- Longer-term data from study of previously treated patients who received nivolumab as a single agent showed a two-year survival rate of 24% across doses; results from 3 mg/kg dose also presented (Study -003)
- In chemotherapy-naïve patients who received nivolumab 3 mg/kg as a single agent, the overall response rate (ORR) was 50% in PD-L1 positive tumors and 0% in PD-L1 negative tumors (CheckMate -012)
- The types of treatment-related serious adverse events (SAEs) in CheckMate -012 were consistent with those in other nivolumab trials; of the chemotherapy-naïve patients who received nivolumab as a single agent, 15% experienced grade 3-4 treatment-related SAEs
PRINCETON, NJ, USA I May 14, 2014 I Bristol-Myers Squibb Company (NYSE: BMY) today announced results from a Phase1b study evaluating the safety and efficacy of its investigational PD-1 immune checkpoint inhibitor nivolumab as a single agent in patients with advanced non-small cell lung cancer (NSCLC) who were previously treated (Study -003) and a Phase 1b study evaluating nivolumab as a single agent in chemotherapy-naïve patients (CheckMate -012). In Study -003, the two-year survival rate was 24% across doses (n=129) for previously-treated patients who received nivolumab as a single agent and highest at 45% in patients who received the 3 mg/kg dose (n=37). In CheckMate -012, the overall response rate (ORR) was 50% in PD-L1 positive tumors and 0% in PD-L1 negative tumors for chemotherapy-naïve patients who received nivolumab as a single agent (n=20). The types of treatment-related serious adverse events (SAEs) in CheckMate -012 were consistent with those in other nivolumab trials with 15% of patients experiencing grade 3-4 treatment-related SAEs. These data will be presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) taking place in Chicago May 30-June 3.
“As the leading cause of cancer death, lung cancer remains an area of significant unmet medical need,” said Michael Giordano, senior vice president, Head of Development, Oncology & Immunology. “Bristol-Myers Squibb has the largest clinical development program in the industry evaluating the potential of immuno-oncology compounds in lung cancer as single agents and as part of combination regimens across lines of therapy, histologies and biomarker expression. These Phase 1b data from both previously treated and chemotherapy-naïve patients add to our understanding of the role of PD-L1 expression and reinforce our belief in nivolumab – as a single agent and as part of a combination regimen – as a potential treatment option for patients with lung cancer.”
Results from Phase 1b Single Agent Study in Previously-Treated Patients (Study -003)
Study -003 is a Phase 1b dose escalation study (n=306) evaluating the safety, antitumor activity and pharmacokinetics of nivolumab as a single agent in previously-treated patients with advanced melanoma (n=107), NSCLC (n=129), renal cell carcinoma (n=34), castration-resistant prostate cancer (n=17) or colorectal cancer (n=19). Based on an amendment to the protocol, patients were followed for survival. Eligible patients were administered nivolumab as an intravenous infusion every two weeks of each eight-week treatment cycle. Cohorts of three to six patients per dose level (0.1, 0.3, 1.0, 3.0 or 10 mg/kg) were enrolled sequentially. Patients continued treatment ≤2 years (12 cycles), unless they experienced complete response, unacceptable toxicity, progressive disease or withdrew consent.
Efficacy and safety results from this study were initially presented at ASCO and published in the New England Journal of Medicine in 2012. Updated results from the lung cancer cohort, including those shown below, will be presented at ASCO on May 31 at 1:15 p.m. CDT (Abstract #8112).
Long-Term Nivolumab Single Agent Efficacy Data in Previously-Treated NSCLC Patients
| Patients | mOS,* mo (95% CI) | OS Rate,* % (95% CI) [Pts at Risk] | |||||||
| 1 Year | 2 Year | ||||||||
| All†
n=129 |
9.9 (7.8, 12) | 42 (34, 51) [48] | 24 (16, 32) [20] | ||||||
| 1 mg/kg
n=33 |
9.2 (5.3, 11) | 32 (16, 49) [8] | 12 (3, 27) [2] | ||||||
| 3 mg/kg
n=37 |
14.9 (7.3, NR) | 56 (38, 71) [17] | 45 (27, 61) [9] | ||||||
| 10 mg/kg
n=59 |
9.2 (5.2, 12) | 40 (27, 52) [23] | 19 (10, 31) [9] | ||||||
| Squamous
n=54 |
9.2 (7.3, 12) | 40 (27, 54) [19] | 24 (13, 37) [9] | ||||||
| Non-squamous
n=74 |
10.1 (5.7, 14) | 43 (32, 54) [28] | 23 (13, 34) [10] | ||||||
| NR= not reached. *Sept 2013 analysis. †One pt had unknown histology. | |||||||||
Data to be presented at the 2014 ASCO annual meeting, with all patients having greater than or equal to one year of follow up, demonstrated a spectrum, frequency and severity of treatment-related adverse events (AEs) that were consistent with those initially reported in the study at ASCO in 2012. Common drug-related AEs included fatigue, decreased appetite, diarrhea, nausea, constipation, cough and dyspnea. Drug-related select AEs with potential immunologic etiologies, defined as adverse events that may require more frequent monitoring and/or unique intervention, included rash, diarrhea and pruritus. These data support the ongoing evaluation of nivolumab as a single agent at the 3 mg/kg dose in patients with previously treated advanced NSCLC in the Phase 3 CheckMate -017 and CheckMate -057 studies.
