Pembrolizumab, CRT Combo Misses EFS End Point in Unresected Locally Advanced HNSCC


The phase 3 KEYNOTE-412 trial assessing pembrolizumab and consolidation chemoradiotherapy plus maintenance pembrolizumab in unresected locally advanced head and neck squamous cell carcinoma missed its primary end point of event-free survival improvement vs matched placebo.

Despite a numerical improvement in event-free survival (EFS) following treatment with pembrolizumab (Keytruda), consolidation chemoradiotherapy (CRT), and maintenance pembrolizumab in patients with unresected locally advanced head and neck squamous cell carcinoma (HNSCC), investigators reported that the benefit was not statistically significant vs placebo plus CRT per the pre-specified statistical plan, according to a press release from Merck.1

The findings came from the phase 3 KEYNOTE-412 trial (NCT03040999) comparing the pembrolizumab regimen vs placebo and CRT. The EFS findings from the final analysis did not meet the trial’s primary end point. Safety findings were consistent with previous findings in patients with HNSCC. Findings from the analysis are set to be presented at an upcoming medical meeting.

“There have been limited advances for patients with locally advanced HNSCC, and unfortunately, these results suggest that this disease remains very challenging to treat,” Eliav Barr, MD, senior vice president, head of global clinical development, and chief medical officer at Merck Research Laboratories, said in the press release. “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.”

The trial included approximately 780 patients with oropharyngeal or larynx, hypopharynx, and oral cavity squamous cell carcinoma. Patients were randomly assigned to receive either the experimental regimen consisting of 200 mg of pembrolizumab every 3 weeks plus cisplatin and radiation therapy followed by pembrolizumab maintenance for 1 year or placebo plus CRT and placebo maintenance. Secondary end points included overall survival and safety.

To enroll on the trial, patients needed to have pathologically confirmed, newly diagnosed p16-positive or -negative oropharyngeal or larynx, hypopharynx, or oral cavity squamous cell carcinoma. Disease needed to be unresectable. Moreover, those with multiple synchronous tumors were not eligible for enrollment. Patients also needed to be able to provide tissue via a core or excisional biopsy for PD-L1 biomarker analysis.

A combination of PDS0101 and pembrolizumab received fast track designation from the FDA in June 2022 for the treatment of recurrent or metastatic human papillomavirus 16–positive head and neck cancer.2 Additionally, single-agent pembrolizumab was approved by the FDA as a first-line treatment for metastatic or unresectable recurrent HNSCC in June 2019.3


  1. 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.
  2. PDS Biotechnology granted FDA fast track designation for lead candidate PDS0101. News Release. PDS Biotechnology. June 2, 2022. Accessed July 20, 2022.
  3. FDA approves pembrolizumab for first-line treatment of head and neck squamous cell carcinoma. News release. FDA. June 10, 2019, Accessed July 20, 2022.
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