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Bristol-Myers Squibb Receives FDA Approval for Opdivo (nivolumab) as Adjuvant Therapy in Patients with Completely Resected Melanoma with Lymph Node Involvement or Metastatic Disease

Bristol-Myers Squibb Receives FDA Approval for Opdivo (nivolumab) as Adjuvant Therapy in Patients with Completely Resected Melanoma with Lymph Node Involvement or Metastatic Disease

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PRINCETON, N.J.–(BUSINESS WIRE)– December 20, 2017 Bristol-Myers Squibb Company (NYSE:BMY) announced today that the U.S. Food and Drug Administration (FDA) has approved Opdivo (nivolumab) injection for intravenous use for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.1 The purpose of adjuvant therapy is to reduce the risk of recurrence following surgical removal of the tumor and lymph nodes that contain cancer. In the Phase 3 CheckMate -238 trial, Opdivo significantly improved recurrence-free survival (RFS) versus an active comparator, Yervoy (ipilimumab), in patients with stage IIIB/C or stage IV melanoma after surgery.1,2 This benefit was observed across important subgroups, including in both BRAF mutant and BRAF wild-type patients.1 Opdivo is the first and only agent approved for the adjuvant treatment of melanoma based on a head-to-head trial against an active comparator with a proven overall survival benefit.1-3

“Today’s approval builds on our leadership in melanoma, offering physicians a new option with the potential to change the course of the disease through earlier intervention. Opdivo is the first PD-1 inhibitor approved as an adjuvant treatment for any cancer,” said Johanna Mercier, head, U.S. Commercial, Bristol-Myers Squibb. “Our decision to study Opdivo versus Yervoy – an established standard of care with a proven survival benefit – represents our relentless pursuit to bring more effective treatments to patients.”

In the CheckMate -238 clinical trial, Opdivo demonstrated an 18-month RFS rate of 66.4% [95% confidence interval (CI): 61.8 to 70.6] compared with 52.7% for Yervoy (95% CI: 47.8 to 57.4), with the median RFS not yet reached in either group. Opdivo reduced the risk of disease recurrence by 35% versus Yervoy [hazard ratio (HR): 0.65; 95% CI: 0.53 to 0.80; p <0.0001].1,2

Opdivo is associated with the following Warnings and Precautions: immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; and embryo-fetal toxicity. Please see the Important Safety Information section below, including Boxed WARNING for Yervoy regarding immune-mediated adverse reactions, as well as additional information on the CA 184-029 trial.1,3

Opdivo received Breakthrough Therapy Designation from the FDA for the adjuvant treatment of patients with high-risk, fully resected melanoma in September 2017. Approximately three in every 10 patients with stage III melanoma currently receive adjuvant therapy after surgery.4 Even with available treatment options, the majority of stage IIIB and IIIC melanoma patients (71% and 85%, respectively) experience disease recurrence within five years.5

Opdivo is the first programmed death-1 (PD-1) immune checkpoint inhibitor to demonstrate superiority, including better tolerability, versus Yervoy, a standard of care in this patient population. Based on data from the CheckMate -238 trial, the National Comprehensive Cancer Network® (NCCN®) recently added nivolumab to its treatment guidelines for completely resected stage IIIB/C melanoma and completely resected stage III melanoma with clinical satellite or in-transit metastases.6

In CheckMate -238, adverse events (AEs) leading to discontinuation were reported in 9% of Opdivo-treated patients (n=44/452) and in 42% of Yervoy-treated patients (n=193/453). Adverse reactions leading to one or more omitted doses occurred in 28% of patients who received Opdivo. Grade 3 or 4 AEs were experienced by 25% of patients (n=115/452) in the Opdivo group and 55% of patients (n=250/453) in the Yervoy group. Serious adverse reactions occurred in 18% of patients treated with Opdivo.1

“Immuno-Oncology has transformed the treatment of metastatic melanoma and many other cancers over the last decade, and we are now extending the use of novel agents to help prevent the recurrence of melanoma,” said Jeffrey S. Weber, M.D., Ph.D., deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, and Professor of Medicine at NYU School of Medicine. “When melanoma has been removed surgically, physicians and patients alike sometimes struggle with the idea of further adjuvant treatment because the disease is no longer detectable, even though it may be likely to return. We recognized a need to develop new adjuvant treatments with lower toxicity compared to ipilimumab to help address this challenge. With its impressive efficacy and broad applicability within stage III and IV melanoma, nivolumab has the potential to become the next standard of care in preventing recurrence of melanoma following surgical resection.”

Bristol-Myers Squibb pioneered the use of immune checkpoint inhibitors for the adjuvant treatment of melanoma, beginning with Yervoy. Five-year overall survival data from the Phase 3 CA184-029 trial were recently added to the prescribing information for Yervoy for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.3 In the trial, 65% of patients treated with Yervoy were alive at five years, compared with 54% of patients who received placebo (HR: 0.72; 95% CI: 0.58-0.88; p <0.002).3,7 This analysis was conducted at a median follow-up of 5.3 years.7

“Although there are approved therapies to help prevent melanoma recurrence, around seven out of 10 patients with stage III disease do not receive treatment following surgery,” said Valerie Guild, co-founder and president, AIM at Melanoma Foundation. “As an advocate, I have witnessed countless times the frustration and fear patients experience when their cancer returns – even after it was removed by surgery. Today’s approval offers new hope for people with melanoma that their disease may not come back.”

