Matthew J Ahearne, Matthew A Timmins, Charlotte Gaskell, Aimee Jackson, Clare Morland, Sonia Fox, Louise Hopkins, Nadia Nawaz, Susann Lehmann, Marc Wadsley, Caroline Cowley, Jacqueline Shaw, Naeem Khan, Nagesh Kalakonda, Christopher Trethewey, Ram Malladi, Paul Fields, Dima El Sharkawi, Michael Quinn, Nimish Shah, Andrew Davies, Kim Linton, Pam McKay, Rod Johnson, Simon D Wagner, David Lewis, Graham P Collins, Christopher P Fox, Kate Cwynarski
Peripheral T-cell lymphomas (PTCL) are rare chemoresistant malignancies with poor outcomes, necessitating novel therapies. The programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) axis is frequently overexpressed in PTCL and represents a potential therapeutic target; however, PD-L1 inhibition has not been explored. We conducted a phase IIa trial evaluating avelumab, an anti-PD-L1 antibody, in relapsed/refractory PTCL. The primary end-point was overall response. Translational substudies included PD-L1 expression, circulating tumour DNA and baseline mass cytometry in a subset of patients. Of 35 recruited patients, 32 initiated treatment, although 13 discontinued early due to progression before the 3-month evaluation. Intention-to-treat analysis showed an overall response rate of 14.3%, median progression-free survival of 2.8 months (95% confidence interval [CI]; 1.8-3.4) and median overall survival of 10.3 months (95% CI; 6.0-12.3). In the five responding patients, median duration of response was not reached (12-month duration of response [DoR] rate 60% [95% CI; 13-88]). In a subset of patients, mass cytometry revealed marked perturbations in circulating T-cell subsets. Pathogenic variants detected in cell-free deoxyribonucleic acid (DNA) underscore the utility of liquid biopsy in PTCL, and longitudinal analysis revealed clonal dynamics. While avelumab demonstrated durable responses in a minority, most patients progressed early. Further studies are needed to define mechanisms of response and develop predictive biomarkers to guide strategies.