Additivity Predicts the Clinical Efficacy of Approved Combination Therapies

Combinations of drugs are used to treat advanced cancers, and prioritization of those drug combinations that are most likely to succeed is critical. Current rational combination designs aim to identify synergistic drug combinations, which are those where two or more drugs enhance each other's efficacy, but current metrics are only applicable to preclinical data with preclinical synergy not being significantly associated with clinical success. Superior efficacy could also potentially result from additive effects, but no current method distinguishes the difference between additive and synergistic clinical efficacy. To determine if a drug extends time to progression by the same amount when in combination with other drugs as when used as a single-agent, Hwangbo and colleagues proposed a model of clinical drug additivity that adds progression-free survival (PFS) sampled from Kaplan-Meier distributions to assess if clinical efficacies of approved drug combinations are synergistic or additive. This additivity model, which encompasses the benefit predicted by the highest single agent plus the added effect of the lesser agent and accounts for patient-to-patient variability, was applied to PFS results from advanced cancer combination trials that led to FDA approval between 1995 and 2020 for which both matched combination and monotherapy data are available and showed that, of the 37 combination therapies across 13 cancer types included for analysis, most approved drug combinations (95%) have additive efficacy or less, suggesting that more-than-additive durations of tumor control are rarely experienced. Moreover, the model of additivity was able to predict the significant improvement to PFS for every positive phase III trial over a 5-year period (2014–2018, 100% sensitivity) while also being able to predict most failures of negative trials (78% specificity). Additionally, the concept that most effective drug combinations are usually achieved by the additive effect of highly active new drugs, which can be superior to synergy among less active drugs, was also demonstrated, indicating that synergy is not necessarily synonymous with clinical superiority. In summary, the results of this study show that the clinical efficacy of most drug combinations approved for advanced cancers can be predicted by the efficacy of the highest single agent or the additivity model and suggests that use of the additivity model could improve the success of phase III clinical trials in cancer.

Hwangbo H, Patterson SC, Dai A, Plana D, and Palmer AC. Additivity predicts the efficacy of most approved combination therapies for advanced cancer. Nat Cancer 2023 Nov 16 [Epub ahead of print].

Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.