PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) today announced results from Study 004, a dose-ranging Phase 1 trial (n=86) evaluating the safety and anti-tumor activity of its investigational PD-1 receptor blocker, nivolumab, combined either concurrently (n=53) or sequentially (n=33) with Yervoy® (ipilimumab) in patients with advanced melanoma. In patients who received the dose used in the Phase 3 trial (1 mg/kg nivolumab + 3 mg/kg Yervoy) in the concurrent regimen, 53% (n= 9 of 17) had confirmed objective responses (OR) by mWHO criteria. In all nine of these responders, tumors shrank by at least 80% by the time of the first scheduled clinical treatment assessment (12 weeks), including three complete responses (CRs). In response-evaluable patients across all concurrent cohorts, 40% (n= 21 of 52) had an OR. Sixteen patients (31%) had tumor shrinkage of at least 80% by the time of the first clinical trial assessment, including five CRs. Responses were ongoing among 19 of 21 responders, with responses lasting from between 6.1+ to 72.1+ weeks at the time of data analysis. Clinical activity was observed in both the concurrent and sequenced regimens. Median overall survival has not been reached after approximately 13 months of median follow up in the concurrent cohorts. The estimated one-year survival rate across all concurrent cohorts was 82% (95% CI 69.0 – 94.4%).
Grade 3-4 treatment-related adverse events occurred in 53% of patients on the concurrent-regimen and 18% of patients on the sequenced-regimen. No treatment-related deaths were reported.
The data on nivolumab in combination with Yervoy were published today in the New England Journal of Medicine (NEJM). The estimated survival data were presented at the 49th Annual Meeting of the American Society of Clinical Oncology (Abstract # 9012).
“This is the first clinical trial to evaluate the safety and efficacy of combining two immune-checkpoint inhibitors, which are agents that target the pathways tumor cells use to evade recognition and destruction by the immune system,” said Dr. Jedd D. Wolchok, Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center, presenter of the results and lead author on the New England Journal of Medicine paper. “The responses observed with the concurrent combination of nivolumab and ipilimumab in this Phase 1 trial of patients with advanced melanoma are very encouraging and support further research in randomized trials to evaluate the concept of combining agents that target different, but complementary, immune checkpoint pathways.”
“An unmet medical need remains for many types of advanced cancer and Bristol-Myers Squibb is committed to leading advances in a new field of research, immuno-oncology, which is a rapidly evolving, innovative treatment modality centered on harnessing the natural capabilities of a patient’s own immune system to fight cancer,” said Brian Daniels, senior vice president, Global Development and Medical Affairs, Bristol-Myers Squibb. “Results from this Phase 1 study provide important insights about the potential of combinations in immuno-oncology and deepen our understanding of how cancer cells evade the immune system.”
Bristol-Myers Squibb is developing a robust pipeline of compounds that directly modulate the immune system across a broad range of cancers. This includes the development program for nivolumab, which now consists of seven potentially registrational trials in three tumor types: non-small cell lung cancer (NSCLC), advanced renal cell carcinoma and advanced melanoma, including one in combination with Yervoy. The Phase 3 development program for Yervoy is also ongoing and includes Phase 3 trials in adjuvant melanoma, NSCLC and metastatic castrate-resistant prostate cancer.
Study 004 Results
Clinical activity was observed in both the concurrent and sequenced regimens. In the concurrent-regimen cohort, confirmed OR by mWHO criteria was observed in nine of 17 (53%) patients treated at a dose of 1 mg/kg nivolumab + 3 mg/kg Yervoy, the dose used in the Phase 3 trial. All nine responders achieved 80% or greater tumor reduction by the time of the first scheduled clinical trial assessment (12 weeks), including three CRs. In response-evaluable patients across all concurrent cohorts, OR was observed in 21 of 52 (40%) of patients. Sixteen patients (31%) had tumor shrinkage of at least 80% by the time of the first clinical trial assessment (12 weeks). Four patients experienced an OR by immune-related response criteria and two patients had unconfirmed responses. These six patients were not included in the calculation of objective response rates. Responses were ongoing among 19 of 21 responders, with responses lasting from between 6.1+ to 72.1+ weeks at the time of data analysis. The median overall survival has not been reached after approximately 13 months of median follow up in the combined concurrent cohorts. The estimated one-year survival rate across all concurrent cohorts was 82% (95% CI 69.0 – 94.4%).
