Nivolumab was previously granted accelerated approval by the FDA for the treatment of patients with small cell lung cancer (SCLC) whose disease had progressed after platinum-based chemotherapy and at least 1 other line of therapy, but phase 3 trial results led to a decision to withdraw the indication.
In consultation with the FDA, Bristol Myers Squibb has decided to withdraw nivolumab (Opdivo) from the United States market for the treatment of patients with small cell lung cancer (SCLC) whose disease has progressed after platinum-based chemotherapy and at least 1 other line of therapy.1
The company took this action in accordance with the FDA’s standard procedures for evaluating agents with accelerated approvals that have not met their post-marketing requirements and as part of a broader industry-wide evaluation. Bristol Myers Squibb indicated that individuals who are currently being treated with nivolumab for SCLC should consult with their healthcare provider.
Nivolumab was granted accelerated approval by the FDA for this patient population in 2018 based on data observed in the phase 1/2 CheckMate-032 trial (NCT01928394) in patients with advanced or metastatic solid tumors, which demonstrated promising rates and duration of response with the PD-1 inhibitor in SCLC. However, when evaluated in different treatment settings within the phase 3 CheckMate 451 (NCT02538666) and CheckMate 331 (NCT02481830) trials, the agent did not meet either study’s primary end point of overall survival (OS) superiority over the control.2,3
“We believe in the power of science to address some of the most challenging diseases of our time, and so we pursue innovations with the goal of transforming patients’ lives,” Abderrahim Oukessou, MD, vice president and thoracic cancers development lead at Bristol Myers Squibb, said in a press release. “Although we are disappointed by the withdrawal, we appreciate that the FDA shared our commitment to bringing an innovative new therapy to patients with high unmet need when the science pointed in that direction. Similarly, we respect the FDA’s efforts to evaluate accelerated approvals across the industry to ensure the integrity of this important program.”
In the double-blind, randomized CheckMate 451 study, 834 patients with extensive-stage small cell lung cancer (ES-SCLC), an ECOG performance state 0 or 1, and a response or stable disease after 4 cycles of first-line platinum-based chemotherapy were randomized 1:1:1 to receive maintenance therapy with either nivolumab plus ipilimumab (Yervoy), nivolumab alone, or placebo. Patients were treated for up to 2 years or until progression or unacceptable toxicity.
The primary end point of the study was OS for nivolumab plus ipilimumab versus placebo. Key secondary end points included OS for nivolumab versus placebo and progression-free survival (PFS) per blinded independent central review for both nivolumab plus ipilimumab and nivolumab alone versus placebo.
Overall, maintenance therapy with nivolumab plus ipilimumab or nivolumab alone did not prolong OS versus placebo for patients with ES-SCLC who did not progress on first-line chemotherapy. Notably, the safety profiles of nivolumab plus ipilimumab and nivolumab were consistent with that previously observed in SCLC.
Moreover, in the global, open-label CheckMate 331 trial, 569 patients with limited- or ES-SCLC and recurrence or progression after first-line platinum-based chemotherapy were randomized 1:1 to receive either nivolumab (n = 284) or chemotherapy (n = 285). Patients were treated until progression or unacceptable toxicity. The primary end point for the study was OS with nivolumab versus chemotherapy.
Ultimately, the trial did not meet its primary end point in second-line SCLC. However, the investigators noted that late separation of the survival curves and potential activity observed in the platinum-refractory setting suggested possible long-term benefit for some individuals.
Regarding safety, there were no new safety signals observed, and lower rates of adverse events were reported with nivolumab.
1. Bristol Myers Squibb Statement on Opdivo (nivolumab) Small Cell Lung Cancer U.S. Indication. News release. Bristol Myers Squibb. Published December 29, 2020. Accessed January 4, 2021. https://news.bms.com/news/details/2020/Bristol-Myers-Squibb-Statement-on-Opdivo-nivolumab-Small-Cell-Lung-Cancer-US-Indication/default.aspx
2. Owonikoko TK, Kim HR, Govindan R, et al. Nivolumab (nivo) plus ipilimumab (ipi), nivo, or placebo (pbo) as maintenance therapy in patients (pts) with extensive disease small cell lung cancer (ED-SCLC) after first-line (1L) platinum-based chemotherapy (chemo): Results from the double-blind, randomized phase III CheckMate 451 study. Ann Oncol.2019;30(suppl 2):ii77–ii80. Abstract 683. doi: 10.1093/annonc/mdz094
3. Reck M, Vicente D, Ciuleanu T, et al. Efficacy and safety of nivolumab (nivo) monotherapy versus chemotherapy (chemo) in recurrent small cell lung cancer (SCLC): Results from CheckMate 331. Ann Oncol. 2018;29(suppl 10):X43. doi: 10.1093/annonc/mdy511.004