Merck & Co.’s Keytruda has become the first immunotherapy approved by the FDA to be used around surgery to treat resectable locally advanced head and neck cancer.
But the breakthrough approval comes with a limitation. For the perioperative head and neck squamous cell carcinoma (HNSCC) indication where Keytruda is used both before and after surgery, the PD-1 inhibitor is only allowed in patients whose tumors express PD-L1 at a combined positive score of at least 1.
It remains unclear whether Merck sought the restriction, or if the FDA installed the requirement upon examination of clinical data. Merck declined to comment on its regulatory strategy.
The approval is built on data from the phase 3 Keynote-689 trial. Keytruda, used before surgery and then continued after surgery in combination with standard-of-care radiotherapy with or without chemo, reduced the risk of disease recurrence, progression or death by 30% versus standard postsurgical treatment alone in PD-L1-positive patients.
Patients who received Keytruda went a median of 59.7 months without disease recurrence or worsening, whereas the median event-free survival was 29.6 months for the control arm.
“The introduction of Keytruda as a perioperative treatment option for certain patients with resectable locally advanced head and neck squamous cell carcinoma represents a potentially significant shift in how we manage this disease,” the Keynote-689 trial’s principal investigator, Ravindra Uppaluri M.D., Ph.D., from Brigham and Women’s Hospital and the Dana-Farber Cancer Institute, said in a statement Friday.
The trial also enrolled a small group of PD-L1-negative patients. When those individuals were counted, Keytruda’s event-free survival improvement dropped to 27% in the overall trial population, even though the showing was still statistically significant.
Because PD-L1-negative disease only make up about 5% of cases in this HNSCC setting, Keytruda should be for all participants, Uppaluri argued during the American Association for Cancer Research annual meeting in April.
In a separate interview at the time, Marjorie Green, M.D., Merck’s head of oncology global clinical development, noted that Keytruda’s other perioperative indications in early-stage cancers are broad without PD-L1 restrictions.
Before the latest perioperative nod, Keytruda has been approved in combination with chemotherapy for the first-line treatment of all patients—regardless of PD-L1 status—with metastatic or with unresectable, recurrent HNSCC. The drug is also allowed as a single agent for first-line HNSCC but only in PD-L1-positive tumors.
The FDA reviewed the new approval under Project Orbis, a framework for concurrent review of oncology drugs among multiple global regulatory agencies. Under the program, applications for perioperative Keytruda in HNSCC are also being reviewed in Israel, Canada, Australia, Singapore, Brazil and Switzerland. Authorities in Europe and Japan are separately weighing their decisions.
Editor's Note: The story was updated to clarify that Merck declined to comment on whether it proactively sought the PD-L1-positive label from the FDA.