the former President and CEO of Moffitt Cancer Center, and past president of the Society of Hematologic Oncology. Currently, Dr. List serves as Chief Medical Officer at Precision Biosciences. Dr. Balducci, a renowned geriatric oncologist, was formerly a Senior Member of the Senior Adult Oncology Program and Medical Director of Affiliates & Referring Physician Relations at Moffitt Cancer Center, and Professor of Oncologic Sciences, University of South Florida College of Medicine, in Tampa, Florida.

A webcast of the event will be available under the Investors and Media section on Aileron’s website at View Source A replay of the webcast will be archived on Aileron’s website for 90 days following the event.

To register for the event, please click here.

Aileron’s first-in-class dual MDM2/MDMX inhibitor, ALRN-6924, is currently in clinical development as a therapeutic agent designed to deliver selective chemoprotection for patients with p53-mutated cancers. 50% of all cancer patients have p53-mutated cancer.

ALRN-6924 has demonstrated a protective effect against chemotherapy-induced bone marrow toxicities, including neutropenia, thrombocytopenia and anemia, in a Phase 1b trial in patients with p53-mutated small cell lung cancer (SCLC) undergoing treatment with topotecan in second line of therapy. In the second quarter of 2021, Aileron plans to initiate a Phase 1b randomized, placebo-controlled trial of ALRN-6924 in patients with p53-mutated non-small cell lung cancer (NSCLC) who are receiving first-line carboplatin plus pemetrexed (with or without immune checkpoint inhibitors).

On May 19, 2021 Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) ("Takeda") reported that primary analysis data from the Phase 2 OPTIC (Optimizing Ponatinib Treatment In CML) trial will be presented during an oral session at the virtual 57th American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, and as an oral session at the virtual 26th European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting (Press release, Takeda, MAY 19, 2021, View Source [SID1234580307]). The OPTIC trial is a randomized, open-label study prospectively evaluating response-based dosing regimens of ICLUSIG (ponatinib) over a range of three starting doses (45-, 30-, or 15-mg) with the aim of optimizing its efficacy and safety in patients with chronic-phase chronic myeloid leukemia (CP-CML) who are resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy.

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!

"The OPTIC data, along with the recently updated U.S. FDA indication, demonstrate the benefit ICLUSIG can offer as a third-generation TKI."

Tweet this
The OPTIC trial, which evaluated treatment in patients with resistant disease, with and without mutations, met its primary endpoint. The study demonstrates that the optimal benefit-risk profile for ICLUSIG in patients with CP-CML is achieved with a daily starting dose of 45-mg and, upon achieving ≤1% BCR-ABL1IS, dose reduction to 15-mg. The results also suggest a clinically manageable safety and arterial occlusive event (AOE) profile for ICLUSIG.

"The primary analysis of the OPTIC data reinforce that ICLUSIG is very valuable in the management of patients with resistant and intolerant chronic-phase CML. ICLUSIG should be considered following failure of two or more TKIs. This approach minimizes the need to use back-to-back second-generation TKIs, which is usually associated with low probability of response and poor outcomes," said Jorge Cortes, MD, Georgia Cancer Center at Augusta University, and an OPTIC trial principal investigator. "These findings further demonstrate that the optimal ICLUSIG benefit-risk profile can be achieved with a response-based dosing regimen, providing efficacy while reducing risk for arterial occlusive events."

The first presentation of OPTIC data at the 56th ASCO (Free ASCO Whitepaper) and the 25th EHA (Free EHA Whitepaper) virtual Annual Meetings in 2020 showcased revised benefit-risk outcomes of ICLUSIG from the interim analysis (cutoff date of July 2019), which evaluated 216 patients with a median follow-up of 21 months. The primary analysis evaluated 283 patients with a median follow-up time of 32 months, reinforcing the positive and prolonged duration of response in this resistant CP-CML patient population while maintaining a manageable safety profile at a longer follow-up period.

"There is a misconception that chronic-phase CML is a ‘good cancer’ due to the fact it can be well controlled, but for patients with resistant and intolerant disease, continued investigation and treatment options are critical. The primary analysis of OPTIC solidifies our understanding of how ICLUSIG can address gaps in care for these patients," said Christopher Arendt, Ph.D., Head, Oncology Therapeutic Area Unit, Takeda. "The OPTIC data, along with the recently updated U.S. FDA indication, demonstrate the benefit ICLUSIG can offer as a third-generation TKI."

In December 2020, the U.S. Food and Drug Administration (FDA) approved a supplemental New Drug Application (sNDA) for ICLUSIG based on the OPTIC data. The updated label includes an expanded indication for adult patients with CP-CML that is resistant or intolerant to at least two prior kinase inhibitors, as well as the optimized response-based dosing regimen.

OPTIC Primary Analysis: A Dose-Optimization Study of Three Starting Doses of Ponatinib (PON).

Key findings, to be presented by Dr. Jorge Cortes, include:

By the primary analysis (cutoff date of May 2020) with median follow-up time of 32 months, 100% of patients in the OPTIC trial were evaluable for the primary endpoint.
The maximum rates of ≤1% BCR-ABL1IS at 12 months were achieved in the 45-mg/day starting dose cohort (44.1%), and 73.3% of patients in this cohort maintained responses with the dose reduction to 15-mg/day. 30-mg/day and 15-mg/day cohorts also demonstrated benefit (29% and 23%, respectively), especially in patients with less-resistant disease and without the T315I mutation.
Positive survival outcomes were observed in all three arms, with an 89% 36-month overall survival (OS) probability anticipated for the 45-mg starting dose cohort and 73% progression-free survival (PFS) anticipated for the same cohort.
This indicates the dose-reduction strategy did not impact overall survival regardless of prior second-generation TKI resistance or the presence of BCR-ABL1 mutations.
Rates of arterial occlusive events (AOEs) observed at the time of primary analysis (6% overall and 9.6% in the 45-mg cohort) suggest a clinically manageable safety and AOE profile.
Safety data include:
Among all patients (N=283), the most common treatment emergent adverse events (TEAEs) Grade 3 or greater were thrombocytopenia (27%), neutropenia (17%) and anemia (7%).
Reported AOEs were 10%, 5% and 3% for the 45-, 30-, 15-mg/day starting dose cohorts, respectively. Grade 3 or greater AOEs were 5%, 5% and 3% for the 45-, 30-, 15-mg/day starting dose cohorts, respectively.
Reported serious AOEs were 4%, 4% and 3% for the 45-, 30-, 15-mg/day starting dose cohorts, respectively. There were 4 deaths related to AEs (2 sudden deaths and 2 pneumonia).
Learn more about Takeda Oncology’s presence at this year’s ASCO (Free ASCO Whitepaper) and EHA (Free EHA Whitepaper) annual meetings. Takeda will host a webcast for analysts and investors on Tuesday, June 8, at 6:30 p.m. ET to discuss these and other data being presented at ASCO (Free ASCO Whitepaper), and to provide an update on the oncology pipeline. Please contact [email protected] for further details. Presentation slides and an archived replay of the webcast will be available at View Source

About the OPTIC Trial

OPTIC (Optimizing Ponatinib Treatment In CML) is an ongoing randomized, dose-ranging trial designed to evaluate three starting doses of ICLUSIG (45-, 30-, and 15-mg) in patients with resistant chronic-phase chronic myeloid leukemia (CP-CML) or who had documented history of presence of T315I mutation after receiving any number of prior TKIs. Dose reduction at response occurred per study protocol. The trial is expected to inform the optimal use of ICLUSIG (ponatinib) in these patients. 282 patients were enrolled at clinical sites around the world, with 94 patients receiving the 45-mg starting dose. The primary endpoint of the trial is achieving ≤1% BCR-ABL1IS at 12 months.

