Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.
BACKGROUND
Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy.


METHODS
In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647.


RESULTS
Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6-13·1). The proportion of patients who achieved an objective response was 28 (31·8% [95·9% CI 21·9-43·1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each).


CONCLUSIONS
Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma.


BACKGROUND
Merck KGaA, Darmstadt, Germany.
Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA. Electronic address: hk553@cinj.rutgers.edu.
Howard L
HL
Kaufman
H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Jeffery
J
Russell
The Angeles Clinic & Research Institute, Los Angeles, CA, USA.
Omid
O
Hamid
Division of Oncology, University of Washington Medical Center at South Lake Union, Seattle, WA, USA.
Shailender
S
Bhatia
Department of Dermatology, University of Lübeck, Lübeck, Germany.
Patrick
P
Terheyden
Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA.
Sandra P
SP
D'Angelo
Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA.
Kent C
KC
Shih
APHP Service de Dermatologie and CIC, INSERM U976, Faculté Paris Diderot Hôpital Saint Louis, Paris, France.
Céleste
C
Lebbé
Division of Oncology, Washington University School of Medicine, St Louis, MO, USA.
Gerald P
GP
Linette
Regina Elena National Cancer Institute, Rome, Italy.
Michele
M
Milella
National Cancer Institute, Bethesda, MD, USA.
Isaac
I
Brownell
Division of Medical Oncology, University of Colorado Denver School of Medicine, Aurora, CO, USA.
Karl D
KD
Lewis
Dana-Farber Cancer Institute, Boston, MA, USA.
Jochen H
JH
Lorch
EMD Serono, Billerica, MA, USA.
Kevin
K
Chin
EMD Serono, Billerica, MA, USA.
Lisa
L
Mahnke
Merck KGaA, Darmstadt, Germany.
Anja
A
von Heydebreck
EMD Serono, Billerica, MA, USA.
Jean-Marie
JM
Cuillerot
Division of Dermatology, University of Washington Medical Center at South Lake Union, Seattle, WA, USA.
Paul
P
Nghiem
D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors*; D015266:Carcinoma, Merkel Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011446:Prospective Studies; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C000609138:avelumab