Possible Causes of Failing to Meet Primary Endpoints: A Systematic Review of Randomized Controlled Phase 3 Clinical Trials in Patients With Non-Small Cell Lung Cancer.

Background: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related mortality worldwide and represents a huge unmet medical need. Despite the favorable results of phase 2 clinical trials, many phase 3 clinical trials fail to meet primary endpoints. Therefore, we investigated the causes of failure to meet primary endpoints in phase 3 clinical trials.

Methods: We performed a systematic review of phase 3 clinical trials in patients with NSCLC. The results of phase 3 clinical trials collected from the survey were categorized as "negative" (failed to meet the primary endpoint) or "positive" (met the primary endpoint).

Results: Of a total of 106 trials collected from this survey, 40 positive trials (38%) and 66 negative trials (62%) were identified. The majority of the primary endpoints were overall survival (OS) or progression-free survival (PFS) (94%). More trials using OS as the primary endpoint were negative (42 of 56 trials), and more trials using PFS as the primary endpoint were positive (24 of 44 trials). The median OS in the control arm in negative trials was significantly longer than the pretrial estimate ( P < .001), whereas the median PFS in the control arm in positive trials was relatively consistent with the pretrial estimate.

Conclusions: Our findings suggest that the selection of the primary endpoint and the pretrial estimate can potentially impact the results of phase 3 clinical trials in patients with NSCLC and are critical success factors when planning phase 3 clinical trials.