Neoadjuvant PD-1 blockade in resectable lung cancer

Patrick Forde, Jamie E. Chaft, Kellie Smith, Valsamo Anagnostou, Tricia R. Cottrell, Matthew D. Hellmann, Marianna Zahurak, Stephen Broderick, Stephen C Yang, David R. Jones, Richard J Battafarano, Moises J. Velez, Natasha Rekhtman, Zachary Olah, Franco Verde, Jarushka Naidoo, Kristen Marrone, Haidan Guo, John William Sidhom, Jiajia ZhangJustina X. Caushi, Hok Yee Chan, Robert B Scharpf, James White, Edward Gabrielson, Hao Wang, Gary Rosner, Valerie Rusch, Jedd D. Wolchok, Taha Merghoub, Janis M Taube, Victor E Velculescu, Suzanne Topalian, Julie Brahmer, Andrew Mark Pardoll

Research output: Contribution to journalArticle

Abstract

BACKGROUND Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. METHODS In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses. RESULTS Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab. CONCLUSIONS Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood.

Original languageEnglish (US)
Pages (from-to)1976-1986
Number of pages11
JournalNew England Journal of Medicine
Volume378
Issue number21
DOIs
StatePublished - May 24 2018

    Fingerprint

ASJC Scopus subject areas

  • Medicine(all)

Cite this