Oncology clinical trials submitted for regulatory review have become increasingly complex in their design and conduct. The Pragmatica-Lung Study (NCT05633602), sponsored by the US National Cancer Institute (NCI) and catalysed through an effort by the NCI and US Food and Drug Administration (FDA) to modernise clinical trials, represents a fundamental shift from this course, deploying a much simpler and more pragmatic design. The Pragmatica-Lung Study aims to confirm an initial signal for improved overall survival with pembrolizumab and ramucirumab versus investigator’s choice of chemotherapy, observed in a small, randomised trial (Lung-MAP S1800A) in patients with advanced non-small-cell lung cancer who had progressed on or following front-line immunotherapy.