Early objective response to avelumab treatment is associated with improved overall survival in patients with metastatic Merkel cell carcinoma

Sandra P D’Angelo,Gerald P Linette,Michele Milella,Andrew S Brohl,Michael Schlichting,Céleste Lebbé,Patrick Terheyden,Karl D Lewis,Kent C Shih,Isaac Brownell,Matthias Hunger,Janice M Mehnert,Meliessa H Hennessy,Shailender Bhatia,Murtuza Bharmal,Paul Nghiem,Omid Hamid

doi:10.1007/s00262-018-02295-4

Abstract

BackgroundResponse rates are primary endpoints in many oncology trials; however, correlation with overall survival (OS) is not uniform across cancer types, treatments, or lines of therapy. This study explored the association between objective response (OR) and OS in patients with chemotherapy-refractory metastatic Merkel cell carcinoma who received avelumab (anti-PD-L1).MethodsEighty-eight patients enrolled in JAVELIN Merkel 200 (part A; NCT02155647) received i.v. avelumab 10 mg/kg every 2 weeks until confirmed progression, unacceptable toxicity, or withdrawal. Using conditional landmark analyses, we compared OS in patients with and without confirmed OR (RECIST v1.1). We applied a Cox model that included OR as a time-varying covariate and adjusted for age, visceral disease, and number of previous therapies.ResultsTwenty-nine patients had confirmed OR; 20 by study week 7 and 7 more between study weeks 7 and 13. Survival probabilities 18 months after treatment initiation were 90% [95% confidence interval (CI) 65.6–97.4] in patients with OR at week 7 and 26.2% (95% CI 15.7–37.8) in patients without OR but who were alive at week 7. Median OS was not reached in patients with OR and was 8.8 months (95% CI 6.4–12.9) in patients without. Similar results were observed for the week 13 landmark. The adjusted Cox model showed OR was associated with a 95% risk reduction of death [hazard ratio 0.052 (95% CI 0.018–0.152)] compared with a nonresponse.ConclusionsPatients with OR by 7 or 13 weeks had significantly longer OS than patients without, confirming that early OR is an endpoint of major importance.

Highlights

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin [2,3,4,5]
The objective of this study is to investigate the association between objective response (OR) and overall survival (OS) in patients with Metastatic MCC (mMCC) who were treated with avelumab
Confirmed ORs to avelumab were achieved in 29 patients [33.0%; 95% confidence interval (CI) 23.3–43.8%), 19 of whom had partial response (PR)

Summary

Introduction

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin [2,3,4,5]. Despite the objective response rates (ORR) to chemotherapy as a first-line therapy for mMCC being relatively high, 52–61%, these responses were short-lived, with the median duration of response with first-line chemotherapy being approximately 3 months [8]. Response rates are primary endpoints in many oncology trials; correlation with overall survival (OS) is not uniform across cancer types, treatments, or lines of therapy. This study explored the association between objective response (OR) and OS in patients with chemotherapy-refractory metastatic Merkel cell carcinoma who received avelumab (anti-PD-L1). Survival probabilities 18 months after treatment initiation were 90% [95% confidence interval (CI) 65.6–97.4] in patients with OR at week 7 and 26.2% (95% CI 15.7–37.8) in patients without OR but who were alive at week 7. Conclusions Patients with OR by 7 or 13 weeks had significantly longer OS than patients without, confirming that early OR is an endpoint of major importance

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