Bristol-Myers Squibb has announced long-term follow-up results ( median follow up of 20.3 months ) from the lung cancer cohort ( n=129 ) of the expanded Phase 1 dose-ranging study ( 003 ) of Nivolumab, an investigational PD-1 immune checkpoint inhibitor. Results showed sustained activity in heavily pre-treated patients with non-small-cell lung cancer ( NSCLC ) as defined by one- and two-year survival rates of 42% and 24%, respectively, across dose cohorts.
This analysis is reflective of 129 NSCLC patients, including both squamous and non-squamous histologies. All patients had at least one therapy prior to Nivolumab and 54% received three or more therapies prior to Nivolumab. Across dose cohorts, the one- and two-year survival rates were 42% and 24%, respectively, based on Kaplan-Meier estimates, and median overall survival ( mOS ) was 9.9 months. In all treated patients, the objective response rate ( ORR ) was 17%, as measured by RECIST criteria.
An analysis of the 129 NSCLC patients in this study by select patient characteristics demonstrated that Nivolumab had activity across a broad range of patients, including those with mutations in key signaling pathways in lung cancer such as EGFR and KRAS.
Data presented at the 2013 American Society of Clinical Oncology ( 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 that were consistent with those initially reported in the study in 2012.
As reported at ASCO 2013, common drug-related adverse events included fatigue, decreased appetite, diarrhea, nausea, constipation, cough and dyspnea. Drug-related select adverse reactions with potential immunologic etiologies, defined as adverse events that may require more frequent monitoring and/or unique intervention, included rash, diarrhea and pruritus.
Study 003 is a Phase 1 study ( n=306 ) evaluating the safety, antitumor activity and pharmacokinetics of Nivolumab in patients with non-small-cell lung cancer ( n=129 ), advanced melanoma ( n=107 ), renal cell carcinoma ( n=34 ), castration-resistant prostate cancer ( n=17 ) and colorectal cancer ( n=19 ). Based on an amendment to the protocol, patients were followed-up 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 less than or equal to 2 years ( maximum of 12 cycles; 4 doses per 8-week cycle ), unless they experienced complete response, unacceptable toxicity, progressive disease or withdrew consent.
In clinically stable patients, treatment could be continued beyond apparent initial disease progression until confirmed progression, as defined by proposed immune response criteria.
Patients with stable disease or an ongoing objective response at the completion of treatment were followed for less than or equal to 1 year and offered retreatment for one additional year if their disease progressed. Objective response was defined as complete or partial response.
Cancer cells may exploit regulator pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor against immune attack.
Nivolumab is an investigational, fully-human IgG4 PD-1 immune checkpoint inhibitor 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 restore an anti-tumor immune response.
The development program for Nivolumab consists of more than 25 studies ( as monotherapy or in combination with other therapies ) in multiple tumors types, including: non-small-cell lung cancer, small cell lung cancer, melanoma, renal cell carcinoma, hepatocellular carcinoma, hematological cancers, triple negative breast cancer, gastric cancer and pancreatic cancer. ( Xagena )
Source: BMS, 2013