UXBRIDGE, England--(BUSINESS WIRE)--Bristol-Myers Squibb Company 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).1,2 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% (5/10) in PD-L1 positive tumours, 0% (0/7) in PD-L1 negative tumours, and 1/3 (33%) in patients with tumours unavailable for analysis 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 worldwide, 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 PDL1 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 2 weeks of each 8-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 2012.3 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).
Data for 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 2012.3 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.
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. | |||||||
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 ipilimumab, at different doses and schedules. Secondary outcomes include overall response rate (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), 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.
The objective response rate (ORR) was 50% in patients whose tumours were PD-L1 positive and 0% for tumours 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 Tumour 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 tumour samples for analysis
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 ipilimumab 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 tumours. A Phase 3 trial evaluating the combination regimen of nivolumab and ipilimumab 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 (men and women), resulting in more than 1.5 million deaths each year according the World Health Organization.4 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.5 Globally, the five-year survival rate for Stage I NSCLC is between 47 and 50 percent; for Stage IV NSCLC, the 5-year survival rate drops to 2 percent.6
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 programme 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 ipilimumab 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 ipilimumab in chemotherapy-naïve patients with advanced NSCLC by the end of 2014.
About Nivolumab and Ipilimumab
Cancer cells may exploit “regulatory” pathways, such as checkpoint pathways, to hide from the immune system and shield the tumour from immune attack. Nivolumab and ipilimumab 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 recognise, attack and destroy cancer cells.
Bristol-Myers Squibb has a broad, global development programme to study nivolumab in multiple tumour 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.
Ipilimumab is a fully human monoclonal antibody that works by stimulating the body’s own immune system to fight cancer. Its mechanism of action in patients with melanoma is indirect, possibly through T-cell mediated anti-tumour immune responses.7
In July 2011, ipilimumab received a European licence for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy.8 Ipilimumab is now licensed in more than 40 countries in this setting. In November 2013, ipilimumab was granted an extension to its licence to include its use as a treatment for advanced (unresectable or metastatic) melanoma in adults who have not yet received prior therapy.7
Safety information on ipilimumab as monotherapy in melanoma7
The safety profile of ipilimumab is considered to be related to its mechanism of action as an immunotherapy. In a pivotal Phase III clinical trial, drug-related adverse events related to the study drug were mostly immune-related adverse events (irAEs). Immune-related adverse events described to date have included gastrointestinal, skin, liver, endocrine or nervous systems. The most frequently reported adverse events (≥ 10% of patients) included diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite, and abdominal pain. The majority were mild to moderate. The safety profile of ipilimumab in previously-untreated (first line) patients is comparable to that seen in those who have been previously-treated (second line). Early diagnosis and appropriate management of adverse events using established product-specific guidelines are essential to minimise complications.
The full Summary of Product Characteristics for ipilimumab can be found online at: http://www.medicines.org.uk/emc/medicine/24779/SPC/YERVOY+5+mg+ml+concentrate+for+solution+for+infusion/
Immuno-Oncology at Bristol-Myers Squibb
Surgery, radiation, cytotoxic or targeted therapies have represented the mainstay of cancer treatment over the last several decades, but long-term survival and a positive quality of life have remained elusive for many patients with advanced/metastasised disease. To address this unmet medical need, Bristol-Myers Squibb is leading advances in a rapidly evolving field of cancer research and treatment known as immuno-oncology, which involves agents whose primary mechanism is to work directly with the body’s immune system to fight cancer. This includes conducting research on the potential of combining immuno-oncology agents that target different and complementary pathways in the treatment of cancer.
Bristol-Myers Squibb is committed to advancing the science of immuno-oncology, with the goal of changing survival expectations and the way patients live with cancer.
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.co.uk
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 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, 2013, 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
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References
1. Brahmer et al. Nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients (pts) with advanced non-small-cell lung cancer (NSCLC): survival and clinical activity by subgroup analysis. Data presented at the 50th Annual Meeting of the American Society of Clinical Oncology (Abstract #8112)
2. Gettinger et al. First-line nivolumab (anti-PD-1; BMS-936558, ONO-4538) monotherapy in advanced NSCLC: safety, efficacy and correlation of outcomes with PD-L1 status. Data presented at the 50th Annual Meeting of the American Society of Clinical Oncology (Abstract #8024)
3. Topalian et al. Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer. N Engl J Med. 2012 June 28; 366(26): 2443–2454. doi:10.1056/NEJMoa1200690
4. World Health Organization Web site. “Cancer.” Available at: http://www.who.int/mediacentre/factsheets/fs297/en/. Accessed on May 13, 2014.
5. American Cancer Society Web site. “Detailed Guideline: Lung Cancer (Non-Small Cell).” Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003115-pdf.pdf. Accessed on May 13, 2014.
6. Rami-Porta, R., et al. “The Revised TNM Staging System for Lung Cancer.” Ann Thorac Cardiovasc Surg Vol 15, No. 1. 2009.
7. Yervoy Summary of Product Characteristics. Current version is available at: http://www.medicines.org.uk/EMC/searchresults.aspx?term=yervoy&searchtype=QuickSearch. Last accessed: May 2014
8. EMA website. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002213/WC500109302.pdf Last accessed May 2014
