PRINCETON, N.J.–(BUSINESS WIRE) October 2, 2020 — Bristol Myers Squibb (NYSE: BMY) today announced that Opdivo (nivolumab) 360 mg every three weeks plus Yervoy (ipilimumab) 1 mg/kg every six weeks (injections for intravenous use) was approved by the U.S. Food and Drug Administration (FDA) for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).1 This approval is based on a pre-specified interim analysis from the Phase 3 CheckMate -743 trial in which Opdivo + Yervoy (n=303) demonstrated superior overall survival (OS) versus the platinum-based standard of care chemotherapy (n=302) (Hazard Ratio [HR]: 0.74 [95% Confidence Interval [CI]: 0.61 to 0.89]; P=0.002), with a median OS (mOS) of 18.1 months (95% CI: 16.8 to 21.5) versus 14.1 months (95% CI: 12.5 to 16.2), respectively.1 These results were observed after 22.1 months of minimum follow-up.3 At two years, 41% of patients treated with Opdivo + Yervoy were alive and 27% with chemotherapy.^1,3

“Malignant pleural mesothelioma is a rare cancer with limited treatment options. When it is diagnosed in advanced stages, the five-year survival rate is approximately 10 percent,” said study investigator Anne S. Tsao, M.D., professor and Section Chief Thoracic Medical Oncology and Director of the Mesothelioma Program at The University of Texas M.D. Anderson Cancer Center.2,4 “The survival results from the CheckMate -743 trial show that the combination of nivolumab and ipilimumab could become a new front-line standard of care option. This is exciting news, instilling hope for patients with this devastating disease and for the healthcare providers who care for them.”^1,3

Opdivo and Yervoy are associated with Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; complications of stem-cell transplant that uses donor stem cells (allogeneic); embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when Opdivo is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.¹Yervoy is associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplant after Yervoy, embryo-fetal toxicity and risks associated when administered in combination with Opdivo.⁵

This is the third indication for an Opdivo + Yervoy-based combination in the first-line treatment of a form of thoracic cancer.¹Opdivo + Yervoy is approved by the FDA as a first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1≥1% as determined by an FDA-approved test, and without EGFR or ALK genomic tumor aberrations.¹ It is also approved in combination with limited chemotherapy for the first-line treatment of adult patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations regardless of PD-L1 expression.¹

“Thoracic cancers can be complex and difficult to treat, and we are focused on developing immunotherapy options that may have the potential to extend patients’ lives,” said Adam Lenkowsky, general manager and head, U.S., Oncology, Immunology, Cardiovascular, Bristol Myers Squibb.^2,6 “Just a few months ago, Opdivo + Yervoy-based combinations received two first-line indications for certain patients with non-small cell lung cancer. Now, Opdivo + Yervoy is approved for use in another type of thoracic cancer, previously untreated unresectable MPM. With today’s announcement, Opdivo + Yervoy becomes the first new systemic therapy approved in more than 15 years in this setting, and may offer these patients a chance for a longer life.” ¹

Opdivo + Yervoy is a unique combination of two immune checkpoint inhibitors that features a potentially synergistic mechanism of action, targeting two different checkpoints (PD-1 and CTLA-4) to help destroy tumor cells: Yervoy helps activate and proliferate T cells, while Opdivo helps existing T cells discover the tumor.1,7 Some of the T cells stimulated by Yervoy can become memory T cells, which may allow for a long-term immune response.^{7,8,9,10,11,12} Targeting of normal cells can also occur and result in immune-mediated adverse reactions, which can be severe and potentially fatal.¹

This approval was granted less than six weeks following the submission of a new supplemental Biologics License Application (sBLA), which was reviewed under the FDA’s Real-Time Oncology Review (RTOR) pilot program. The RTOR program aims to ensure that safe and effective treatments are available to patients as early as possible.13 The review was also conducted under the FDA’s Project Orbis initiative, enabling concurrent review by the health authorities in Australia, Brazil, Canada and Switzerland.

About CheckMate -743

CheckMate -743 is an open-label, multi-center, randomized Phase 3 trial evaluating Opdivo plus Yervoy compared to chemotherapy (pemetrexed and cisplatin or carboplatin) in patients with histologically confirmed unresectable malignant pleural mesothelioma and no prior systemic therapy or palliative radiotherapy within 14 days of initiation of therapy (n=605).¹ Patients with interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, or active brain metastasis were excluded from the trial.¹In the trial, 303 patients were randomized to receive Opdivo 3 mg/kg every two weeks and Yervoy 1 mg/kg every six weeks; 302 patients were randomized to receive cisplatin 75 mg/m² or carboplatin AUC 5 plus pemetrexed 500 mg/m² in 3-week cycles for six cycles.1 Treatment in both arms continued until disease progression or unacceptable toxicity or, in the Opdivo + Yervoy arm, up to 24 months.¹ The primary endpoint of the trial was OS in all randomized patients.¹ Additional efficacy outcome measures included progression-free survival (PFS), objective response rate (ORR) and duration of response (DOR), as assessed by BICR utilizing modified RECIST criteria.¹

Select Safety Profile from CheckMate -743 Study

Treatment was permanently discontinued for adverse reactions in 23% of patients treated with Opdivo + Yervoy, and 52% had at least one dose withheld for an adverse reaction.¹ An additional 4.7% of patients permanently discontinued Yervoy alone due to adverse reactions. Serious adverse reactions occurred in 54% of patients receiving Opdivo + Yervoy.¹ The most frequent (≥2%) serious adverse reactions in patients receiving Opdivo + Yervoy were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism.¹ Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis.¹ The most common (≥20%) adverse reactions were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%) and pruritus (21%).¹ The median number of doses was 12 for Opdivo and 4 for Yervoy.³

About Malignant Pleural Mesothelioma

Mesothelioma is a rare but aggressive form of cancer that often forms in the lining of the lungs.^2,14 There are approximately 3,000 cases diagnosed in the United States each year.¹⁴ Malignant pleural mesothelioma is the most common type of the disease.² It is most frequently caused by exposure to asbestosand diagnosis is often delayed, with the majority of patients presenting with advanced disease.^2,15 Prognosis is generally poor: in patients with advanced malignant pleural mesothelioma, median survival is approximately one year and the five-year survival rate is approximately 10%.²

INDICATIONS

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

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.

