On November 23, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported that the U.S. Food and Drug Administration (FDA) has approved Opdivo (nivolumab) injection, for intravenous use, for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy (Press release, Bristol-Myers Squibb, NOV 23, 2015, View Source [SID:1234508329]).

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!

Today’s announcement marks the approval of the first and only PD-1 inhibitor to deliver significant overall survival (OS) in patients with advanced RCC who have received prior anti-angiogenic therapy.1 In the CheckMate -025 trial, patients treated with Opdivo achieved a median OS of 25 months (95% CI: 21.7-not estimable [NE]) versus 19.6 months (95% CI: 17.6-23.1) for everolimus, a current standard of care (SOC) in this patient population (hazard ratio [HR]: 0.73; [95% CI: 0.60-0.89; p=0.0018]), based on a prespecified interim analysis.1,2 In the study, the safety profile was consistent with prior Opdivo studies.2

"This is the fifth approval for Opdivo across three distinct tumor types. This latest approval reflects our commitment to delivering on our promise to provide cancer patients with a potential for long-term survival," said Francis Cuss, MB BChir, FRCP, executive vice president and chief scientific officer at Bristol-Myers Squibb. "We believe our pioneering approach to Immuno-Oncology is driving change in how cancer may be treated."

Opdivo is associated with immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash, encephalitis, other adverse reactions; infusion reactions; and embryofetal toxicity. Please see the Important Safety Information section below.1

The U.S. approval was based on data from CheckMate -025, an open-label, randomized Phase 3 study which demonstrated a median OS benefit of 25 months (95% CI: 21.7-NE) compared with 19.6 months (95% CI: 17.6-23.1) for everolimus (HR: 0.73; [95% CI: 0.60-0.89; p=0.0018]).1,2 This is the first time an immune checkpoint inhibitor has delivered a significant survival benefit in this patient population.1 On September 16, 2015, the FDA granted Breakthrough Therapy Designation to Opdivo for advanced RCC patients treated with prior anti-angiogenic therapy, also based on positive results from the CheckMate -025 study, reinforcing the unmet need in the treatment of RCC.2

"As an Immuno-Oncology agent that works directly with the body’s immune system, Opdivo offers a new approach for physicians to use when treating patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy," continued Cuss. "For the first time, these patients have a PD-1 inhibitor treatment option, which has the potential to provide an unprecedented survival advantage compared to a standard of care."

Proven Significant Overall Survival vs. a Standard of Care

CheckMate -025 is a landmark, open-label, randomized Phase 3 study, evaluating Opdivo compared to an active comparator (everolimus) in patients with advanced RCC who have received prior anti-angiogenic therapy.1,2 Clinical results from CheckMate -025 were recently presented at the 2015 European Cancer Congress with simultaneous publication in The New England Journal of Medicine.2

In CheckMate -025, 821 patients were randomized to receive Opdivo (3 mg/kg administered intravenously every two weeks; n=410) compared to a SOC (everolimus, 10 mg administered orally daily; n=411).1,2 The primary endpoint was OS.1,2 Objective response rate (ORR) was evaluated as a secondary endpoint.1,2 The prespecified interim analysis was conducted when 398 events were observed (70% of the planned number of events for final analysis).1 In this trial, Opdivo demonstrated a median OS of 25 months (95% CI: 21.7-NE) versus 19.6 months (95% CI: 17.6-23.1) for everolimus (HR: 0.73; [95% CI: 0.60-0.89; p=0.0018]), offering a 5.4 month survival benefit.1 With Opdivo, the OS benefit was observed independent of PD-L1 expression.1 In addition to improving survival, Opdivo demonstrated a superior ORR compared to everolimus (21.5%; 95% CI: 17.6–25.80 vs. 3.9%; 95% CI: 2.2–6.2) with a higher median duration of response (23.0 months; 95% CI: 12.0-NE vs. 13.7 months; 95% CI: 8.3-21.9).1

"Results from CheckMate -025 mark the first time an Immuno-Oncology treatment has demonstrated a survival advantage in patients with advanced renal cell carcinoma compared to a standard of care in this population," said Robert J. Motzer, M.D., medical oncologist, Memorial Sloan Kettering Cancer Center. "For patients with advanced renal cell carcinoma, treatment options are limited and new approaches that extend survival are desperately needed. With the FDA approval of Opdivo, the kidney cancer community is now a step closer toward achieving long-term survival, which has remained elusive for many patients. This represents a true shift in our treatment paradigm."

