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

• Among the 82 patients who received prior treatment with a fluoropyrimidine, oxaliplatin and irinotecan, 46% (95% CI: 35-58; n = 38/82) responded to treatment with Opdivo + Yervoy as assessed by Independent Radiographic Review Committee (IRRC).1
  • The percentage of these patients with a complete response was 3.7% (n = 3/82), and the percentage of patients with a partial response was 43% (n = 35/82).1 Among these 38 responders, the median DOR was not reached (range: 1.9-23.2+ months); 89% of those patients had responses of six months or longer, and 21% had responses of 12 months or longer.1,5,6 This trial is ongoing.3
• Among all enrolled patients, 49% (95% CI: 39-58; n = 58/119) responded to treatment with Opdivo + Yervoy; 4.2% (n = 5/119) experienced a complete response, while 45% (n = 53/119) experienced a partial response.1 Among these 58 responders, the median DOR was not reached (range: 1.9-23.2+ months)5,6; 83% of those patients had responses of six months or longer, and 19% had responses of 12 months or longer.1 In the combination cohort, 51 of 58 responders were ongoing at the time of database lock; 78% of these ongoing responders had not reached 12 months of follow-up from the date of onset of response.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.1Efficacy 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