ASCO2016: Bristol-Myers Squibb Release: Opdivo (Nivolumab) And Yervoy (Ipilimumab) Combination Regimen Shows Clinically Meaningful Responses In First-Line Advanced Non-Small Cell Lung Cancer, In Updated Phase Ib Study Checkmate -012
Confirmed objective response rate in patients with >1% PD-L1 expression for both Opdivo and Yervoy combination regimen cohorts was 57%, a doubling of response rate previously reported in Opdivo monotherapy arm
Combination regimen cohorts showed enhanced efficacy with increasing PD-L1 expression, with up to a 92% response rate for those patients with =50% PD-L1 expression
Improved safety and tolerability observed with current Opdivo and Yervoy combination cohorts compared to those previously studied in non-small cell lung cancer
PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) announced today updated results from CheckMate -012, a multi-arm, Phase 1b trial evaluating two Immuno-Oncology agents, Opdivo and Yervoy, in patients with chemotherapy-naïve advanced non-small cell lung cancer (NSCLC). In this study, Opdivo was administered as monotherapy or as part of a combination with other agents, including Yervoy, at different doses and schedules. Data from the Opdivo monotherapy arm and other cohorts were previously reported. These updated results include findings from a pooled analysis of two Opdivo and Yervoy combination regimen cohorts, [3 mg/kg of Opdivo every two weeks plus 1 mg/kg of Yervoy either every six (Q6W) or 12 weeks (Q12W) (n=77)] which showed the magnitude of response rate from the combination regimen was enhanced with increased PD-L1 expression. In these combination regimen cohorts, the confirmed objective response rate (ORR) in patients with =1% PD-L1 expression was 57% and the confirmed ORR was up to 92% (n=12/13) in patients with =50% PD-L1 expression. In patients with <1% PD-L1 expression, the confirmed ORR was 15%. The ORR was 47% and 39% for the Q12W and Q6W, respectively in the overall population which included all patients regardless of PD-L1 expression level.
In the study, the rate of treatment related Grade 3/4 adverse events (AEs) was 37%, 33%, and 19% for the Q12W, Q6W and Opdivo monotherapy cohorts, respectively. The rate of treatment-related Grade 3/4 AEs leading to discontinuation was 5%, 8%, and 10% of patients in the Q12W, Q6W and Opdivo monotherapy arms, respectively. There were no treatment-related deaths.
These data will be presented today at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) during an oral presentation on Saturday, June 4, from 1:27 PM - 1:39 PM CDT (Abstract #3001).
“The results from this study provide important insight into the combination immunotherapy with Opdivo and Yervoy, and supports the potential for this combination as a first-line treatment option for patients with advanced non-small cell lung cancer,” said Matthew D. Hellmann, M.D., Memorial Sloan Kettering Cancer Center. “The frequency, depth, and durability of responses among patients in this study treated with the combination regimen, and particularly among those with increased PD-L1 expression, are promising. We look forward to additional research of this combination in the first-line setting of patients with non-small cell lung cancer.”
Results from CheckMate -012 continue to support the dosing schedule selected – 3 mg/kg of Opdivo every two weeks plus 1 mg/kg of Yervoy every six weeks – for evaluation in further studies, including the Phase 3 trial, CheckMate -227, comparing Opdivo, the Opdivo and Yervoy combination regimen or Opdivo and platinum-based doublet chemotherapy versus platinum-based doublet chemotherapy in chemotherapy-naïve Stage IV or recurrent NSCLC.
Jean Viallet, M.D., Global Clinical Research Lead, Oncology, Bristol-Myers Squibb, commented, “We find these Opdivo and Yervoy combination regimen results in first-line advanced non-small cell lung cancer compelling. These data reinforce our approach to identify an optimized combination dosing schedule for further study in patients with advanced non-small cell lung cancer. As we continue to advance our Immuno-Oncology clinical research, our goal is to offer patients with first-line lung cancer the potential for improved outcomes.”
