Pembrolizumab plus chemoradiotherapy (CRT) may be no more effective than CRT alone in locally advanced head and neck squamous cell carcinoma (HNSCC), according to phase 3 results presented at ESMO Congress 2022.

These results, from the KEYNOTE-412 trial, showed that adding pembrolizumab to CRT did not improve event-free survival (EFS) or overall survival (OS). 

“Pembrolizumab plus chemoradiation was associated with a favorable trend toward improved event-free survival vs placebo plus chemoradiation…. This difference did not reach statistical significance,” said study presenter Jean-Pascal Machiels, MD, PhD, of Cliniques Universitaires Saint-Luc in Brussels, Belgium. 


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The KEYNOTE-412 trial (ClinicalTrials.gov Identifier: NCT03040999) included 804 patients with treatment-naïve, locally advanced HNSCC. They were randomly assigned to receive pembrolizumab plus CRT followed by pembrolizumab maintenance (n=402) or placebo plus CRT followed by placebo (n=402). 

The median age at baseline was 59 years in both arms (overall range, 27-81). Roughly 82% of patients in each arm were men, and about 77% were White. About 85% of patients had a PD-L1 combined positive score (CPS) of 1 or higher, and roughly 26% were HPV positive. 

Overall, 86.2% of patients in the pembrolizumab arm and 88.2% of those in the placebo arm completed the initial treatment and continued with maintenance. Maintenance was completed by 60.3% of patients in the pembrolizumab arm and 63.2% in the placebo arm. 

At a median follow-up of 47.7 months, there was no significant difference in EFS between the treatment arms. The median EFS was not reached in the pembrolizumab arm and was 46.6 months in the placebo arm (hazard ratio [HR], 0.83; 95% CI, 0.68-1.03; P =.0429). 

The 24-month EFS rate was 63.2% in the pembrolizumab arm and 56.2% in the placebo arm. The 36-month EFS rate was 57.4% and 52.1%, respectively.

Similarly, there was no significant difference in OS between the arms. The median OS was not reached in either arm (HR, 0.90; 95% CI, 0.71-1.15). The 24-month OS rate was 77.9% in the pembrolizumab arm and 76.8% in the placebo arm. The 36-month OS rate was 71.9% and 70.1%, respectively.

Dr Machiels noted, however, that PD-L1 expression may be a predictive biomarker.

Among patients with a PD-L1 CPS of 1 or higher, the 36-month EFS rate was 58.0% in the pembrolizumab arm and 51.8% in the placebo arm (HR, 0.80; 95% CI, 0.64-1.00). The 36-month OS rate was 71.4% and 70.2%, respectively (HR, 0.88; 95% CI, 0.68-1.14).

Among patients with a CPS of 20 or higher, the 36-month EFS rate was 66.7% in the pembrolizumab arm and 57.2% in the placebo arm (HR, 0.73; 95% CI, 0.49-1.06). The 36-month OS rate was 79.1% and 73.0%, respectively (HR, 0.67; 95% CI, 0.43-1.04).

Grade 3-5 adverse events (AEs) were frequent in both arms. The rate of grade 3-5 AEs was 92.2% in the pembrolizumab arm and 88.4% in the placebo arm. The most common grade 3-5 AEs were neutropenia, stomatitis, leukopenia, anemia, and dysphagia.

Grade 3-5 immune-mediated AEs occurred in 8.3% of patients in the pembrolizumab arm and 2.3% of those in the placebo arm. The most common grade 3-5 immune-mediated AEs were severe skin reactions, hepatitis, pneumonitis, and colitis.

There were 4 treatment-related deaths in the pembrolizumab arm and 6 in the placebo arm. 

Disclosures: This study was supported by Merck Sharp & Dohme LLC. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

Machiels J-P, Tao Y, Burtness B, et al. Primary results of the phase III KEYNOTE-412 study: Pembrolizumab (pembro) with chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced (LA) head and neck squamous cell carcinoma (HNSCC). Presented at ESMO 2022; September 9-13, 2022. Abstract LBA5.