Avelumab Plus Chemotherapy Fails in HNSCC Phase 3 Trial, Raises Future Research Questions

Despite the success of immune checkpoint blockade in the treatment of recurrent or metastatic head and neck squamous cell carcinoma, the use of the PD-L1 inhibitor avelumab failed to prolong progression-free survival for patients with locally advanced disease.

A phase 3 trial examining the immune checkpoint inhibitor avelumab (Bavencio) plus chemoradiation as therapy for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) failed to meet the primary end point of progression-free survival (PFS) improvement versus placebo/chemoradiation, despite earlier research pointing to efficacy in this patient population.1

These results are notable given the success of immunotherapeutic agents in patients with recurrent or metastatic HNSCC in phase 3 studies, which have led to approvals of PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) in this setting.

“The results of our trial showed no improvement with the addition of avelumab to current standard-of-care chemoradiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck,” wrote the study investigators who were led by Nancy Y. Lee, MD. “These findings will help inform ongoing and future trials investigating the combination of immunotherapy and chemoradiotherapy, particularly with radiation, and highlight the need for more research including potential biomarkers that may predict response with this treatment approach.”

The investigators did report a potential trend toward PFS benefit in patients with high PD-L1 expression in 25% of tumor cells or more (HR, 0.59; 95% CI, 0.28-1.22), although the trial was not powered to analyze this end point in patient subgroups.

The rationale for investigating the combination of immune checkpoint blockade and chemoradiotherapy were derived from data from several trials, including a phase 1b trial (NCT02586207) of patients with locally advanced HNSCC who received concurrent chemotherapy and radiation plus avelumab that showed the regimen was safe and that immune inhibition did not hinder the receipt of other modalities.2

“Given the strong rationale to investigate the addition of immune checkpoint inhibitors to definitive chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck, the observed lack of improvement in progression-free survival with the addition of avelumab to chemoradiotherapy was unexpected,” the study authors wrote.

Given that the hazard ratio for the comparison of the experimental and control arms favored the placebo group (HR, 1.21; 95% CI, 0.93-1.57), the investigators proposed that a potential antagonistic effect between avelumab and chemoradiotherapy may exist. Some reasons for this that were proposed include dysfunction or depletion of T cells or disruptions to the tumor microenvironment following radiation, which affects the ability of the immune system to eradicate microscopic disease.

As this study investigated concurrent chemoradiotherapy with avelumab followed by maintenance avelumab, the authors noted it may be worth exploring chemoradiotherapy treatment alone followed by maintenance avelumab, which is similar to the design of the phase 3 PACIFIC trial (NCT02125461) that led to the approval of durvalumab (Imfinzi) in the maintenance setting for locally advanced non–small cell lung cancer following similar treatment.3

“Given the high unmet medical need for this patient population, future translational and clinical studies must advance knowledge in this area to improve the duration and quality of life of these patients,” the investigators concluded.


1. Lee NY, Ferris RL, Psyrri A, et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 2021;22(4):450-462. doi: 10.1016/S1470-2045(20)30737-3

2. Powell SF, Gold KA, Gitau MM, et al. Safety and efficacy of pembrolizumab with chemoradiotherapy in locally advanced head and neck squamous cell carcinoma: A Phase IB Study. J Clin Oncol. 2020;38(21):2427-2437. doi: 10.1200/JCO.19.03156

3. FDA approves durvalumab after chemoradiation for unresectable stage III NSCLC. FDA. February 16, 2018. Accessed April 2, 2021. https://bit.ly/3cGuyDv