OPTIC data showed that optimal benefit-risk with ICLUSIG can be obtained with a response-based dosing regimen, 45-mg/day to 15-mg/day upon achieving ≤1% BCR-ABL1IS in patients with CP-CML highly resistant to prior TKI therapies both with or without mutations. At 12 months, 44% (41/93) of patients who received the 45-mg starting dose achieved ≤1% BCR-ABL1IS. At a median follow up time of 32 months, the OPTIC study showed that, among patients receiving ICLUSIG 45- to 15-mg, 73% maintained their response. In these patients, 10% experienced an AOE of any Grade, 5% experienced Grade 3 or higher. The most common TEAEs occurring in > 15% of patients were thrombocytopenia, hypertension, headache, neutropenia, anemia, headache, lipase increased, alanine aminotransferase (ALT) increased, and arthralgia.

About CML and Ph+ ALL

CML – a rare malignancy – is one of four main types of leukemia; it is a result of a genetic mutation that takes place in early, immature versions of myeloid cells, which form red blood cells, platelets and most types of white blood cells. Subsequently, an abnormal gene called BCR-ABL1 forms, turning the damaged cell into a CML cell. CML typically progresses slowly, but it can change into a fast-growing acute leukemia that is hard to treat.

Ph+ ALL is a rare form of ALL that affects approximately 25% of adult ALL patients in the U.S. and is characterized by the presence of an abnormal gene, known as the Philadelphia chromosome. In patients who are Philadelphia chromosome-positive (Ph+), an abnormal chromosome is formed when pieces of chromosomes 9 and 22 switch with each other. This forms a longer chromosome 9 and a shorter chromosome 22, which leads to the development of BCR-ABL1 and is associated with Ph+ ALL.

About ICLUSIG (ponatinib) tablets

ICLUSIG is a kinase inhibitor targeting BCR-ABL1, an abnormal tyrosine kinase that is expressed in CML and Ph+ ALL. ICLUSIG is a targeted cancer medicine developed using a computational and structure-based drug-design platform, specifically designed to inhibit the activity of BCR-ABL1 and its mutations. ICLUSIG inhibits native BCR-ABL1, as well as all BCR-ABL1 treatment-resistant mutations, including the most resistant T315I mutation. ICLUSIG is the only approved TKI that demonstrates activity against the T315I gatekeeper mutation of BCR-ABL1. This mutation has been associated with resistance to all other approved TKIs. ICLUSIG received full approval from the FDA in November 2016. ICLUSIG is indicated for the treatment of adult patients with chronic-phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors, accelerated-phase (AP) or blast-phase (BP) CML or Ph+ ALL for whom no other kinase inhibitor is indicated, and T315I+ CML (CP, AP or BP) or T315I-positive Ph+ ALL. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

IMPORTANT SAFETY INFORMATION

WARNING: ARTERIAL OCCLUSIVE EVENTS, VENOUS THROMBOEMBOLIC EVENTS, HEART FAILURE, and HEPATOTOXICITY

See full prescribing information for complete boxed warning.

Arterial occlusive events (AOEs), including fatalities, have occurred in ICLUSIG-treated patients. AOEs included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue ICLUSIG based on severity. Consider benefit-risk to guide a decision to restart ICLUSIG.
Venous thromboembolic events (VTEs) have occurred in ICLUSIG-treated patients. Monitor for evidence of VTEs. Interrupt or discontinue ICLUSIG based on severity.
Heart failure, including fatalities, occurred in ICLUSIG-treated patients. Monitor for heart failure and manage patients as clinically indicated. Interrupt or discontinue ICLUSIG for new or worsening heart failure.
Hepatotoxicity, liver failure and death have occurred in ICLUSIG-treated patients. Monitor liver function tests. Interrupt or discontinue ICLUSIG based on severity.
WARNINGS AND PRECAUTIONS

Arterial Occlusive Events (AOEs): AOEs, including fatalities, have occurred in patients who received ICLUSIG in OPTIC and PACE. These included cardiovascular, cerebrovascular, and peripheral vascular events. The incidence of AOEs in OPTIC (45 mg→15 mg) was 13% of 94 patients; 5% experienced Grade 3 or 4. In PACE, the incidence of AOEs was 26% of 449 patients; 14% experienced Grade 3 or 4. Fatal AOEs occurred in 2.1% of patients in OPTIC, and in 2% of patients in PACE. Some patients in PACE experienced recurrent or multisite vascular occlusion. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. The most common risk factors observed with these events in PACE were history of hypertension, hypercholesterolemia, and non-ischemic cardiac disease. In OPTIC and PACE, AOEs were more frequent with increasing age.

In OPTIC, patients with uncontrolled hypertension or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease were excluded. In PACE, patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease within the 3 months prior to the first dose of ICLUSIG were excluded. Consider whether the benefits of ICLUSIG are expected to exceed the risks.

Monitor for evidence of AOEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity. Consider benefit-risk to guide a decision to restart ICLUSIG.

Venous Thromboembolic Events (VTEs): Serious or severe VTEs have occurred in patients who received ICLUSIG. In PACE, VTEs occurred in 6% of 449 patients including serious or severe (Grade 3 or 4) VTEs in 5.8% of patients. VTEs included deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, retinal vein occlusion, and retinal vein thrombosis with vision loss. The incidence was higher in patients with Ph+ ALL (9% of 32 patients) and BP-CML (10% of 62 patients). One of 94 patients in OPTIC experienced a VTE (Grade 1 retinal vein occlusion). Monitor for evidence of VTEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity.

Heart Failure: Fatal, serious or severe heart failure events have occurred in patients who received ICLUSIG. In PACE, heart failure occurred in 9% of 449 patients; 7% experienced serious or severe (Grade 3 or higher). Heart failure occurred in 12% of 94 patients in OPTIC; 1.1% experienced serious or severe (Grade 3 or 4). In PACE, the most frequently reported heart failure events (≥2%) were congestive cardiac failure (3.1%), decreased ejection fraction (2.9%), and cardiac failure (2%). In OPTIC, the most frequently reported heart failure events (>1 patient each) were left ventricular hypertrophy (2.1%) and BNP increased (2.1%). Monitor patients for signs or symptoms consistent with heart failure and manage heart failure as clinically indicated. Interrupt, then resume at reduced dose or discontinue ICLUSIG for new or worsening heart failure.