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

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

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

Bristol Myers Squibb: Advancing Cancer Research

At Bristol Myers Squibb, patients are at the center of everything we do. The goal of our cancer research is to increase patients’ quality of life, long-term survival and make cure a possibility. We harness our deep scientific experience, cutting-edge technologies and discovery platforms to discover, develop and deliver novel treatments for patients.

Building upon our transformative work and legacy in hematology and Immuno-Oncology that has changed survival expectations for many cancers, our researchers are advancing a deep and diverse pipeline across multiple modalities. In the field of immune cell therapy, this includes registrational CAR T cell agents for numerous diseases, and a growing early-stage pipeline that expands cell and gene therapy targets, and technologies. We are developing cancer treatments directed at key biological pathways using our protein homeostasis platform, a research capability that has been the basis of our approved therapies for multiple myeloma and several promising compounds in early- to mid-stage development. Our scientists are targeting different immune system pathways to address interactions between tumors, the microenvironment and the immune system to further expand upon the progress we have made and help more patients respond to treatment. Combining these approaches is key to delivering potential new options for the treatment of cancer and addressing the growing issue of resistance to immunotherapy. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines a reality for patients.

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, as well as co-pay assistance for eligible, commercially insured patients. More information about our access and reimbursement support can be obtained by calling BMS Access Supportat 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, Facebook and Instagram.

Celgene and Juno Therapeutics are wholly owned subsidiaries of Bristol-Myers Squibb Company. In certain countries outside the U.S., due to local laws, Celgene and Juno Therapeutics are referred to as, Celgene, a Bristol Myers Squibb company and Juno Therapeutics, a Bristol Myers Squibb company.

Cautionary Statement Regarding Forward-Looking Statements

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on historical performance and current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others whether Opdivo plus Yervoy for the additional indication described in this release will be commercially successful and that continued approval of such combination treatment for such additional indication described in this release may be contingent upon verification and description of clinical benefit in confirmatory trials. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2019, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

References

1. 1. OpdivoPrescribing Information. Opdivo U.S. Product Information. Last updated: October, 2020. Princeton, NJ: Bristol-Myers Squibb Company.
   2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines: Malignant Pleural Mesothelioma. https://www.nccn.org/professionals/physician_gls/pdf/mpm.pdf. Updated November 27, 2019. Accessed September 11, 2020.
   3. Baas P, Scherpereel A, Nowak A, et al. First-line nivolumuab + ipilimumab vs chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. Lecture presented at: World Conference on Lung Cancer (WCLC) Virtual Presidential Synposium. August 8, 2020.
   4. SEER. Mesothelioma, CSR 1975-2016. https://seer.cancer.gov/csr/1975_2017/results_merged/sect_17_mesothelioma.pdf. Accessed September 11, 2020
   5. YervoyPrescribing Information. YervoyU.S. Product Information. Last updated: October, 2020. Princeton, NJ: Bristol-Myers Squibb Company.
   6. National Cancer Institute. Non-Small Cell Lung Cancer Treatment (PDQ®) – Health Professional Version. https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq. Updated May 7, 2020. Accessed September 11, 2020.
   7. Weber J, Hamid Omid, Chasalow S, et al. Ipilimumab increases activated T cells and enhances humoral immunity in patients with advanced melanoma. J Immunother.2012;35(1):89-97.
   8. Pico de Coana Y, Wolodarski M, Poschke I, et al. Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma. Oncotarget.2017;8(13):21539-21553.
   9. Pedicord V, Montalvo W, Leiner I, et al. Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc Natl Acad Sci USA.2011;8(1):266-271.
   10. Felix J, Lambert J, Roelens M, et al. Ipilimumab reshapes T cell memory subsets in melanoma patients with clinical response. Oncoimmunology.2016;5(7):1-10.
   11. Ansell S, Hurvitz S, Keonig P, et al. Phase I study of ipilimumab, an anti–CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non–Hodgkin lymphoma. Clin Cancer Res.2009;15(20):6446-6453.
   12. Farber D, Yudanin N, Restifo N. Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol.2014;14(1):24-35.
   13. U.S. Food & Drug Administration. Real-Time Oncology Review Pilot Program. https://www.fda.gov/about-fda/oncology-center-excellence/real-time-oncology-review-pilot-program. Accessed September 11, 2019.
   14. American Cancer Society. Key Statistics for Mesothelioma. https://www.cancer.org/cancer/malignant-mesothelioma/about/key-statistics.html. Updated January 9, 2020. Accessed September 11, 2020.
   15. American Cancer Society. Risk Factors for Mesothelioma. https://www.cancer.org/cancer/malignant-mesothelioma/causes-risks-prevention/risk-factors.html. Updated January 9, 2020. Accessed September 11, 2020.

Source: Bristol Myers Squibb

Posted: October 2020

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Opdivo (nivolumab) FDA Approval History