Trends in FDA approval of solid tumor therapies with analysis of single-agent vs. combination therapies.

e13659 Background: Single agents replacing previous therapies are ideal, but combination therapies with two or more active agents have been proposed to decrease drug resistance, promote mechanistic synergy, and/or have additive cytotoxic effects in cancer treatment. However, approval of combination therapies may increase exposure to new and former drugs, leading to more costs and time commitments to patients. Methods: This retrospective analysis examines all FDA-approved drugs for malignant solid tumors from January 2011 to December 2022. We used the data presented in the package inserts on the US FDA website. At least two reviewers selected all new and clinically meaningful indication changes for data extraction. Drug approvals for topical medications, precancerous conditions, hematologic conditions, primarily pediatric cancers, primary genetic syndrome neoplasms, biosimilars, and minor indication changes were all excluded. The primary endpoint was the proportion of new approvals that replaced former therapies rather than adding to existing therapy to become multi-agent combinations. We also compared single and combination regimes with the differences regarding cancer types, line of therapy, primary endpoints leading to approval, year of approval, type of approval, and type of expedited programs at the FDA. Results: Our analysis identified 247 FDA solid tumor drug indication approvals among 279 drugs from 2011 to 2022, with non-small cell lung cancer (52, 21%), followed by breast cancer (28, 11.3%) and melanoma (22, 8.9%), being the most common. The most common class of drug was small molecular targeted therapies (99, 40%), followed by immunotherapy checkpoint inhibitors (84, 34%). Most approvals were for 1st line (111, 44.9%), followed by 2nd line (106, 42.9%), and adjuvant setting (17, 6.9%). Among 247 approvals, 167 (67.6%) replaced a former therapy to become a new single standard of cancer therapy for that clinical setting, while 80 (32%) added to an existing regimen as a combination. 32 (12.9%) approvals have 3 or more drugs in the new therapy, 49 (19.8%) with 2 drugs in the new therapy. When comparing single-agent vs. combination regimen approvals, there was difference in cancer types, type of regimen, line of therapy, highest endpoints leading to approval, novel therapy, and type of drug approval (p-value < 0.05; test statistic > critical value). However, the year of approval, fast-track, and priority-review status were not statistically significant. Conclusions: Approximately two-thirds (68%) of drug approvals over the past 12 years for non-hematologic solid cancers are replacing or adding a new standard. Still, a significant minority (32%) are adding to existing regimens increasing the complexity of cancer therapies, especially in highly prevalent solid tumors, increasing potential time commitment for patients, costs, and exposure to therapies with notable side effects.