Hepatotoxicity: ICLUSIG can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in 3 patients, with hepatic failure occurring within 1 week of starting ICLUSIG in one of these patients. These fatal cases occurred in patients with BP-CML or Ph+ ALL. Hepatotoxicity occurred in 25% of 94 patients in OPTIC and 32% of 449 patients in PACE. Grade 3 or 4 hepatotoxicity occurred in OPTIC (6% of 94 patients) and PACE (13% of 449 patients). The most frequent hepatotoxic events were elevations of ALT, AST, GGT, bilirubin, and alkaline phosphatase. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, then resume at a reduced dose or discontinue ICLUSIG based on recurrence/severity.

Hypertension: Serious or severe hypertension, including hypertensive crisis, has occurred in patients who received ICLUSIG. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. Monitor blood pressure at baseline and as clinically indicated and manage hypertension as clinically indicated. Interrupt, dose reduce, or stop ICLUSIG if hypertension is not medically controlled. For significant worsening, labile or treatment-resistant hypertension, interrupt ICLUSIG and consider evaluating for renal artery stenosis.

Pancreatitis: Serious or severe pancreatitis has occurred in patients who received ICLUSIG. Elevations of lipase and amylase also occurred. In the majority of cases that led to dose modification or treatment discontinuation, pancreatitis resolved within 2 weeks. Monitor serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on severity. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms.

Increased Toxicity in Newly Diagnosed Chronic Phase CML: In a prospective randomized clinical trial in the first line treatment of newly diagnosed patients with CP-CML, single agent ICLUSIG 45 mg once daily increased the risk of serious adverse reactions 2-fold compared to single agent imatinib 400 mg once daily. The median exposure to treatment was less than 6 months. The trial was halted for safety. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the ICLUSIG arm compared to the imatinib arm. Compared to imatinib-treated patients, ICLUSIG-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

Neuropathy: Peripheral and cranial neuropathy occurred in patients in OPTIC and PACE. Some of these events in PACE were Grade 3 or 4. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity.

Ocular Toxicity: Serious or severe ocular toxicity leading to blindness or blurred vision have occurred in ICLUSIG-treated patients. The most frequent ocular toxicities occurring in OPTIC and PACE were dry eye, blurred vision, and eye pain. Retinal toxicities included age-related macular degeneration, macular edema, retinal vein occlusion, retinal hemorrhage, and vitreous floaters. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Fatal and serious hemorrhage events have occurred in patients who received ICLUSIG. Fatal hemorrhages occurred in PACE and serious hemorrhages occurred in OPTIC and PACE. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Gastrointestinal hemorrhage and subdural hematoma were the most frequently reported serious hemorrhages. Events often occurred in patients with Grade 4 thrombocytopenia. Monitor for hemorrhage and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity.

Fluid Retention: Fatal and serious fluid retention events have occurred in patients who received ICLUSIG. In PACE, one instance of brain edema was fatal and serious events included pleural effusion, pericardial effusion, and angioedema. Monitor for fluid retention and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity.

Cardiac Arrhythmias: Cardiac arrhythmias, including ventricular and atrial arrhythmias, occurred in patients in OPTIC and PACE. For some patients, events were serious or severe (Grade 3 or 4) and led to hospitalization. Monitor for signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness) and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity.

Myelosuppression: Grade 3 or 4 events of neutropenia, thrombocytopenia, and anemia occurred in patients in OPTIC and PACE. The incidence of myelosuppression was greater in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated. If ANC less than 1 x 109/L or platelets less than 50 x 109/L, interrupt ICLUSIG until ANC at least 1.5 x 109/L and platelets at least 75 x 109/L, then resume at same or reduced dose.

Tumor Lysis Syndrome (TLS): Serious TLS was reported in ICLUSIG-treated patients in OPTIC and PACE. Ensure adequate hydration and treat high uric acid levels prior to initiating ICLUSIG.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS (also known as Posterior Reversible Encephalopathy Syndrome) has been reported in patients who received ICLUSIG. Along with neurological signs and symptoms, hypertension may be present. Diagnosis is made with supportive findings on magnetic resonance imaging (MRI) of the brain. Interrupt ICLUSIG until resolution. The safety of resumption of ICLUSIG in patients upon resolution of RPLS is unknown.

Impaired Wound Healing and Gastrointestinal Perforation: Impaired wound healing occurred in patients receiving ICLUSIG. Withhold ICLUSIG for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of ICLUSIG after resolution of wound healing complications has not been established. Gastrointestinal perforation or fistula occurred in patients receiving ICLUSIG. Permanently discontinue in patients with gastrointestinal perforation.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal studies, ICLUSIG can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, adverse developmental effects occurred at exposures lower than human exposures at the recommended human dose. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose.

ADVERSE REACTIONS

The most common (>20%) adverse reactions are rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, pyrexia, nausea, pancreatitis/lipase elevation, hemorrhage, anemia, hepatic dysfunction and AOEs. The most common Grade 3 or 4 laboratory abnormalities (>20%) are platelet count decreased, neutrophil cell count decreased, and white blood cell decreased.

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceutical Co. Ltd. At 1-844-817-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid coadministration or reduce ICLUSIG dose if coadministration cannot be avoided.

Strong CYP3A Inducers: Avoid coadministration.

USE IN SPECIFIC POPULATIONS

Females and Males of Reproductive Potential: Verify pregnancy status of females of reproductive potential prior to initiating ICLUSIG.

Ponatinib may impair fertility in females, and it is not known if these effects are reversible.

Lactation: Advise women not to breastfeed during treatment with ICLUSIG and for 6 days following last dose.

For more information about ICLUSIG, visit www.ICLUSIG.com. For the Prescribing Information including the Boxed Warning for arterial occlusion, venous thromboembolism, heart failure, and hepatoxicity, please visit View Source For more information about ongoing research, please visit www.clinicaltrials.gov.

Takeda’s Commitment to Oncology

Our core R&D mission is to deliver novel medicines to patients with cancer worldwide through our commitment to science, breakthrough innovation and passion for improving the lives of patients. Whether it’s with our hematology therapies, our robust pipeline, or solid tumor medicines, we aim to stay both innovative and competitive to bring patients the treatments they need. For more information, visit www.takedaoncology.com.

On May 19, 2021 Oncopeptides AB (publ) (Nasdaq Stockholm: ONCO), a global biotech company focused on the development of therapies for difficult-to-treat hematological diseases, reported that three abstracts with data on melflufen (INN melphalan flufenamide) in relapsed refractory multiple myeloma, RRMM, have been accepted by the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), ASCO (Free ASCO Whitepaper), and have now been published online (Press release, Oncopeptides, MAY 19, 2021, View Source [SID1234580323]). The clinical data presentations include updates on Oncopeptides’ ANCHOR and LIGHTHOUSE studies as well as a pooled analysis of the O-12-M1 and HORIZON studies in patients who have been exposed to or become refractory to prior alkylators.

