EFS Not Met With Pembrolizumab/Chemoradiation for Locally Advanced HNSCC

Pembrolizumab plus chemoradiation did not meet statistically significant improvement in event-free survival for patients with locally advanced head and neck squamous cell carcinoma.

At the 2022 European Society for Medical Oncology Congress (ESMO), results from the phase 3 KEYNOTE-412 study (NCT03040999) of pembrolizumab (Keytruda) plus chemoradiation vs chemoradiation alone for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) did not meet the statistically significant improvement in event-free survival (EFS).

The results showed that the median EFS was not reached (NR; 95% CI, 44.7-NR) with pembrolizumab plus chemoradiation vs 46.6 months (95% CI, 27.5-NR) with chemoradiation alone, failing to meet the superiority threshold of a 1-sided alpha of 0.0242 (HR, 0.83; 95% CI, 0.68-1.03; P = .0429). The 24-month EFS rate was 63.2% with pembrolizumab/chemoradiation vs 56.2% with chemoradiation alone; the 36-month EFS rates were 57.4% and 52.1%, respectively.

“Pembrolizumab plus chemoradiation was associated with a favorable trend toward improved EFS vs placebo plus chemoradiation in patients with locally advanced HNSCC, and PD-L1 expression may be an informative predictive biomarker” lead study author Jean-Pascal Machiels, MD, PhD, head of the Department of Medical Oncology at the Cliniques Universitaires Sain-Luc in Brussels, Belgium, said.

HNSCC originates from the mucosa of the oral cavity, hypopharynx, larynx, and oropharynx. Owing primarily to alcohol and tobacco exposure or human papilloma virus, the disease represents the seventh most common cancer, with an annual global incidence of 600,000 cases.

The standard of care for locally advanced unresected HNSCC, concurrent chemoradiation with high-dose cisplatin, is associated with less than a 50% disease-free survival rate and a 5-year overall survival (OS) rate of approximately 50%.

Pembrolizumab monotherapy in patients with a PD-L1 combined positive score (CPS) of at least 1 or in combination with chemotherapy improves survival as first-line therapy in recurrent or metastatic HNSCC, serving in part as the rationale for the study.

The study enrolled patients with newly diagnosed, treatment-naïve, unresected locally advanced HNSCC eligible for definitive high-dose cisplatin-based chemoradiation.

A total of 804 patients were randomly assigned 1:1 to 200 mg of intravenous (IV) pembrolizumab every 3 weeks plus chemoradiation followed by 14 cycles of maintenance pembrolizumab or IV placebo every 3 weeks plus chemoradiation followed by 14 cycles of maintenance placebo.

Treatment was continued until progressive disease or intolerable toxicity; 17 cycles of pembrolizumab or placebo had been administered; or the investigator or patient decided to withdraw.

The primary end point was EFS, with secondary end points including OS and safety/tolerability.

The median OS was NR in either arm (HR, 0.90; 95% CI, 0.71-1.15). The 24-month OS rates in the pembrolizumab/chemoradiation and chemoradiation alone arms, respectively, were 77.9% and 76.8%; the 36-month OS rates were 71.9% and 70.1%.

In a post-hoc analysis of EFS and OS in patients with a PD-L1 CPS of at least 20, the addition of pembrolizumab to chemoradiation appeared to result in greater benefit compared with chemoradiation alone. Here, the median EFS was NR in either arm but demonstrated a 24-month EFS rate of 71.2% with pembrolizumab/chemoradiation vs 62.6% with chemoradiation alone; the 36-month EFS rates were 66.7% and 57.2%, respectively (HR, 0.73; 95% CI, 0.49-1.06). The median OS was also NR in either arm, but indicated a 24-month OS rate of 83.3% with pembrolizumab/chemoradiation vs 79.9% with chemoradiation alone; the 36-month OS rates were 79.1% and 73.0%, respectively (HR, 0.67; 95% CI, 0.43-1.04).

Machiels stated that no new safety signals were reported with the combination of pembrolizumab and chemoradiation.

“In this study, pembrolizumab given as a lead-in dose, concomitantly with chemoradiotherapy and then adjuvantly for 1 year failed to deliver a statistically significant improvement in EFS as a primary end point when compared with placebo,” Kevin Harrington, PhD, head of the Division of Radiotherapy and team leader at The Institute for Cancer Research in London, said.

“Even though there was a trend in favor of the pembrolizumab arm in the intention-to-treat and PD-L1–positive populations, the current study cannot be interpreted as an indication for use of anti–PD-1 therapy in combination with chemoradiotherapy in any patient group. Indeed, in light of the recent presentations of negative findings from the JAVELIN Head and Neck 100 [NCT02952586], REACH [NCT02999087], and PembroRad [NCT02707588] studies, these data should signal the need for a change in thinking in how to design optimal combination regimens. Focus is now likely to shift to neoadjuvant and true adjuvant therapy approaches,” Harrington concluded.


Machiels JP, Tao Y, Burtness B, et al. Primary results of the phase 3 KEYNOTE-412 study: pembrolizumab plus chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced head and neck squamous cell carcinoma. Presented at: ESMO Congress 2022; September 9-13, 2022; Paris, France. Abstract LBA5.