Keytruda's Keynote-689 marks the first positive trial in more than two decades in resected locally advanced head and neck squamous cell carcinoma.
Ending a 20-year-plus drought, Merck & Co.’s Keytruda demonstrated that its use around surgery can reduce the risk of certain head and neck cancers from returning.Continuous use of Keytruda—both before and after surgery—reduced the risk of recurrence or death by 27% in patients with stage 3 or 4a, resected, locally advanced head and neck squamous cell carcinoma (HNSCC), according to results from the phase 3 Keynote-689 trial presented at the American Association for Cancer Research Annual Meeting 2025.In the study, Keytruda was added to postoperative radiotherapy with or without chemo. Investigators compared the perioperative Keytruda regimen with the sans-Keytruda standard treatment.Keynote-689 marks the first positive trial in more than two decades in resected locally advanced HNSCC, making Keytruda the first PD-1 inhibitor to mount such a benefit.The study’s findings suggest that the Keyturda regimen represents a new standard of care in this disease setting, Ravindra Uppaluri, M.D., Ph.D., from Brigham and Women’s Hospital and Dana-Farber Cancer Institute, said during a press conference Sunday. Uppaluri is a co-principal investigator of Keynote-689.The 27% event-free survival (EFS) improvement, though statistically significant, isn’t numerically among Keytruda’s best performances in its use around surgery, an approach known as perioperative treatment. In 2023, Keytruda won its perioperative non-small cell lung cancer approval after slashing the risk of disease recurrence, worsening or death by 42% when added to presurgical chemo alone.The 27% number is still clinically meaningful, Marjorie Green, M.D., Merck’s head of oncology global clinical development, said in an interview with Fierce Pharma.At three years, 57.6% of patients in the Keytruda arm remained recurrence free, versus 46.4% in the control arm. That 11.2-percentage-point absolute difference is also clinically meaningful for patients, she added.“There have been uptakes and adoptions of therapies for 2% to 3% absolute difference in outcomes, because we know most of the recurrences that have happened on the study were distant,” which increases the risk of death, she said.Further, Keytruda’s 51.8-month median EFS time was notably longer than the control arm’s 30.4 months. Despite the overall trial win, there remains a question about whether Keytruda is appropriate for patients whose tumors have low to no expression of PD-L1.The magnitude of Keytruda’s EFS benefit deteriorated as patients with lower levels of PD-L1 were included in the analysis. In patients with PD-L1 expression at a combined positive score (CPS) of 10 or above, the EFS risk reduction reached 34%. The number dropped to 30% when those with at least 1 CPS score were included, and then to 27% when PD-L1-negative disease was also counted.Green wouldn’t disclose what level of PD-L1 coverage Merck is seeking in the drug’s FDA label. She did note that Keytruda’s existing perioperative indications in other curative disease settings are broad approvals across the PD-L1 spectrum. In this HNSCC setting, patients with CPS of 10 or greater make up about 65% of the population, and only 5% have CPS below 1. Because of the small number of patients, it would be hard to draw conclusions about the PD-L1-negative group, Uppaluri said during the press conference.“Given that as a whole, I would say yes, this should be for all participants,” Uppaluri said.Another question that Keynote-689 cannot conclusively answer is whether Keytruda is necessary both before and after surgery. That question is even more relevant because Roche’s PD-L1 inhibitor Tecentriq failed in its own study when used as an adjuvant therapy after head and neck cancer surgery.Uppaluri admitted that the contribution of components is clearly a limitation of the study. Before Keynote-689 was launched, some investigator-initiated studies showed the potential of a perioperative regimen. Plus, there’s been a theory that giving a checkpoint inhibitor early before surgery—when the immune system is more robust and the tumors intact—may lead to better outcomes, Green noted.On a key secondary endpoint, Keytruda recorded a 9.4% major pathological response rate—defined as 10% or lower residual invasive cancer cells in resected tissues—versus 0% in the standard-of-care arm.Green acknowledged that 9.4% is a fairly small number. But it could indicate that adjuvant Keytruda provided some contribution to the EFS benefit.Neoadjuvant treatment with Keytruda appeared to have led to fewer uses of chemo in the adjuvant setting because more patients were deemed to have lower risk post-surgery.Green called that element out because removing the need for chemo could mean better tolerability. In Keynote-689, the Keytruda arm recorded numerically fewer chemo-related side effect incidents such as severe skin reactions.Finally, data on whether Keytruda could extend patients’ lives remained immature. Keytruda showed a favorable 28% reduction in the risk of death in the CPS 10 or above population. Because the statistical significance bar was not met, testing of this endpoint in the rest of the study population was not formally performed, and additional follow-up is ongoing. Merck’s application based on Keynote-689 is under FDA priority review with a target decision date of June 23, 2025.
