Additivity, Not Synergy, Underlies the Efficacy of Current Combination Regimens in Urothelial Cancer

PD-1/PD-L1 immune checkpoint inhibitor (ICI)-based combination regimens have transformed metastatic urothelial cancer treatment. However, phase III trials of these regimens have shown varied results. We sought to understand these differences by assessing whether these combinations are synergistic, additive, or less-than-additive, which is crucial for translational research and clinical development. We systematically identified five randomized phase III trials of ICI-based combinations for metastatic urothelial carcinoma and tested whether progression-free survival (PFS) distributions of combinations were as predicted by a null hypothesis of additivity, defined as the sum of PFS durations of individual drugs. For KEYNOTE-361 and IMvigor130, which allowed cisplatin or carboplatin, we evaluated platinum-specific predictions. We found that PFS distributions in trials adding PD-1/PD-L1 ICI to enfortumab vedotin (EV-302), gemcitabine plus cisplatin (CheckMate 901), or CTLA-4 blockade (DANUBE) were statistically indistinguishable from additivity. In trials using choice of cisplatin or carboplatin (KEYNOTE-361, IMvigor130), ICI combinations with cisplatin-gemcitabine yielded additive PFS, whereas ICI combinations with carboplatin-gemcitabine yielded less-than-additive PFS, indicating that carboplatin blunts the potential benefits of PD-1/PD-L1 inhibitors. The predictable success of EV-302 and CheckMate 901 demonstrate that substantial improvements in clinical outcomes can be achieved by additive combinations of individually effective agents. Overall, modeling PFS from single-agent data could have anticipated most contemporary phase III trial outcomes, potentially informing rational trial design and prioritization.

Practice-changing PD-1/PD-L1 immune checkpoint combinations in urothelial cancer show additive, not synergistic, efficacy in phase III trials. However, carboplatin was significantly less-than-additive with immunotherapy, helping explain negative results of KEYNOTE-361 and IMvigor130.