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FDA Approves Opdivo (nivolumab) + Yervoy (ipilimumab) Combination as First-Line Treatment for Patients with Intermediate- and Poor-Risk Advanced Renal Cell Carcinoma

PRINCETON, N.J.--(BUSINESS WIRE) April 16, 2018 --Bristol-Myers Squibb Company (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) as the first Immuno-Oncology combination therapy for previously untreated patients with intermediate- and poor-risk advanced renal cell carcinoma (RCC).1,2 In the Phase 3 CheckMate -214 clinical trial, the Opdivo + Yervoy combination demonstrated a significant and unprecedented increase in overall survival (OS) in this patient population compared to a current standard of care, sunitinib. An OS benefit was observed regardless of PD-L1 expression level.1,2,3 Opdivo + Yervoy also delivered durable responses, with a higher objective response rate (ORR) compared to sunitinib.1,2 Patients in the CheckMate -214 trial received four cycles of the Opdivo + low-dose Yervoy combination, followed by Opdivo maintenance therapy.1,2 In the combination arm of the trial, 79% of patients received all four doses of Opdivo + Yervoy and went on to the Opdivo monotherapy phase.4 Flexible dosing options are available during the Opdivo maintenance phase (480 mg infused every four weeks or 240 mg infused every two weeks).

“Our goal is to provide cancer patients with medicines that have the potential to extend their lives. As the first treatment option to increase overall survival for subgroups of patients with advanced RCC compared to sunitinib, the Opdivo plus low-dose Yervoy combination helps deliver on that promise,” said Johanna Mercier, head, U.S. Commercial, Bristol-Myers Squibb. “This approval demonstrates our commitment to bringing Immuno-Oncology treatments that may improve outcomes to a broader range of RCC patients.”

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.1,2

Results from the CheckMate -214 trial in patients with previously untreated intermediate- and poor-risk advanced RCC include:

  • Overall Survival: Opdivo + Yervoy reduced the risk of death by 37% versus sunitinib (hazard ratio [HR] 0.63; 99.8% confidence interval [CI]: 0.44 to 0.89; p<0.0001).1,2 The median OS was not yet reached for Opdivo + Yervoy (95% CI: 28.2 to not estimable [NE]) and was 25.9 months for sunitinib (95% CI: 22.1 to NE).1,2,3
  • Objective Response Rate: Opdivo + Yervoy was associated with a 41.6% ORR (95% CI: 36.9 to 46.5; p<0.0001; n=177/425) versus 26.5% for sunitinib (95% CI: 22.4 to 31.0; n=112/422).1,2
    • Complete and Partial Response Rates: The complete response (CR) rate was 9.4% for Opdivo + Yervoy (n=40/425) and 1.2% for sunitinib (n=5/422), and the partial response (PR) rate was 32.2% for Opdivo + Yervoy (n=137/425) and 25.4% for sunitinib (n=107/422).1,2
    • Duration of Response: Among patients who responded, median duration of response (durability) for Opdivo + Yervoy was not yet reached (95% CI: 21.8 to NE), compared to 18.2 months for sunitinib (95% CI: 14.8 to NE).1,2
  • Progression-Free Survival: Progression-free survival (PFS) was 11.6 months for the Opdivo + Yervoy combination, compared to 8.4 months for sunitinib (HR 0.82; 99.1% CI: 0.64 to 1.05; p=not significant), which did not reach statistical significance.1,2

Among those with advanced RCC, 75% to 80% have one or more risk factors and are considered intermediate- and poor-risk patients according to International Metastatic Renal Cell Carcinoma Database Consortium criteria.5,6 These patients historically had a poor prognosis, and although there have been a number of treatment advances over the past decade, additional options to improve overall survival are still needed.7,8 Currently, only 36% of patients with advanced RCC survive beyond one year, and only 8% will live past five years.7,9

“Physicians treating advanced RCC have had few options to help achieve the goal of improved survival,” said Robert J. Motzer, M.D., medical oncologist, Jack and Dorothy Byrne chair in clinical oncology, Memorial Sloan Kettering Cancer Center. “Data from the CheckMate -214 trial demonstrated superior overall survival with Opdivo + Yervoy, showing the potential for the combination to become a new standard of care for patients with intermediate- and poor-risk advanced RCC. What's more, the combination resulted in fewer overall Grade 3 and 4 adverse reactions compared to sunitinib. Because of these encouraging results, we now have a new treatment option for newly diagnosed advanced RCC patients across PD-L1 expression levels.”

In CheckMate -214, the combination was associated with fewer overall Grade 3 or 4 adverse events than sunitinib (65% versus 76%).1,2 Treatment discontinuation due to adverse events occurred in 31% of patients in the Opdivo + Yervoy arm, compared to 21% in the sunitinib arm. Fifty-four percent (54%) of patients receiving Opdivo + Yervoy and 43% of patients receiving sunitinib had a dose delay for an adverse reaction. In the sunitinib group, 53% of patients required a dose reduction, which was not permitted for patients treated with the Opdivo + Yervoy combination. Serious adverse reactions occurred in 59% of patients receiving Opdivo + Yervoy and in 43% of patients receiving sunitinib.1,2

“Kidney cancer is the deadliest of all urological cancers, and too many patients are faced with this grim diagnosis,” said Dena Battle, president, KCCure. “Today’s approval of Opdivo + Yervoy for advanced RCC has the potential to transform the first-line treatment landscape for kidney cancer. But for patients, it is more than just a new therapy option – it represents hope for a longer life.”