While the treatment landscape for RCC has improved over the last decade, patients are in need of new treatment options that demonstrate longer-term effects and overall survival benefits.3

"This approval of Opdivo represents a major milestone for the kidney cancer community," said William P. Bro, chief executive officer and patient coordinator, Kidney Cancer Association. "We thank Bristol-Myers Squibb and the FDA for working swiftly to bring this important new treatment option and potential for extended survival to patients."

The safety profile of Opdivo in CheckMate -025 was consistent with prior studies.2 Serious adverse events occurred in 47% of patients receiving Opdivo.1 The most frequent serious adverse reactions reported in at least 2% of patients receiving Opdivo were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia.1 In the study, the most common adverse reactions (≥20%) reported in patients receiving Opdivo versus everolimus were asthenic conditions (56% vs. 57%), cough (34% vs. 38%), nausea (28% vs. 29%), rash (28% vs. 36%), dyspnea (27% vs. 31%), diarrhea (25% vs. 32%), constipation (23% vs. 18%), decreased appetite (23% vs. 30%), back pain (21% vs. 16%), and arthralgia (20% vs. 14%).1

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in the U.S., accounting for approximately 9 out of 10 kidney cancers.3 An estimated 61,560 new cases of kidney cancer will be diagnosed in 2015 in the U.S., and the disease is more common in men than women.3 Clear-cell RCC is the most prevalent type of RCC, which includes 70% of all cases.3 Approximately 14,000 people will die from kidney cancer in the U.S. in 2015 and the five-year survival rate for patients diagnosed with advanced kidney cancer is 8%.3

On November 23, 2015 Seattle Genetics, Inc. (Nasdaq: SGEN) reported initiation of a phase 1/2 clinical trial of SGN-CD33A (vadastuximab talirine) in patients with relapsed or refractory acute myeloid leukemia (AML) (Press release, Seattle Genetics, NOV 23, 2015, View Source [SID:1234508327]).

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 trial will evaluate SGN-CD33A monotherapy as a pre-conditioning regimen prior to an allogeneic stem cell transplant (alloSCT) and also for use as maintenance therapy following transplant. SGN-CD33A is a novel antibody-drug conjugate (ADC) targeted to CD33 utilizing Seattle Genetics’ newest ADC technology. CD33 is expressed on almost all AML cells regardless of subtype, cytogenetic abnormality, or underlying mutations.

"Relapsed and refractory acute myeloid leukemia, or AML, remains among the most challenging unmet needs in cancer, and there continues to be little success in treating AML patients utilizing conventional salvage therapies," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "Our strategy with this trial is to evaluate the potential for SGN-CD33A to increase the percentage of patients who have no detectable leukemic cells prior to allogeneic transplant. Data suggest that patients who test negative for minimal residual disease prior to transplant are less likely to relapse. Separately, we will evaluate the potential for SGN-CD33A to maintain remissions after allogeneic transplant."

The phase 1/2, open-label, multi-center, clinical trial is a two-part (A and B) study designed to evaluate the safety and activity of SGN-CD33A administered in patients with relapsed chemotherapy-resistant AML. Part A of the study will examine SGN-CD33 as cytoreduction pre-conditioning and Part B will evaluate SGN-CD33A in post-alloSCT as a maintenance regimen. Each part will consist of a phase 1 safety evaluation followed by a phase 2 expansion for activity. Parts A and B will enroll concurrently.

