Clinical Trials

Date: 2015-09-27

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 2015 European Cancer Congress (ECC 2015)

Company: BMS (USA - NY)

Product: Opdivo® (nivolumab)

Action mechanism:

• monoclonal antibody. 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. PD-1, a receptor expressed on the surface of lymphocytes, plays a role in a regulatory pathway that suppresses activated lymphocytes in the body. Available evidence suggests that cancer cells exploit this pathway to escape from immune responses. Opdivo® is thought to provide benefit by blocking PD-1-mediated negative regulation of lymphocytes (i.e., the interaction of PD-1 with its ligands PD-L1 and PD-L2), thereby enhancing the ability of the immune system to recognize cancer cells as foreign and eliminate them. Opdivo® is the world’s first approved drug targeting PD-1.
• This monoclonal antibody has been generated under a research collaboration entered into in May 2005 between Ono and Medarex. When Medarex was acquired by BMS in 2009, it also granted BMS its rights to develop and commercialize the anti-human PD-1 monoclonal antibody in North America. Through the collaboration agreement entered into in September 2011 between Ono and BMS, Ono granted BMS exclusive rights to develop and commercialize Opdivo® in the rest of the world, except in Japan, Korea and Taiwan where Ono has retained all rights to develop and commercialize the compound.

Disease: non-squamous non-small cell lung cancer (NSCLC)

Therapeutic area: Cancer - Oncology

Country: Argentina, Australia, Austria, Brazil, Canada, Chile, Czech Republic, France, Germany, Hong Kong, Hungary, Italy,Mexico, Norway, Peru, Poland, Romania, Russian Federation, Singapore, Spain, Switzerland, USA

Trial details:

• CheckMate -057 is a Phase III, open-label, randomized study of Opdivo® versus docetaxel in previously treated patients with advanced or metastatic non-squamous NSCLC. The trial randomized 582 patients to receive either nivolumab 3 mg/kg intravenously every two weeks or docetaxel 75 mg/m2 intravenously every three weeks. The primary endpoint is overall survival. Secondary endpoints include objective response rate and progression free survival. (NCT01673867)

Latest news:

• • On September 27, 2015, BMS announced longer term (18 month) survival data from CheckMate -057, an open-label, randomized Phase 3 study evaluating Opdivo (n=292) versus docetaxel (n=290) in previously treated patients with advanced, non-squamous (NSQ) non-small cell lung cancer (NSCLC). Opdivo® continued to demonstrate superior overall survival (OS) – the study’s primary endpoint – with an estimated 39% of patients alive at 18 months (95% CI, 34-45) versus 23% for docetaxel, based on a minimum follow-up of 17.1 months. Opdivo® also continued to demonstrate a reduction in the risk of death by 28% (a hazard ratio of 0.72; 95% CI, 0.60 - 0.88). In the study, Grade 3-4 treatment-related adverse events were reported in 10% of patients treated with Opdivo versus 54% in the docetaxel arm. These data will be presented on Monday, September 28 during the 2015 European Cancer Congress (ECC 2015) (Abstract # 3010) and published in the New England Journal of Medicine.
• CheckMate -057 is a Phase 3, open-label, randomized clinical trial that evaluated patients with advanced NSQ NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. The trial included patients regardless of their PD-L1 status. Secondary endpoints included objective response rate (ORR) and progression-free survival (PFS). Patients enrolled in the trial received Opdivo® 3 mg/kg every two weeks versus standard of care, docetaxel, at 75 mg/m2 every three weeks. In the trial, Opdivo demonstrated continued superior OS benefit, with an estimated 51% of patients alive at one year versus 39% for docetaxel, and an estimated 39% of patients alive at 18 months (95% CI, 34-45) versus 23% for docetaxel, based on a minimum follow-up of 17.1 months.
• CheckMate -057 also evaluated the efficacy of Opdivo® by tumor PD-L1 expression. Of randomized patients, 78% (455/582) had tumor samples evaluable for PD-L1 expression. Rates of PD-L1 expressing tumors were balanced between groups. PD-L1 status was predictive for benefit from Opdivo®, across pre-specified 1%, 5%, and 10% expression levels. In PD-L1 non-expressors, OS was similar between Opdivo® and docetaxel, with improved durability of responses seen in patients treated with Opdivo® versus docetaxel. In addition, clinical results showed confirmed ORR was significantly higher for Opdivo® (19%) than docetaxel (12%). For patients administered Opdivo®, median duration of response was 17.2 months and 5.6 months for docetaxel. One-year PFS was 19% for Opdivo (95% CI, 14-23) and 8% for docetaxel (95% CI, 5-12). Median PFS was 2.3 months for Opdivo® (95% CI, 2.2-3.3) and 4.2 months for docetaxel (95% CI, 3.5-4.9).
• The safety profile of Opdivo® in CheckMate -057 was consistent with prior studies and similar across expressors and non-expressors. Treatment-related adverse events were low in severity with Opdivo® and occurred less frequently (any grade: 69%; grade 3-4: 10%) than docetaxel (any grade: 88%; grade 3-4: 54%), including both hematologic and non-hematologic toxicities. Treatment-related serious adverse events were reported less frequently with Opdivo® (any grade: 7%; grade 3-4: 5%) than docetaxel (any grade: 20%; grade 3-4: 18%). Discontinuation due to treatment–related adverse events was less frequent with Opdivo (5%) than docetaxel (15%).
• • On May 29, 2015, BMS announced that Opdivo® (nivolumab) is the first PD-1 inhibitor to demonstrate superior overall survival versus standard of care (docetaxel) in an open-label, randomized Phase III study (CheckMate -057) evaluating previously-treated patients with advanced, non-squamous non-small cell lung cancer (NSCLC). A 27% reduction in the risk of progression or death – the primary study endpoint – was reported for Opdivo® (n=292) versus docetaxel (n=290) based upon a hazard ratio of 0.73 (96% CI, 0.59-0.89; P = 0.0015). Opdivo® was associated with a doubling of overall median survival across the continuum of PD-L1 expression, starting at 1% level of expression, in the trial. The safety profile of Opdivo® in CheckMate -057 was favorable versus docetaxel with grade 3–5 treatment-related adverse events reported in 10% of patients who were treated with Opdivo® versus 54% in the docetaxel arm. These data have been featured during the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) press briefing at 1:00 – 2:00 PM CDT and presented during a clinical science symposium on Saturday, May 30 from 8:51 – 9:03 AM CDT (Late Breaking Abstract #109).
• In addition to improving overall survival, Opdivo® demonstrated a superior objective response rate of 19% versus 12% for docetaxel (P = 0.0246). The median duration of response for Opdivo® was 17.2 months versus 5.6 months for docetaxel, and median time to response of 2.1 months vs. 2.6 months, respectively.
• CheckMate -057 also evaluated the efficacy of Opdivo® by tumor PD-L1 expression. Of randomized patients, 78% (455/582) had tumor samples allowing the assessment of PD-L1 expression. Rates of PD-L1 expressing tumors were balanced between groups. Across pre-specified 1%, 5%, and 10% expression levels, PD-L1 status was predictive for benefit from Opdivo®. In patients with PD-L1 expressing tumors, Opdivo® demonstrated improved efficacy across all endpoints at all expression levels (chart below).

