RegenerativeMedicine.net

Neoadjuvant PD-1 blockade in resectable lung cancer

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

Summary:

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. (Funded by Cancer Research Institute–Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621.)

Source: New England Journal of Medicine, 2018