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!

"The phase 1/2 ANCHOR study of melflufen plus dexamethasone in combination with either daratumumab or bortezomib shows encouraging clinical activity in heavily pre-treated patients with relapsed refractory multiple myeloma, and the optimal dose of melflufen has now been established for both regimens," says Klaas Bakker, MD, PhD, Executive Vice President and Chief Medical Officer, Oncopeptides AB. "We will now complete patient enrolment in the bortezomib arm, while the daratumumab arm is already fully accrued, as presented at the American Hematology Association meeting in December 2020, where updated safety and efficacy data from ANCHOR were presented. The data presented here at ASCO (Free ASCO Whitepaper) data clearly support further development of melflufen in triplet regimens and reinforce the rational for the ongoing phase 3 LIGHTHOUSE study, comparing melflufen plus dexamethasone in combination with subcutaneous daratumumab with daratumumab alone."

Below is a brief description of the abstracts that have been accepted by the ASCO (Free ASCO Whitepaper). They will be available online at View Source, on May 19th at 23:00 (CET).

1. ANCHOR (OP-104): MELFLUFEN PLUS DEXAMETHASONE AND BORTEZOMIB IN RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS
The ANCHOR study determined that the optimal dose of melflufen is 30 mg plus dexamethasone and bortezomib and the results showed clinical activity in heavily pretreated RRMM patients. Recruitment for this study is ongoing and updated data including efficacy and safety will be presented at ASCO (Free ASCO Whitepaper).

2. LIGHTHOUSE (OP-108): A PHASE 3 STUDY OF MELFLUFEN IN COMBINATION WITH DEXAMETHASONE AND DARATUMUMAB IN RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS
The phase 3 LIGHTHOUSE study is a randomized, controlled, open-label study of melflufen plus dexamethasone in combination with daratumumab vs daratumumab alone in patients with RRMM previously treated with an immunomodulatory agent and a proteasome inhibitor, similar to the indication for daratumumab monotherapy. The primary objective is superiority of PFS. Key secondary endpoints include ORR (≥ PR), DOR, and safety. Patient recruitment is ongoing with a planned enrolment of 240 patients.

3. A POOLED ANALYSIS OF THE O-12-M1 AND HORIZON STUDIES: MELFLUFEN PLUS DEXAMETHASONE IN RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS (RRMM) WHO ARE EXPOSED OR REFRACTORY TO PRIOR ALKYLATORS
This pooled analysis of the O-12-M1 and HORIZON studies showed that melflufen in combination with dexamethasone showed meaningful efficacy and demonstrated a clinically manageable safety profile in patients with RRMM who had been exposed or become refractory to prior alkylators.

PEPAXTO (melphalan flufenamide, also known as melflufen), in combination with dexamethasone, was granted accelerated approval by the FDA on February 26, 2021, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.

For more information, please contact:

Rolf Gulliksen, Global Head of Corporate Communications, Oncopeptides AB (publ)
E-mail: [email protected]
Cell phone: + 46 70 262 96 28

Linda Holmström, Director of Investor Relations, Oncopeptides AB (publ)
E-mail: [email protected]
Cell phone: +46 70 873 40 95

About melphalan flufenamide

Melphalan flufenamide, also known as melflufen, is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly releases alkylating agents inside cancer cells. Aminopeptidases are overexpressed in multiple myeloma cells and are associated with advanced disease and tumor mutational burden. Targeting aminopeptidases causes selective activity in cancer cells, sparing healthy cells.

In the US, PEPAXTO (melphalan flufenamide) is indicated in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma, who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.

On May 19, 2021 Merus N.V. (Nasdaq: MRUS) ("Merus", "the Company", "we", or "our"), a clinical-stage oncology company developing innovative, full-length multispecific antibodies (Biclonics and Triclonics), reported the publication of the abstract highlighting interim data, as of a January 12, 2021 cutoff, from the phase 1/2 eNRGY trial and Early Access Program (EAP) of bispecific antibody zenocutuzumab (Zeno) in patients with NRG1+ cancers, on the ASCO (Free ASCO Whitepaper) website (Press release, Merus, MAY 19, 2021, View Source [SID1234580372]). An oral presentation containing an updated interim analysis with a data cutoff date of April 13, 2021 will be presented virtually by Lead Author, Dr. Alison Schram of Memorial Sloan Kettering Cancer Center (MSKCC) at the 2021 ASCO (Free ASCO Whitepaper) Annual Meeting on Friday, June 4, 2021 from 11:00 AM -2:00 PM ET.

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!

Dr. Andrew Joe, Chief Medical Officer at Merus stated, "We continue to be encouraged by the observed clinical activity and safety profile of Zeno in the ongoing eNRGy trial, especially in previously treated patients with pancreatic cancer. The clinical activity and durability data continue to mature, and we look forward to Dr. Schram’s presentation of an updated interim analysis of 45 evaluable patients with multiple tumor types at the ASCO (Free ASCO Whitepaper) Annual Meeting on June 4."

The reported data are from the ongoing phase 1/2 eNRGy trial and EAP, which are investigating the safety and anti-tumor activity of Zeno monotherapy in NRG1+ cancers. The eNRGy trial consists of three cohorts: NRG1+ pancreatic cancer; NRG1+ non-small cell lung cancer; and NRG1+ other solid tumors.

Key findings in the abstract include:

As of January 12, 2021, 51 patients were treated with Zeno, of whom 33 were evaluable for response. Tumor regression was observed in 25 out of 33 patients, with confirmed partial responses in 9 of 33 (27% ORR), including 4 of 10 patients (40% ORR) with pancreatic cancer.
Zeno continues to be well tolerated with the majority of adverse events of mild or moderate (Grade 1 or 2) severity, regardless of causality.
Presentation Details:

Title: Efficacy and safety of zenocutuzumab in advanced pancreas cancer and other solid tumors harboring NRG1 fusions
Lead Author: Alison Schram, MD, Memorial Sloan Kettering Cancer Center, NY
Abstract #: 3003
Session Title: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology
Session Date and Time: June 4, 2021, 11:00 AM-2:00 PM EDT
Presentation Time: 12:00-12:12 PM EDT

Company Conference Call and Webcast Information

Merus will hold a conference call and webcast for investors on Sunday, June 6, 2021 at 6:00 pm ET to discuss the Zeno clinical data and provide a program update. A replay will be available after the completion of the call on the Investors and Media section of our website.

Date: Sunday, June 6, 6:00 pm ET
Webcast link: available on our website
Dial-in: Toll-Free: 1-877-260-1463 / International: 1-706-643-5907
Conference ID: 9678617

About the eNRGy Clinical Trial
Merus is currently enrolling patients in the phase 1/2 eNRGy trial to assess the safety and anti-tumor activity of Zeno monotherapy in NRG1+ cancers. The eNRGy trial consists of three cohorts: NRG1+ pancreatic cancer; NRG1+ non-small cell lung cancer; and NRG1+ other solid tumors. Further details, including current trial sites, can be found at www.ClinicalTrials.gov and Merus’ trial website at www.nrg1.com or by calling 1-833-NRG-1234.

