A phase 2 study to determine the pathological (path) response to neoadjuvant nivolumab (nivo) and relatlimab (rela) in stage I to III resectable Merkel cell carcinoma (Neo-MCC).

TPS9613 Background: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cancer of the skin with viral and sun related aetiologies, and an overall mortality rate twice that observed in cutaneous melanoma (33% vs 15%). The 5-year disease specific survival is 60% to 87% for those presenting with local disease, 39% to 62% for nodal disease and 11% to 20% for metastatic disease (1). Neoadjuvant therapy (NAT) is a powerful treatment platform to rapidly assess drug activity in resectable cancers. In melanoma, using International Neoadjuvant Melanoma Consortium (INMC) path response criteria (2), a major path response to immunotherapy (≤10% viable tumor) correlates with low risk of recurrence in resectable stage III disease (Menzies et al., 2021), and improved survival and EFS when immunotherapy is given neoadjuvantly as compared to adjuvant (adj) treatment (Patel et al., 2022). In a study of NAT anti-PD1 monotherapy with nivolumab, in patients (pts) with resectable IIA-IV MCC (N=36), 47.2% of pts achieved a complete path response (pCR) (Topalian et al., 2020). Other benefits of NAT include early insight into response, feedback to pts regarding their individual response and prognosis, ability to tailor subsequent management, and collection of translational specimens to explore mechanisms of response and resistance. The Neo-MCC trial will examine whether combination PD-1 blockade plus lymphocyte-activation 3 (LAG3) checkpoint inhibition will achieve a high rate of path response with manageable toxicity in pts with resectable stage I-III MCC. Methods: Pts with histologically confirmed resectable clinical stage I (≥ 10 mm), II or III Merkel cell carcinoma, are eligible (N=20). All pts undergo complete resection (RES) at wk 6 following NAT with 2 doses of nivo (480 mg, IV) plus rela (160 mg, IV) at wk 0 and 4. Standard of care sentinel lymph node biopsy will be completed as indicated. Pts with non-path response (>50% viable tumor) or partial path response (>10% - ≤50% viable tumor) at RES will receive adj radiotherapy (RT) to all disease sites, including the draining lymph node basin. Pts with pCR (0% viable tumor) or near-pCR response (≤10% viable tumor) will receive no further adj treatment. Pts with involved RES path margins will be considered for adj RT, following multidisciplinary team consultation to determine the role of further surgery. CT, and FDG PET/CT will be performed at baseline (BL), prior to RES to measure NAT response, and 6-monthly over a 10-year follow-up period. Tumor and fecal samples are collected at BL, RES, and recurrence. Blood samples are collected at BL, wk 4, RES, and recurrence. The primary endpoint is the rate of pCR at RES after NAT using INMC response criteria. Secondary endpoints include RFS, OS, safety/tolerability, surgical outcomes, QOL, and biomarker analyses. 1. Mistry, et al., 2022. 2. Tetzlaff et al., 2018. Clinical trial information: NCT06151236 .