Suzanne L Topalian1, Shailender Bhatia2, Asim Amin3, Ragini R Kudchadkar4, William H Sharfman1, Celeste Lebbé5, Jean-Pierre Delord6, Lara A Dunn7, Michi M Shinohara2, Rima Kulikauskas2, Christine H Chung8, Uwe M Martens9, Robert L Ferris10, Julie E Stein1, Elizabeth L Engle1, Lot A Devriese11, Christopher D Lao12, Junchen Gu13, Bin Li13, Tian Chen13, Adam Barrows13, Andrea Horvath13, Janis M Taube1, Paul Nghiem2. 1. Johns Hopkins Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD. 2. University of Washington, Seattle Cancer Care Alliance, Seattle, WA. 3. Levine Cancer Institute, Atrium Healthcare, Charlotte, NC. 4. Winship Cancer Institute of Emory University, Atlanta, GA. 5. Université de Paris, INSERM U976, and Dermatology and CIC, AP-HP, Saint Louis Hospital, Paris, France. 6. Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France. 7. Memorial Sloan Kettering Cancer Center, New York, NY. 8. H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. 9. SLK-Clinics, MOLIT Institute, Heilbronn, Germany. 10. University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA. 11. University Medical Center Utrecht, Cancer Center, Utrecht, the Netherlands. 12. University of Michigan Comprehensive Cancer Center, Ann Arbor, MI. 13. Bristol Myers Squibb, Princeton, NJ.
Abstract
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 = 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. 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.
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 = 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. 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.
Authors: Kurt A Schalper; Maria E Rodriguez-Ruiz; Ricardo Diez-Valle; Alvaro López-Janeiro; Angelo Porciuncula; Miguel A Idoate; Susana Inogés; Carlos de Andrea; Ascensión López-Diaz de Cerio; Sonia Tejada; Pedro Berraondo; Franz Villarroel-Espindola; Jungmin Choi; Alfonso Gúrpide; Miriam Giraldez; Iosune Goicoechea; Jaime Gallego Perez-Larraya; Miguel F Sanmamed; Jose L Perez-Gracia; Ignacio Melero Journal: Nat Med Date: 2019-02-11 Impact factor: 53.440
Authors: Ata S Moshiri; Ryan Doumani; Lola Yelistratova; Astrid Blom; Kristina Lachance; Michi M Shinohara; Martha Delaney; Oliver Chang; Susan McArdle; Hannah Thomas; Maryam M Asgari; Meei-Li Huang; Stephen M Schwartz; Paul Nghiem Journal: J Invest Dermatol Date: 2016-11-01 Impact factor: 8.551
Authors: Stephen Q Wong; Kelly Waldeck; Ismael A Vergara; Jan Schröder; Jason Madore; James S Wilmott; Andrew J Colebatch; Ricardo De Paoli-Iseppi; Jason Li; Richard Lupat; Timothy Semple; Gisela Mir Arnau; Andrew Fellowes; J Helen Leonard; George Hruby; Graham J Mann; John F Thompson; Carleen Cullinane; Meredith Johnston; Mark Shackleton; Shahneen Sandhu; David D L Bowtell; Ricky W Johnstone; Stephen B Fox; Grant A McArthur; Anthony T Papenfuss; Richard A Scolyer; Anthony J Gill; Rodney J Hicks; Richard W Tothill Journal: Cancer Res Date: 2015-12-01 Impact factor: 12.701
Authors: Howard L Kaufman; Jeffery Russell; Omid Hamid; Shailender Bhatia; Patrick Terheyden; Sandra P D'Angelo; Kent C Shih; Céleste Lebbé; Gerald P Linette; Michele Milella; Isaac Brownell; Karl D Lewis; Jochen H Lorch; Kevin Chin; Lisa Mahnke; Anja von Heydebreck; Jean-Marie Cuillerot; Paul Nghiem Journal: Lancet Oncol Date: 2016-09-01 Impact factor: 41.316
Authors: Kelly G Paulson; Joseph J Carter; Lisa G Johnson; Kevin W Cahill; Jayasri G Iyer; David Schrama; Juergen C Becker; Margaret M Madeleine; Paul Nghiem; Denise A Galloway Journal: Cancer Res Date: 2010-10-19 Impact factor: 12.701
Authors: E A Eisenhauer; P Therasse; J Bogaerts; L H Schwartz; D Sargent; R Ford; J Dancey; S Arbuck; S Gwyther; M Mooney; L Rubinstein; L Shankar; L Dodd; R Kaplan; D Lacombe; J Verweij Journal: Eur J Cancer Date: 2009-01 Impact factor: 9.162