The primary endpoints in phase 1 are determination of the maximum tolerated dose (MTD) and the safety and tolerability profiles of SGN-CD33A in both pre- and post-alloSCT settings. The primary endpoints in phase 2 are to evaluate the one-year survival rates of patients treated with SGN-CD33A at the recommended dose pre- and post-alloSCT; to assess the rate of minimal residual disease negativity; and to further assess the safety and tolerability of SGN-CD33A at the recommended dose. The secondary endpoints include assessments of best response on study treatment, duration of response and overall survival. The two-part, phase 1/2 trial will enroll approximately 100 patients at multiple centers in the United States.

SGN-CD33A is also under evaluation in two other ongoing clinical trials including a phase 1 dose escalation trial as a single-agent or in combination with hypomethylating agents (HMAs) for the treatment of patients who have relapsed AML or have declined intensive frontline therapy; and a phase 1b clinical trial in combination with standard of care intensive chemotherapy, including cytarabine and daunorubicin, for younger fit patients with newly diagnosed AML. The phase 1 clinical data for SGN-CD33A in AML as monotherapy and in combination with HMAs will be presented in two oral sessions (Abstracts #324 and #454) and preclinical data supporting HMA combination strategy will be presented in a poster session (Abstract #3785) at the upcoming American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting from December 5-8, 2015.

With more than 15 years of experience and innovation, Seattle Genetics is the leader in developing ADCs. ADCs are monoclonal antibodies that are designed to selectively deliver cell-killing agents to tumor cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.

For more information about the trial, including enrolling centers, please visit www.clinicaltrials.gov.

About Acute Myeloid Leukemia

Acute myeloid leukemia, also called acute myelocytic leukemia or AML, is an aggressive type of cancer of the bone marrow and blood that progresses rapidly without treatment. AML is a cancer that starts in the cells that are supposed to mature into different types of blood cells. AML starts in the bone marrow (the soft inner part of the bones, where new blood cells are made) and quickly moves into the blood. According to the American Cancer Society, in 2015 more than 20,500 new cases of AML (mostly in adults) will be diagnosed and nearly 10,500 deaths will occur from AML (almost all will be in adults).

About SGN-CD33A (Vadastuximab Talirine)

SGN-CD33A (vadastuximab talirine) is a novel investigational ADC targeted to CD33 utilizing Seattle Genetics’ newest ADC technology. CD33 is expressed on almost all AML cells. The CD33 antibody is attached to a highly potent DNA binding agent, a pyrrolobenzodiazepine (PBD) dimer, via a proprietary site-specific conjugation technology to a monoclonal antibody with engineered cysteines (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the site-specific conjugation technology (EC-mAb) allows uniform drug-loading of the cell-killing PBD agent to the anti-CD33 antibody. The ADC is designed to be stable in the bloodstream and to release its potent DNA binding agent upon internalization into CD33-expressing cells. SGN-CD33A is being evaluated in ongoing phase 1 and phase 1/2 clinical trials for patients with AML.

On November 23, 2015 Merrimack (Nasdaq: MACK) and Baxalta Incorporated (NYSE: BXLT) reported that The Lancet has published the article "Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomized, open-label phase 3 trial" online in advance of its print issue (Press release, Merrimack, NOV 23, 2015, View Source [SID:1234508325]). The Lancet is considered one of the most prestigious peer-reviewed general medical journals in the world.

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 publication of the NAPOLI-1 data in The Lancet is significant, as it will provide physicians with comprehensive data on this recently approved treatment that has demonstrated improved overall survival for patients with metastatic adenocarcinoma of the pancreas who had progressed after gemcitabine-based therapy," said Prof. Li-Tzong Chen, M.D., Ph.D., corresponding author, Investigator on the NAPOLI-1 trial and Director, National Institute of Cancer Research, National Health Research Institutes in Tainan, Taiwan. "We thank the patients and their caregivers, study sites, steering committee members and the chairs for their contributions to this important study."

