Neoadjuvant Nivolumab for Patients With Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial

被引：179

作者：

Topalian, Suzanne L. ^{[1
]}

Bhatia, Shailender ^{[2
]}

Amin, Asim ^{[3
]}

Kudchadkar, Ragini R. ^{[4
]}

Sharfman, William H. ^{[1
]}

Lebbe, Celeste ^{[5
,6
,7
]}

Delord, Jean-Pierre ^{[8
]}

Dunn, Lara A. ^{[9
]}

Shinohara, Michi M. ^{[2
]}

Kulikauskas, Rima ^{[2
]}

Chung, Christine H. ^{[10
]}

Martens, Uwe M. ^{[11
]}

Ferris, Robert L. ^{[12
]}

Stein, Julie E. ^{[1
]}

Engle, Elizabeth L. ^{[1
]}

Devriese, Lot A. ^{[13
]}

Lao, Christopher D. ^{[14
]}

Gu, Junchen ^{[15
]}

Li, Bin ^{[15
]}

Chen, Tian ^{[15
]}

Barrows, Adam ^{[15
]}

Horvath, Andrea ^{[15
]}

Taube, Janis M. ^{[1
]}

Nghiem, Paul ^{[2
]}

机构：

[1] Johns Hopkins Bloomberg Kimmel Inst Canc Immunoth, Sidney Kimmel Comprehens Canc Ctr, 1550 Orleans St,Canc Res Bldg 2,Room 508, Baltimore, MD 21287 USA

[2] Univ Washington, Seattle Canc Care Alliance, Seattle, WA 98195 USA

[3] Atrium Healthcare, Levine Canc Inst, Charlotte, NC USA

[4] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA

[5] Univ Paris, INSERM, U976, Paris, France

[6] St Louis Hosp, AP HP, Dermatol, Paris, France

[7] St Louis Hosp, AP HP, CIC, Paris, France

[8] Inst Claudius Regaud, IUCT Oncopole, Toulouse, France

[9] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[10] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA

[11] SLK Clin, MOLIT Inst, Heilbronn, Germany

[12] Univ Pittsburgh, Med Ctr, Hillman Canc Ctr, Pittsburgh, PA USA

[13] Univ Med Ctr Utrecht, Canc Ctr, Utrecht, Netherlands

[14] Univ Michigan, Comprehens Canc Ctr, Ann Arbor, MI 48109 USA

[15] Bristol Myers Squibb, Princeton, NJ USA

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2020年 / 38卷 / 22期

关键词：

POLYOMAVIRUS; CHEMOTHERAPY; ANTIBODIES; EXPRESSION;

D O I：

10.1200/JCO.20.00201

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

PURPOSEMerkel 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.METHODSIn 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.RESULTSThirty-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 = 1) or adverse events (n = 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.CONCLUSIONNivolumab 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.

引用

页码：2476 / +

页数：13

共 39 条

[1] Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma [J].

Amaria, Rodabe N. ;

Reddy, Sangeetha M. ;

Tawbi, Hussein A. ;

Davies, Michael A. ;

Ross, Merrick, I ;

Glitza, Isabella C. ;

Cormier, Janice N. ;

Lewis, Carol ;

Hwu, Wen-Jen ;

Hanna, Ehab ;

Diab, Adi ;

Wong, Michael K. ;

Royal, Richard ;

Gross, Neil ;

Weber, Randal ;

Lai, Stephen Y. ;

Ehlers, Richard ;

Blando, Jorge ;

Milton, Denai R. ;

Woodman, Scott ;

Kageyama, Robin ;

Wells, Daniel K. ;

Hwu, Patrick ;

Patel, Sapna P. ;

Lucci, Anthony ;

Hessel, Amy ;

Lee, Jeffrey E. ;

Gershenwald, Jeffrey ;

Simpson, Lauren ;

Burton, Elizabeth M. ;

Posada, Liberty ;

Haydu, Lauren ;

Wang, Linghua ;

Zhang, Shaojun ;

Lazar, Alexanderj ;

Hudgens, Courtney W. ;

Gopalakrishnan, Vancheswaran ;

Reuben, Alexandre ;

Andrews, Miles C. ;

Spencer, Christine N. ;

Prieto, Victor ;

Sharma, Padmanee ;

Allison, James ;

Tetzlaff, Michael T. ;

Wargo, Jennifer A. .

NATURE MEDICINE, 2018, 24 (11) :1649-+

[2]

[Anonymous], 2019, ANN ONCOL S5

[3] A CONFIDENCE-INTERVAL FOR THE MEDIAN SURVIVAL-TIME [J].

BROOKMEYER, R ;

CROWLEY, J .

BIOMETRICS, 1982, 38 (01) :29-41

[4] Bioinformatic Methods and Bridging of Assay Results for Reliable Tumor Mutational Burden Assessment in Non-Small-Cell Lung Cancer [J].

