Clinical Trials

Date: 2016-10-09

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the European Society for Medical Oncology (ESMO) 2016 Congress

Company: BMS (USA - NY) Ono Pharmaceutical (Japan)

Product: Opdivo® (nivolumab)

Action mechanism: monoclonal antibody. Nivolumab is a 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: recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN)

Therapeutic area: Cancer - Oncology

Country: Argentina, Brazil, Canada, France, Germany, Hong Kong, Italy, Japan, Republic of Korea, The Netherlands, Spain, Switzerland, Taiwan, UK, USA

Trial details:

• CheckMate -141 is a Phase 3, open-label, randomized trial evaluating Opdivo versus investigator’s choice of therapy in patients with recurrent or metastatic SCCHN with tumor progression within six months of platinum therapy in the adjuvant, primary, recurrent or metastatic setting. Patients were randomized 2:1 to receive Opdivo 3 mg/kg intravenously over 60 minutes every two weeks, or one of the following single agents: methotrextate 40 mg/m2 intravenously weekly, docetaxel 30 mg/m2 intravenously weekly, or cetuximab 400 mg/m2 intravenously once then 250 mg/m2 weekly. Therapies chosen for the control arm represent the most commonly used therapies in the platinum refractory setting. The primary endpoint was OS. Secondary endpoints included objective response rate (ORR) and progression-free survival (PFS). Additional endpoints included safety.
• Patient-reported outcomes (PRO) data were collected using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), EORTC Head and Neck Cancer-Specific Module (EORTC QLQ-H&N35) and the 3-level EQ-5D questionnaire (EQ-5D). The questionnaires were administered at baseline (cycle 1, day 1), week 9 and at six-week intervals thereafter while patients were on treatment. (NCT02105636 )

Latest news:

