OBJECTIVES: Metastatic Merkel cell carcinoma (mMCC) is a rare aggressive skin cancer with high mortality. Efficacy of second-line or later (2L+) chemotherapy is unclear due to disease rarity and limited literature. This study investigated treatment patterns and outcomes in patients with distant mMCC who received 2L+ chemotherapy. METHODS: This retrospective observational study included adult patients with mMCC receiving 2L+ chemotherapy from 11/2004 to 9/2014 with follow-up until 6/2015. Data were obtained from the US Oncology Network/McKesson Specialty Health electronic health record database and medical charts. Patients with prior immunotherapy, in clinical trials, or diagnosed with certain solid tumors ≤3 years prior to 2L+ chemotherapy were excluded. Objective response rate (ORR) was assessed using RECIST 1.1 as a guide. Duration of response (DOR), progression-free survival (PFS), overall survival (OS), and time to treatment discontinuation (TTD) were estimated using the Kaplan-Meier method in the overall population and immunocompetent patients. RESULTS: Of 686 identified patients with MCC, 20 patients qualified for analysis. Median age at start of 2L+ chemotherapy was 74 years, 70% were male, 80% had an ECOG performance status of 1, and most patients were initially diagnosed with stage I-III disease with a primary tumor located in the upper/lower limb, trunk, or face. Topotecan was the most frequently utilized 2L+ chemotherapy (35%). In the overall population, ORR was 20.0% (95%CI 5.7-43.7), median TTD was 1.5 mo (95%CI, 0.3-2.5), median DOR was 1.7 mo (95%CI 0.5-3.0), median PFS was 2.1 mo (95%CI 1.0-3.2) and median OS was 4.4 mo (95%CI 2.2-6.2). No patient had response lasting 6 months. Results were consistent in the immunocompetent group (n=14). CONCLUSIONS: In patients with distant mMCC treated with 2L+ chemotherapy, response rate was low with brief duration, and poor OS. The failure of chemotherapy to improve prognosis in mMCC highlights the need for novel therapies.