Significantly longer progression-free survival and higher objective response rates with Opdivo and Yervoy combination and Opdivo monotherapy versus Yervoy alone, with a minimum of 18-month follow-up, from CheckMate -067
In CheckMate -067, median duration of response had not been reached with the combination regimen, and was 22.3 months for Opdivo monotherapy and 14.4 months for Yervoy alone
With longer follow-up, the Opdivo and Yervoy combination regimen had a consistent safety profile with previously reported studies of the combination
PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today results from two trials evaluating the Opdivo and Yervoy combination regimen in advanced melanoma. In the pivotal Phase 3 trial, CheckMate -067 trial, at a minimum follow-up of 18 months, the Opdivo and Yervoy combination demonstrated continued clinical benefit with a 58% reduction in the risk of disease progression versus Yervoy monotherapy (HR=0.42 [99.5% CI: 0.31-0.57; p<0.0001]), while Opdivo monotherapy demonstrated a 45% risk reduction versus Yervoy alone (HR=0.55 [99.5% CI: 0.43-0.76; p<0.0001]). Durable responses were also observed with the combination regimen in a subgroup of patients who discontinued therapy due to treatment-related adverse events (n=35) and appeared consistent with the overall randomized patient population (n=95), based on a post-hoc analysis from the Phase 2 study, CheckMate -069. Among this subgroup of patients, the objective response rate was 66%, and 20% achieved a complete response, with a minimum follow-up of two years. At two years, the median duration of response was not reached and 74% remain in response. The safety profile of the Opdivo and Yervoy combination regimen in both CheckMate -067 and -069 was consistent with previously reported studies of the combination, and most treatment-related adverse events were managed using established algorithms.
“The data from CheckMate -067 provide new insights on the long-term durability of the progression-free survival benefit seen with the nivolumab and ipilimumab combination regimen in advanced melanoma relative to ipilimumab monotherapy”
“The data from CheckMate -067 provide new insights on the long-term durability of the progression-free survival benefit seen with the nivolumab and ipilimumab combination regimen in advanced melanoma relative to ipilimumab monotherapy,” said Jedd D. Wolchok, M.D., Ph.D., Chief, Melanoma and Immunotherapeutics Service, at Memorial Sloan Kettering Cancer Center. “In addition, in a post-hoc analysis from CheckMate -069, we observed that even for patients who discontinue treatment with the combination regimen due to toxicity, efficacy outcomes appeared consistent with that seen in the overall study population. These data are encouraging and provide additional important information about the efficacy and safety of the combination regimen in these patients.”
The CheckMate -067 data will be presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in an oral abstract session on Monday, June 6, from 2:39 PM – 2:51 PM CDT (Abstract #9505). The CheckMate -069 data were presented in a poster discussion session on Saturday, June 4 (Abstract #9518).
Vicki Goodman, M.D., Development Lead, Melanoma and Genitourinary Cancers, Bristol-Myers Squibb, commented, “With the CheckMate -067 and -069 data presented at ASCO, we observe, with longer follow-up, the durability of progression-free survival and response for the Opdivo and Yervoy combination regimen in advanced melanoma. These findings further validate our research strategy to study the combination of Immuno-Oncology agents, and we remain committed to building on this research and evaluating more ways to improve long-term survival and patient outcomes in advanced cancers.”
About CheckMate -067
CheckMate -067 is a Phase 3, double-blind, randomized study that evaluated the Opdivo and Yervoy combination regimen or Opdivo monotherapy versus Yervoy monotherapy in patients with previously untreated advanced melanoma, including both BRAF V600 mutation positive or BRAF wild-type advanced melanoma. A total of 945 patients were randomized to receive the Opdivo and Yervoy combination regimen (Opdivo 1 mg/kg plus Yervoy 3 mg/kg every 3 weeks administered intravenously for 4 doses followed by Opdivo 3 mg/kg every 2 weeks thereafter; n=314), Opdivo monotherapy (Opdivo 3 mg/kg every 2 weeks administered intravenously; n=316) or Yervoy monotherapy (Yervoy 3 mg/kg every 3 weeks administered intravenously for 4 doses followed by placebo every 2 weeks; n=315). Patients were treated until progression or unacceptable toxic effects. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS); secondary endpoints included PFS and objective response rate (ORR), as well as safety and tolerability. The study is ongoing in its evaluation for OS.
