Clinical Combinations Including PD-1 or PD-L1 Inhibitors Demonstrate More Clinical Activity

In this study, most clinical combinations including PD-1 or PD-L1 inhibitors demonstrated more clinical activity than the monotherapy activity of the checkpoint inhibitor alone.

In this cross-sectional study published in JAMA Network Open, most clinical combinations including PD-1 or PD-L1 inhibitors demonstrated more clinical activity than the monotherapy activity of the checkpoint inhibitor alone. 

Overall, according to the researchers, the success of these combinations will likely support the continued development of combinations of orthogonal agents with PD-1 pathway inhibitors. 

“This clinical snapshot should add value to decisions about advancing immunotherapy combinations in the clinic,” the authors wrote. “It highlights platinum compound-containing agents as benefitting from both independent and clinical synergy, and it identifies angiogenesis inhibition as an additional promising approach to immune therapy combinations.”

To evaluate whether the objective response rates (ORRs) of various combinations might be greater than the independent contribution of each agent, researchers used a Bliss independent activity model to analyze observed combination ORRs, and a Z score was generated to measure the difference.  

Evaluating 319 results from 98 clinical trials across 24,915 patients with metastatic cancer, ORRs for monotherapy were compared with combination data by indication and line of therapy, demonstrating an increased ORR in 105 of 127 results (82.7%) where ORRs were available for both PD-1 pathway inhibitor monotherapy and combination therapy. A few of these combinations showed increases above the Bliss-estimated activity, which researchers suggested possibly identifies limited clinical synergy. 

For all trials, the mean Z score was 0.0430 (SD, 0.0243). Furthermore, the mean score was 0.0923 (SD, 0.0628) for platinum chemotherapy regimen combinations, 0.0547 (0.0821) for vascular endothelial growth factor or vascular endothelial growth factor receptor tyrosine kinase inhibitor combinations, 0.0893 (SD, 0.086) for indoleamine 2,3-dioxygenase inhibitor combinations, and 0.0558 (SD, 0.0849) for cytotoxic T-lymphocyte–associated protein 4 inhibitor combinations. 

“The most effective therapies, with the highest observed ORRs, were platinum chemotherapy and VEGF/R combinations; these therapies benefited from both independent additivity and clinical synergy – an unexpected finding for those advocating immune synergy,” the authors wrote. 

To identify optimal combinations, researchers indicated that given the relatively poor mechanistic understanding of PD-1 combination therapies, using smaller patient cohorts in clinical studies to look for large effect sizes may be the best approach. Additionally, the researchers indicated that the observation that active drugs combine most successfully is consistent with a long-understood finding in cancer drug development and the monotherapy ORR for new agents remains the best predictor of eventual approval by regulatory agencies.

“Clinicians will likely choose to use therapies with the highest observed ORRs regardless of the approach used to identify the combination,” the authors wrote. “However, as future combinations are designed, those developing clinical trials need to consider strategies that achieve the best antitumor effects.”

Notably, this study depended on the use of phase I trial data, however objective response rates do not always translate to the registration end points, suggesting that this cross-sectional survey needs further validation in future randomized phase III studies. 


Schmidt EV, Chisamore MJ, Chaney MF, et al. Assessment of Clinical Activity of PD-1 Checkpoint Inhibitor Combination Therapies Reported in Clinical Trials. JAMA Network Open. doi:10.1001/jamanetworkopen.2019.20833.

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