Pembrolizumab plus chemoradiation failed to demonstrate a statistically significant improvement in event-free survival vs chemoradiation alone in patients with locally advanced head and neck squamous cell carcinoma, but favorable numerical trends were demonstrated, according to results of the phase III KEYNOTE-412 trial, presented at the European Society for Medical Oncology (ESMO) Congress 2022.¹

“Pembrolizumab plus chemoradiation was associated with a favorable trend toward improved event-free survival vs placebo plus chemoradiation in patients with locally advanced head and neck squamous cell carcinoma, and PD-L1 expression may be an informative predictive biomarker,” said Jean-Pascal Machiels, MD, PhD, Head of the Department of Adult and Pediatric Oncology and Hematology at the Cliniques universitaires Saint-Luc (UCLouvain) in Brussels, who presented the findings at a Presidential Symposium.

Jean-Pascal Machiels, MD, PhD

After a median of almost 4 years of follow-up, median event-free survival was not reached with pembrolizumab plus chemoradiation and was 46.6 months with chemoradiation alone (hazard ratio [HR] = 0.83; P = .0429). This difference failed to meet the superiority threshold (efficacy boundary was P = .0242), Dr. Machiels reported.

Background

The standard of care for locally advanced unresected squamous cell carcinoma of the head and neck is concurrent chemoradiation with high-dose cisplatin. Treatment with this regimen is associated with less than a 50% disease-free survival and a 5-year overall survival rate of approximately 50%. Pembrolizumab has been approved as a single agent or in combination with chemotherapy for recurrent or metastatic disease. KEYNOTE-412 studied this approach in locally advanced head and neck cancer.

The rationale for KEYNOTE-412 is based on the activity, in the front-line relapsed/metastatic setting, of pembrolizumab alone in patients with a PD-L1 combined positive score (CPS) ≥ 1 or in combination with chemotherapy.² Additionally, radiotherapy and cisplatin has been shown to increase PD-L1 expression in preclinical models, and the concurrent inhibition of the PD-1/PD-L1 pathway may boost the antitumor activity of radiotherapy.

About KEYNOTE-412

The study enrolled 804 patients with newly diagnosed, treatment-naive, unresected locally advanced head and neck squamous cell carcinoma who were eligible for definitive high-dose cisplatin-based chemoradiation. Patients with tumors of the larynx, hypopharynx, p16-negative oropharynx, or oral cavity had T3–T4 (N0–N3) or T1–T4 (any N2a–3) disease; those with p16-positive oropharyngeal cancer had T4 or N3.

Of note, the vast majority of patients had a history of smoking and alcohol consumption. At baseline, 26% of patients were p16-positive, 85% had a PD-L1 CPS ≥ 1 ,and 36% had a CPS ≥ 20, and only about 32% of patients had N0–N1 disease.

Patients were randomly assigned to pembrolizumab at 200 mg every 3 weeks plus chemoradiation followed by 14 cycles of pembrolizumab maintenance or chemoradiation alone (and intravenous placebo) followed by placebo as maintenance. The primary endpoint was event-free survival; the efficacy boundary was P = .0242.

The concurrent chemoradiation phase was completed by 86% of both the arms and the maintenance phase by 60% of the pembrolizumab/chemoradiation arm and 63% of the chemoradiation arm. The median overall duration on pembrolizumab or placebo was 11 months in both arms. Almost 93% of both arms received the planned dosed of radiation (70 Gy), and 46% of the pembrolizumab arm and 52% of the placebo arm received cisplatin at a total dose ≥ 300 mg/m². Slightly more patients needed dose reductions or discontinuations of cisplatin in the pembrolizumab arm.

Numerical Trend, but Not Significant

At a median follow-up of 47.7 months, the 24-month event-free survival rate was 63.2% with pembrolizumab/chemoradiation vs 56.2% with chemoradiation alone; the 36-month rates were 57.4% and 52.1%, respectively. Trends favoring pembrolizumab/chemoradiation were observed in all prespecified subgroups except for patients with a PD-L1 CPS < 1.

Disease progression occurred in the form of locoregional disease progression in 13% of the pembrolizumab arm and 14% of the placebo arm and was distant disease in 13% and 17%, respectively.

Median overall survival was not reached in either arm (HR = 0.90; 95% confidence interval [CI] = 0.71–1.15). The overall survival rates in the pembrolizumab/chemoradiation and chemoradiation alone arms, respectively, were 77.9% and 76.8% at 24 months and 71.9% and 70.1% at 36 months.

Benefit in PD-L1–Positive Patients

The addition of pembrolizumab to chemoradiation appeared to result in a greater event-free survival benefit compared with chemoradiation alone in PD-L1–positive patients, according to a post hoc analysis. “PD-L1 expression measured by CPS may be an informative predictive biomarker,” he said.

In the PD-L1 ≥ 20 subgroup, median event-free survival was not reached in either arm; at 36 months, 66.7% of patients in the pembrolizumab arm were event-free vs 57.2% in the control arm (HR = 0.73; 95% CI = 0.49–1.06). Median overall survival was also not reached, and at 36 months, 79.1% of patients in the pembrolizumab arm were alive compared with 73.0% of the control arm (HR = 0.67; 95% CI = 0.43–1.04).

For the PD-L1 ≥ 1 subgroup, at 36 months, the event-free survival rate was 58% in the pembrolizumab arm vs 51.8% in the control arm; overall survival was 71.4% vs 70.2%, respectively.

In a media briefing, Dr. Machiels was asked how he could justify the addition of pembrolizumab without selecting the patients based on PD-L1 expression, given there was no difference between the treatment groups for the primary endpoint. He said that when the investigators designed the trial 7 years ago, the CPS score for PD-L1 expression had not yet been developed and validated; otherwise, the researchers might have designed KEYNOTE-412 to explore the pembrolizumab/chemoradiation regimen according to CPS subgroups. He also pointed to the numerically superior 2-year event-free survival and overall rates.

“Locally advanced head and neck squamous cell carcinoma remains a challenging disease to treat,” Dr. Machiels said.

Safety Profile

The addition of pembrolizumab to chemoradiation did not appreciably increase adverse events. Grade 3 to 5 adverse events were reported in 92% of the pembrolizumab arm and 88% of the placebo arm, with four and six deaths, respectively, attributed to treatment. Immune-mediated adverse events of any grade occurred in 43% and 28%, respectively, and were grade 3 to 5 in 8% and 2%, respectively; one death occurred in a patient receiving pembrolizumab/chemoradiation, Dr. Machiels reported. 

DISCLOSURE: Dr. Machiels disclosed financial relationships with Pfizer, Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boehringer Ingelheim, Novartis, Janssen, Incyte, Cue Biopharma, ALX Oncology, iTEOS, eTheRNA, Nektar, F-Star, MSD, Bristol Myers Squibb, Amgen, and Gilead Sciences.

REFERENCES

1. 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. ESMO Congress 2022. Abstract LBA5. Presented September 11, 2022.

2. Burtness B, Harrington KJ, Greil R, et al: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study. Lancet 394:1915-1928, 2019.