About Zeno
Zeno is an antibody-dependent cell-mediated cytotoxicity (ADCC)-enhanced Biclonics that utilizes the Merus Dock & Block mechanism to inhibit the neuregulin/HER3 tumor-signaling pathway in solid tumors with NRG1 gene fusions (NRG1+). Through its unique mechanism of binding to HER2 and potently blocking the interaction of HER3 with its ligand NRG1 or NRG1-fusion proteins, Zeno has the potential to be particularly effective against NRG1+ cancers. In preclinical studies, Zeno also potently inhibits HER2/HER3 heterodimer formation and tumor growth in models harboring NRG1 fusions.

On May 19, 2021 Amgen (NASDAQ: AMGN) reported that new data from its expanding oncology pipeline and marketed portfolio will be presented during the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place virtually from June 4-8, 2021 (Press release, Amgen, MAY 19, 2021, View Source [SID1234580259]).

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!

Overall survival (OS) data from the Phase 2 CodeBreaK 100 trial of LUMAKRAS (sotorasib), a potentially first-in-class KRASG12C inhibitor in non-small cell lung cancer (NSCLC) will be presented for the first time alongside additional exploratory biomarker subgroup analyses in an oral presentation on Friday, June 4, 2021. Updated data for investigational bemarituzumab in combination with chemotherapy from the Phase 2 FIGHT trial will also be shared in an oral presentation on Friday, June 4, 2021, in patients with FGFR2b+ advanced gastric and gastroesophageal junction adenocarcinoma (GEJ).

"Precision medicine is paving the way to the future of cancer care, and Amgen continues to relentlessly pursue breakthroughs by exploring targeted treatment approaches in a diverse range of modalities for patients with difficult-to-treat cancers," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "With new data from across our oncology portfolio, we are proud to drive the advancement of the potential next generation of targeted cancer treatments for patients who need it most."

Additional research to be presented at ASCO (Free ASCO Whitepaper) includes updated safety and efficacy data from the first-in-human (FIH) study of AMG 757 (tarlatamab) in small cell lung cancer (SCLC). Tarlatamab is an investigational first-in-class half-life extended (HLE) bispecific T-cell engager (BiTE) molecule that is uniquely designed to target delta-like ligand 3 (DLL3) in neuroendocrine cancers such as small cell lung cancer (SCLC) and neuroendocrine prostate cancer.

Investigator sponsored study (ISS) presentations include new oral data presentations from the PANAMA trial evaluating VECTIBIX (panitumumab) in combination with 5-fluorouracil/leucovorin (5FU/LV) as maintenance therapy in metastatic colorectal cancer (mCRC), and new data from the CHRONOS trial evaluating anti-EGFR rechallenge therapy with Vectibix in mCRC.

Abstracts are available on the ASCO (Free ASCO Whitepaper) website.

Amgen Webcast Investor Call
Amgen will host a webcast call for the investment community in conjunction with ASCO (Free ASCO Whitepaper) on Friday, June 4, 2021 at 4:00 p.m. ET. David M. Reese, M.D., executive vice president of Research and Development at Amgen, along with members of Amgen’s clinical development team will discuss clinical data being presented on the Company’s investigational KRASG12C inhibitor LUMAKRAS, anti-FGFR2b antibody bemarituzumab and DLL3-targeting HLE BiTE tarlatamab.

Live audio of the conference call will be broadcast over the internet simultaneously and will be available to members of the news media, investors and the general public.

The webcast, as with other selected presentations regarding developments in Amgen’s business given at certain investor and medical conferences, can be accessed on Amgen’s website, www.amgen.com, under Investors. Information regarding presentation times, webcast availability and webcast links are noted on Amgen’s Investor Relations Events Calendar. The webcast will be archived and available for replay for at least 90 days after the event.

Key Abstracts and Presentation Times:

LUMAKRAS

Overall Survival and Exploratory Subgroup Analyses From the Phase 2 CodeBreaK100 Trial Evaluating Sotorasib in Pretreated KRAS p.G12C Mutated Non-Small Cell Lung Cancer
Abstract #9003, Oral Presentation, Session: Lung Cancer—Non-Small Cell Metastatic, Friday, June 4 from 1:00 – 4:00 p.m. ET
Patient-Reported Outcomes (PRO) From the Phase 2 CodeBreaK 100 Trial Evaluating Sotorasib in KRAS p.G12C Mutated Non-Small Cell Lung Cancer
Abstract #9057, Poster, Session: Lung Cancer—Non-Small Cell Metastatic, Friday, June 4 at 9:00 a.m. ET
Trial-in-Progress: A Phase 1b Study of Sotorasib, A Specific and Irreversible KRAS G12C Inhibitor, as Monotherapy in Non-Small Cell Lung Cancer (NSCLC) with Brain Metastasis and in Combination with Other Anticancer Therapies in Advanced Solid Tumors (CodeBreaK 101)
Abstract #TPS2669, Poster, Session: Developmental Therapeutics—Immunotherapy, Friday, June 4 at 9:00 a.m. ET
Bemarituzumab

FIGHT: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Bemarituzumab (Bema) Combined with Modified FOLFOX6 in 1L FGFR2b+ Advanced Gastric/Gastroesophageal Junction Adenocarcinoma (GC/GEJ)
Abstract #4010, Oral Presentation, Session: Biomarker-Driven Approaches for the Treatment of Gastrointestinal Cancers, Friday, June 4 at 9:00 a.m. ET
AMG 757 (Tarlatamab)

Updated Results from a Phase 1 Study of AMG 757 (Tarlatamab), a Half-Life Extended Bispecific T-Cell Engager (BiTE) Immuno-Oncology Therapy Against Delta-Like Ligand 3 (DLL3), in Small-Cell Lung Cancer (SCLC)
Abstract #8510, Poster Discussion, Session: Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers, Friday, June 4 at 9:00 a.m. ET
Trial-in-Progress: A Phase 1b Study of AMG 757 (Tarlatamab) in Subjects with Neuroendocrine Prostate Cancer
Abstract #TPS5100, Poster, Session: Genitourinary Cancer—Prostate, Testicular, and Penile, Friday, June 4 at 9:00 a.m. ET
AMG 160 (Acapatamab)

Trial-in-Progress: Safety and Efficacy of AMG 160 Half-Life Extended BiTE Immune Therapy Targeting Prostate-Specific Membrane Antigen (PSMA) and Other Therapies for Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Abstract #TPS5088, Poster, Session: Genitourinary Cancer—Prostate, Testicular, and Penile, Friday, June 4 at 9:00 a.m. ET
AMG 650

