U.S. Food and Drug Administration Approves Opdivo® (nivolumab) + Yervoy® (ipilimumab) as First-Line Treatment of Patients with Metastatic Non-Small Cell Lung Cancer Whose Tumors Express PD-L1≥1%

In CheckMate -227 Part 1a, Opdivo + Yervoy showed superior and durable long-term overall survival versus chemotherapy^1,2,3

Fifth indication for Opdivo + Yervoy, the first and only FDA-approved dual immunotherapy

PRINCETON, NJ, USA I May 15, 2020 IBristol Myers Squibb (NYSE: BMY) today announced that Opdivo (nivolumab) 3 mg/kg plus Yervoy (ipilimumab) 1 mg/kg (injections for intravenous use) was approved by the U.S. Food and Drug Administration (FDA) 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.¹

This approval is based on Part 1a of the Phase 3 CheckMate -227 trial in which Opdivo + Yervoy (n=396) demonstrated superior overall survival (OS) versus chemotherapy (n=397) (hazard ratio [HR] 0.79; 95% confidence interval [CI]: 0.67 to 0.94; P=0.0066) regardless of tumor histology with a minimum follow up of 29.3 months.^1,2 The median OS was 17.1 months (95% CI: 15.0 to 20.1) versus 14.9 months (95% CI: 12.7 to 16.7).¹ In the trial, 63% of patients treated with Opdivo + Yervoy and 56% treated with chemotherapy were alive at one year, and 40% and 33% at two years, respectively.⁴ At three years (median 43.1 months follow up), 33% of patients treated with Opdivo + Yervoy and 22% of those treated with chemotherapy were still alive.³ As assessed by Blinded Independent Central Review (BICR), the confirmed overall response rate (ORR) with a minimum follow up of 28.3 months was 36% (142/396, 95% CI: 31 to 41) with Opdivo + Yervoy (5.8% complete response [CR] and 30.1% partial response [PR]) and 30% (119/397, 95% CI: 26 to 35) with chemotherapy (1.8% CR and 28.2% PR).^1,2,5 Among patients who responded, the median duration of response (DOR) was 23.2 months (95% CI: 15.2 to 32.2) for patients treated with Opdivo + Yervoy and 6.2 months (95% CI: 5.6 to 7.4) for chemotherapy.^1,2,5 ORR and DOR were pre-specified descriptive analyses.^1,2

“Patients with metastatic lung cancer remain in need of new treatment options that may provide durable responses,” said Matthew D. Hellmann, M.D., CheckMate -227 study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center. “The results from the CheckMate -227 trial show that a dual immunotherapy approach offers a chance at long-term survival for appropriate patients with metastatic NSCLC.”^1,2,3

Opdivo is associated with the following Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion-related reactions; 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.¹ Please see the Important Safety Information section below, including Boxed WARNING for Yervoy (ipilimumab) regarding immune-mediated adverse reactions.⁶

“Metastatic lung cancer is a complex and challenging disease. Patients impacted by metastatic NSCLC have been closely watching advances in the field of immunotherapy for additional treatment options that have the potential to significantly extend their lives,”⁷ said Bonnie J. Addario, co-founder and chair, GO2 Foundation. “The fact that certain previously untreated patients now have access to a combination immunotherapy that is chemotherapy-free and has shown a continued survival benefit with more than three years of follow up is an important step in the treatment of the disease.”^1,2,3

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.^1,6,8 Some of the T cells stimulated by Yervoy can become memory T cells, which may allow for a long-term immune response.^{8,9,10,11,12,13} Targeting of normal cells can also occur and result in immune-mediated adverse reactions, which can be severe and potentially fatal.¹ Please see the Important Safety Information section, including Boxed WARNING for Yervoy (ipilimumab) regarding immune-mediated adverse reactions.⁶

“Opdivo ushered in a new era that changed the way NSCLC is treated when in 2015 it became the first immunotherapy approved for use in previously treated patients,” said Chris Boerner, chief commercialization officer, Bristol Myers Squibb. “As the first dual immunotherapy approved in the first-line setting, Opdivo + Yervoy builds on this legacy and is a testament to our commitment to helping patients with metastatic lung cancer to live longer.”

