Efficacy of targeted therapies for oncogene-driven lung cancer in early single-arm versus late phase randomized clinical trials: A comparative analysis

There is an expanding number of approved targeted therapies for oncogene-driven lung cancer and many emerging therapies with promising efficacy data. Regulatory approvals are increasingly based on early phase trials (often single-arm phase II trials), in which the primary endpoint is objective response rate (ORR) or progression-free survival (PFS). Efficacy outcomes from early phase trials may not always correlate with those observed in later-phase randomized trials. In the precision oncology era with effective targeted therapies however, there are arguments for greater confidence in the efficacy outcomes from non-randomized single-arm trials. Nevertheless, there remain numerous challenges in understanding and interpreting efficacy outcomes for novel targeted therapies in trials that may have dose finding and safety as the primary objective and lack a standard-ofcare control arm. Therefore, we sought to review the efficacy outcomes in early versus late phase clinical trials for approved targeted therapies in lung cancer - to better understand the interpretation of preliminary measures of clinical benefit. Nine pairs of early and late phase trials were identified, according to line of therapy for six targeted therapies in lung cancer (afatinib, ceritinib, crizotinib, dacomitinib, lorlatinib and osimertinib). Key efficacy outcomes, including ORR, PFS and overall survival (OS) were compared. Importantly, we found that in oncogene-driven lung cancer, early phase trial outcomes have historically been consistent with subsequent late phase trials. This suggests efficacy outcomes from early phase trials of targeted therapies in lung cancer may translate reliably to larger randomized trials. This has many potential implications for drug development in lung cancer, with regards to regulatory approvals and the design and conduct of clinical trials.