Today’s announcement marks the first and only FDA approval of a Regimen of two Immuno-Oncology agents in cancer. This indication is approved under accelerated approval based on tumor response rate and durability of response.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.1
The approval is based on data from the pivotal study, CheckMate -069, which was the first to report outcomes of the Opdivo + Yervoy Regimen in previously untreated patients with unresectable or metastatic melanoma. Results from the trial demonstrated a statistically significant (p<0.001) increase in confirmed objective response rate – the study’s primary endpoint – in patients with BRAF wild-type melanoma treated with the Opdivo + Yervoy Regimen [60% (95% CI: 48-71; p<0.001)] compared to those treated with Yervoy monotherapy [11% (95% CI: 3-25)]. Complete responses were seen in 17% of patients.
Partial responses were seen in 43% of the Regimen group and 11% of the Yervoy monotherapy group. The Opdivo + Yervoy Regimen demonstrated a 60% reduction in the risk of progression vs. Yervoy alone (HR=0.40; 95% CI: 0.22-0.71; p<0.002). Median PFS was 8.9 months with the Regimen (95% CI: 7.0, NA) and 4.7 months with Yervoy alone (95% CI: 2.8-5.3).1 This trial provides clinical rationale for targeting the immune system with two Immuno-Oncology agents in metastatic melanoma.
Opdivo is associated with immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash, other adverse reactions; infusion reactions; and embryofetal toxicity.1 Please see the Important Safety Information section below, including Boxed WARNING for Yervoy regarding immune-mediated adverse reactions.
Bristol-Myers Squibb CEO Giovanni Caforio said: "Targeting the immune system in the treatment of cancer has been of interest to the oncology community for decades,4 and our first Immuno-Oncology agent, Yervoy, was approved in 2011 for metastatic melanoma. Opdivo reinforced the power of the immune system in the fight against cancer, and is quickly becoming a foundational component in how the oncology community treats this devastating disease.
"Today’s approval of the Opdivo + Yervoy Regimen marks another first for our research in Immuno-Oncology and represents our unwavering commitment to continually redefine cancer care, and offer patients new treatment options with the goal of improved outcomes."
About the Opdivo + Yervoy Regimen: Advancing Metastatic Melanoma Treatment
CheckMate -069 is a Phase 2, double-blind, randomized study which enrolled 140 patients with previously untreated unresectable or metastatic melanoma,1 and included patients with both BRAF wild-type and BRAF mutation-positive melanoma.2 The primary endpoint was objective response rate (ORR) in patients with BRAF wild-type tumors.1 Additional efficacy outcome measures were investigator-assessed duration of response and progression-free survival (PFS) in patients with BRAF V600 wild-type melanoma. Randomization was stratified by BRAF mutation status.2 The Regimen includes four cycles of the Opdivo + Yervoy combination followed by Opdivo monotherapy.
In the clinical study, patients in the Opdivo + Yervoy Regimen group received Opdivo 1mg/kg plus Yervoy 3mg/kg every 3 weeks for 4 doses during the combination phase, followed by Opdivo 3mg/kg every 2 weeks during the monotherapy phase. Treatment was continued until progression or unacceptable toxicity.
In the Yervoy monotherapy group, patients were treated with Yervoy 3mg/kg every 3 weeks for 4 doses with matched placebo. Of the 95 patients randomized to receive the Opdivo + Yervoy Regimen, 50% were 65 years or older and 13% were 75 years or older.3 Fifty-nine percent of patients completed all 4 doses in the initial combination phase over a median of 9.1 weeks (range: 9.0 weeks to 26.3 weeks).
Among patients (n=109) with BRAF wild-type melanoma, the Regimen demonstrated a significantly superior response rate of 60% (95% CI: 48-71; p<0.001) vs. Yervoy alone, 11% (95% CI: 3-25).1 Seventeen percent of patients experienced a complete response in the BRAF wild-type population.