Andrea Wang-Gillam, M.D., Ph.D., lead author of the NAPOLI-1 article and Associate Professor of Medicine, Clinical Director of GI Oncology Program, Division of Oncology, at Washington University School of Medicine, St. Louis added, "ONIVYDE in combination with fluorouracil and leucovorin extends median overall survival to six months, a 45% increase, with a well-defined safety profile in patients with metastatic adenocarcinoma of the pancreas who previously received gemcitabine-based therapy, representing a new treatment option for this patient population."

The NAPOLI-1 study results were the basis of the recent U.S. Food and Drug Administration (FDA) and Taiwan FDA approval of ONIVYDE (irinotecan liposome injection) in combination with fluorouracil (5-FU) and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. ONIVYDE is not indicated for use as a single agent. ONIVYDE, also known as MM-398 or "nal-IRI," is the first and only FDA approved therapy in this setting. ONIVYDE is irinotecan encapsulated in liposome nanoparticles. The liposome is designed to keep irinotecan in the circulation — sheltered from conversion to its active metabolite (SN-38) — longer than unencapsulated irinotecan, which would increase and prolong intratumoral levels of both irinotecan and SN-38 compared with free irinotecan1. Data from the NAPOLI-1 study were previously presented at the 2014 European Society for Medical Oncology World Congress on Gastrointestinal Cancer and the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2015 Gastrointestinal Cancers Symposium.

The NAPOLI-1 Study and Results1

NAPOLI-1 was a randomized, open label Phase 3 study in patients with metastatic adenocarcinoma of the pancreas who received prior gemcitabine-based therapy, and was the largest Phase 3 study in this setting to date. Patients were enrolled at 76 sites in North America, South America, Europe, Asia and Oceania.

The study evaluated ONIVYDE, in combination with 5-FU and leucovorin administered every two weeks and as a monotherapy administered every three weeks. Each ONIVYDE containing arm was compared to a control arm of 5-FU and leucovorin. A total of 417 patients were randomized across the three arms. The primary endpoint of the study was overall survival. Key findings of the study as published in The Lancet include:

The ONIVYDE combination regimen demonstrated a significant increase in median overall survival versus 5-FU and leucovorin alone: 6.1 months vs 4.2 months (p=0.012, unstratified hazard ratio for death (HR) =0.67, 95% CI: [0.49-0.92]). The monotherapy regimen in this study did not show improvement over the 5-FU and leucovorin arm: 4.9 vs 4.2 months (p=0.94, HR=0.99, 95% CI: [0.77-1.28]).

ONIVYDE in combination with 5-FU and leucovorin achieved a longer progression-free survival compared with the 5-FU and leucovorin arm (3.1 months versus 1.5 months; unstratified HR=0.56 [95% CI, 0.41-0.75]).

Unconfirmed objective response rate was higher in the ONIVYDE in combination with 5-FU and leucovorin arm than in the 5-FU and leucovorin arm: 16% (19/117) versus 1% (1/119) (difference 15.4 percentage points, 95% CI, 8.5-22.3; p < 0.0001).
The most common grade 3 or 4 adverse events that occurred more frequently in the ONIVYDE in combination with 5-FU and leucovorin arm ( > 2% incidence versus 5-FU and leucovorin) were neutropenia, diarrhea, vomiting, and fatigue.

Baxalta Incorporated is responsible for the development and commercialization of ONIVYDE outside of the United States and Taiwan under the exclusive licensing agreement with Merrimack. In May 2015, the European Medicines Agency accepted for review Baxalta’s marketing authorization application for ONIVYDE based on the same clinical results.

PharmaEngine, Inc. (Taipei, Taiwan) holds the rights to commercialize ONIVYDE in Taiwan. PharmaEngine filed a New Drug Application with the Taiwan FDA on May 29, 2015, and received the approval of ONIVYDE on October 22, 2015.

