Bristol Myers Squibb Withdraws Opdivo from Small Cell Lung Cancer Indication Following Repeated Phase III Trial Failures

Compiled by Fan Dongdong

Bristol-Myers Squibb (BMS) recently announced that, following discussions with the U.S. FDA, it has decided to withdraw the approved indication for Opdivo in the treatment of small cell lung cancer (SCLC) in the United States.

In August 2018, Opdivo became the first PD-1/PD-L1 inhibitor approved by the FDA for small cell lung cancer (SCLC). According to the results of the CheckMate 032 study at that time, the objective response rate (ORR) in patients with recurrent limited-stage or extensive-stage SCLC treated with Opdivo reached 12%. Among patients who responded to Opdivo treatment, the majority achieved a duration of response (DOR) of up to 17.9 months. Overall, Opdivo was well tolerated. However, in two subsequent confirmatory studies conducted in different treatment settings, the drug failed to meet its primary endpoints.

In October 2018, Bristol-Myers Squibb (BMS) announced the failure of the CheckMate-331 clinical trial for Opdivo. CheckMate-331 was a large Phase III clinical study comparing the efficacy of Opdivo versus chemotherapy as second-line treatment for small cell lung cancer (SCLC). The trial results showed that the median overall survival (OS) in the Opdivo group was unexpectedly shorter than that in the chemotherapy group (7.5 months vs. 8.4 months). Meanwhile, the objective response rate (ORR) in the Opdivo group was only 14%, with a median progression-free survival (PFS) of merely 1.4 months. In contrast, the chemotherapy group achieved an ORR of 16% and a median PFS of 3.8 months.

In November 2018, the drug suffered another setback with a failed clinical trial. In the CheckMate-451 study involving patients with extensive-stage small cell lung cancer (SCLC) who had not experienced disease progression after first-line platinum-based chemotherapy, Opdivo combined with the CTLA-4 inhibitor Yervoy (ipilimumab) failed to meet the primary endpoint compared with placebo. The trial results showed that the efficacy of the Opdivo-Yervoy combination was worse than that of placebo. After nine months of patient follow-up, the overall survival in the combination therapy group was not significantly prolonged compared with the placebo group. The median overall survival was 9.6 months in the placebo group versus only 9.2 months in the combination therapy group. In addition to the combination therapy results, Opdivo monotherapy also failed to extend overall survival compared with placebo.

At the time, the approval of Opdivo indeed expanded treatment options for patients with small cell lung cancer (SCLC) in the United States. According to data from the American Cancer Society, approximately 84% of lung cancer cases in the U.S. are non-small cell lung cancer (NSCLC), while the remainder are SCLC. The vast majority of SCLC patients are diagnosed at the extensive-stage. Because SCLC tumors have often metastasized widely by the time of diagnosis, the disease is frequently incurable. Following a series of consecutive clinical trial failures involving Opdivo, industry insiders have grown skeptical about maintaining its approved indication for SCLC, raising broader concerns about the drug’s future prospects.

The purpose of the FDA’s accelerated approval pathway is to bring innovative drugs for serious conditions to market more quickly. Drugs approved under this pathway must demonstrate sufficient therapeutic benefit in subsequent confirmatory trials. However, the FDA rarely withdraws drug approvals following failed confirmatory trials. For example, Roche’s Tecentriq retained its bladder cancer indication approval despite the failure of the IMvigor211 trial.

However, in certain circumstances, pharmaceutical manufacturers may deem it pointless to further promote a failed drug, even if the FDA takes no action. In 2019, Eli Lilly and Company announced the withdrawal of Lartruvo, a treatment for advanced soft tissue sarcoma, from the market following the failure of its Phase 3 clinical trial.

In terms of competitors, Merck’s Keytruda received accelerated approval for small cell lung cancer (SCLC) in June 2019, based on positive data from the KEYNOTE-158 and KEYNOTE-028 trials. However, this January, the drug’s Phase III clinical trial, KEYNOTE-604, also encountered a setback. The trial results showed that while Keytruda combined with chemotherapy (etoposide plus platinum agents) improved progression-free survival (PFS) in patients with extensive-stage small cell lung cancer (ES-SCLC), it did not achieve a statistically significant improvement in overall survival (OS).

In contrast, Roche’s Tecentriq, used in combination with chemotherapy, has also been approved for first-line treatment of small cell lung cancer, with the combination therapy reducing the risk of death by 30%. AstraZeneca’s Imfinzi was also approved in March last year, with the combination therapy improving patient survival by reducing the risk of death by 27%.

Reference Sources:

1.Opdivo's in small cell lung cancer no more as Bristol Myers pulls out after trial failure

2.Bristol-Myers Squibb Pulls Small Cell Lung Cancer Indication for Opdivo