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Opdivo (nivolumab) + Low-Dose Yervoy (ipilimumab) Combination Approved for Previously Treated MSI-H/dMMR Metastatic Colorectal Cancer

PRINCETON, N.J.-- July 11, 2018 (BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) today announced Opdivo (nivolumab) 3 mg/kg plus low-dose Yervoy (ipilimumab) 1 mg/kg (injections for intravenous use) received approval from the U.S. Food and Drug Administration (FDA) for the treatment of adult and pediatric patients 12 years and older with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin and irinotecan.1 Approval for this indication has been granted under accelerated approval based on overall response rate (ORR) and duration of response (DOR).1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

“Bristol-Myers Squibb is pleased to bring forward Opdivo plus Yervoy as the first I-O/I-O combination therapy to be approved in this type of colorectal cancer,” said Ian M. Waxman, M.D., development lead, gastrointestinal cancers, Bristol-Myers Squibb. “Our commitment to studying Opdivo plus Yervoy, which target distinct but complementary immune pathways, results from our strong belief that rational combinations in biomarker-selected populations may improve clinical benefit for patients.”

Opdivo + Yervoy 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 CheckMate -142.1,2

Today’s approved indication was based on data from the ongoing Phase 2 CheckMate -142 study evaluating the Opdivo + Yervoy combination in patients with MSI-H or dMMR mCRC previously treated with a fluoropyrimidine-, oxaliplatin- or irinotecan-based chemotherapy.1,3,4 The application was granted Priority Review and Breakthrough Therapy Designation by the FDA.

The Opdivo + Yervoy cohort of the CheckMate -142 trial enrolled MSI-H/dMMR mCRC patients who had received at least one prior line of therapy for metastatic disease, and efficacy was analyzed for both patients who had received prior treatment with a fluoropyrimidine, oxaliplatin and irinotecan (82 of the total 119 patients) as well as for all enrolled patients.1

The recommended dosing schedule includes the Opdivo + low-dose Yervoy combination (Opdivo 3 mg/kg, administered as an I.V. infusion over 30 minutes, followed by Yervoy 1 mg/kg, administered as an I.V. infusion over 30 minutes, on the same day, every three weeks for four doses), followed by Opdivo maintenance therapy (240 mg, administered as an I.V. infusion over 30 minutes, every two weeks) after completion of four doses of the combination until disease progression or unacceptable toxicity.1 Please review the U.S. Full Prescribing Information for Yervoy prior to initiation.

In the Opdivo + Yervoy cohort of CheckMate -142, 86% of patients received all four doses of Opdivo + Yervoy.7 Opdivo was discontinued in 13% of patients and delayed in 45% of patients due to an adverse reaction.1 Serious adverse reactions occurred in 47% of patients.1

“Metastatic colorectal cancers with dMMR or MSI-H biomarkers can be difficult to treat and some patients may need additional options,” said Heinz-Josef Lenz, M.D., FACP, L. Terrence Lanni Chair in Gastrointestinal Cancer Research, Keck School of Medicine of University of Southern California and principal investigator of the study at USC Norris Comprehensive Cancer Center. “The FDA’s approval of an I-O/I-O combination provides us with an encouraging approach to address this challenging disease in patients who have progressed following treatment with three standard chemotherapy options.”

The Opdivo + Yervoy combination is also approved in two other tumor types. The Opdivo (3 mg/kg) + low-dose Yervoy (1 mg/kg) combination is approved for previously untreated patients with intermediate- or poor-risk advanced renal cell carcinoma. Opdivo (1 mg/kg) + Yervoy (3 mg/kg) is approved for patients with unresectable or metastatic melanoma under accelerated approval based on progression-free survival. Opdivo as a single agent is approved for the treatment of adult and pediatric (12 years and older) patients with MSI-H or dMMR metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin and irinotecan under accelerated approval based on ORR and DOR. Continued approval for these accelerated approval indications may be contingent upon verification and description of clinical benefit in the confirmatory trials. The infusion time for each indication differs, please see U.S. Full Prescribing Information for Opdivo and Yervoy for details.1