Approval Based on CheckMate -214 Trial: Demonstrating Superior Overall Survival and Objective Response Rate vs. Sunitinib

CheckMate -214 is a Phase 3, randomized, open-label study evaluating the combination of Opdivo + Yervoy versus sunitinib in patients with previously untreated advanced RCC. In the intermediate- and poor-risk study population, 425 patients received Opdivo 3 mg/kg plus Yervoy 1 mg/kg every three weeks for four doses, followed by Opdivo 3 mg/kg every two weeks, and 422 patients received sunitinib 50 mg once daily for four weeks, followed by two weeks off every cycle.1,2 The recommended dosing for the Opdivo + Yervoy combination is Opdivo 3 mg/kg followed by Yervoy 1 mg/kg each infused intravenously over 30 minutes on the same day every three weeks for four doses. After completing four doses of the combination, Opdivo should be administered intravenously 240 mg every two weeks or 480 mg every four weeks over 30 minutes until disease progression or unacceptable toxicity.1,2

The primary efficacy outcome measures of the trial were OS, ORR (CR+PR) and PFS as determined by an independent radiographic review committee (IRRC) in intermediate- and poor-risk patients. Patients were included regardless of their PD-L1 status.1,2 Data from CheckMate -214 were presented at the European Society for Medical Oncology Congress in September 2017 and the Society for Immunotherapy of Cancer Annual Meeting in November 2017 and were published in the New England Journal of Medicine in March 2018.3,10,11

Select Safety Profile for the CheckMate -214 Trial

The most frequent serious adverse reactions reported in at least 2% of patients receiving Opdivo + Yervoy were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency and colitis. The most common adverse reactions (≥20%) reported in patients receiving Opdivo + Yervoy were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%) and vomiting (20%).1,2

About Renal Cell Carcinoma

Renal cell carcinoma is the most common type of kidney cancer in adults, accounting for nearly 15,000 deaths in the United States each year.12,13 Clear-cell RCC is the most prevalent type of RCC and constitutes 70% to 80% of all patients.14 Renal cell carcinoma is approximately twice as common in men as in women.15 In the United States, the five-year survival rate for those diagnosed with metastatic, or advanced, kidney cancer is 8%.7

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 advancing 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 24 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. Through our leading translational capabilities, we are pioneering immune biology research and identifying a number of potentially predictive biomarkers, including PD-L1, TMB, MSI-H/dMMR and LAG-3, advancing the possibility of precision medicine for more patients with cancer.

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, 2017 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.

References

1. Opdivo Prescribing Information. Opdivo U.S. Product Information. Last updated: April 2018. Princeton, NJ: Bristol-Myers Squibb Company.
2. Yervoy Prescribing Information. Yervoy U.S. Product Information. Last updated: April 2018. Princeton, NJ: Bristol-Myers Squibb Company.
3. Motzer R, Tannir N, McDermott D, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277-1290.
4. Data on file. NIVO 136. Princeton, NJ: Bristol-Myers Squibb.
5. Ko JJ, Xie W, Kroeger N, et al. The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study. Lancet Oncol. 2015;16(3):293-300.
6. Heng DYC, Xie W, Regan M, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2):141-148.
7. American Cancer Society. Survival Rates for Kidney Cancer by Stage. https://www.cancer.org/cancer/kidney-cancer/detection-diagnosis-staging/survival-rates.html. Accessed March 27, 2018.
8. Sun M, Thuret R, Abdollah F, et al. Age-adjusted incidence, mortality, and survival rates of stage specific renal cell carcinoma in North America: a trend analysis. Eur Urol. 2011;59(1):135-141.
9. Surveillance, Epidemiology, and End Results Program. Kidney and Renal Pelvis Cancer SEER Survival Rates by Time Since Diagnosis, 2003-2013 By Stage at Diagnosis. National Cancer Institute. https://seer.cancer.gov/explorer/application.php?site=72&data_type=4&graph_type=6&compareBy=stage&chk_sex_1=1&chk_sex_3=3&chk_sex_2=2&chk_race_1=1&chk_age_range_1=1&chk_stage_101=101&chk_stage_106=106&advopt_precision=1&showDataFor=sex_1_and_race_1_and_age_range_1. Published April 14, 2016. Updated December 1, 2018. Accessed March 27, 2018.
10. Escudier B, Tannir N, McDermott D, et al. CheckMate 214: efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. Presentation at: European Society of Medical Oncology Annual Meeting; September, 2017; Madrid, Spain.
11. Motzer R, Tannir N, McDermott D, et al. Nivolumab + ipilimumab (N+I) vs sunitinib (S) for treatment‐naïve advanced or metastatic renal cell carcinoma (aRCC): results from CheckMate 214, including overall survival by subgroups. Presentation: Society for Immunotherapy of Cancer Annual Meeting; November, 2017; National Harbor, Maryland.
12. American Cancer Society. Key Statistics About Kidney Cancer. https://www.cancer.org/cancer/kidney-cancer/about/key-statistics.html. Accessed January 12, 2018.
13. Cancer.net. Kidney Cancer: Introduction. https://www.cancer.net/cancer-types/kidney-cancer/introduction. Published August 2017. Accessed March 27, 2018.
14. Mehdi A, Riazalhosseini Y. Epigenome aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma. Int J Mol Sci. 2017 Aug 16;18(8)1774.
15. Terris M, Klaassen Z, Kabaria R. Renal Cell Carcinoma: Links and Risks. Int J Nephrol Renovasc Dis. 2016 ;9:45-52.

Source: Bristol-Myers Squibb Company

Posted: April 2018

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