At a minimum follow-up of 18 months, the Opdivo and Yervoy combination demonstrated a 58% reduction in the risk of disease progression versus Yervoy monotherapy in previously untreated patients with advanced melanoma (HR=0.42 [99.5% CI: 0.31-0.57; p<0.0001]), while Opdivo monotherapy demonstrated a 45% risk reduction versus Yervoy monotherapy (HR=0.55 [99.5% CI: 0.43-0.76; p<0.0001]). At a minimum follow-up of 18 months, the median PFS for the combination regimen was 11.5 months (95% CI: 8.9-16.7) and 6.9 months (95% CI: 4.3-9.5) for Opdivo monotherapy versus 2.9 months (95% CI: 2.8-3.4) for Yervoy monotherapy. At 18 months, the PFS rate was 46% for the combination regimen (HR=0.42 [99.5% CI: 0.31-0.57; p<0.00001]), 39% for Opdivo monotherapy (HR=0.55 [99.5% CI: 0.43-0.76; p<0.00001]), and 14% for Yervoy.
The Opdivo and Yervoy combination regimen and Opdivo monotherapy also demonstrated a higher ORR (58% and 44%, p<0.0001, respectively) versus Yervoy monotherapy (19%). There were 38 (12%) complete responses and 143 (46%) partial responses seen in patients treated with the combination regimen, and 31 (10%) complete responses and 107 (34%) partial responses seen in patients treated with Opdivo monotherapy, versus 7 (2%) complete responses and 53 (17%) partial responses seen in patients treated with Yervoy alone. The median duration of response had not been reached for those patients treated with the Opdivo and Yervoy combination regimen, and was 22.3 months for Opdivo monotherapy and 14.4 months for Yervoy alone. In the study, a change in tumor burden was seen with the Opdivo and Yervoy combination regimen and Opdivo monotherapy, with a median decrease of 51.9% and 34.5%, respectively, and 5.9% increase for Yervoy alone.
As part of a pre-planned, descriptive analysis of data from CheckMate -067, a greater improvement in PFS for the combination of Opdivo with Yervoy, relative to Opdivo monotherapy, was only observed in patients with low tumor PD-L1 expression. Overall response rates were higher for the combination of Opdivo and Yervoy relative to Opdivo monotherapy, regardless of tumor PD-L1 expression levels. In addition, efficacy of the Opdivo and Yervoy combination regimen and Opdivo monotherapy was observed, regardless of BRAF mutational status.
With longer follow-up, the safety of the Opdivo and Yervoy combination regimen in CheckMate -067 was consistent with previously reported studies of the combination regimen and most treatment-related select adverse events (AEs) were managed with immune-modulating medications. Grade 3-4 treatment-related AEs were reported more frequently with the combination regimen (56.5%), relative to the Opdivo monotherapy (19.8%) versus Yervoy alone (27%). Treatment-related AEs of any grade led to discontinuation in 38.7% of patients treated with the combination regimen, 10.5% for patients treated with Opdivo monotherapy, and 15.4% of patients treated with Yervoy alone. No treatment-related deaths occurred in the Opdivo and Yervoy combination regimen arm. The most common treatment-related select AEs of any grade with the combination regimen versus Yervoy alone included increased ALT (17.9% vs. 3.9%), increased AST (15.7% vs. 3.9%), diarrhea (45.4 % vs. 33.8%), colitis (11.5% vs. 11.3%), rash (28.4% vs. 21.2%), pruritus (35.1% vs. 36.3%), hypothyroidism (16% vs. 4.5%), hyperthyroidism (10.2% vs. 1%), elevated creatinine (4.2% vs. 1.6%), and pneumonitis (6.7% vs. 1.6%).
