KEYNOTE-412 Fails to Show EFS Advantage in Unresected Locally Advanced HNSCC


Patients with unresected locally advanced head and neck squamous cell carcinoma did not show a significant improvement in event-free survival when treated with pembrolizumab and concurrent chemoradiation followed by pembrolizumab maintenance in the phase 3 KEYNOTE-412 study.

Treatment with pembrolizumab (Keytruda) combined with concurrent chemoradiation (CRT) followed by pembrolizumab maintenance therapy in patients with unresected locally advanced head and neck squamous cell carcinoma (HNSCC) did not demonstrate a statistically significant improvement in event-free survival (EFS), missing the primary end point of the phase 3 KEYNOTE-412 (NCT03040999).1

Findings from the final analysis of the KEYNOTE-412 were announced in a press release by Merck. The report stated that the safety profile of pembrolizumab in the study was consistent with previous findings in the HNSCC patient population. Full results from the study will be presented during an upcoming medical meeting.

KEYNOTE-412 is a randomized, double-blind study that investigated the efficacy and safety of pembrolizumab with CRT followed by maintenance pembrolizumab in approximately 780 patients with locally advanced HNSCC. In addition to EFS, the study sought to assess overall survival as a secondary efficacy end point, as well as safety determined by the number of patients with adverse events (AEs), treatment discontinuations due to AEs, change from baseline in health status and quality-of-life, change from baseline in swallowing, speech, and pain symptoms, and change from baseline in physical functioning.2

Patients eligible for inclusion in the study were those with pathologically proven disease, an ECOG performance score of 0 or 1, evaluable tumor burden, and who have tissue available for PD-L1 biomarker analysis. All female patients were required to produce a negative pregnancy test within 72 hours prior to receiving the first dose of pembrolizumab in the study. Both male and female patients were also required to use contraception throughout the course of the study.

Patients who received another investigational agent within 4 weeks of dose 1 of pembrolizumab were ineligible to enroll in KEYNOTE-412 as were patients who were previously treated with a PD-1/PD-L1 inhibitor, live vaccine within 30 days of the first study dose prior systemic, target, or radiation therapy for HNSCC, transplant, or prior radical surgery. were also excluded. Patients who had not recovered from major surgery were also ineligible toexcluded from enrollment.

Conditions that prevented patients for being eligible for the study included Hepatitis B or C, HIV, diagnosis of immunodeficiency, history, or current pneumonitis, active autoimmune disease that required treatment within the past 2 years, history of another malignancy, active central nervous system metastases and/or carcinomatous meningitis, and infection requiring systemic therapy. Hypersensitivity to pembrolizumab, cisplatin, or radiotherapy was an exclusion criterion.

“There have been limited advances for patients with locally advanced HNSCC, and unfortunately, these results suggest that this disease remains very challenging to treat,” said Eliav Barr, MD, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories, in a press release.1 “We are proud of the significant role Keytruda plays in the treatment of certain later stages of HNSCC, and we are committed to investigating Keytruda-based regimens for this debilitating type of cancer in earlier stages of disease. We are grateful to the patients and investigators for their participation in this study.”

Pembrolizumab is FDA approved for the treatment formetastatic or with unresectable, recurrent HNSCC as a single-agent and in combination with other drugs. Pembrolizumab is also approved for HNSCC in Europe, China, Japan, and other countries. Other ongoing studies of pembrolizumab will continue despite the KEYNOTE-412 result.

One study, KEYNOTE-689 (NCT03765918) is exploring pembrolizumab administered prior to surgery and in combination with radiotherapy administered after surgery in patients with advanced HNSCC.

Merck provides update on phase 3 KEYNOTE-412 trial in unresected locally advanced head and neck squamous cell carcinoma. News release. Merck. July 20, 2022. Accessed July 20, 2022.
Study of pembrolizumab (MK-3475) or placebo with chemoradiation in participants with locally advanced head and neck squamous cell carcinoma (MK-3475-412/KEYNOTE-412). Updated July 1, 2022. Accessed July 20, 2022.
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