Optimal Use of Targeted Therapy and Immunotherapy in Early-Stage, Resectable Non-Small Cell Lung Cancer

As systemic therapies for non-small cell lung cancer (NSCLC) have become more effective, interest in their use for improving long-term surgical outcomes has rapidly increased. Imperfect as it is, stage remains the primary means for identifying patients who might benefit from systemic therapy. Recent clinical trials have led to US Food and Drug Administration approval of osimertinib and alectinib as adjuvant treatments for resected pathologic stage II/III EGFR and ALK-mutated NSCLC; their use in the neoadjuvant setting remains subject to trials. Systemic therapy for less common oncogene-addicted NSCLC is also the subject of intense clinical trial activity. An effusion of trials has established the benefit of chemotherapy and immune checkpoint inhibitor therapy combinations in the adjuvant, neoadjuvant, and perioperative settings for patients with clinical or pathologic stage IB to III NSCLC, each of which is now part of the standard of care. Evidence-free consensus expert statements notwithstanding, two very important questions remain to be answered: Which is better-adjuvant or neoadjuvant/perioperative chemoimmunotherapy (and for whom)?; do patients who have pathologic complete response to neoadjuvant immunotherapy benefit from adjuvant immunotherapy? These questions are the subject of two ongoing National Clinical Trials Network trials: CTIU2317-A082304-S2402-Perioperative versus Adjuvant Systemic Therapy in Patients with Resectable NSCLC (PROSPECT-Lung; ClinicalTrials.gov Identifier: NCT04267848)-and S2414-A Randomized Phase III Trial Incorporating Pathologic Response in Participants with Early-Stage NSCLC to Optimize Immunotherapy in the Adjuvant Setting (INSIGHT; ClinicalTrials.gov Identifier: NCT06498635). We discuss why there is sufficient equipoise to justify seeking answers to these two extremely important, patient-centered questions.