Trial-in-Progress: A Phase 1, Multicenter, Open-Label, Dose-Exploration and Dose-Expansion Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 650 in Subjects with Advanced Solid Tumors
Abstract #TPS5600, Poster, Session: Gynecologic Cancer, Friday, June 4 at 9:00 a.m. ET
BLINCYTO (blinatumomab)

Trial-in-Progress: A Phase 4 Study to Evaluate Outpatient Blinatumomab in Patients with Minimal/Measurable Residual Disease (MRD) of B-cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL)
Abstract #TPS7051, Poster, Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant, Friday, June 4 at 9:00 a.m. ET
IMLYGIC (talimogene laherparepvec)

Final Analysis of a Phase 1b, Randomized, Multicenter Study of Talimogene Laherparepvec (T-VEC) Plus Pembrolizumab (Pembro) Combination for the Treatment of Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck (R/M HNSCC): MASTERKEY-232
Abstract #6036, Poster, Session: Head and Neck Cancer, Friday, June 4 at 9:00 a.m. ET
VECTIBIX (panitumumab)

Rarity of Acquired Mutations (MTs) after First-Line Therapy with Anti-EGFR Therapy (EGFRi)
Abstract #3514, Poster Discussion, Session: Gastrointestinal Cancer—Colorectal and Anal, Friday, June 4 at 9:00 a.m. ET
Investigator Sponsored Studies (ISS)

Maintenance Therapy with 5-Fluorouracil/Leucovorin (5FU/LV) Plus Panitumumab (pmab) or 5FU/LV Alone in RAS Wildtype (WT) Metastatic Colorectal Cancer (mCRC) – The PANAMA Trial (AIO KRK 0212)
Abstract #3503, Oral Presentation, Session: Gastrointestinal Cancer—Colorectal and Anal, Monday, June 7, 1:15 – 4:15 p.m. ET
Phase II Study of Anti-EGFR Rechallenge Therapy with Panitumumab Driven by Circulating Tumor DNA Molecular Selection in Metastatic Colorectal Cancer: The CHRONOS Trial
Abstract #3506, Oral Presentation, Session: Gastrointestinal Cancer—Colorectal and Anal, Monday, June 7, 1:15 – 4:15 p.m. ET
XGEVA (denosumab)

Risk Factors Associated with Skeletal-Related Events Following Denosumab Cessation Among Patients with Bone Metastases from Solid Tumors: A Real-World Machine Learning Approach
Abstract #1567, Poster, Session: Care Delivery and Regulatory Policy, Friday, June 4 at 9:00 a.m. ET
Learn more about Amgen’s development of innovative medicines for novel targets in difficult-to-treat solid tumors at AmgenOncology.com

About LUMAKRAS (sotorasib)
Amgen has taken on one of the toughest challenges of the last 40 years in cancer research by developing LUMAKRAS, an investigational KRASG12C inhibitor.2 LUMAKRAS was the first KRASG12C inhibitor to enter the clinic and is being studied in the largest clinical program exploring 11 combinations with global sites spanning five continents. In just under three years from first patient dosed, the LUMAKRAS clinical program CodeBreaK has established the deepest clinical data set with more than 800 patients studied across 13 tumor types.

LUMAKRAS has demonstrated a positive benefit-risk profile with fast, deep and durable anticancer activity in patients with advanced non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation with a once daily oral formulation. LUMAKRAS is also being studied in multiple other solid tumors.2,3

About CodeBreaK
The CodeBreaK clinical development program for Amgen’s drug sotorasib is designed to treat patients with an advanced solid tumor with the KRAS G12C mutation and address the longstanding unmet medical need for these cancers. As the most advanced KRAS G12C clinical development program, CodeBreaK has enrolled more than 800 patients across 13 tumor types since its inception.

CodeBreaK 100, the Phase 1 and 2, first-in-human, open-label multicenter study, enrolled patients with KRAS G12C-mutant solid tumors. Eligible patients must have received a prior line of systemic anticancer therapy, consistent with their tumor type and stage of disease. The primary endpoint for the Phase 2 study was centrally assessed objective response rate. The Phase 2 trial in NSCLC enrolled 126 patients, 124 of whom had centrally evaluable lesions by RECIST at baseline. The Phase 2 trial in colorectal cancer (CRC) is fully enrolled and topline results are expected in 2021.

A global Phase 3 randomized active-controlled study comparing sotorasib to docetaxel in KRAS G12C-mutated NSCLC patients (CodeBreaK 200) completed enrollment in April 2021. Amgen has several Phase 1b combination studies across various advanced solid tumors (CodeBreaK 101) open for enrollment.

About Bemarituzumab
Bemarituzumab (anti-FGFR2b) is a potential first-in-class investigational targeted antibody that is designed to block specific fibroblast growth factors (FGFs) from binding and activating FGFR2b, inhibiting several downstream pro-tumor signaling pathways and potentially slowing cancer progression. Bemarituzumab is being developed in gastric and GEJ cancer as a targeted therapy for tumors that overexpress FGFR2b. The company is also evaluating the potential for bemarituzumab in other cancers that overexpress FGFR2b. In April 2021, bemarituzumab was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration.

Zai Lab (Shanghai) Co. Ltd. was granted an exclusive license to develop and commercialize bemarituzumab in Greater China, and Zai Lab collaborated with Five Prime on the Phase 2 FIGHT trial in Greater China.

About BiTE Technology
BiTE (bispecific T cell engager) technology is a targeted immuno-oncology platform that is designed to engage a patient’s own T cells to any tumor-specific antigen, activating the cytotoxic potential of T cells to eliminate detectable cancer. The BiTE immuno-oncology platform has the potential to treat different tumor types through tumor-specific antigens. The BiTE platform has a goal of leading to off-the-shelf solutions, which have the potential to make innovative T cell treatment available to all providers when their patients need it. Amgen is advancing BiTE molecules across a broad range of hematologic malignancies and solid tumors and further investigating BiTE technology with the goal of enhancing patient experience and therapeutic potential.

About BLINCYTO (Blinatumomab)
BLINCYTO is a BiTE (bispecific T-cell engager) immuno-oncology therapy that targets CD19 surface antigens on B cells. BiTE molecules fight cancer by helping the body’s immune system detect and target malignant cells by engaging T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. By bringing T cells near cancer cells, the T cells can inject toxins and trigger cancer cell death (apoptosis). BiTE immuno-oncology therapies are currently being investigated for their potential to treat a wide variety of cancers.