About CheckMate -069
CheckMate -069 is a Phase 2, double-blind, randomized study that evaluated 142 patients with previously untreated unresectable or metastatic melanoma who received either the Opdivo and Yervoy combination regimen (n=95) or Yervoy alone (n=47). The trial included patients with BRAF wild-type and BRAF V600 mutation-positive melanoma, and randomization was stratified by BRAF mutation status. The primary endpoint was objective response rate (ORR) in patients with BRAF wild-type tumors. Secondary endpoints included progression-free survival (PFS) in patients with BRAF wild-type tumors, ORR in patients with BRAF V600 mutation positive tumors, and safety. Overall survival (OS) was an exploratory endpoint.
Based on a post-hoc analysis at a minimum follow-up of two years, OS and response rates in patients who discontinued treatment with the Opdivo and Yervoy combination regimen due to treatment-related adverse events (AEs, n=35) appeared consistent with the overall population. The two-year OS rate in patients who discontinued treatment with the Opdivo and Yervoy combination regimen due to AEs was 71%. In the original exploratory analysis of the overall study population, the OS rate was 64% at two years for the Opdivo and Yervoy combination regimen and 54% for Yervoy alone (HR=0.74 [95% CI: 0.43-1.26]).
For the overall patient population and the subgroup of patients who discontinued the Opdivo and Yervoy combination regimen due to AEs, the median PFS has still not been reached. In addition, based on the post-hoc analysis, the PFS rate at two years for those patients who discontinued the Opdivo and Yervoy combination regimen due to treatment-related AEs was 52% (95% CI: NR; 7.03-NR). The PFS rate observed in the original exploratory analysis at two years was 51% (95% CI: NR; 7.36-NR) in all patients treated with the combination regimen and 12% with Yervoy alone.
Objective response rates among patients who discontinued the Opdivo and Yervoy combination regimen was 66% (95% CI: 48-81), and 20% achieved a complete response. The ORR observed in the original exploratory analysis was 59% (95% CI: 48-69), and 22% achieved a complete response. Median duration of response was not reached in either group, with ongoing responses seen in 80% of the overall patient population, and in 74% patients who discontinued the combination regimen due to AEs. In addition, exploratory results showed a median reduction of 69% in tumor burden in those patients who discontinued the Opdivo and Yervoy combination regimen.
The rates of overall treatment-related adverse events (AEs) leading to discontinuation remained consistent with previously reported results from CheckMate -069. The most common treatment-related select AEs of any grade for patients treated with the Opdivo and Yervoy combination regimen were rash (43%), pruritus (40%), diarrhea (45%), colitis (18%), increased ALT (26%), increased AST (28%), hypothyroidism (17%), hypophysitis (13%), pneumonitis (10%), and increased creatinine (2%).
About Advanced Melanoma
Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease, and occurs when cancer spreads beyond the surface of the skin to the other organs, such as the lymph nodes, lungs, brain or other areas of the body. Melanoma is mostly curable when treated in its early stages. However, in its late stages, the average five-year survival rate is 15% - 20%.
Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research
At Bristol-Myers Squibb, we have a vision for the future of cancer care that is focused on Immuno-Oncology, now considered a major treatment choice alongside surgery, radiation, chemotherapy and targeted therapies for certain types of cancer.
We have a comprehensive clinical portfolio of investigational and approved Immuno-Oncology agents, many of which were discovered and developed by our scientists. Our ongoing Immuno-Oncology clinical program is looking at broad patient populations, across multiple solid tumors and hematologic malignancies, and lines of therapy and histologies, with the intent of powering our trials for overall survival and other important measures like durability of response. We pioneered the research leading to the first regulatory approval for the combination of two Immuno-Oncology agents, and continue to study the role of combinations in cancer.
We are also investigating other immune system pathways in the treatment of cancer including CTLA-4, CD-137, KIR, SLAMF7, PD-1, GITR, CSF1R, IDO, and LAG-3. These pathways may lead to potential new treatment options – in combination or monotherapy – to help patients fight different types of cancers.
Our collaboration with academia, as well as small and large biotech companies, to research the potential of Immuno-Oncology and non-Immuno-Oncology combinations, helps achieve our goal of providing new treatment options in clinical practice.