In the sequenced-regimen cohorts, six of 30 patients achieved OR (20%) including one CR. Four (13%) patients achieved 80% or greater tumor reduction at 8 weeks. Three patients had immune-related responses and three patients had unconfirmed responses. These six patients were not included in the calculation of objective response rates. These findings showed that patients who did not respond to prior Yervoy responded to subsequent nivolumab.
AEs were more frequent in patients treated with the concurrent combination compared to each single agent. No treatment-related deaths were reported. In the concurrent-regimen, treatment-related AEs occurred in 93% of patients with the most common being rash (55%), pruritus (47%), fatigue (38%), and diarrhea (34%). Grade 3-4 treatment-related AEs were observed in 53% of patients, the most common being elevations in lipase (13%), aspartate aminotransferase (13%) and alanine aminotransferase (11%). Three patients had Grade 1-2 pneumonitis (6%) and one patient had Grade 3 pneumonitis (2%). In the sequenced regimen, treatment-related AEs occurred in 73% of patients with the most common being pruritus (18%) and lipase elevation (12%). Grade 3-4 treatment-related AEs were observed in 18% of patients with lipase elevation (6%) as the most common. One patient had Grade 1-2 pneumonitis (3%).
About Study 004
Study 004 is a dose-ranging Phase 1 study (n=86) evaluating the safety, antitumor activity and pharmacokinetics of nivolumab in concurrent and sequenced combination with Yervoy in patients with advanced melanoma.
The study consists of two treatment regimens, both of which are administered as intravenous infusions. In the concurrent regimen (n=53), eligible patients received nivolumab and Yervoy every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses. Combined treatment was subsequently continued every 12 weeks for up to 8 doses. Cohorts of a maximum of seventeen patients per dose level (0.3 mg/kg nivolumab + 3 mg/kg Yervoy; 1 mg/kg nivolumab + 3 mg/kg Yervoy; 3 mg/kg nivolumab + 1 mg/kg Yervoy; 3 mg/kg nivolumab + 3 mg/kg Yervoy) were enrolled. In the sequenced regimen (n=33), patients previously treated with Yervoy received nivolumab alone every 2 weeks. Cohorts of six patients per dose level (1, 3 mg/kg) were enrolled. After completion of therapy, patients without confirmed disease progression were followed for ≤2.5 years. Patients with initial disease control and subsequent disease progression could be retreated with the original regimen. Initial disease control was defined as complete response, partial response, or stable disease for ≥24 weeks. All cohorts were enrolled in sequence from each other.
Two Distinct Immune Checkpoint Inhibitors
Nivolumab and Yervoy are both immune checkpoint inhibitors, but they are monoclonal antibodies that target different receptors for distinct T-cell checkpoint pathways.
Nivolumab is an investigational, fully-human IgG4 anti-PD-1 receptor blocking monoclonal antibody that binds to the checkpoint receptor PD-1 (programmed death-1) expressed on activated T cells. Nivolumab inhibits the binding of PD-1 with its tumor-expressed ligands, programmed death-ligand 1 (PD-L1/B7-H1) and PD-L2 (B7-DC). Blocking of the interaction of the PD-1 receptor with its ligands may allow T-cells to elicit an anti-tumor immune response.
Yervoy, which is a recombinant, human monoclonal antibody, blocks the cytotoxic T- lymphocyte antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect through T-cell mediated anti-tumor immune responses. On March 25, 2011, the FDA approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is now approved in 41 countries.
Important Safety Information
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. 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) and thyroid function tests at baseline and before each dose.
Permanently discontinue YERVOY for any of the following:
Other Immune-mediated Adverse Reactions, Including Ocular Manifestations:
Pregnancy & Nursing:
Common Adverse Reactions:
Please see full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions available at packageinserts.bms.com/yervoy.
About the Bristol-Myers Squibb and Ono Pharmaceutical Partnership
Through a collaboration agreement with Ono Pharmaceutical in 2011, Bristol-Myers Squibb expanded its territorial rights to develop and commercialize nivolumab (BMS-936558/ONO-4538) globally except in Japan, Korea and Taiwan where Ono has retained all rights to the compound.
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, please visit www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.
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 product development. 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. Among other risks, there can be no guarantee that the late-stage clinical trials described in this release will support regulatory filings, that nivolumab will receive regulatory approval, that the combination use of nivolumab and Yervoy will receive regulatory approval, or that, if approved, they will become commercially successful. 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, 2012, 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.