Durability of response to immune checkpoint blockade following treatment discontinuation and efficacy of rechallenge in advanced Merkel cell carcinoma

Abstract

Background Advanced Merkel cell carcinoma (MCC) has a high response rate to immune checkpoint blockade (ICB) therapy, but the durability of responses once treatment is discontinued remains unclear. We therefore reviewed the long-term outcomes of advanced patients with MCC who discontinued ICB treatment after achieving favorable initial response.Methods We performed a retrospective review of advanced patients with MCC treated at a single high-volume referral center, including all patients who received at least one dose of anti-programmed death receptor 1 (ligand) monotherapy for unresectable or metastatic disease, achieved stable disease (SD) or better, and discontinued treatment for a reason other than disease progression.Results Of 195 advanced patients with MCC treated with ICB, we identified 45 who met the study criteria. Of these, 21 (46.6%) had a complete response (CR) to initial ICB treatment, 23 (51.1%) a partial response and 1 (2.2%) SD. 25 (55.6%) patients discontinued ICB electively and 20 (44.4%) discontinued due to toxicity. In total, 21 of the 45 patients (46.6%) experienced disease progression at a median of 11.3 months (range 2.1–22.7 months) from ICB cessation. There was a lower rate of progression in patients who achieved CR versus non-CR (23.8% vs 66.7%, p=0.006) and a trend towards a lower rate in those who discontinued electively versus due to toxicity (36.0% vs 60.0%, p=0.14). There was a higher risk for progression in patients with viral positive MCC compared with viral negative MCC (75.0 vs 30.8%, p=0.02). 16 of the 21 patients who experienced progression were retreated subsequently with ICB therapy, including both single-agent rechallenge (12) and escalation to combination ICB (4). 11 of 15 evaluable ICB-retreated patients (73.3%) achieved an objective response.Conclusions Patients with advanced MCC have a substantial risk of disease progression following treatment discontinuation despite initial favorable ICB response, particularly in those that achieve less than a CR. Most of these patients maintain sensitivity to retreatment with the same drug class. Virus-positive MCC may be a risk factor for post-discontinuation relapse, which should be validated in future studies.