TY - JOUR
T1 - Neoadjuvant nivolumab for patients with resectable merkel cell carcinoma in the CheckMate 358 trial
AU - Topalian, Suzanne L.
AU - Bhatia, Shailender
AU - Amin, Asim
AU - Kudchadkar, Ragini R.
AU - Sharfman, William H.
AU - Lebbé, Celeste
AU - Delord, Jean Pierre
AU - Dunn, Lara A.
AU - Shinohara, Michi M.
AU - Kulikauskas, Rima
AU - Chung, Christine H.
AU - Martens, Uwe M.
AU - Ferris, Robert L.
AU - Stein, Julie E.
AU - Engle, Elizabeth L.
AU - Devriese, Lot A.
AU - Lao, Christopher D.
AU - Gu, Junchen
AU - Li, Bin
AU - Chen, Tian
AU - Barrows, Adam
AU - Horvath, Andrea
AU - Taube, Janis M.
AU - Nghiem, Paul
N1 - Funding Information:
Supported by Bristol Myers Squibb and ONO Pharmaceutical Company Limited (CheckMate 358 study); by The Mark Foundation for Cancer Research and National Cancer Institute R01 CA142779 (J.M.T.; multispectral immunofluorescence tissue staining and analysis at the Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy); and by P30-CA015704 and P01-CA225517 (P.N.).
Funding Information:
We thank the patients and their families for making this study possible; the clinical study teams who participated in the study; Dako, an Agilent Technologies, Inc. company, for collaborative development of the PD-L1 IHC 28-8 pharmDx assay; and Bristol Myers Squibb (Princeton, NJ) and ONO Pharmaceutical Company Ltd. (Osaka, Japan). We gratefully acknowledge the efforts of Evan Lipson, MD, Trish Brothers, RN, and the clinical research team at the Johns Hopkins Kimmel Cancer Center, as well as Benjamin Green, Charles Roberts, Daphne Wang, and Morenike Jackson of the Tumor Microenvironment Technology Development Center in the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins. Professional medical writing and editorial assistance were provided by Richard Daniel, PhD, of Parexel, funded by Bristol Myers Squibb.
Publisher Copyright:
© 2020 by American Society of Clinical Oncology
PY - 2020/4/23
Y1 - 2020/4/23
N2 - PURPOSE Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the Merkel cell polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunosuppressive pathway is often upregulated in MCC, and advanced metastatic MCC frequently responds to PD-1 blockade. We report what we believe to be the first trial of anti-PD-1 in the neoadjuvant setting for resectable MCC. METHODS In the phase I/II CheckMate 358 study of virus-associated cancer types, patients with resectable MCC received nivolumab 240 mg intravenously on days 1 and 15. Surgery was planned on day 29. Tumor regression was assessed radiographically and microscopically. Tumor MCPyV status, PD-L1 expression, and tumor mutational burden (TMB) were assessed in pretreatment tumor biopsies. RESULTS Thirty-nine patients with American Joint Committee on Cancer stage IIA-IV resectable MCC received $ 1 nivolumab dose. Three patients (7.7%) did not undergo surgery because of tumor progression (n 5 1) or adverse events (n 5 2). Any-grade treatment-related adverse events occurred in 18 patients (46.2%), and grade 3-4 events in 3 patients (7.7%), with no unexpected toxicities. Among 36 patients who underwent surgery, 17 (47.2%) achieved a pathologic complete response (pCR). Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) had tumor reductions $ 30%. Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status. At a median follow-up of 20.3 months, median recurrence-free survival (RFS) and overall survival were not reached. RFS significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumor relapse during observation. CONCLUSION Nivolumab administered approximately 4 weeks before surgery in MCC was generally tolerable and induced pCRs and radiographic tumor regressions in approximately one half of treated patients. These early markers of response significantly predicted improved RFS. Additional investigation of these promising findings is warranted.
AB - PURPOSE Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the Merkel cell polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunosuppressive pathway is often upregulated in MCC, and advanced metastatic MCC frequently responds to PD-1 blockade. We report what we believe to be the first trial of anti-PD-1 in the neoadjuvant setting for resectable MCC. METHODS In the phase I/II CheckMate 358 study of virus-associated cancer types, patients with resectable MCC received nivolumab 240 mg intravenously on days 1 and 15. Surgery was planned on day 29. Tumor regression was assessed radiographically and microscopically. Tumor MCPyV status, PD-L1 expression, and tumor mutational burden (TMB) were assessed in pretreatment tumor biopsies. RESULTS Thirty-nine patients with American Joint Committee on Cancer stage IIA-IV resectable MCC received $ 1 nivolumab dose. Three patients (7.7%) did not undergo surgery because of tumor progression (n 5 1) or adverse events (n 5 2). Any-grade treatment-related adverse events occurred in 18 patients (46.2%), and grade 3-4 events in 3 patients (7.7%), with no unexpected toxicities. Among 36 patients who underwent surgery, 17 (47.2%) achieved a pathologic complete response (pCR). Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) had tumor reductions $ 30%. Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status. At a median follow-up of 20.3 months, median recurrence-free survival (RFS) and overall survival were not reached. RFS significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumor relapse during observation. CONCLUSION Nivolumab administered approximately 4 weeks before surgery in MCC was generally tolerable and induced pCRs and radiographic tumor regressions in approximately one half of treated patients. These early markers of response significantly predicted improved RFS. Additional investigation of these promising findings is warranted.
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U2 - 10.1200/JCO.20.00201
DO - 10.1200/JCO.20.00201
M3 - Article
C2 - 32324435
AN - SCOPUS:85087211102
SN - 0732-183X
VL - 38
SP - 2476
EP - 2487
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 22
ER -