Benefit, burden, and impact for a cohort of post-approval cancer combination trials.

Background: After approval, drug developers often pursue trials aimed at extending the uses of a new drug by combining it with other drugs. Little is known about the risk and benefits associated with such research. Methods: To establish a historic benchmark of risk and benefit, we searched Medline and Embase for clinical trials testing anti-cancer drugs in combination within 5 years of approval by the Food and Drug Administration of 12 anti-cancer "index" drugs first licensed 2005-2007 inclusive. Risk was assessed based on grade 3 or above drug-related adverse events; benefit was assessed based on efficacy outcomes and advancement of combinations into clinical practice guidelines or approval by the Food and Drug Administration. Results: We captured 323 published post-approval trials exploring combinations, including 266 unique combination-indication pairings and enrolling 29,835 patients. The pooled risk ratios for treatment-related grade 3-4 severe adverse events and deaths attributed to the study drugs for trials randomized between a combination arm and a comparator were 1.54 (1.33-1.79) and 1.51 (1.16-1.97), respectively. The pooled hazard ratios for overall survival and progression-free survival were 0.99 (0.92-1.05) and 0.85 (0.79-0.93), respectively. None of the combination-indication pairings launched after initial drug approval received approval by the Food and Drug Administration, and 13 pairings (4.9%) were recommended by the National Comprehensive Cancer Network within 5 years of the first trial within that pairing. The proportion of patients in our sample who participated in trials leading to an approval by the Food and Drug Administration or a National Comprehensive Cancer Network guideline recommendation was 12.7% with 5 years of follow-up, and 22.3% among pairings for which there were 8 years of follow-up. Conclusion: Patients were just as likely to benefit in the treatment arm as the control arm in terms of overall survival, but they were more likely to experience a treatment-related severe adverse event in post-approval trials of combination therapy.