Approval Based on CheckMate -142 Trial

CheckMate -142 included a multicenter, non-randomized, multiple-parallel cohort, open-label study investigating Opdivo + Yervoy in patients with locally determined dMMR or MSI-H mCRC whose disease had progressed during or after prior treatment with a fluoropyrimidine-, oxaliplatin- or irinotecan-based chemotherapy.1,8 In the combination cohort, patients received Opdivo 3 mg/kg with Yervoy 1 mg/kg every three weeks for four doses, followed by Opdivo 3 mg/kg as a single agent every two weeks.1 Treatment continued until unacceptable toxicity or radiographic progression.1 Tumor assessments were conducted every six weeks for the first 24 weeks and every 12 weeks thereafter.1 Efficacy outcome measures included ORR as assessed by IRRC using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and DOR.1 Data from this study were presented in January at the 2018 Gastrointestinal Cancers Symposium and published simultaneously in the Journal of Clinical Oncology.

Select Safety Profile for the CheckMate -142 Trial

The most frequent serious adverse reactions reported in at least 2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration.1 The most common adverse reactions (reported in at least 20% of patients) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%).1

About MSI-H or dMMR Colorectal Cancer

Colorectal cancer (CRC) is cancer that develops in the colon or the rectum, which are part of the body’s digestive or gastrointestinal system.10 In the United States, CRC is the third most common cancer.10 In 2018, it is estimated that there will be approximately 140,000 new cases of the disease and that it will be the third leading cause of cancer-related deaths among men and women combined.10

DNA mismatch repair deficiency (dMMR) occurs when the proteins that repair mismatch errors in DNA replication are missing or non-functional, leading to microsatellite instability-high (MSI-H) tumors.11,12 Approximately 5% of metastatic CRC patients have dMMR or MSI-H tumors.13 Patients with these biomarkers are less likely to benefit from conventional chemotherapy and typically have a poor prognosis.11,13,14

Indications

Opdivo® (nivolumab), in combination with Yervoy® (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

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), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients 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 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 approved 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 (10 mg/mL) and Yervoy (5 mg/mL) are injections for intravenous use.

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: July 2018. Princeton, NJ: Bristol-Myers Squibb Company.
2. Yervoy Prescribing Information. Yervoy U.S. Product Information. Last Updated: July 2018. Princeton, NJ: Bristol-Myers Squibb Company.
3. ClinicalTrials.gov. An investigational immune-therapy study of nivolumab, and nivolumab in combination with other anti-cancer drugs, in colon cancer that has come back or has spread (CheckMate142). https://clinicaltrials.gov/ct2/show/NCT02060188?term=NCT02060188&rank=11. Published November 22, 2017. Updated January 23, 2018. Accessed April 23, 2018.
4. The ASCO Post. FDA accepts sBLA for nivolumab plus ipilimumab in previously treated MSI-H or dMMR metastatic colorectal cancer. http://www.ascopost.com/News/58676. Published March 30, 2018. Accessed April 23, 2018.
5. Overman M, Lonardi S, Yeung KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773-779.
6. Data on file. NIVO 319, Princeton, NJ: Bristol-Myers Squibb.
7. Data on file. NIVO 377, Princeton, NJ: Bristol-Myers Squibb.
8. Bever K, Le D. An expanding role for immunotherapy in colorectal cancer. J Natl Compr Canc Netw. 2017;15(3):410-410.
9. McLean J, Rho YS, Kuruba G, et al. Clinical practice patterns in chemotherapeutic treatment regimens for metastatic colorectal cancer. Clin Colorectal Cancer. 2016;15(2):135-140.
10. American Cancer Society. About Colorectal Cancer. https://www.cancer.org/content/dam/CRC/PDF/Public/8604.00.pdf. Updated February 21, 2018. Accessed May 18, 2018.
11. Koopman M, Kortman G, Mekenkamp L, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Brit J Cancer. 2009;100:266-273.
12. Yacoub G, Nagalla S, Aklilu M. Oncologic Management of Hereditary Colorectal Cancer. Clin Colon Rectal Surg. 2012;25:118–122.
13. Venderbosch S, Nagteagaal ID, Maughan TS, et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res. 2014;20:5322-5330.
14. Müller CI, Schulmann K, Reinacher-Schick A, et al. Predictive and prognostic value of microsatellite instability in patients with advanced colorectal cancer treated with a fluoropyrimidine and oxaliplatin containing first-line chemotherapy. A report of the AIO Colorectal Study Group. Int J Colorectal Dis. 2008;23:1033-1039.

Source: Bristol-Myers Squibb Company

Posted: July 2018

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