About the Pivotal CheckMate -238 Study

CheckMate -238 is an ongoing Phase 3, randomized double-blind study of Opdivo versus Yervoy in patients who have undergone complete resection of stage IIIB/C or stage IV melanoma.1,2 The trial randomized 906 patients 1:1 to receive either Opdivo 3 mg/kg every two weeks (n=453) or Yervoy 10 mg/kg (n=453) every three weeks for four doses and then every 12 weeks starting at week 24.1 Patients were treated until disease recurrence, unacceptable toxicity or consent withdrawal for up to one year. The primary endpoint is RFS defined as the time between randomization and the date of first recurrence, new primary melanoma or death. After meeting the primary endpoint, the trial will continue to evaluate for overall survival, a secondary endpoint.1 Interim data were presented at the European Society for Medical Oncology 2017 Congress in Madrid, Spain, with simultaneous publication in The New England Journal of Medicine.2

Select Safety Profile from the CheckMate -238 Trial

The most frequent Grade 3 and 4 adverse reactions reported in at least 2% of Opdivo-treated patients were diarrhea and increased lipase and amylase. The most common adverse reactions, reported in at least 20% of Opdivo-treated patients, were fatigue, diarrhea, rash, musculoskeletal pain, pruritus, headache, nausea, upper respiratory infection and abdominal pain. The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%) and hepatitis (3%).1

About the CA184-029 Study

The Phase 3 CA184-029 trial, a randomized (1:1), double-blind, placebo-controlled study, investigated the use of Yervoy for the adjuvant treatment of melanoma. A total of 951 enrolled patients with resected stage IIIA (>1 mm nodal involvement), IIIB and IIIC (with no in-transit metastases) melanoma received either Yervoy 10 mg/kg (n=475) or placebo (n=476) every three weeks for four doses, followed by every 12 weeks from week 24 to week 156 or until documented disease recurrence or unacceptable toxicity. The major efficacy outcomes were independent review committee-assessed RFS and OS. Yervoy reduced the risk of recurrence or death by 25% versus placebo (HR: 0.75; 95% CI: 0.64 to 0.90; p <0.002). Median RFS was 26 months for Yervoy (95% CI: 19 to 39) and 17 months for placebo (95% CI: 13 to 22). There were 234 RFS events in the Yervoy arm (49% of patients; 220 recurrences, 14 deaths) and 294 events in the placebo arm (62% of patients; 289 recurrences, 5 deaths).3

Select Safety Profile from the CA184-029 Trial

In the CA184-029 trial, severe to fatal immune-mediated adverse reactions were reported, and included enterocolitis (16%), hepatitis (11%), endocrinopathy (8%), hypopituitarism (7%), dermatitis (4%), neuropathy (1.7%), hyperthyroidism (0.6%), meningitis (0.4%), primary hypothyroidism (0.2%), myocarditis (0.2%), pericarditis (0.2%), pneumonitis (0.2%), and uveitis (0.2%). The most common adverse reactions were rash (50%), diarrhea (49%), fatigue (46%), pruritus (45%), headache (33%), weight loss (32%), nausea (25%), pyrexia (18%), colitis (16%), decreased appetite (14%), vomiting (13%), and insomnia (10%). Yervoy was discontinued for adverse reactions in 52% of patients.3

About the Opdivo Clinical Development Program

Bristol-Myers Squibb’s global development program is founded on scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials studying Opdivo, across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 14 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how patients’ tumor biology can be used as a guide for treatment decisions throughout their journey.

We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Bristol-Myers Squibb’s Patient Access Support

Bristol-Myers Squibb remains committed to providing assistance so that cancer patients who need our medicines can access them and expedite time to therapy.

BMS Access Support®, the Bristol-Myers Squibb patient access and reimbursement program, is designed to help appropriate patients initiate and maintain access to BMS medicines during their treatment journey. BMS Access Support offers benefit investigation, prior authorization assistance and co-pay assistance for eligible, commercially insured patients. More information about our access and reimbursement support can be obtained by calling BMS Access Support® at 1-800-861-0048 or by visiting www.bmsaccesssupport.com.

About the Bristol-Myers Squibb and Ono Pharmaceutical Collaboration

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

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube and Facebook.

Bristol-Myers Squibb Forward-Looking Statement

This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb’s business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2016 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Referenced with permission from NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Melanoma Version 1.2018. ©National Comprehensive Cancer Network, Inc. 2017. All rights reserved. Accessed October 23, 2017. To view the most recent and complete version of the guideline, go online to NCCN.org.

The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

References

  1. Opdivo Prescribing Information. Opdivo U.S. Product Information. Last updated: December 2017. Princeton, NJ: Bristol-Myers Squibb Company.
  2. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017 Nov 9; 377(19):1824-1835.
  3. Yervoy Prescribing Information. Yervoy U.S. Product Information. Last updated: December 2017 Princeton, NJ: Bristol-Myers Squibb Company.
  4. Harlan LC, Lynch CF, Ballard-Barbash R, Zeruto C. Trends in the Treatment and Survival for Local and Regional Cutaneous Melanoma in a US Population-Based Study. Melanoma Res. 2011 Dec; 21(6):547-54.
  5. Romano, E., Scordo, M., Dusza, S., Coit, D. and Chapman, P. Site and Timing of First Relapse in Stage III Melanoma Patients: Implications for Follow-Up Guidelines. J Clin Oncol. 2010; 28(18), pp.3042-3047.
  6. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Melanoma. October 11, 2017.
  7. Eggermont, A, Chiarion-Sileni V, Grob J, et al. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med. 2016 Nov 10; 375:1845-1855.

Source: Bristol-Myers Squibb Company

Posted: December 2017

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Opdivo (nivolumab) FDA Approval History

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