Results from Phase 1b Study of Chemotherapy-Naïve Patients (CheckMate -012)
CheckMate -012 is a multi-arm Phase 1b trial evaluating the safety and tolerability of nivolumab in patients with chemotherapy-naïve advanced NSCLC, as either a single agent or as part of a regimen with other agents, including in combination with Yervoy® (ipilimumab), at different doses and schedules. Secondary outcomes include ORR and progression free survival (PFS). Results from patients who received nivolumab as a single agent, including those shown below, will be presented at ASCO on June 3 at 11:30 a.m. CDT (Abstract #8024).
In patients who received nivolumab 3 mg/kg as a single agent (n=20), the objective response rate (ORR) was 50% in patients whose tumors were PD-L1 positive and 0% for tumors that were PD-L1 negative. Responses were observed in both squamous and non-squamous histological subtypes. Median duration of response has not been reach after a median of 15 months of follow up.
Efficacy Results for Nivolumab Single Agent and by PD-L1 Tumor Status
| ORR | mDOR | |||||
| n/N (%) | wk (range) | |||||
| All patients | 6/20 (30) |
NR (24+, 71+) |
||||
| PD-L1+ | 5/10 (50) |
NR (24+, 71+) |
||||
| PD-L1- | 0/7 (0) | n/a | ||||
| PD-L1 unavailable* | 1/3 (33) | n/a |
NR = Not Reached; *3 of the 20 treated patients had insufficient tumor samples for analysis
After a median of 15 months of follow up, grade 3/4 treatment-related SAEs were reported in 3 patients (15%) and included AST (5%) or ALT (5%) elevations, cardiac failure and hyperglycemia (5%). No pneumonitis (any grade) was observed. These data support the ongoing evaluation of nivolumab as a single agent at the 3 mg/kg dose in the first-line treatment of advanced NSCLC patients in the Phase 3 CheckMate -026 study.
Preliminary data from a cohort of patients who received the combination regimen of nivolumab and Yervoy at different doses (n=49) will be presented at ASCO on June 3 at 11:30 a.m. CDT (Abstract #8023) and showed activity, as assessed by ORR, in patients with both PD-L1 positive and PD-L1 negative tumors. A Phase 3 trial evaluating the combination regimen of nivolumab and Yervoy in chemotherapy-naïve patients will be initiated by the end of 2014.
Data from additional arms of CheckMate -012, including nivolumab as part of a regimen with chemotherapy doublets and erlotinib, will also be presented at ASCO (Abstract #8113, #8022).
About Lung Cancer
Lung cancer is the leading cause of cancer deaths globally, resulting in more than 1.5 million deaths each year according the World Health Organization. NSCLC is one of the most common types of the disease and accounts for approximately 85 percent of 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 percent; for Stage IV NSCLC, the five-year survival rate drops to two percent.
About Bristol-Myers Squibb Immuno-Oncology Trials in Lung Cancer
Bristol-Myers Squibb is committed to the research and development of immuno-oncology as an innovative approach to treating lung cancer and has a broad global development program evaluating its approved and investigational immunotherapies – either as single agents or as part of combination regimens – across lines of therapy, histologies and biomarker expression. Among these are six ongoing Phase 3 trials. Three Phase 3 trials are evaluating nivolumab as a single agent in patients who have been previously treated (CheckMate -017 and CheckMate -057) as well as chemotherapy-naïve patients (CheckMate -026). Two Phase 3 trials evaluating Yervoy in combination with chemotherapy in newly diagnosed small cell lung cancer (Study -156) and squamous NSCLC (Study -104) are ongoing. Additionally, the company plans to initiate a Phase 3 trial evaluating the combination regimen of nivolumab and Yervoy in chemotherapy-naïve patients with advanced NSCLC by the end of 2014.
About Nivolumab and Yervoy
Cancer cells may exploit “regulatory” pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Nivolumab and Yervoy are both monoclonal antibodies and immune checkpoint inhibitors, but target different receptors for distinct T-cell checkpoint pathways.
Nivolumab is an investigational, fully-human PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 (programmed death-1) expressed on activated T-cells. We are investigating whether by blocking this pathway, nivolumab would enable the immune system to resume its ability to recognize, attack and destroy cancer cells.
Bristol-Myers Squibb has a broad, global development program to study nivolumab in multiple tumor types consisting of more than 35 trials – as monotherapy or in combination with other therapies – in which more than 7,000 patients have been enrolled worldwide. Among these are several potentially registrational trials in NSCLC, melanoma, renal cell carcinoma (RCC), head and neck cancer, glioblastoma and non-Hodgkin lymphoma. In 2013, the FDA granted Fast Track designation for nivolumab in NSCLC, melanoma and RCC.
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 more than 40 countries.
SOURCE: Bristol-Myers Squibb
