EACH: A phase II study evaluating the safety and anti-tumour activity of avelumab and cetuximab in recurrent/metastatic squamous cell carcinomas

ABSTRACT

Background: Patients with R/M SCC have low response rates to second line therapies, including PD-1 inhibitors nivolumab and pembrolizumab, representing an area of unmet clinical need. Cetuximab has modest activity as a single agent but potentiates the activity of radiotherapy in locally advanced head & neck SCC (HNSCC) and chemotherapy in R/M HNSCC. Cetuximab initiates Natural Killer cell antibody-dependent cell-mediated cytotoxicity, resulting in an anti-tumour immune response and the potential to augment the activity of PD-1/PD-L1 inhibition. Methods: Trial entry required histologically confirmed R/M SCC of any site, unselected by PD-L1 expression, considered incurable by local therapies and no previous treatment with cetuximab for recurrent/metastatic disease. Prior therapy with anti-PD-1, anti-PD-L1 or anti-PD-L2 was excluded. Patients had avelumab 10 mg/kg + cetuximab 500 mg/m2 intravenously every 2 weeks, for up to 1 year. Primary endpoint was occurrence of dose-limiting toxicity within 42 days of treatment starting, graded using CTCAE v5. Secondary endpoints were objective response (ORR) and disease control rate (DCR) at 6 and 12 months using iRECIST. Results: 16 patients, median age 58 years (range 34 – 88), were enrolled from 2 UK hospitals between July 2018 and October 2019. The trial stopped after completing the safety run-in. 5 patients remain on treatment, 9 stopped treatment early (7 disease progression, 1 patient choice, 1 due to risk of COVID-19). 2 patients died whilst on treatment (both unrelated to trial treatment). Grade 3 AEs were seen in 4 patients and grade 5 in 1 patient. None were related to trial treatment. No patients experienced dose-limiting toxicity. Of 10 patients evaluable for response by iRECIST 2 (20%) had complete response, 3 (30%) had partial response and 4 (40%) had stable disease as their best response, representing an ORR of 50%. One patient had confirmed disease progression. In 6 patients who remained on trial for >6 months, all 6 had disease control at 6 months (2 CR, 1 PR, 3 SD). Conclusions: Avelumab + cetuximab is safe and tolerable, and demonstrates promising efficacy in R/M SCC patients. Clinical trial identification NCT03494322;20/03/2018;Sponsor reference UCL/17/0560. Legal entity responsible for the study University College London. Funding: Merck KGaA. Disclosure M. Forster Advisory/Consultancy, Travel/Accommodation/Expenses BMS;Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses Merck;Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses MSD;Advisory/Consultancy Novartis;Advisory/Consultancy PharmaMar;Advisory/Consultancy, Travel/Accommodation/Expenses Roche;Advisory/Consultancy Nanobiotix;Advisory/Consultancy, Travel/Accommodation/Expenses Guardant Health;Advisory/Consultancy Oxford VacMedix;Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses AstraZeneca;Advisory/Consultancy Takeda;Research grant/Funding (institution) Boehringer Ingelheim;Travel/Accommodation/Expenses Celgene. J. Sacco Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses BMS;Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses MSD;Honoraria (self), Advisory/Consultancy Amgen;Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution) Immunocore;Honoraria (self), Advisory/Consultancy Delcath;Honoraria (self) Pierre Fabre;Research grant/Funding (institution) AstraZeneca. A. Kong Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses Merck;Honoraria (self), Speaker Bureau/Expert testimony BMS;Advisory/Consultancy Centauri Therapeutics;Advisory/Consultancy Amgen;Advisory/Consultancy, Research grant/Funding (institution) Puma Biotechnology;Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses MSD;Research grant/Funding (institution) AstraZeneca. G. Wheeler Honoraria (self) AstraZeneca. J. Hartley Full/Part-t me employment AstraZeneca;Advisory/Consultancy, Shareholder/Stockholder/Stock options ADC Therapeutics. All other authors have declared no conflicts of interest.