Assessment of Clinical Activity of PD-1 Checkpoint Inhibitor Combination Therapies Reported in Clinical Trials

Abstract

IMPORTANCE Because cancer drugs given in combination have the potential for increased tumorcell killing, finding the best combination partners for programmed cell death 1 (PD-1) checkpoint inhibitors could improve clinical outcomes for patients with cancer.OBJECTIVE To identify optimal strategies for combining PD-1 immune checkpoint inhibitors with other cancer therapies. DESIGN, SETTING, AND PARTICIPANTSThis cross-sectional study compiled 319 results from 98 clinical trials testing PD-1 pathway inhibitors alone or in combination with other agents among 24 915 patients with metastatic cancer. All clinical trials had a primary completion EXPOSURES Patients with metastatic cancer were treated with PD-1 immune checkpoint inhibitors alone or with other cancer therapies. MAIN OUTCOMES AND MEASURES Clinical activity was measured as objective response rates (ORRs). Combination measures included fold change from monotherapy to combination ORR, comparison of observed combination ORRs with estimated combination ORRs based on independent additivity, and a computational model to assess clinical synergy. To assess whether theORRs of various combinations may be greater than the independent contribution of each agent, a Bliss independent activity model was used to analyze observed combination ORRs, and a Z score, measuring the difference between observed and calculated ORRs, was generated. RESULTSIn 319 results from 98 clinical trials among 24 915 patients, 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 combinations showed increases above the Blissestimated activity, possibly identifying limited clinical synergy. The mean (SD) Z score for all trials was 0.0430 (0.0243). The mean (SD) Z score was 0.0923 (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 (0.086) for indoleamine 2,3-dioxygenase inhibitor combinations, and 0.0558 (0.0849) for cytotoxic T-lymphocyteassociated protein 4 inhibitor combinations. CONCLUSIONS AND RELEVANCEIn this cross-sectional study, most combination trials showed the expected benefit of combining 2 active anticancer agents, but few combination trials showed clinical synergy according to the Bliss independent activity model. Question What therapies are best combined with programmed cell death 1 (PD-1) checkpoint inhibitors to improve outcomes for patients with cancer who do not respond to PD-1 pathway inhibitor monotherapy? Findings This cross-sectional study of 98 clinical trials, which included 24 915 patients with metastatic cancer, compared objective response rates of PD-1 checkpoint immunotherapies used alone and in combination. Most combinations succeeded, given that the fold change from monotherapy ORR to combination ORR increased in 82.7% ...

Predictable clinical benefits without synergy in trials of combination therapies with immune checkpoint inhibitors

“…We found that the duration of response (as measured by PFS) as well as changes in tumor volume were precisely consistent with independent action. Additional evidence for independent action in PD-1 inhibitor combinations was recently reported by Schmidt et al 11 based on analysis of objective response rates. In this paper we analyze PFS data from all clinical trials of ICI combination therapies as of April 2020 for which data on single agent and combination arms are available and look for evidence of additive or synergistic drug interaction.…”

Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors

“…We found that the duration of response (as measured by PFS) as well as changes in tumor volume were precisely consistent with independent action. Additional evidence for independent action in PD-1 inhibitor combinations was recently reported by Schmidt et al 11 based on analysis of objective response rates. In this paper we analyze PFS data from all recent clinical trials of ICI combination therapies for which data on single agent and combination arms are available and look for evidence of additive or synergistic drug interaction.…”

Immunotherapy in Colorectal Cancer: Current and Future Strategies

“…The intermediate analysis showed that this regimen has great treatment potential, with an ORR of 63%, CR of 31%, and a DCR of 63% [46]. In a cross-sectional study of 98 clinical trials testing ICIs alone or in combination with other agents, the most compatible partner of ICIs would be the platinum chemotherapy or an anti-angiogenetic inhibitor, supporting combination treatment utilizing an angiogenetic inhibitor and platinum chemotherapy with ICIs [47]. Currently, as described in the previous section regarding anti-angiogenetic inhibitors, several trials using such treatment strategy are ongoing: the phase III COMMIT trial [37] and the phase II AtezoTRIBE trial [38].…”