• • On October 9, 2016, BMS announced new patient-reported quality-of-life data from an exploratory endpoint in the pivotal Phase 3 CheckMate -141 trial evaluating Opdivo® in patients with recurrent or metastatic squamous cell carcinoma of the head and neck after platinum therapy compared to investigator’s choice of therapy (methotrexate, docetaxel or cetuximab). Outcome assessments showed Opdivo® stabilized patients’ symptoms and functioning, including physical, role and social functioning across three separate instruments. Both PD-L1 expressors and non-expressors treated with investigator’s choice of therapy experienced statistically significant worsening of patient-reported outcomes from baseline to week 15 versus Opdivo®. In addition, Opdivo® more than doubled the time to deterioration for most functional domains measured and significantly delayed the time to worsening symptoms of fatigue, dyspnea and insomnia, compared to investigator’s choice of therapy. These findings have been presented at the 2016 European Society for Medical Oncology Congress (Abstract #LBA4) and will be simultaneously published in The New England Journal of Medicine.
• Both the EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires showed there were significant differences in PROs between patients treated with Opdivo and those treated with investigator’s choice of therapy at 15 weeks. In the EORTC QLQ-C30, while patients treated with Opdivo had stable PROs relative to baseline, those treated with investigator’s choice of therapy had significant and clinically meaningful worsening of physical, role and social functioning (p<0.001 versus Opdivo), fatigue (p<0.001 versus Opdivo), dyspnea (p<0.001 versus Opdivo) and appetite loss (p=0.004 versus Opdivo). Opdivo more than doubled the median time to deterioration for global health status (7.7 versus 3.0 months), physical functioning (7.8 versus 3.6 months), role functioning (8.6 versus 3.8 months), cognitive functioning (7.8 versus 3.3 months) and social functioning (7.7 versus 3.0 months), compared with investigator’s choice of therapy. In emotional functioning, Opdivo demonstrated a median time to deterioration of 6.7 months versus 4.7 months for investigator’s choice of therapy. Opdivo also reduced the rate of clinically meaningful deterioration in fatigue, insomnia and dypsnea by 50% (p=0.008).
• Responses to the QLQ-H&N35 questionnaire showed while patients treated with Opdivo reported stable PROs relative to baseline, those treated with investigator’s choice of therapy had significant worsening in pain (p=0.022 versus Opdivo) as well as significant and clinically meaningful worsening in sensory problems (p<0.001 versus Opdivo) and social contact problems (p=0.001 versus Opdivo). Compared with investigator’s choice of therapy, Opdivo reduced the rate of clinically meaningful deterioration in pain by 74% (p<0.001 versus investigator’s choice of therapy), sensory problems by 62% (p=0.002 versus investigator’s choice of therapy) and opening mouth problems by 51% (p=0.029 versus investigator’s choice of therapy).
• Patients treated with Opdivo experienced stable health status, as measured by the EQ-5D VAS, whereas those in the investigator’s choice arm experienced worsening of health status, with a statistically significant difference at 15 weeks (p=0.037). Median time to deterioration of health status was nearly triple with 9.1 months for patients receiving Opdivo versus 3.3 months for those in the investigator’s choice arm.
• • On April 19, 2016, BMS announced the first presentation of data from CheckMate -141, a Phase 3 open-label, randomized trial, evaluating Opdivo® (nivolumab) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) after platinum therapy compared to investigator’s choice of therapy (methotrexate, docetaxel, or cetuximab). In the trial, which evaluated overall survival (OS) as the primary endpoint, patients treated with Opdivo experienced a 30% reduction in the risk of death, with a median OS of 7.5 months (95% CI: 5.5-9.1) compared to 5.1 months (95% CI: 4.0-6.0) for investigator’s choice (HR=0.70 [97.73% CI: 0.51-0.96] p=0.0101). The one-year survival rate for Opdivo was 36% compared to 16.6% for investigator’s choice. The safety profile of Opdivo® in CheckMate -141 was consistent with prior studies, with no new safety signals identified. These data were featured during the 2016 Annual Meeting of the American Association for Cancer Research (AACR).
• Based on a planned interim analysis, this trial was stopped early in January 2016 because an assessment conducted by the independent Data Monitoring Committee concluded the study met its primary endpoint of OS in patients receiving Opdivo® compared to the control arm. In the trial, patients treated with Opdivo experienced a significant reduction (30%) in the risk of death, with a median OS of 7.5 months (95% CI: 5.5-9.1) compared to 5.1 months (95% CI: 4.0-6.0) for the control arm (HR=0.70 [97.73% CI: 0.51-0.96] p=0.0101). The one-year OS rate was 36% for Opdivo compared to 16.6% for the control arm.
• CheckMate -141 also evaluated the efficacy of Opdivo® by HPV status and PD-L1 expression compared to investigator’s choice of therapy. HPV testing was performed for patients identified by investigators with oropharyngeal tumors. In the study, Opdivo® demonstrated improved survival in this overall population, regardless of HPV status. HPV-positive status was associated with greater magnitude of effect with Opdivo versus investigator’s choice. In HPV-positive patients treated with Opdivo®, median OS was 9.1 months vs. 4.4 months for patients treated with investigator’s choice of therapy (HR=0.56 [95% CI: 0.32-0.99]). In HPV-negative patients treated with Opdivo®, median OS was 7.5 months vs. 5.8 months for patients treated with investigator’s choice of therapy (HR=0.73 [95% CI: 0.42-1.25]). Of randomized patients, 72% (260) were evaluable for PD-L1 expression. Rates of PD-L1 expression were balanced between subgroups. Opdivo® demonstrated improved survival in the overall population, regardless of PD-L1 expression level (chart below).
• Efficacy Summary: Median Overall Survival by PD-L1 Expression

Hazard Ratio (HR) for Opdivo vs. Investigator’s Choice Therapy (Median OS, mos)
>1% PD-L1 expression level	HR=0.55 [95% CI: 0.36-0.83] 8.7 mos vs. 4.6 mos (95% CI: 5.7-9.1) (95% CI: 3.8-5.8)
<1% PD-L1 expression level	HR=0.89 [95% CI: 0.54-1.45] 5.7 mos vs. 5.8 mos (95% CI: 4.4-12.7) (95% CI: 4.0-9.8)

• The safety profile of Opdivo in CheckMate -141 was consistent with prior studies with no new safety signals identified. Treatment-related adverse events (TRAEs) of any grade occurred in 58.9% of patients on Opdivo vs. 77.5% of patients on investigator’s choice. Grade 3-4 TRAEs were reported in 13.1% of patients on Opdivo vs. 35.1% of patients on investigator's choice. Two drug-related deaths were reported as related to Opdivo (pneumonitis and hypercalcemia), and one Grade 5 event of lung infection on the investigator’s choice arm.

Is general: Yes