About Pancreatic Cancer

Pancreatic cancer is a rare and deadly disease. There are approximately 49,000 patients diagnosed with pancreatic cancer each year in the United States2, the overwhelming majority of whom have adenocarcinoma3. Globally there are approximately 338,000 new cases each year4. Most patients receive gemcitabine-based therapy during either adjuvant/neoadjuvant treatment for locally advanced disease or during first- or second-line therapy for metastatic disease5, but are left with no standard of care therapy upon progression. ONIVYDE in combination with 5-FU and leucovorin is now approved in the U.S. and Taiwan for these patients whose disease has progressed following gemcitabine-based therapy.

About ONIVYDE [pronounced \ ‘on – ih – vide \]

ONIVYDE (irinotecan liposome injection), also known as MM-398 or "nal-IRI," is a novel encapsulation of irinotecan in a liposomal formulation. The activated form of irinotecan is SN-38, which functions by inhibiting topoisomerase I (an essential enzyme involved in DNA transcription and replication) and promoting cell death. ONIVYDE was recently approved by the U.S. Food and Drug Administration in combination with fluorouracil and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. For full prescribing information, including Boxed WARNING, please visit www.ONIVYDE.com.

IMPORTANT SAFETY INFORMATION

INDICATION

ONIVYDE (irinotecan liposome injection) is indicated, in combination with fluorouracil (5-FU) and leucovorin (LV), for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.

Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.

WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEA

Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil (5-FU) and leucovorin (LV). Withhold ONIVYDE for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment.

Severe diarrhea occurred in 13% of patients receiving ONIVYDE in combination with 5-FU/LV. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity.

CONTRAINDICATION

ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction to ONIVYDE or irinotecan HCl.

WARNINGS AND PRECAUTIONS

Severe Neutropenia

ONIVYDE can cause severe or life-threatening neutropenia and fatal neutropenic sepsis. In a clinical study, the incidence of fatal neutropenic sepsis was 0.8% among patients receiving ONIVYDE, occurring in 1/117 patients in the ONIVYDE/5-FU/LV arm and 1/147 patients receiving ONIVYDE as a single agent. Severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE/5-FU/LV vs 2% of patients receiving 5-FU/LV. Grade 3/4 neutropenic fever/neutropenic sepsis occurred in 3% of patients receiving ONIVYDE/5-FU/LV, and did not occur in patients receiving 5-FU/LV.

In patients receiving ONIVYDE/5-FU/LV, the incidence of Grade 3/4 neutropenia was higher among Asian (18/33 [55%]) vs White patients (13/73 [18%]). Neutropenic fever/neutropenic sepsis was reported in 6% of Asian vs 1% of White patients.

Severe Diarrhea

ONIVYDE can cause severe and life-threatening diarrhea. Do not administer ONIVYDE to patients with bowel obstruction. Severe and life-threatening late-onset (onset > 24 hours after chemotherapy) and early-onset diarrhea (onset < 24 hours after chemotherapy, sometimes with other symptoms of cholinergic reaction) were observed. An individual patient may experience both early- and late-onset diarrhea.

In a clinical study, Grade 3/4 diarrhea occurred in 13% of patients receiving ONIVYDE/5-FU/LV vs 4% receiving 5-FU/LV. Grade 3/4 late-onset diarrhea occurred in 9% of patients receiving ONIVYDE/5-FU/LV vs 4% in patients receiving 5-FU/LV; the incidences of early-onset diarrhea were 3% and no Grade 3/4 incidences, respectively. Of patients receiving ONIVYDE/5-FU/LV, 34% received loperamide for late-onset diarrhea and 26% received atropine for early-onset diarrhea.

Interstitial Lung Disease (ILD)

Irinotecan HCl can cause severe and fatal ILD. Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD.

Severe Hypersensitivity Reactions

Irinotecan HCl can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction.

Embryo-Fetal Toxicity

Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and for 1 month after ONIVYDE treatment.