BLINCYTO was granted breakthrough therapy and priority review designations by the U.S. Food and Drug Administration and is approved in the U.S. for the treatment of:

relapsed or refractory CD-19 positive B-cell precursor ALL in adults and children.
CD-19 positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adults and children. This indication is approved under accelerated approval based on MRD response rate and hematological relapse-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
In the European Union (EU), BLINCYTO is indicated as monotherapy for the treatment of:

adults with Philadelphia chromosome negative CD19 positive relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL).
adults with Philadelphia chromosome negative CD19 positive B-precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%.
paediatric patients aged 1 year or older with Philadelphia chromosome negative CD19 positive B-precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation
IMPORTANT SAFETY INFORMATION

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO and treat with corticosteroids as recommended.
Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Contraindications

BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

Cytokine Release Syndrome (CRS): CRS, which may be life-threatening or fatal, occurred in 15% of patients with R/R ALL and in 7% of patients with MRD-positive ALL. The median time to onset of CRS is 2 days after the start of infusion and the median time to resolution of CRS was 5 days among cases that resolved. Closely monitor and advise patients to contact their healthcare professional for signs and symptoms of serious adverse events such as fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), and disseminated intravascular coagulation (DIC). The manifestations of CRS after treatment with BLINCYTO overlap with those of infusion reactions, capillary leak syndrome, and hemophagocytic histiocytosis/macrophage activation syndrome. If severe CRS occurs, interrupt BLINCYTO until CRS resolves. Discontinue BLINCYTO permanently if life-threatening CRS occurs. Administer corticosteroids for severe or life-threatening CRS.
Neurological Toxicities: Approximately 65% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. The median time to the first event was within the first 2 weeks of BLINCYTO treatment and the majority of events resolved. The most common (≥ 10%) manifestations of neurological toxicity were headache and tremor. Severe, life–threatening, or fatal neurological toxicities occurred in approximately 13% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI.
Infections: Approximately 25% of patients receiving BLINCYTO in clinical trials experienced serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed.
Tumor Lysis Syndrome (TLS), which may be life-threatening or fatal, has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events.
Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs.
Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.
Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment with a median time to onset of 3 days. In patients receiving BLINCYTO, although the majority of these events were observed in the setting of CRS, some cases of elevated liver enzymes were observed outside the setting of CRS, with a median time to onset of 19 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase, and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.
Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical trials and the post-marketing setting. Evaluate patients who develop signs and symptoms of pancreatitis and interrupt or discontinue BLINCYTO and dexamethasone as needed.
Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and antileukemic chemotherapy.
Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).
Immunization: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.
Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol Preservative: Serious and fatal adverse reactions including "gasping syndrome," which is characterized by central nervous system depression, metabolic acidosis, and gasping respirations, can occur in neonates and infants treated with benzyl alcohol-preserved drugs including BLINCYTO (with preservative). When prescribing BLINCYTO (with preservative) for pediatric patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Due to the addition of bacteriostatic saline, 7-day bags of BLINCYTO solution for infusion with preservative contain benzyl alcohol and are not recommended for use in any patients weighing < 22 kg.
Adverse Reactions

The most common adverse reactions (≥ 20%) in clinical trial experience of patients with MRD-positive B-cell precursor ALL (BLAST Study) treated with BLINCYTO were pyrexia (91%), infusion-related reactions (77%), headache (39%), infections (pathogen unspecified 39%), tremor (31%), and chills (28%). Serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal infection.
The most common adverse reactions (≥ 20%) in clinical trial experience of patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (TOWER Study) treated with BLINCYTO were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia.
Adverse reactions that were observed more frequently (≥ 10%) in the pediatric population compared to the adults with relapsed or refractory B-cell precursor ALL were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increased (17% vs. 6%).
In pediatric patients less than 2 years old (infants), the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%).
Dosage and Administration Guidelines

BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm.
It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).
Please see full Prescribing Information and medication guide for BLINCYTO at www.BLINCYTO.com.

About IMLYGIC (talimogene laherparepvec)
IMLYGIC is a genetically modified herpes simplex type 1 virus that is injected directly into tumors. IMLYGIC replicates inside tumor cells and produces GM-CSF, an immunostimulatory protein. IMLYGIC then causes the cell to rupture and die in a process called lysis. The rupture of the cancer cells causes the release of tumor-derived antigens, which together with virally derived GM-CSF may help to promote an anti-tumor immune response. The exact mechanism of action continues to be investigated.

IMLYGIC is the first and only oncolytic viral therapy approved by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and other regulatory authorities, based on therapeutic benefit demonstrated in a pivotal Phase 3 study. IMLYGIC is indicated for the local treatment of melanoma in patients with unresectable cutaneous, subcutaneous, or nodal lesions after initial surgery.

The IMLYGIC clinical program continues to investigate the role of IMLYGIC both as monotherapy and in combination with other therapies across a variety of cancers and treatment settings.

INDICATION & LIMITATIONS OF USE
IMLYGIC (talimogene laherparepvec) is a genetically modified oncolytic viral therapy indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.

Limitations of use: IMLYGIC has not been shown to improve overall survival or have an effect on visceral metastases.

IMPORTANT SAFETY INFORMATION

Contraindications

Do not administer IMLYGIC to immunocompromised patients, including those with a history of primary or acquired immunodeficient states, leukemia, lymphoma, AIDS or other clinical manifestations of infection with human immunodeficiency viruses, and those on immunosuppressive therapy, due to the risk of life-threatening disseminated herpetic infection.
Do not administer IMLYGIC to pregnant patients.
Warnings and Precautions

Accidental exposure to IMLYGIC may lead to transmission of IMLYGIC and herpetic infection, including during preparation and administration. Health care providers, close contacts, pregnant women, and newborns should avoid direct contact with injected lesions, dressings, or body fluids of treated patients. The affected area in exposed individuals should be cleaned thoroughly with soap and water and/or a disinfectant.
Caregivers should wear protective gloves when assisting patients in applying or changing occlusive dressings and observe safety precautions for disposal of used dressings, gloves, and cleaning materials. Exposed individuals should clean the affected area thoroughly with soap and water and/or a disinfectant.
To prevent possible inadvertent transfer of IMLYGIC to other areas of the body, patients should be advised to avoid touching or scratching injection sites or occlusive dressings.
Herpetic infections: Herpetic infections (including cold sores and herpetic keratitis) have been reported in IMLYGIC-treated patients. Disseminated herpetic infection may also occur in immunocompromised patients. Patients who develop suspicious herpes-like lesions should follow standard hygienic practices to prevent viral transmission.
Patients or close contacts with suspected signs or symptoms of a herpetic infection should contact their health care provider to evaluate the lesions. Suspected herpetic lesions should be reported to Amgen at 1-855-IMLYGIC (1-855-465-9442). Patients or close contacts have the option of follow-up testing for further characterization of the infection.
IMLYGIC is sensitive to acyclovir. Acyclovir or other antiviral agents may interfere with the effectiveness of IMLYGIC. Consider the risks and benefits of IMLYGIC treatment before administering antiviral agents to manage herpetic infection.
Injection Site Complications: Necrosis or ulceration of tumor tissue may occur during IMLYGIC treatment. Cellulitis and systemic bacterial infection have been reported in clinical studies. Careful wound care and infection precautions are recommended, particularly if tissue necrosis results in open wounds.
Impaired healing at the injection site has been reported. IMLYGIC may increase the risk of impaired healing in patients with underlying risk factors (e.g., previous radiation at the injection site or lesions in poorly vascularized areas). If there is persistent infection or delayed healing of the injection site, consider the risks and benefits of continuing treatment.
Immune-Mediated events including glomerulonephritis, vasculitis, pneumonitis, worsening psoriasis, and vitiligo have been reported in patients treated with IMLYGIC. Consider the risks and benefits of IMLYGIC before initiating treatment in patients who have underlying autoimmune disease or before continuing treatment in patients who develop immune-mediated events.
Plasmacytoma at the Injection Site: Plasmacytoma in proximity to the injection site has been reported in a patient with smoldering multiple myeloma after IMLYGIC administration in a clinical study. Consider the risks and benefits of IMLYGIC in patients with multiple myeloma or in whom plasmacytoma develops during treatment.
Obstructive Airway Disorder: Obstructive airway disorder has been reported following IMLYGIC treatment. Use caution when injecting lesions close to major airways.
Adverse Reactions