Chang, Han ;

Sasson, Ariella ;

Srinivasan, Sujaya ;

Golhar, Ryan ;

Greenawalt, Danielle M. ;

Geese, William J. ;

Green, George ;

Zerba, Kim ;

Kirov, Stefan ;

Szustakowski, Joseph .

MOLECULAR DIAGNOSIS & THERAPY, 2019, 23 (04) :507-520

[5] Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma [J].

Cloughesy, Timothy F. ;

Mochizuki, Aaron Y. ;

Orpilla, Joey R. ;

Hugo, Willy ;

Lee, Alexander H. ;

Davidson, Tom B. ;

Wang, Anthony C. ;

Ellingson, Benjamin M. ;

Rytlewski, Julie A. ;

Sanders, Catherine M. ;

Kawaguchi, Eric S. ;

Du, Lin ;

Li, Gang ;

Yong, William H. ;

Gaffey, Sarah C. ;

Cohen, Adam L. ;

Mellinghoff, Ingo K. ;

Lee, Eudocia Q. ;

Reardon, David A. ;

O'Brien, Barbara J. ;

Butowski, Nicholas A. ;

Nghiemphu, Phioanh L. ;

Clarke, Jennifer L. ;

Arrillaga-Romany, Isabel C. ;

Colman, Howard ;

Kaley, Thomas J. ;

De Groot, John F. ;

Liau, Linda M. ;

Wen, Patrick Y. ;

Prins, Robert M. .

NATURE MEDICINE, 2019, 25 (03) :477-+

[6] Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC) [J].

Cottrell, T. R. ;

Thompson, E. D. ;

Forde, P. M. ;

Stein, J. E. ;

Duffield, A. S. ;

Anagnostou, V. ;

Rekhtman, N. ;

Anders, R. A. ;

Cuda, J. D. ;

Illei, P. B. ;

Gabrielson, E. ;

Askin, F. B. ;

Niknafs, N. ;

Smith, K. N. ;

Velez, M. J. ;

Sauters, J. L. ;

Isbell, J. M. ;

Jones, D. R. ;

Battafarano, R. J. ;

Yang, S. C. ;

Danilova, L. ;

Wolchok, J. D. ;

Topalian, S. L. ;

Velculescu, V. E. ;

Pardoll, D. M. ;

Brahmer, J. R. ;

Hellmann, M. D. ;

Chaft, J. E. ;

Cimino-Mathews, A. ;

Taube, J. M. .

ANNALS OF ONCOLOGY, 2018, 29 (08) :1853-1860

[7] Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma A Preplanned Interim Analysis of a Clinical Trial [J].

D'Angelo, Sandra P. ;

Russell, Jeffery ;

Lebbe, Celeste ;

Chmielowski, Bartosz ;

Gambichler, Thilo ;

Grob, Jean-Jacques ;

Kiecker, Felix ;

Rabinowits, Guilherme ;

Terheyden, Patrick ;

Zwiener, Isabella ;

Bajars, Marcis ;

Hennessy, Meliessa ;

Kaufman, Howard L. .

JAMA ONCOLOGY, 2018, 4 (09)

[8]

Edge SB, 2010, AJCC CANC STAGING MA, V7

[9] New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) [J].

Eisenhauer, E. A. ;

Therasse, P. ;

Bogaerts, J. ;

Schwartz, L. H. ;

Sargent, D. ;

Ford, R. ;

Dancey, J. ;

Arbuck, S. ;

Gwyther, S. ;

Mooney, M. ;

Rubinstein, L. ;

Shankar, L. ;

Dodd, L. ;

Kaplan, R. ;

Lacombe, D. ;

Verweij, J. .

EUROPEAN JOURNAL OF CANCER, 2009, 45 (02) :228-247

[10] Neoadjuvant PD-1 Blockade in Resectable Lung Cancer [J].

Forde, P. M. ;

Chaft, J. E. ;

Smith, K. N. ;

Anagnostou, V. ;

Cottrell, T. R. ;

Hellmann, M. D. ;

Zahurak, M. ;

Yang, S. C. ;

Jones, D. R. ;

Broderick, S. ;

Battafarano, R. J. ;

Velez, M. J. ;

Rekhtman, N. ;

Olah, Z. ;

Naidoo, J. ;

Marrone, K. A. ;

Verde, F. ;

Guo, H. ;

Zhang, J. ;

Caushi, J. X. ;

Chan, H. Y. ;

Sidhom, J. -W. ;

Scharpf, R. B. ;

White, J. ;

Gabrielson, E. ;

Wang, H. ;

Rosner, G. L. ;

Rusch, V. ;

Wolchok, J. D. ;

Merghoub, T. ;

Taube, J. M. ;

Velculescu, V. E. ;

Topalian, S. L. ;

Brahmer, J. R. ;

Pardoll, D. M. .

NEW ENGLAND JOURNAL OF MEDICINE, 2018, 378 (21) :1976-1986

← 1 2 3 4 →