Alessandro Riva, MD
A collaboration between Novartis and Bristol-Myers Squibb (BMS) has resulted in the establishment of several clinical trials combining the PD-1 inhibitor nivolumab (Opdivo) with targeted therapies against ALK, c-MET, and T790M for patients with non-small cell lung cancer (NSCLC).
As part of the collaboration, 3 phase I/II clinical trials will be launched exploring nivolumab in combination with the targeted therapies. In the first study, nivolumab will be combined with the ALK inhibitor ceritinib (Zykadia). In the remaining studies, nivolumab will be explored with the c-MET inhibitor INC280 and the EGFR T790M-targeted therapy EGF816. The exact details of the studies were not released.
"Preclinical data suggests that combining molecularly targeted agents with immunotherapies such as nivolumab may have synergistic effects and lead to better outcomes for patients," Alessandro Riva, MD, the global head of Novartis Oncology Development and Medical Affairs, said in a statement. "This collaboration enables us to study several key compounds, including our new highly-potent ALK inhibitor Zykadia, together with a promising, novel immunotherapy agent, paving the way for potential new treatment approaches for patients with NSCLC."
In April 2014, ceritinib received an accelerated approval from the FDA for the treatment of ALK-positive metastatic NSCLC after initial treatment with crizotinib (Xalkori). This approval was based on data from the phase I single-arm ASCEND-1 trial, which examined ceritinib in 246 patients with NSCLC.
According to updated data presented at the 2014 ESMO Congress, the overall response rate (ORR) was 61.8% and the median progression-free survival (PFS) was 9.0 months. In patients who had not received treatment with a prior ALK inhibitor (n = 83), the ORR with ceritinib was 72.3% with a median PFS of 18.4 months. The ORR was 56.4% and the median PFS was 6.9 months among crizotinib-treated patients (n = 163).
The ORR in patients with brain metastases (n = 124) treated with ceritinib was 55.6%. In patients with measurable brain lesions (n = 29), ceritinib demonstrated tumor shrinkage in approximately 33% of patients.
“Combining Opdivo with select targeted agents from Novartis complements our broad global development strategy of immuno-oncology combinations across the spectrum of lung cancer settings, and supports our goal of improving outcomes for patients," Michael Giordano, senior vice president, Oncology Development, Bristol-Myers Squibb, said in a statement. "We look forward to working with Novartis to fully explore how the combination of these agents can potentially advance care for lung cancer patients.”
In 2013, the FDA granted a fast track designation to nivolumab as treatment for patients with NSCLC. In a large phase I study of 129 patients with NSCLC, nivolumab was explored across several doses. In an analysis presented at the 2014 ASCO Annual Meeting, activity was observed in patients with KRAS and EGFR mutations. Additionally, responses were seen in patients treated with more than 3 prior therapies.
Across all doses, the median OS was 9.2-14.9 months. The 1-year OS rates were 32-56% and the 2-year rates were 12-45%. At the 3 mg/kg dose of nivolumab, the median OS was 14.9 months. The 1-year OS rate was 56% and the 2-year rate was 45%. The ORR was 17% with a 17-month median duration of response.
Earlier this year, BMS initiated a rolling submission to the FDA for nivolumab as treatment for patients with NSCLC. Additionally, a phase III trial is currently evaluating the 3 mg/kg dose of nivolumab in NSCLC patients with PD-L1 status as a potential predictor of clinical outcomes.