ASCO: Merck gives final look at Keytruda study in first-line cervical cancer. Will FDA change its mind?

Keytruda’s first-in-class FDA approval as a first-line therapy in metastatic cervical cancer arrived in 2021 with a restriction. Now, researchers say new patient survival data suggest the Merck drug could be used in a broader patient population.

Adding Keytruda to chemotherapy reduced the risk of death by 37% in patients with persistent, recurrent or metastatic cervical cancer who had not previously received systemic chemo. Some patients in both arms also received Roche's Avastin.

The data came from the final overall survival analysis of the phase 3 KEYNOTE-826 trial, presented at the American Society of Clinical Oncology's (ASCO's) 2023 annual meeting. The analysis included all patients regardless of their PD-L1 expression status.

In a press release, ASCO said the study shows that Keytruda could be an effective first-line treatment for cervical cancer regardless of whether a patient's cancer expresses PD-L1.

“Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population,” Merry Jennifer Markham, M.D., from the University of Florida, said in a statement facilitated by ASCO.  

Still, the FDA may have its reservations.

At a prior analysis, the KEYNOTE-826 trial had shown Keytruda’s addition to chemo could cut the risk of death by 33% regardless of PD-L1 expression. But the FDA left out PD-L1-negative patients in the drug's label when it approved Keytruda in 2021 as the first immunotherapy for first-line treatment of cervical cancer.

Merck will share the updated data with the FDA. But Eliav Barr, M.D., chief medical officer of Merck Research Laboratories, said it’s unlikely that the FDA will expand Keytruda’s label to include PD-L1-negative patients, because the agency probably won’t change its interpretation of the previous primary analysis.

In the original readout, conducted after a median follow-up of 22 months, the Keytruda-chemo combo showed no survival benefit over chemo alone in PD-L1-negative patients. Further, the combo demonstrated a marginal 6% improvement in preventing tumor progression in that subgroup.

This time around, at a median follow-up of 39.1 months, Keytruda’s performance in the PD-L1-negative group remained a drag. Excluding the PD-L1-negative patients, Keytruda’s death-risk reduction widened to 40%.

During a press briefing, Bradley Monk, M.D., from the University of Arizona College of Medicine, who presented the KEYNOTE-826 data, said he wouldn’t worry too much about the PD-L1-negative group. Within that group, he noted, patients who had low tumor burden and with low microsatellite instability—who are expected to respond poorly to PD-1/L1 inhibitors—only represented about 5% of the trial.

Instead, he said he’s excited about the potential of antibody-drug conjugates.

Beyond chemo, Seagen and partner Genmab are evaluating the potential of pairing antibody-drug conjugate Tivdak with Keytruda in first-line cervical cancer. Interim data from an early-stage trial that also included other Tivdak combos showed an objective response rate of 41% for the Keytruda regimen, according to results presented at last year’s ASCO. But the exact strategy for late-stage development remains unclear.

In a report back in February, analysts with SVB Securities argued that Tivdak’s black-box warning on ocular toxicity and the requirement for eye exams will limit any market potential it may have in first-line cervical cancer.

Outside of metastatic cervical cancer, Merck is running the KEYNOTE-A18 trial testing Keytruda on top of chemoradiation in patients with locally advanced cervical cancer. That phase 3 study bears a primary completion date in February 2024, according to Previously, AstraZeneca’s PD-L1 inhibitor, Imfinzi, had failed in combination with chemoradiation in the same setting.