Efficacy Summary: Median Overall Survival by PD-L1 Expression
			Opdivo		Docetaxel
	?1% PD-L1 expression level HR = 0.59 (95% CI, 0.43- 0.82)		17.2 months		9.0 months
	<1% PD-L1 expression level HR = 0.90 (95% CI, 0.66- 1.24)		10.4 months		10.1 months
	?5% PD-L1 expression level HR = 0.43 (95% CI, 0.30-0.63)		18.2 months		8.1 months
	<5% PD-L1 expression level HR = 1.01 (95% CI, 0.77- 1.34)		9.7 months		10.1 months
	?10% PD-L1 expression level HR = 0.40 (95% CI, 0.26-0.59)		19.4 months		8.0 months
	<10% PD-L1 expression level HR = 1.00 (95% CI, 0.76- 1.31)		9.9 months		10.3 months

• The safety profile of Opdivo® in CheckMate -057 was consistent with prior studies and favorable versus docetaxel. Safety profile also was similar across expressers and non-expressers. Treatment-related adverse events were low in severity with Opdivo® and occurred less frequently (any grade: 69%; grade 3–4: 10%) than docetaxel (any grade: 88%; grade 3–4: 54%), including both hematologic and non-hematologic toxicities. Treatment-related serious adverse events were reported less frequently with Opdivo® (any grade: 7.3%; grade 3–4: 5.2%) than docetaxel (any grade: 20%; grade 3–4: 18%). Discontinuation due to treatment–related adverse events was less frequent with Opdivo® (5%) than docetaxel (15%).
• Proven Efficacy Across Histologies in Lung Cancer: CheckMate -057 is the second positive Phase III trial to demonstrate superior overall survival for Opdivo® in non-small cell lung cancer. Earlier this year, the Phase III CheckMate -017 trial was stopped early due to superior overall survival versus docetaxel in previously-treated advanced squamous non-small cell lung cancer and formed the basis of the company’s first indication in lung cancer from the FDA approval for Opdivo®. Trial results from CheckMate -017 will be presented at ASCO during an oral abstract session on Sunday, May 31 from 4:30 – 4:42 PM CDT (Abstract #8009).
• • On April 17, 2015, BMS announced that an open-label, randomized Phase III study evaluating Opdivo® (nivolumab) versus docetaxel in previously treated patients with advanced non-squamous non-small cell lung cancer (NSCLC) was stopped early because an assessment conducted by the independent Data Monitoring Committee (DMC) concluded that the study met its endpoint, demonstrating superior overall survival in patients receiving Opdivo® compared to the control arm. The company looks forward to sharing these data with health authorities soon. “The results of CheckMate -057 mark the second time Opdivo has demonstrated a survival advantage in lung cancer,” said Michael Giordano, senior vice president, Head of Development, Oncology, BMS. “Through our Opdivo clinical development program, we seek to bring the potential for long-term survival to a broad range of patients, across lines of therapy and stages of disease.” CheckMate -057 investigators are being informed of the decision to stop the comparative portion of the trial. Bristol-Myers Squibb is working to ensure that eligible patients will be informed of the opportunity to continue or start treatment with Opdivo in an open-label extension as part of the company’s commitment to providing patient access to Opdivo, and characterizing long-term survival. The company will complete a full evaluation of the final CheckMate -057 data and work with investigators on the future presentation and publication of the results.

Is general: Yes