Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma

Abstract

Background: Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with poor survival. Programmed cell death-1 (PD-1) pathway inhibitors have shown high rates of durable tumor regression compared with chemotherapy for MCC. The current study was undertaken to assess baseline and on-treatment factors associated with MCC regression and 3-year survival, and to explore the effects of salvage therapies in patients experiencing initial non-response or tumor progression after response or stable disease following first-line pembrolizumab therapy on Cancer Immunotherapy Trials Network-09/KEYNOTE-017.

Methods: In this multicenter phase II trial, 50 patients with advanced unresectable MCC received pembrolizumab 2 mg/kg every 3 weeks for ≤2 years. Patients were followed for a median of 31.8 months.

Results: Overall response rate to pembrolizumab was 58% (complete response 30%+partial response 28%; 95% CI 43.2 to 71.8). Among 29 responders, the median response duration was not reached (NR) at 3 years (range 1.0+ to 51.8+ months). Median progression-free survival (PFS) was 16.8 months (95% CI 4.6 to 43.4) and the 3-year PFS was 39.1%. Median OS was NR; the 3-year OS was 59.4% for all patients and 89.5% for responders. Baseline Eastern Cooperative Oncology Group performance status of 0, greater per cent tumor reduction, completion of 2 years of treatment and low neutrophil-to-lymphocyte ratio were associated with response and longer survival. Among patients with initial disease progression or those who developed progression after response or stable disease, some had extended survival with subsequent treatments including chemotherapies and immunotherapies.

Conclusions: This study represents the longest available follow-up from any first-line anti-programmed death-(ligand) 1 (anti-PD-(L)1) therapy in MCC, confirming durable PFS and OS in a proportion of patients. After initial tumor progression or relapse following response, some patients receiving salvage therapies survived. Improving the management of anti-PD-(L)1-refractory MCC remains a challenge and a high priority.

Trial registration number: NCT02267603.

Keywords: immunotherapy; programmed cell death 1 receptor; skin neoplasms.

Figure 1

Duration of response (DOR). Kaplan-Meier curve showing duration of response among 29 patients having a complete or partial tumor regression by Response Evaluation Criteria in Solid Tumors V.1.1. Patients without an event were censored (tick mark) at the last disease assessment date. Rates of ongoing response at 12, 24 and 36 months are indicated. NR, not reached.

Figure 2

Kinetics of response to pembrolizumab, and subsequent treatments received by patients with tumor relapse or with no response. Each lane in these swimmer plots depicts an individual patient. Dotted vertical lines indicate the maximum on-study pembrolizumab treatment interval (24 months). (A) Patients with a confirmed complete response (CR) to pembrolizumab (n=15). ^{a, b}Two patients were censored for progression/response because they started a new anticancer therapy without documented disease progression. (B) Patients with a confirmed partial response (PR) to pembrolizumab therapy (n=14). ^aThis patient was censored for progression/response because they started a new anticancer therapy without documented disease progression. (C) Patients with CR (red triangle), PR (yellow triangle) or stable disease (SD) (patients #9, 10, 11) after receiving pembrolizumab on-study, who later experienced disease progression (n=11). Subsequent treatments are shown. Patients with CR or PR are also depicted in panels (A) and (B), respectively. Details of subsequent treatments are presented in online supplemental table S6. (D) Patients with initial progressive disease (PD) (no CR, PR or SD) on pembrolizumab (n=16), showing subsequent treatments received. Details of subsequent treatments are presented in online supplemental table S6.

Figure 3

Survival among patients with advanced Merkel cell carcinoma (aMCC) receiving pembrolizumab. (A) Progression-free survival (PFS). Kaplan-Meier curve depicting PFS measured from the time of treatment initiation until either disease progression (Response Evaluation Criteria in Solid Tumors V.1.1) or death, whichever occurred first. At 36 months, the estimated PFS was 39.1%. Median PFS was 16.8 months (95% CI 4.6 to 43.4). (B) Overall survival (OS). Kaplan-Meier curves depicting OS among all 50 patients in green, or among those with objective tumor regression (complete response (CR)+partial response (PR)) in blue. At 36 months, the estimated OS was 59.4% for all patients, and 89.5% for those with objective response. Median OS was not reached in either group at the time of analysis. NR, not reached.

Figure 4

Association between magnitude of tumor burden reduction and overall survival (OS). Waterfall plot showing the maximum change in tumor burden (sum of target lesion diameters) compared with baseline, for radiographically evaluable patients (n=45). Horizontal dashed lines indicate Response Evaluation Criteria in Solid Tumors V.1.1 criteria for partial response (≥30% decrease in sum of target lesion diameters from baseline, in the absence of new lesions) and progressive disease (≥20% increase in sum of target lesion diameters). Vertical bars are color-coded to indicate OS duration in individual patients.

Figure 5

Association of overall survival with 30 months’ follow-up, with baseline demographics and tumor and treatment characteristics. Forest plot showing overall survival HRs (with 95% CI) for characteristics which are listed from top to bottom in increasing order of HR magnitude. Total numbers of evaluable patients in each category are shown. Patients with baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 1 vs 0 had significantly reduced survival, while those who completed 2 years of pembrolizumab therapy experienced significantly longer survival. programmed death-ligand 1 (PD-L1) positive, ≥1% of tumor cells expressed cell surface PD-L1, assessed by immunohistochemistry.