Overcoming immunotherapy resistance in NSCLC.

Abstract

Systemic therapy regimens that contain immune checkpoint blockade immunotherapy, primarily monoclonal antibodies directed against PD-1, PD-L1, or CTLA-4, can induce substantial therapeutic responses in patients with advanced non-small-cell lung cancer (NSCLC). With immune checkpoint blockade, improved survival can be attained for a minority of patients who would otherwise have a poor prognosis; some might even be cured. Key randomised controlled trials have revolutionised the management of newly diagnosed, non-driver mutation-driven NSCLC by showing improved overall survival for regimens containing immune checkpoint inhibitors compared with chemotherapy alone 1 Reck M Rodríguez-Abreu D Robinson AG et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019; 37: 537-546 Google Scholar , 2 Gadgeel S Rodríguez-Abreu D Speranza G et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol. 2020; 38: 1505-1517 Google Scholar , 3 Paz-Ares L Vicente D Tafreshi A et al. A randomized, placebo-controlled trial of pembrolizumab plus chemotherapy in patients with metastatic squamous NSCLC: protocol-specified final analysis of KEYNOTE-407. J Thorac Oncol. 2020; 15: 1657-1669 Google Scholar and for immunotherapy with a PD-1 inhibitor plus a CTLA-4 inhibitor combined with chemotherapy compared with chemotherapy alone. 4 Paz-Ares L Ciuleanu T-E Cobo M et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021; 22: 198-211 Google Scholar Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trialRadiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD(L)-1 therapy. However, PD-L1 plus CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting. Full-Text PDF