Durability of immune checkpoint inhibitor (ICI) response following treatment discontinuation in advanced merkel cell carcinoma (MCC).
Authors: Ramadoss Tanya , Nichols Matthew , Palacios Christian , Eroglu Zeynep , Markowitz Joseph , Karapetyan Lilit , Tarhini Ahmad A. , Wuthrick Evan John , Sondak Vernon K. , Khushalani Nikhil I. , Tsai Kenneth Yee , Brohl Andrew Scott 
Published: July 2024

9596 Background: Advanced MCC has a high response rate to ICI therapy, but the durability of responses once treatment is discontinued remains unclear. We therefore reviewed the long-term outcomes of advanced MCC patients at our institution who discontinued ICI treatment after achieving favorable initial response. Methods: In an IRB-approved single institution retrospective review of advanced MCC patients, we analyzed all patients who received at least one dose of anti-PD(L)1 monotherapy for unresectable or metastatic disease, achieved stable disease (SD) or better, and discontinued treatment for a reason other than disease progression. Duration of response and outcomes of subsequent therapy were assessed. Results: Of 195 advanced MCC patients treated with ICI, we identified 45 who met study criteria. Of these, 21 (47%) had a complete response (CR) to initial ICI treatment, 23 (51%) a partial response (PR) and 1 (2%) SD. Twenty-five (56%) patients discontinued ICI electively and 20 (44%) discontinued due to toxicity. In total, 21 of the 45 patients (47%) experienced disease progression at a median of 11.2 months (range 2.1-22.7 months) from ICI cessation. The median follow-up after ICI discontinuation for patients who have not experienced progression is 22.8 months (5.8-82.0 months). There was a lower rate of progression in patients who achieved CR vs. non-CR (24% vs 67%, p=0.006) and a trend towards a lower rate in those who discontinued electively vs. due to toxicity (36% vs 60%, p=0.14). For patients in whom the molecular subtype was known, there was a higher risk for progression in patients with viral MCC (12 of 16, 75%) compared to UV-associated MCC (4 of 13, 31%, p=0.02). Fifteen of the 21 patients (71%) who experienced progression were rechallenged with ICI therapy, including both single agent (12 patients, 57%) and combination (3, 14%) therapy. The remaining patients received locally-directed therapy only (3, 14%), chemotherapy (1, 5%), declined further treatment (1, 5%), or transferred care and were lost to follow up (1, 5%). Eleven of 15 ICI-retreated patients (73%) achieved an objective response to rechallenge, including all 3 patients who received combination therapy with ipilimumab+nivolumab. Twelve of the 45 patients have expired; 6 due to progressive MCC and remaining 6 known or suspected from unrelated causes. Conclusions: Patients with advanced MCC have a substantial risk of disease progression following treatment discontinuation despite initial favorable ICI response, 47% in our series with a median time to event of 11.2 months, particularly in those that achieve less than a complete response. In the setting of disease progression post-ICI discontinuation, most 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.