A phase II study of neoadjuvant lenvatinib plus pembrolizumab in Merkel cell carcinoma.

9514 Background: Given the success of checkpoint inhibitor therapy in the advanced setting in Merkel cell carcinoma (MCC), there is interest in exploring immunotherapy as a neoadjuvant approach, which additionally allows a window of opportunity to assess the efficacy of new immunotherapy combinations. Methods: We conducted a single center, phase II open label trial (NCT04869137) in patients (pts) with resectable stage II-IV MCC. All pts were to receive six weeks of neoadjuvant therapy with pembrolizumab 200mg IV q3 weeks plus lenvatinib 20mg PO daily before planned surgery ± adjuvant radiation therapy. Following local therapy, pts were to receive continued adjuvant pembrolizumab monotherapy to complete 1 year total of systemic therapy. Target accrual was 26 pts. Pathological complete response (pCR) rate was the primary endpoint of the study, with ≥15 pCR needed for the combination therapy to be considered as promising compared to a historical benchmark of ~40% pCR for single-agent anti-PD1. Results: Twenty-six pts were enrolled between 06/2021 and 09/2024, including 5 (19.2%) with clinical stage II disease, 20 (76.9%) with stage III, and 1 (3.8%) with stage IV. Pts were predominantly male (77%) and with a median age of 69 (range 53-88). Following neoadjuvant treatment, 2 pts (7.7%) were unable to undergo planned surgery, one due to progressive disease (PD) and one due to toxicity. Two pts who achieved a clinical response to neoadjuvant therapy declined surgery and underwent post-neoadjuvant therapy biopsies for pathological assessment. On intention to treat, 15 of the 26 pts (57.7%) achieved a pCR. With a median follow-up of 20 months, 6 pts (23.1%) have experienced disease progression, 2 during neoadjuvant therapy, 2 during and 2 after adjuvant treatment. Among pts with pathological assessment of response, pCR was associated with a lower risk of relapse, though this result was not statistically significant (13.3% vs. 33.3%, p = 0.33). Thirteen of 15 pts who achieved pCR following surgery omitted adjuvant radiation therapy and there have been no local recurrences in pCR cases. Thirteen pts (50%) experienced at least one G3 treatment related adverse event (TRAE), most commonly G3 hypertension in 10 pts (40%) that improved with dose interruption and/or dose reduction of lenvatinib. No G4-5 TRAEs were observed. At the time of analysis, one pt (neoadjuvant PD) has died from progressive MCC. Two pts have died from other causes without evidence of recurrence at last follow-up. Conclusions: Lenvatinib plus pembrolizumab demonstrated encouraging efficacy with anticipated toxicity when used as neoadjuvant therapy for Merkel cell carcinoma. The primary endpoint of the study was met with 57.7% of patients achieving a pathological complete response. Pts with a pCR had a lower risk of recurrence vs those without, but recurrences were seen even after pCR. Ongoing correlative studies may help to identify biomarkers for response. Clinical trial information: NCT04869137 .