Neoadjuvant checkpoint inhibition in non-small cell lung cancer: Is earlier unquestionably better than later?

On March 4th 2022, nivolumab received regular US Food and Drug Administration approval, based on the CheckMate 816 trial results, for use "with platinum-doublet chemotherapy for adult patients with resectable NSCLC in the neoadjuvant setting". This is the first neoadjuvant approval of a checkpoint inhibitor, a unique event in the history of lung cancer treatment. However, open questions remains. First, the co-primary endpoints of the CheckMate 816 trial (event-free survival and pathological complete response) are not yet validated surrogate endpoints in this setting. Second, the control arm was not reflecting the most common approach, being upfront surgery followed by adjuvant chemotherapy. Third, protocol changes were not plainly justified, questioning the analytic plan of the trial. Fourth and last, a subpar access to checkpoint inhibitor for patients upon progression may weaken overall survival results. Neoadjuvant strategies allow to study initial response under treatment, and constitute an encouraging therapeutic avenue. However, the best sequence of treatment is the key question in the neoadjuvant or adjuvant settings: is treating everyone upfront better than treating only patients that will eventually recur?Investigating optimal sequence strategy is even more critical within the checkpoint-inhibitor era, where patients with advanced or metastatic disease may present long-term advantage. Trials with optimal post-progression treatment are needed to help optimize our treatment algorithm, and spare toxicity for patients who don't derive benefit.