Bristol Myers Squibb Withdraws Nivolumab SCLC Indication From US Market

Bristol Myers Squibb has withdrawn nivolumab (Opdivo) from the US market for the treatment of patients with small cell lung cancer (SCLC) who have experienced disease progression after a platinum-based chemotherapy and at least 1 other line of therapy, according to an announcement from the pharmaceutical company.¹

The accelerated approval of nivolumab had been based on data from the phase 1/2 CheckMate-032 trial (NCT01928394), in which the agent had showcased promising response rates and duration of response in patients with SCLC.^2,3

Here, nivolumab elicited an objective response rate (ORR) of 12% (95% CI, 6.5%-19.5%) when given after platinum-based chemotherapy and 1 other previous line of treatment; this was comprised of a partial response rate of 11% and a complete response rate of 0.9%. The median duration of response with the immunotherapy was 17.9 months (95% CI, 7.9-42.1), with more than half of the 109 patients (62%) experiencing a continued response at 12 months. Thirty-nine percent of patients continued to respond to nivolumab at 18 months.

Nivolumab had been the first new therapy to receive FDA approval in this setting after nearly 2 decades, according to the press release.

However, CheckMate-451 (NCT02538666) and CheckMate-331 (NCT02481830), the confirmatory trials that have since been conducted in different treatment settings, failed to meet their primary end points of overall survival (OS).

Following a consultation with the FDA, the pharmaceutical company decided to withdraw the SCLC indication from the US market. This action was done in accordance with the regulatory agency’s standard procedures for evaluating accelerated approvals that have not satisfied their post-marketing requirements and as part of a larger industry-wide assessment.

“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, stated 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 phase 3 CheckMate-451 trial, investigators enrolled a total of 834 patients with extensive-stage SCLC who had achieved stable disease following 4 cycles of chemotherapy.⁴ Participants were randomized 1:1:1 to receive either nivolumab/ipilimumab (Yervoy), nivolumab monotherapy, or placebo. Treatment was given until either progressive disease was observed or for up to 2 years.

In the doublet arm, a total of 279 patients were given a maximum of 4 cycle of nivolumab at a dose of 1 mg/kg in combination with ipilimumab at a dose of 3 mg/kg every 3 weeks. Single-agent nivolumab was given to 280 patients, at a dose of 240 mg every 2 weeks. Additionally, a total of 275 patients received placebo.

The primary end point of the trial was OS, and this had not been met.

Results presented during the 2019 European Lung Cancer Congress showed that maintenance treatment with nivolumab alone (HR, 0.84; 95% CI, 0.69-1.02) or in combination with ipilimumab (HR, 0.92; 95% CI, 0.75-1.12; P = .3693) failed to provide an OS advantage over placebo when evaluated in patients with extensive-stage SCLC.

In the open-label, randomized, phase 3 CheckMate-331 trial, investigators examined single-agent nivolumab vs chemotherapy in patients with relapsed SCLC after platinum-based chemotherapy.⁵ Here, participants were randomized to either nivolumab or either topotecan or amrubicin per investigator’s choice. The primary end point of the trial was OS, while key secondary end points comprised progression-free survival and objective response rate.

Topline results from the trial indicated that nivolumab monotherapy did not improve OS vs standard chemotherapy in this patient population.

“[Nivolumab] and [nivolumab]-based combinations are important treatment option in multiple forms of cancer, with established long-term survival benefits in complex diseases, including thoracic cancers like non–small cell lung cancer and malignant pleural mesothelioma,” according to Bristol Myers Squibb. “As an organization, we remain focused on investigating the potential of [nivolumab] for people with cancer who may benefit and pursuing the next breakthroughs for patients in need.”

References

1. Bristol Myers Squibb statement on Opdivo (nivolumab) small cell lung cancer US indication. News release. Bristol Myers Squibb. December 29, 2020. Accessed December 30, 2020. http://bit.ly/2WUCoR9.
2. Antonia SJ, Lopez-Martin JA, Bendell JC, et al. Checkmate 032: Nivolumab (N) alone or in combination with ipilimumab (I) for the treatment of recurrent small cell lung cancer (SCLC). J Clin Oncol. 2016;34(suppl 15):100. doi:10.1200/JCO.2016.34.15_suppl.100
3. Antonia SJ, Lopez-Martin JA, Bendell JC, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(7):883-895. doi:10.1016/S1470-2045(16)30098-5.
4. Owonikoko T, Kim H, 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. Presented at: 2019 European Lung Cancer Congress; April 11-13, 2019; Geneva, Switzerland. Abstract LBA1.
5. Bristol-Myers Squibb announces phase 3 CheckMate-331 study does not meet primary endpoint of overall survival with Opdivo versus chemotherapy in patients with previously treated relapsed small cell lung cancer. News release. Bristol Myers Squibb. October 12, 2018. Accessed December 30, 2020. http://bit.ly/2L34szg.