Merck Voluntarily Withdraws KEYTRUDA (pembrolizumab) Indication for Metastatic Small Cell Lung Cancer in the U.S.

Compiled by Keke

On March 1, MSD announced that it would voluntarily withdraw the indication for Keytruda (pembrolizumab) in the United States for the treatment of patients with metastatic small cell lung cancer (SCLC) whose disease has progressed during or after platinum-based chemotherapy and at least one other prior line of chemotherapy. According to reports, the withdrawal of this indication was completed following consultations with the U.S. Food and Drug Administration (FDA), and MSD is working to finalize this change within the next few weeks. MSD stated that this decision does not affect the use of Keytruda, an anti-PD-1 therapy, for its other indications.

Based on the tumor response rate and durability of response data from KEYNOTE-158 (Cohort G) and KEYNOTE-028 (Cohort C1), Keytruda received accelerated approval from the U.S. FDA in June 2019. However, continued approval for this indication is contingent upon fulfilling post-marketing requirements mandated by regulatory authorities—namely, demonstrating the benefit of Keytruda in terms of overall survival (OS). In January 2020, Merck Sharp & Dohme announced the results of the Phase 3 confirmatory trial KEYNOTE-604 for the small cell lung cancer (SCLC) indication. The trial met one of the two primary endpoints, progression-free survival, but did not achieve statistical significance for the other primary endpoint, OS.

Even after it became evident that MSD had failed to meet the required standards, the U.S. FDA took more than a year to finally determine that Keytruda should not remain a treatment option for metastatic small cell lung cancer (SCLC). MSD consulted with the U.S. FDA regarding this voluntary withdrawal, which was part of an industry-wide evaluation of accelerated approval indications that had not fulfilled post-marketing requirements. The “industry-wide evaluation” cited by MSD may serve as a warning that the U.S. FDA will not overlook pharmaceutical companies that fail to deliver on their commitments.

Meanwhile, MSD is notifying healthcare professionals that patients with metastatic SCLC receiving Keytruda should discuss their care with their healthcare providers.

In recent months, Merck & Co. (MSD) has not been the only company to face setbacks with the U.S. FDA. In late December last year, Bristol Myers Squibb (BMS) sought final approval to advance the checkpoint inhibitor Opdivo for third-line or later treatment of small cell lung cancer (SCLC). However, confirmatory trials revealed that Opdivo similarly failed to demonstrate a survival benefit in patients.

Based on the results of the CheckMate-451 and CheckMate-331 trials, which showed that Opdivo, both as a monotherapy and in combination with Yervoy, failed to meet the primary overall survival (OS) endpoint, Bristol Myers Squibb (BMS) decided to withdraw its approval application in accordance with the U.S. FDA’s recommendation to “follow post-marketing scientific research evidence.”

Furthermore, in February, AstraZeneca chose to withdraw the indication for the PD-(L)1 inhibitor Imfinzi in the treatment of bladder cancer. The U.S. FDA had initially granted accelerated approval for this indication in May 2017. The pharmaceutical company stated that this decision was made following “consultations” with the U.S. FDA, citing similar reasons related to an “industry-wide evaluation.”

So, when confirmatory trials have already been widely accepted by regulatory agencies as surrogate endpoints, what lessons do the experiences of MSD and BMS offer to the industry? The foreign media outlet Endpoint News pointed out that indication withdrawals may depend on the therapeutic area: in oncology, the boundary between survival and death is clear. However, in other diseases, the data are not so straightforward.

Private investor Brad Loncar stated in an interview, “It is clear that the U.S. FDA has proposed an initiative requiring these tumor indications to meet operational standards. This approach helps maintain the integrity of the accelerated approval concept, which is a positive development. However, such scenarios may be less common for indications involving rare diseases.”

For example, Sarepta’s exon-skipping therapy Vyondys 53 for the treatment of Duchenne muscular dystrophy received accelerated approval in December 2019. Where a therapy demonstrates an effect on motor function, it may be considerably more difficult for the U.S. FDA to withdraw the treatment from a rare-disease patient population. The same applies to multiple sclerosis drugs. However, if the U.S. FDA takes a firm stance on enforcing post-marketing requirements for approved drugs, it could ultimately lead to a major reckoning.

References:

1.Merck Provides Update on KEYTRUDA® (pembrolizumab) Indication in Metastatic Small Cell Lung Cancer in the US

2.Merck & Co. pulls small-cell lung cancer indication for Keytruda in US

3.UPDATED: Merck pulls Keytruda in SCLC after accelerated nod. Is the FDA getting tough on drugmakers that don't hit their marks?