*Dr. Matthew D. Hellmann has provided compensated consulting and advisory services for BMS.

About CheckMate -227

CheckMate -227 is a randomized, open-label, multi-center Phase 3 trial, evaluating Opdivo + Yervoy versus platinum-doublet chemotherapy in patients with previously untreated metastatic or recurrent NSCLC across non-squamous and squamous tumor histologies.^1,2 Part 1a of the trial enrolled patients whose tumors express PD-L1 (≥1%).¹ Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory.¹ Key eligibility criteria included patients 18 years or older with Stage IV or recurrent NSCLC, ECOG PS 0/1 and no prior systemic anticancer therapy.¹ Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease or medical conditions requiring systemic immunosuppression were excluded from the study.¹ Three hundred ninety-six patients received Opdivo 3 mg/kg Q2W + Yervoy 1 mg/kg Q6W and 397 patients received platinum-doublet chemotherapy Q3W.¹ Patients randomized to chemotherapy with non-squamous histology received pemetrexed and cisplatin or carboplatin with optional pemetrexed maintenance following chemotherapy, while patients with squamous histology received gemcitabine and either cisplatin or carboplatin.¹ Treatment continued until disease progression, unacceptable toxicity or for up to 24 months.¹ The primary efficacy outcome measure was OS.¹ Additional descriptive efficacy outcome measures included progression-free survival, ORR and DOR as assessed by BICR.^1,2

Select Safety Profile from CheckMate -227 Study

Serious adverse reactions occurred in 58% of patients.¹ Opdivo + Yervoy was discontinued for adverse reactions in 24% of patients and 53% had at least one dose withheld for an adverse reaction.¹ The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency and hypophysitis.¹ Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure and renal failure.¹ The most common (≥20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%) and pruritus (21%).¹

About Lung Cancer

Lung cancer is the leading cause of cancer death in the United States.¹⁴ The two main types of lung cancer are non-small cell and small cell.¹⁵ Non-small cell lung cancer is one of the most common types of lung cancer, and accounts for approximately 84% of diagnoses.¹⁵ Survival rates vary depending on the stage and type of the cancer when diagnosed.¹⁴

INDICATIONS

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) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

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 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 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, 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.

References

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3. Ramalingam S, Ciuleanu T, Pluzanski A, et al. Nivolumab (NIVO) + ipilimumab (IPI) versus platinum-doublet chemotherapy (chemo) as first-line (1L) treatment for advanced non-small cell lung cancer (aNSCLC): 3-year update from CheckMate 227 Part 1 [abstract]. In: American Society of Clinical Oncology (ASCO) Annual Meeting; May 29 – June 2, 2020; Virtual.
4. Peters S, Ramalingam S, Paz-Ares L, et al. Nivolumab + Low-Dose Ipilimumab Versus Platinum-Doublet Chemotherapy as First-Line Treatment for Advanced Non-Small Cell Lung Cancer: CheckMate 227 Part 1 Final Analysis. In: ESMO Congress; September 27 – October 1, 2019; Barcelona, Spain.
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6. Yervoy Prescribing Information. Yervoy U.S. Product Information. Last updated: May 15, 2020. Princeton, NJ: Bristol-Myers Squibb Company.
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8. 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.
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10. 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.
11. 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.
12. 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.
13. 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.
14. SEER. Lung and Bronchus Cancer, CSR 1975-2016. https://seer.cancer.gov/statfacts/html/lungb.html. Accessed May 11, 2020.
15. American Cancer Society. Key Statistics for Lung Cancer. https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html. Updated January 8, 2020. Accessed May 11, 2020.

SOURCE: Bristol-Myers Squibb