- Merck & Co. will withdraw Keytruda in small-cell lung cancer, or SCLC, in the U.S. roughly a year after a confirmatory trial showed the immunotherapy, when added to chemotherapy, didn't help patients live longer than chemo alone.
- The Food and Drug Administration granted accelerated approval to Keytruda in SCLC in 2019 based on its ability to keep tumors from spreading in patients whose disease had progressed after at least two treatments. But Keytruda had to extend lives in additional testing to retain that approval.
- The withdrawal doesn't impact any other approved indications for Keytruda, the world's top-selling immunotherapy and the standard of care for a majority of patients with the more common non-small cell form of lung cancer. But it's further evidence of an apparent new push by the FDA to review drugs approved on an accelerated basis but lacking confirmatory data.
Accelerated approval is a tool the FDA uses to clear medicines by gauging their impact on a "surrogate" marker, like a lab test, that's thought to predict a real benefit such as a longer life. Those clearances are meant to be upheld only if a drugmaker confirms that benefit in a more rigorous trial. If not, they can be withdrawn.
This regulatory pathway, first enacted in 1992, can help potentially life-saving medicines for serious diseases get to market much faster than they would otherwise. But critics have charged it can lead to the clearance of ineffective, or worse, harmful drugs — and leave questions about their worth lingering while post-marketing studies progress.
In 2008, for instance, the FDA approved the Roche cancer drug Avastin for metastatic breast cancer on a conditional basis, a decision that divided oncologists and patient advocates partly because of the drug's sometimes severe side effects. The agency later pulled Avastin from the market in breast cancer. Additional testing showed the drug wasn't helping patients live longer and was causing health problems, like hemorrhages.
But the Avastin case isn't the norm, partly because the studies required to test real-world benefits aren't always being completed on time. One 2019 study found that between 1992 and 2008, 36% of post-marketing trials weren't finished, and half of them took at least five years to begin. Results from a confirmatory trial of Exondys 51, a Duchenne muscular dystrophy drug from Sarepta granted accelerated approval in 2016, for example, aren't expected until 2024.
The FDA appears to be signaling a tougher stance, at least when it comes to cancer immunotherapy. Since December, three top immunotherapy developers — Bristol Myers Squibb, AstraZeneca and now Merck — have announced plans to voluntarily withdraw their drugs from use in certain cancer types.
Each case occurred after drugs that shrank tumors in early tests didn't extend patients' lives in later studies. And each announcement referenced an "industry-wide evaluation" underway within the agency. Merck's Monday statement, for instance, said the ongoing probe is "based on accelerated approvals that have not yet met their post-marketing requirements."
The FDA didn't respond to BioPharma Dive's request for comment. But its review could encompass other accelerated approvals. Keytruda, for example, retains conditional clearances in liver and bladder cancers despite failed confirmatory studies.
The withdrawals from Merck and Bristol Myers were both in SCLC, a particularly aggressive form of the disease that accounts for 10% to 15% of all cases. AstraZeneca's Imfinzi and Roche's Tecentriq are both approved for SCLC, and both improved patients' overall survival in clinical testing.
Merck is still testing Keytruda in SCLC.