Merck & Co. hopes a new positive trial readout can return Keytruda to glory in head and neck cancer.
After a pivotal trial failure two years ago in unresected locally advanced head and neck squamous cell carcinoma (HNSCC), Merck said Tuesday that a phase 3 study of Keytruda in resected HNSCC has met its main goal. When added to standard of care both before and after surgery, Keytruda significantly reduced the risk of disease recurrence, worsening or death compared with traditional postsurgical radiotherapy alone in resected stage 3 or 4a HNSCC, the company said.
The “statistically significant and clinically meaningful” improvement in event-free survival (EFS) was derived from the first pre-planned interim analysis of the KEYNOTE-689 trial, according to Merck. The study regimen uses Keytruda before surgery as a neoadjuvant therapy, then continued in combination with adjuvant radiotherapy—with or without chemotherapy—after surgery, followed by Keytruda alone as maintenance therapy.
KEYNOTE-689 marks the first positive pivotal trial in two decades for resected, locally advanced HNSCC, and the findings have the potential to be practice-changing, Marjorie Green, head of oncology global clinical development at Merck Research Laboratories, said in a Tuesday statement.
The New Jersey pharma said it will submit the results to regulatory authorities and share the data at a medical meeting.
The resected HNSCC win comes about two years after another Keytruda phase 3 trial, KEYNOTE-412, flunked the primary EFS marker in unresected HNSCC. The PD-1 inhibitor, when used alongside chemoradiation, showed a numerical trend toward improvement compared with concurrent chemoradiation alone but failed to cross the statistical significance bar.
The 2022 flop was a disappointment considering Keytruda has been approved in first-line metastatic or recurrent HNSCC both as a monotherapy in PD-L1-positive tumors and in combination with chemotherapy in an all-comer indication. The approvals were based on evidence that Keytruda may extend patients’ lives versus chemo alone.
Overall survival data from the new KEYNOTE-689 trial are still subject to longer follow-ups. At the current analysis, overall survival didn’t reach statistical significance in patients whose tumors had PD-L1 expression at combined positive score of at least 10. As a result, because of the trial design, survival in the overall trial population was not formally tested. Despite a trend in favor of Keytruda, the study is progressing to its next interim analysis, according to Merck.
Merck changed the design of KEYNOTE-689 about a year ago. The study used to have EFS and major pathological response (mPR)—defined as no more than 10% of invasive squamous cell carcinoma within the resected tumor samples—as dual primary endpoints. But the plan was amended to make EFS the sole primary endpoint and mPR a secondary endpoint.
Keytruda also mounted a statistically significant improvement in mPR, Merck said Tuesday.
The continuous neoadjuvant-and-adjuvant regimen could raise some eyebrows. During a meeting in July, experts on the FDA’s Oncologic Drugs Advisory Committee meeting unanimously agreed that the FDA should demand that new trials for perioperative regimens in resectable non-small cell lung cancer (NSCLC) be designed to assess the contribution of each treatment phase.
The difference, however, is that in NSCLC, PD-1 inhibitors are available both as adjuvant therapies alone and as continuous perioperative therapies; in head and neck cancer, no PD-1 therapy has been approved in resected cancer.