The most commonly reported adverse drug reactions (≥ 25%) in IMLYGIC-treated patients were fatigue, chills, pyrexia, nausea, influenza-like illness, and injection site pain. Pyrexia, chills, and influenza-like illness can occur at any time during IMLYGIC treatment, but were more frequent during the first 3 months of treatment.
The most common Grade 3 or higher adverse reaction was cellulitis.
Please see www.Imlygic.com for full Prescribing Information, including Medication Guide.

About Vectibix (panitumumab)
Vectibix is the first fully human monoclonal anti-EGFR antibody approved by the FDA for the treatment of mCRC. Vectibix was approved in the U.S. in September 2006 as a monotherapy for the treatment of patients with EGFR-expressing mCRC after disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy.

In May 2014, the FDA approved Vectibix for use in combination with FOLFOX, as first-line treatment in patients with wild-type KRAS (exon 2) mCRC. With this approval, Vectibix became the first-and-only biologic therapy indicated for use with FOLFOX, one of the most commonly used chemotherapy regimens, in the first-line treatment of mCRC for patients with wild-type KRAS mCRC.

In June 2017, the FDA approved a refined indication for Vectibix for use in in patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test for this use) mCRC.

INDICATION AND LIMITATION OF USE
Vectibix is indicated for the treatment of patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test for this use) metastatic colorectal cancer (mCRC): as first-line therapy in combination with FOLFOX, and as monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy.

Limitation of Use: Vectibix is not indicated for the treatment of patients with RASmutant mCRC or for whom RAS mutation status is unknown.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: DERMATOLOGIC TOXICITY

Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

In Study 20020408, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.
Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune- related effects (e.g., Stevens Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix concerning dermatologic toxicity are provided in the product labeling.
Vectibix is not indicated for the treatment of patients with colorectal cancer that harbor somatic RAS mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as "RAS."
Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents. Additionally, in Study 20050203, 272 patients with RAS-mutant mCRC tumors received Vectibix in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01-1.45) in patients with RAS-mutant mCRC who received Vectibix and FOLFOX versus FOLFOX alone.
Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 20080763) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix treatment, periodically during Vectibix treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.
In Study 20020408, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.
Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix in combination with chemotherapy.
Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. In the event of acute onset or worsening of pulmonary symptoms interrupt Vectibix therapy. Discontinue Vectibix therapy if ILD is confirmed.
In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix versus the risk of pulmonary complications must be carefully considered.
Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix.
Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix for acute or worsening keratitis.
In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).
NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy.
Vectibix can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment, and for at least 2 months after the last dose of Vectibix.
In monotherapy, the most commonly reported adverse reactions (≥ 20%) in patients with Vectibix were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.
The most commonly reported adverse reactions (≥ 20%) with Vectibix + FOLFOX were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. The most common serious adverse reactions (≥ 2% difference between treatment arms) were diarrhea and dehydration.
To see the Vectibix Prescribing Information, including Boxed Warning visit www.vectibix.com.

About XGEVA (denosumab)
XGEVA targets the RANKL pathway to prevent the formation, function and survival of osteoclasts, which break down bone. XGEVA is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors. XGEVA is also indicated for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity and for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

INDICATIONS
XGEVA is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors. XGEVA is indicated for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. XGEVA is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

IMPORTANT SAFETY INFORMATION

Hypocalcemia
Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

Hypersensitivity
XGEVA is contraindicated in patients with known clinically significant hypersensitivity to XGEVA, including anaphylaxis that has been reported with use of XGEVA. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA therapy permanently.

Drug Products with Same Active Ingredient
Patients receiving XGEVA should not take Prolia (denosumab).

Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported in patients receiving XGEVA, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with cancer, the incidence of ONJ was higher with longer duration of exposure.

Patients with a history of tooth extraction, poor oral hygiene, or use of a dental appliance are at a greater risk to develop ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections.

Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA and periodically during XGEVA therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA. Consider temporarily interrupting XGEVA therapy if an invasive dental procedure must be performed.

Patients who are suspected of having or who develop ONJ while on XGEVA should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture
Atypical femoral fracture has been reported with XGEVA. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone (GCTB) and in Patients with Growing Skeletons
Clinically significant hypercalcemia requiring hospitalization and complicated by acute renal injury has been reported in XGEVA-treated patients with GCTB and in patients with growing skeletons within one year of treatment discontinuation. Monitor patients for signs and symptoms of hypercalcemia after treatment discontinuation and treat appropriately.

Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation
Multiple vertebral fractures (MVF) have been reported following discontinuation of treatment with denosumab. Patients at higher risk for MVF include those with risk factors for or a history of osteoporosis or prior fractures. When XGEVA treatment is discontinued, evaluate the individual patient’s risk for vertebral fractures.

Embryo-Fetal Toxicity
XGEVA can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA is expected to result in adverse reproductive effects.

Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of XGEVA. Apprise the patient of the potential hazard to a fetus if XGEVA is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA.

Adverse Reactions
The most common adverse reactions in patients receiving XGEVA with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

For multiple myeloma patients receiving XGEVA, the most common adverse reactions were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. The most common serious adverse reaction was pneumonia. The most common adverse reaction resulting in discontinuation of XGEVA was osteonecrosis of the jaw.

The most common adverse reactions in patients receiving XGEVA for giant cell tumor of bone were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis.

The most common adverse reactions resulting in discontinuation of XGEVA were osteonecrosis of the jaw and tooth abscess or tooth infection.

The most common adverse reactions in patients receiving XGEVA for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

Please visit www.xgeva.com for Full U.S. Prescribing Information.

About Amgen Oncology
At Amgen Oncology, our mission to serve patients drives all that we do. That’s why we’re relentlessly focused on accelerating the delivery of medicines that have the potential to empower all angles of care and transform lives of people with cancer.

For the last four decades, we have been dedicated to discovering the firsts that matter in oncology and to finding ways to reduce the burden of cancer. Building on our heritage, Amgen continues to advance the largest pipeline in the Company’s history, moving with great speed to advance those innovations for the patients who need them.

At Amgen, we’re advancing oncology at the speed of life.