About CheckMate -012
CheckMate -012 is a multi-arm Phase 1b trial evaluating the safety and tolerability of Opdivo in patients with chemotherapy-naïve advanced non-small cell lung cancer (NSCLC), as either a monotherapy or in combination with other agents including Yervoy, at different doses and schedules. The primary endpoint of the study was safety with secondary endpoints of objective response rate (ORR) and 24-week progression-free survival (PFS). Exploratory endpoints included overall survival (OS) and efficacy by PD-L1 expression. In the study, patients were tested for PD-L1 expression and 68% of patients in the Q12W cohort and 77% of patients in the Q6W cohort expressed PD-L1.
The efficacy and safety results of the three dosing schedules in CheckMate -012 reported at ASCO are below.
|
Nivo 3 Q2W + Ipi 1 Q12W (n = 38) |
Nivo 3 Q2W + Ipi 1 Q6W (n = 39) |
Nivo 3 Q2W (n = 52) |
||||
|
Confirmed ORR, %
(95% CI) |
47 (31, 64) |
39 (23, 55) |
23* (13, 37) |
|||
| Median duration of response, mo (95% CI) | NR (11.3, NR) | NR (8.4, NR) | NR (5.7, NR) | |||
| Median length of follow-up, mo (range) | 12.9 (0.9–18.0) | 11.8 (1.1–18.2) | 14.3 (0.2–30.1) |
*not randomized
CheckMate -012 also evaluated the efficacy by PD-L1 expression, an exploratory endpoint, of Opdivo as monotherapy (previously reported) and in combination with Yervoy across the Q6W and Q12W dosing schedules. The chart below describes the efficacy results based on PD-L1 expression levels presented today at ASCO.
|
Nivo 3 Q2W + Ipi 1 Q12W (n = 38) |
Nivo 3 Q2W + Ipi 1 Q6W (n = 39) |
Nivo 3 Q2W (n = 52) |
||||
|
ORR, % (n/N)
<1% PD-L1 =1% PD-L1 =50% PD-L1 |
30 (3/10)
57 (12/21) 100 (6/6) |
0 (0/7)
57 (13/23) 86 (6/7) |
14 (2/14)
28 (9/32) 50 (6/12) |
|||
|
Median PFS (95% CI), mo
<1% PD-L1 =1% PD-L1 =50% PD-L1 |
4.7 (0.9, NR)
8.1 (5.6, NR) 13.6 (6.4, NR) |
2.4 (1.7, 2.9)
10.6 (3.6, NR) NR (7.8, NR) |
6.6 (2.0, 11.2)
3.5 (2.2, 6.6) 8.4 (2.2, NR) |
|||
|
1-year OS rate (95% CI), %
<1% PD-L1 =1% PD-L1 =50% PD-L1 |
NC
90 (66, 97) NC |
NC
83 (60, 93) 100 (100, 100) |
69 (50, 82) 79 (47, 93) 83 (48, 96) |
The rate of total adverse events in the Q12W (82%) and Q6W (72%) arms were comparable to monotherapy (71%). In the study, Grade 3/4 adverse events (AEs) were 37%, 33%, and 19% for the Q12W, Q6W and Opdivo monotherapy arms, respectively. Treatment-related Grade 3/4 AEs lead to discontinuation in 5% and 8% of patients in the Q12W and Q6W cohorts, respectively and were similar to Opdivo monotherapy. There were no treatment-related deaths. The treatment-related select AEs in patients administered the optimized dosing schedule (3 mg/kg of Opdivo every two weeks plus 1 mg/kg of Yervoy every six weeks) were skin related (36%), gastrointestinal (23%), endocrine (20%), and pulmonary (6%) and there were =5% treatment-related Grade 3/4 AEs per category.
About Lung Cancer
Lung cancer is the leading cause of cancer deaths globally, resulting in more than 1.5 million deaths each year, according to the World Health Organization. Non-small cell lung cancer (NSCLC) is one of the most common types of the disease and accounts for approximately 85% of cases. About 25% to 30% of all lung cancers are squamous cell carcinomas, and non-squamous NSCLC accounts for approximately 50% to 65% of all lung cancer cases. Survival rates vary depending on the stage and type of the cancer when it is diagnosed. Globally, the five-year survival rate for Stage I NSCLC is between 47% and 50%; for Stage IV NSCLC, the five-year survival rate drops to 2%.
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 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 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 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 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 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 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 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 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 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 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 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 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 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.
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