ADVERSE REACTIONS

The most common ( > 20%) adverse reactions in which patients receiving ONIVYDE/5-FU/LV experienced a > 5% higher incidence of any Grade vs the 5-FU/LV arm, were diarrhea (any 59%, 26%; severe 13%, 4%) (early diarrhea [any 30%, 15%; severe 3%, 0%], late diarrhea [any 43%, 17%; severe 9%, 4%]), fatigue/asthenia (any 56%, 43%; severe 21%, 10%), vomiting (any 52%, 26%; severe 11%, 3%), nausea (any 51%, 34%; severe 8%, 4%), decreased appetite (any 44%, 32%; severe 4%, 2%), stomatitis (any 32%, 12%; severe 4%, 1%), pyrexia (any 23%, 11%; severe 2%, 1%).

Of less common ( < 20%) adverse reactions, patients receiving ONIVYDE/5-FU/LV who experienced Grade 3/4 adverse reactions at a ≥2% higher incidence of Grade 3/4 toxicity vs the 5-FU/LV arm, respectively, were sepsis (3%, 1%), neutropenic fever/neutropenic sepsis (3%, 0%), gastroenteritis (3%, 0%), intravenous catheter-related infection (3%, 0%), weight loss (2%, 0%), and dehydration (4%, 2%).

The laboratory abnormalities in which patients receiving ONIVYDE/5-FU/LV experienced a > 5% higher incidence vs the 5-FU/LV arm, were anemia (any 97%, 86%; severe 6%, 5%), lymphopenia (any 81%, 75%; severe 27%, 17%), neutropenia (any 52%, 6%; severe 20%, 2%), thrombocytopenia (any 41%, 33%; severe 2%, 0%), increased alanine aminotransferase (any 51%, 37%; severe 6%, 1%), hypoalbuminemia (any 43%, 30%; severe 2%, 0%), hypomagnesemia (any 35%, 21%; severe 0%, 0%), hypokalemia (any 32%, 19%; severe 2%, 2%), hypocalcemia (any 32%, 20%; severe 1%, 0%), hypophosphatemia (any 29%, 18%; severe 4%, 1%), hyponatremia (any 27%, 12%; severe 5%, 3%), increased creatinine (any 18%, 13%; severe 0%, 0%).
ONIVYDE can cause cholinergic reactions manifesting as rhinitis, increased salivation, flushing, bradycardia, miosis, lacrimation, diaphoresis, and intestinal hyperperistalsis with abdominal cramping and early-onset diarrhea. Grade 1/2 cholinergic symptoms other than early diarrhea occurred in 12 (4.5%) ONIVYDE-treated patients.

Infusion reactions, consisting of rash, urticaria, periorbital edema, or pruritus, occurring on the day of ONIVYDE administration were reported in 3% of patients receiving ONIVYDE or ONIVYDE/5-FU/LV.

The most common serious adverse reactions ( > 2%) of ONIVYDE were diarrhea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia.

DRUG INTERACTIONS

Avoid the use of strong CYP3A4 inducers, if possible, and substitute non-enzyme-inducing therapies > 2 weeks prior to initiation of ONIVYDE. Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible, and discontinue strong CYP3A4 inhibitors > 1 week prior to starting therapy.

USE IN SPECIFIC POPULATIONS

Pregnancy and Reproductive Potential

Advise pregnant women of the potential risk to a fetus. Advise males with female partners of reproductive potential to use effective contraception during and for 4 months after ONIVYDE treatment.

Lactation

Advise nursing women not to breastfeed during and for 1 month after ONIVYDE treatment.

Pediatric

Safety and effectiveness of ONIVYDE have not been established in pediatric patients.

DOSAGE AND ADMINISTRATION

The recommended dose of ONIVYDE is 70 mg/m2 intravenous (IV) infusion over 90 minutes every 2 weeks, administered prior to LV and 5-FU. The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m2 administered by IV infusion over 90 minutes. There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal. Premedicate with a corticosteroid and an anti-emetic 30 minutes prior to ONIVYDE. Withhold ONIVYDE for Grade 3/4 adverse reactions. Resume ONIVYDE with reduced dose once adverse reaction recovered to < Grade 1. Discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction and in patients with a confirmed diagnosis of ILD.

Do not substitute ONIVYDE for other drugs containing irinotecan HCl.