Avelumab Plus Standard-of-Care Chemoradiotherapy vs Chemoradiotherapy Alone in Locally Advanced HNSCC
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for this patient population.
METHODS
In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomisation with block size four (stratified by human papillomavirus status, tumour stage, and nodal stage, and done by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m2 cisplatin every 3 weeks plus intensity-modulated radiotherapy with standard fractionation of 70 Gy [35 fractions during 7 weeks]; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was progression-free survival by investigator assessment per modified Response Evaluation Criteria in Solid Tumors, version 1.1, in all randomly assigned patients. Adverse events were assessed in patients who received at least one dose of avelumab or placebo. This trial is registered with ClinicalTrials.gov, NCT02952586. Enrolment is no longer ongoing, and the trial has been discontinued.
FINDINGS
Between Dec 12, 2016, and Jan 29, 2019, from 907 patients screened, 697 patients were randomly assigned to the avelumab group (n=350) or the placebo group (n=347). Median follow-up for progression-free survival was 14·6 months (IQR 8·5-19·6) in the avelumab group and 14·8 months (11·6-18·8) in the placebo group. Median progression-free survival was not reached (95% CI 16·9 months-not estimable) in the avelumab group and not reached (23·0 months-not estimable) in the placebo group (stratified hazard ratio 1·21 [95% CI 0·93-1·57] favouring the placebo group; one-sided p=0·92). The most common grade 3 or worse treatment-related adverse events were neutropenia (57 [16%] of 348 patients in the avelumab group vs 52 [15%] of 344 patients in the placebo group), mucosal inflammation (50 [14%] vs 45 [13%]), dysphagia (49 [14%] vs 47 [14%]), and anaemia (41 [12%] vs 44 [13%]). Serious treatment-related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group. Treatment-related deaths occurred in two (1%) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and one (<1%) in the placebo group (due to acute respiratory failure).
INTERPRETATION
The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met. These findings may help inform the design of future trials investigating the combination of immune checkpoint inhibitors plus CRT.
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Additional Info
Disclosure statements are available on the authors' profiles:
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 Apr 01;22(4)450-462, NY Lee, RL Ferris, A Psyrri, RI Haddad, M Tahara, J Bourhis, K Harrington, PM Chang, JC Lin, MA Razaq, MM Teixeira, J Lövey, J Chamois, A Rueda, C Hu, LA Dunn, MV Dvorkin, S De Beukelaer, D Pavlov, H Thurm, E CohenFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Immune checkpoint inhibition has demonstrated activity in head and neck squamous cell carcinoma (HNSCC), and two PD-1 inhibitors have received FDA approval on the basis of evidence for improved survival: pembrolizumab alone or in combination with chemotherapy for first-line recurrent/metastatic disease and pembrolizumab or nivolumab for cisplatin-refractory recurrent/metastatic disease. For both agents, there is evidence that higher PD-L1 expression predicts benefit and that PD-L1 staining on both tumor and immune cells is informative. Given the importance of these agents in the recurrent/metastatic setting, there has been great interest in determining whether immune checkpoint inhibition can improve disease control and survival in the definitive setting. The first large study to address this question has now been completed.
The phase III trial reported by Lee et al in The Lancet Oncology randomized 697 patients with HPV-negative or intermediate-risk HPV-associated HNSCC between conventional chemoradiation (70 Gy plus high-dose cisplatin) and the same regimen together with the PD-L1 inhibitor avelumab. The primary endpoint of the study was progression-free survival (PFS). At a median follow-up of 14.6 months in the experimental arm, the study was found to be negative, with the hazard ratio of 1.21 for PFS favoring the placebo arm. Toxicity, treatment-related death, and treatment discontinuation were highly comparable between the two arms of the study, and the cumulative cisplatin dose at 260 mg/m2 in the avelumab arm and 278 mg/m2 in the placebo arm were similar as well. The difficulties of employing a PFS endpoint in locally advanced head and neck cancer (HNC) are widely appreciated, but the complex definition here—including not only evidence of disease progression but also requirement for primary-site surgical salvage or late salvage neck dissection—appears to have performed well, with few patients in either arm requiring salvage surgery at the primary site and similar numbers requiring neck dissection. Further, the numerically greater hazard for progression is matched by a tendency toward worse survival with the use of avelumab as well (HR, 1.31). Thus, the surprising result of worse outcome with avelumab appears to genuinely indicate that some patients were more likely to progress when avelumab was included in their therapy. The only subgroup for which the hazard for progression did not favor placebo was that of patients with PD-L1 expression >25%: For these patients in the avelumab arm, 2-year PFS was 72% for PD-L1–high and 52% for PD-L1–low patients, compared with 52% and 59%, respectively, in the control arm. While this was not a prospectively powered analysis, the relationship of PD-L1 expression with benefit has been consistent for immune checkpoint inhibitors in HNSCC, and, here, the study did not capitalize on these insights with the inclusion of PD-L1–low patients who did not benefit from avelumab, the failure to stratify on PD-L1 expression, the lack of a powered subgroup analysis in PD-L1–expressing patients, and—at least to date—an absence of more exploratory biomarker analyses of PD-L2 expression, inflammatory signatures, and tumor mutation burden. However, beyond these concerns, this study leaves us with an important question about how PD-L1 inhibition with avelumab could actually hasten progression. The multidimensional interactions among radiation, inflammation, hypoxia, and immune regulation of immune effector and suppressor cells may require much more intensive interrogation in order to design an appropriately biomarker-driven successor study and realize the promise of immune checkpoint inhibition in the definitive setting in HNC.