Neoadjuvant PD-1 Blockade in Resectable Lung Cancer

By P. Forde, J. Chaft, Kellie N. Smith, Valsamo Anagnostou, T. Cottrell, M. Hellmann, M. Zahurak, Stephen C. Yang, David R. Jones, S. Broderick and 25 more. New England Journal of Medicine, 2018

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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.)

Subfields: Immunology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/c06ab6a3c81f39754e8fff78458bc1d7e978cf31

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Citations in the corpus

Neoadjuvant checkpoint blockade for cancer immunotherapy (2020, methodology): “Early reports of safety and substantial pCR rates from neoadjuvant combinations of anti– PD-1 with anti–CTLA-4 (52), or with multidrug chemotherapies for triple-negative breast cancer (76, 77) or NSCLC (78), are encouraging but require longer follow-up for assessment of clinical efficacy endpoints.”
Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability–High/Mismatch Repair–Deficient Metastatic Colorectal Cancer: KEYNOTE-164 (2019, neutral): “Median tumor size, mm (range) 99 (11-408) 60 (10-307)”
Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “Currently, PD-1 blockade therapy has been applied in the immunotherapy of various advanced cancers including melanoma [168], non-small cell lung cancer [169], and colorectal cancer [170].”
Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic (2018, background): “Some mutations such as those in JAK1 and JAK2 are rare and do not validate in all patient cohorts [64, 99].”
Tumor-infiltrating lymphocytes in the immunotherapy era (2020, background): “The application of neoadjuvant ICB has also been successfully demonstrated in multiple tumors characterized by high mutational burden, such as melanoma and small-cell lung cancer, demonstrating impressive response rates of 78% and 45%, respectively.(209,210) In addition, neoadjuvant administration o”