Partial responses were seen in 43% of the Regimen group and 11% of the Yervoy monotherapy group.1 Seventy-nine percent (34/43) of patients had ongoing responses of at least 6 months at the time of analysis. Of these patients, 14 had a duration of response of at least 6 months but less than 9 months, and 20 patients had a duration of response of at least 9 months. The remaining 21% (9/43) of patients had a duration of response ranging from 3 to 7 months and have progressed after response, died, or received subsequent therapy.
Along with higher ORR and more complete responses, the Opdivo + Yervoy Regimen demonstrated a 60% reduction in the risk of progression among BRAF wild-type patients vs. Yervoy alone (HR=0.40, 95% CI: 0.22-0.71; p<0.002).1 Median PFS was 8.9 months with the Regimen (95% CI: 7.0, NA) and 4.7 months with Yervoy alone (95% CI: 2.8-5.3).1
"Historically, metastatic melanoma has been a difficult disease to treat.6 Now, a new treatment option based on the combination of two valued Immuno-Oncology agents demonstrates significant efficacy versus ipilimumab (Yervoy) in metastatic melanoma,"2 said Jedd D. Wolchok, MD, PhD, Chief, Melanoma and Immunotherapeutics Service, Department of Medicine and Ludwig Center at Memorial Sloan Kettering Cancer Center. "Today’s approval represents a step forward for the melanoma community, providing hope for patients with metastatic melanoma."
In CheckMate -069, serious adverse reactions (62% vs. 39%), adverse reactions leading to permanent discontinuation (43% vs. 11%) or dose delays (47% vs. 22%), and Grade 3 or 4 adverse reactions (69% vs. 43%) all occurred more frequently in patients receiving the Opdivo + Yervoy Regimen compared with those receiving Yervoy alone. In the Opdivo + Yervoy Regimen group, 27% (25/94) of patients did not complete all four cycles of the Opdivo + Yervoy Regimen. The first occurrence of a Grade 3 or 4 adverse reaction was during administration of the Opdivo + Yervoy Regimen in 56 patients (59%), while 9 patients (10%) experienced first occurrence of a Grade 3 or 4 adverse reaction during administration of Opdivo alone.
The most common adverse reactions leading to discontinuation of Opdivo, as compared to Yervoy alone, were colitis (16% vs. 2%), diarrhea not treated with corticosteroids (4% vs. 4%), increased ALT levels (4% vs. 0), pneumonitis (3% vs. 0), and AST increase (3% vs. 0). The most frequent serious adverse events with the Opdivo + Yervoy Regimen, as compared to Yervoy alone, were colitis (17% vs. 9%), diarrhea (9% vs. 7%), pyrexia (6% vs. 7%), and pneumonitis (5% vs. 0). The most common adverse reactions (=20%) reported in patients receiving the Opdivo + Yervoy Regimen vs. Yervoy alone were rash (67% vs. 57%), pruritus (37% vs. 26%), headache (24% vs. 20%), vomiting (23% vs. 15%), and colitis (22% vs. 11%).
"We are currently witnessing a turning point in cancer history, based on the significant impact Immuno-Oncology is making in the lives of patients with metastatic melanoma. Today’s approval of the first Regimen of two Immuno-Oncology agents, Opdivo and Yervoy, is an exciting moment for our community because it reinforces we are on a positive path forward, providing new approaches which translate into meaningful results for patients," said Tim Turnham, Executive Director, Melanoma Research Foundation.
About the Opdivo + Yervoy Regimen
The scientific rationale for targeting the immune system via dual immune checkpoint inhibition in cancer has formed the basis of a novel approach to the treatment of metastatic melanoma.
"At Bristol-Myers Squibb, we have been at the forefront of researching the potential of two different immune checkpoint pathways – CTLA-4 and PD-1 – in the treatment of cancer," said Francis Cuss, MB BChir, FRCP, executive vice president and chief scientific officer, Bristol-Myers Squibb.
"From initial pre-clinical research, to pivotal studies resulting in regulatory approval of Yervoy and Opdivo as monotherapies, to today’s FDA approval, we are proud to be leading the way in bringing a dual Immuno-Oncology Regimen to cancer patients for the first time."