Authors: Andrea Necchi; Andrea Anichini; Daniele Raggi; Alberto Briganti; Simona Massa; Roberta Lucianò; Maurizio Colecchia; Patrizia Giannatempo; Roberta Mortarini; Marco Bianchi; Elena Farè; Francesco Monopoli; Renzo Colombo; Andrea Gallina; Andrea Salonia; Antonella Messina; Siraj M Ali; Russell Madison; Jeffrey S Ross; Jon H Chung; Roberto Salvioni; Luigi Mariani; Francesco Montorsi Journal: J Clin Oncol Date: 2018-10-20 Impact factor: 44.544
Authors: Gerald Goh; Trent Walradt; Vladimir Markarov; Astrid Blom; Nadeem Riaz; Ryan Doumani; Krista Stafstrom; Ata Moshiri; Lola Yelistratova; Jonathan Levinsohn; Timothy A Chan; Paul Nghiem; Richard P Lifton; Jaehyuk Choi Journal: Oncotarget Date: 2016-01-19
Authors: Natalie J Miller; Candice D Church; Steven P Fling; Rima Kulikauskas; Nirasha Ramchurren; Michi M Shinohara; Harriet M Kluger; Shailender Bhatia; Lisa Lundgren; Martin A Cheever; Suzanne L Topalian; Paul Nghiem Journal: J Immunother Cancer Date: 2018-11-27 Impact factor: 13.751
Authors: Paul W Harms; Kelly L Harms; Patrick S Moore; James A DeCaprio; Paul Nghiem; Michael K K Wong; Isaac Brownell Journal: Nat Rev Clin Oncol Date: 2018-12 Impact factor: 66.675
Authors: Ravindra Uppaluri; Katie M Campbell; Obi L Griffith; Douglas R Adkins; Ann Marie Egloff; Paul Zolkind; Zachary L Skidmore; Brian Nussenbaum; Randal C Paniello; Jason T Rich; Ryan Jackson; Patrik Pipkorn; Loren S Michel; Jessica Ley; Peter Oppelt; Gavin P Dunn; Erica K Barnell; Nicholas C Spies; Tianxiang Lin; Tiantian Li; David T Mulder; Youstina Hanna; Iulia Cirlan; Trevor J Pugh; Tenny Mudianto; Rachel Riley; Liye Zhou; Vickie Y Jo; Matthew D Stachler; Glenn J Hanna; Jason Kass; Robert Haddad; Jonathan D Schoenfeld; Evisa Gjini; Ana Lako; Wade Thorstad; Hiram A Gay; Mackenzie Daly; Scott J Rodig; Ian S Hagemann; Dorina Kallogjeri; Jay F Piccirillo; Rebecca D Chernock; Malachi Griffith Journal: Clin Cancer Res Date: 2020-07-14 Impact factor: 12.531
Authors: Alexander C J van Akkooi; Tina J Hieken; Elizabeth M Burton; Andrew J Spillane; Merrick I Ross; Charlotte Ariyan; Paolo A Ascierto; Salvatore V M A Asero; Christian U Blank; Matthew S Block; Genevieve M Boland; Corrado Caraco; Sydney Chng; B Scott Davidson; Joao Pedreira Duprat Neto; Mark B Faries; Jeffrey E Gershenwald; Dirk J Grunhagen; David E Gyorki; Dale Han; Andrew J Hayes; Winan J van Houdt; Giorgos C Karakousis; Willem M C Klop; Georgina V Long; Michael C Lowe; Alexander M Menzies; Roger Olofsson Bagge; Thomas E Pennington; Piotr Rutkowski; Robyn P M Saw; Richard A Scolyer; Kerwin F Shannon; Vernon K Sondak; Hussein Tawbi; Alessandro A E Testori; Mike T Tetzlaff; John F Thompson; Jonathan S Zager; Charlotte L Zuur; Jennifer A Wargo Journal: Ann Surg Oncol Date: 2022-01-28 Impact factor: 5.344
Authors: Ashley C Mays; Bharat Yarlagadda; Virginie Achim; Ryan Jackson; Patrik Pipkorn; Andrew T Huang; Karthik Rajasekaran; Shaum Sridharan; Andrew J Rosko; Ryan K Orosco; Andrew M Coughlin; Mark K Wax; Yelizaveta Shnayder; William C Spanos; Donald Gregory Farwell; Lee S McDaniel; Matthew M Hanasono Journal: Head Neck Date: 2021-01-08 Impact factor: 3.147
Authors: Robert L Ferris; William C Spanos; Rom Leidner; Anthony Gonçalves; Uwe M Martens; Chrisann Kyi; William Sharfman; Christine H Chung; Lot A Devriese; Helene Gauthier; Simon I Chiosea; Lazar Vujanovic; Janis M Taube; Julie E Stein; Jun Li; Bin Li; Tian Chen; Adam Barrows; Suzanne L Topalian Journal: J Immunother Cancer Date: 2021-06 Impact factor: 12.469
Authors: Neha Singh; Nora A Alexander; Kristina Lachance; Christopher W Lewis; Aubriana McEvoy; Gensuke Akaike; David Byrd; Sanaz Behnia; Shailender Bhatia; Kelly G Paulson; Paul Nghiem Journal: J Am Acad Dermatol Date: 2020-07-21 Impact factor: 11.527
Authors: Paolo A Ascierto; Carlo Bifulco; Fortunato Ciardiello; Sandra Demaria; Leisha A Emens; Robert Ferris; Silvia C Formenti; Jerome Galon; Samir N Khleif; Tomas Kirchhoff; Jennifer McQuade; Kunle Odunsi; Akash Patnaik; Chrystal M Paulos; Janis M Taube; John Timmerman; Bernard A Fox; Patrick Hwu; Igor Puzanov Journal: J Transl Med Date: 2021-06-02 Impact factor: 5.531