At Bristol-Myers Squibb, we are committed to changing survival expectations in hard-to-treat cancers and the way patients live with cancer.
About Opdivo
Cancer cells may exploit “regulatory” pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo is a PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 expressed on activated T-cells, and blocks the binding of PD-L1 and PD-L2, preventing the PD-1 pathway’s suppressive signaling on the immune system, including the interference with an anti-tumor immune response.
Opdivo’s broad global development program is based on Bristol-Myers Squibb’s understanding of the biology behind Immuno-Oncology. Our company is at the forefront of researching the potential of Immuno-Oncology to extend survival in hard-to-treat cancers. This scientific expertise serves as the basis for the Opdivo development program, which includes a broad range of Phase 3 clinical trials evaluating overall survival as the primary endpoint across a variety of tumor types. The Opdivo trials have also contributed toward the clinical and scientific understanding of the role of biomarkers and how patients may benefit from Opdivo across the continuum of PD-L1 expression. To date, the Opdivo clinical development program has enrolled more than 18,000 patients.
Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in 51 countries including the United States, Japan, and in the European Union.
U.S. FDA APPROVED INDICATIONS FOR OPDIVO®
OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.
OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive 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 confirmatory trials.
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) 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) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.
OPDIVO® (nivolumab) is indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post- transplantation brentuximab vedotin. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.
IMPORTANT SAFETY INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune- mediated reactions may involve any organ system; however, the most common severe immune- mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.
Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.
Immune-Mediated Pneumonitis
Immune-mediated pneumonitis, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. In addition, in Checkmate 069, there were six patients who died without resolution of abnormal respiratory findings. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In Checkmate 069 and 067, immune-mediated pneumonitis occurred in 6% (25/407) of patients receiving OPDIVO with YERVOY: Fatal (n=1), Grade 3 (n=6), Grade 2 (n=17), and Grade 1 (n=1). In Checkmate 037, 066, and 067, immune-mediated pneumonitis occurred in 1.8% (14/787) of patients receiving OPDIVO: Grade 3 (n=2) and Grade 2 (n=12). In Checkmate 057, immune- mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In Checkmate 025, pneumonitis, including interstitial lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and 18% (73/397) of patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1). In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).
Immune-Mediated Colitis
Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. When administered with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 069 and 067, diarrhea or colitis occurred in 56% (228/407) of patients receiving OPDIVO with YERVOY. Immune-mediated colitis occurred in 26% (107/407) of patients: Grade 4 (n=2), Grade 3 (n=60), Grade 2 (n=32), and Grade 1 (n=13). In Checkmate 037, 066, and 067, diarrhea or colitis occurred in 31% (242/787) of patients receiving OPDIVO. Immune-mediated colitis occurred in 4.1% (32/787) of patients: Grade 3 (n=20), Grade 2 (n=10), and Grade 1 (n=2). In Checkmate 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In Checkmate 025, diarrhea or colitis occurred in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of patients receiving everolimus. Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade 1 (n=1). In Checkmate 205 and 039, diarrhea or colitis occurred in 30% (80/263) of patients receiving OPDIVO. Immune-mediated diarrhea (Grade 3) occurred in 1.1% (3/263) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of =7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.
Immune-Mediated Hepatitis
Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune- mediated hepatitis. In Checkmate 069 and 067, immune-mediated hepatitis occurred in 13% (51/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=8), Grade 3 (n=37), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 037, 066, and 067, immune-mediated hepatitis occurred in 2.3% (18/787) of patients receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2 (n=4). In Checkmate 057, one patient (0.3%) developed immune-mediated hepatitis. In Checkmate 025, there was an increased incidence of liver test abnormalities compared to baseline in AST (33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs 3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1). In Checkmate 205 and 039, hepatitis occurred in 11% (30/263) of patients receiving OPDIVO. Immune-mediated hepatitis occurred in 3.4% (9/263): Grade 3 (n=7) and Grade 2 (n=2).
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.
Immune-Mediated Dermatitis
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.
Immune-Mediated Neuropathies
In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.
Immune-Mediated Endocrinopathies
Hypophysitis, adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hyp
