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 tumor-cell 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 participants: This 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 date before September 16, 2018. Data analysis was conducted from November 2018 to August 2019.

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 the ORRs 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.

Results: In 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 Bliss-estimated 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-lymphocyte-associated protein 4 inhibitor combinations.

Conclusions and relevance: In 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.

Figure 1.. Plot of the Objective Response Rates (ORRs) for Various Programmed Cell Death 1 Pathway Inhibitors Tested as Monotherapies

The ORRs shown were for any programmed cell death 1 pathway inhibitor where tested or for the mean of all those tested for a given indication and line of therapy. Various biomarkers and cut points were used in these trials; the details of each trial can be found in eTable 2 in the Supplement. BC indicates breast cancer; CLL, chronic lymphocytic leukemia; CRC, colorectal carcinoma; DLBCL, diffuse large B-cell lymphoma; ER, estrogen receptor; FL, follicular lymphoma; GBM, glioblastoma; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; MSI, microsatellite instable; MSI-H, microsatellite instable–high; MSS, microsatellite stable; NHL, non-Hodgkin lymphoma; NSCLC, non–small cell lung cancer; NPC, nasopharyngeal cancer; PMBCL, primary mediastinal B-cell lymphoma; RCC, renal cell carcinoma; rrPMBCL, relapsed or refractory primary mediastinal B-cell lymphoma; SCC, squamous cell carcinoma; SCLC, small cell lung cancer; STS, soft-tissue sarcoma; and TNBC, triple-negative breast cancer.

Figure 2.. Descriptive Statistics Analyzing Fold Change From Monotherapy to Combination Therapies Using Programmed Cell Death 1 Pathway Checkpoint Inhibitors

A, Combinations on the x-axis are identified in eTable 3 in the Supplement. Orthogonal combinations (ie, chemotherapies and targeted therapies) vs immune synergy combinations (ie, the tumor microenvironment [TME], adaptive immunity, and innate immunity) are shown.

Figure 3.. Contribution of Bliss Independent Combination Outcomes to Combination Trial Response Rates

A, The Bliss model posits that the combination of 2 agents with independent activities will be estimated by the following equation: Y_ab,P = Y_a + Y_b – Y_a × Y_b, in which Y_ab,P represents the estimated proportion of patients responding to agents in combination, Y_a represents the observed proportion responding to agent or regimen 1, and Y_b represents the observed proportion responding to agent or regimen 2. B, Z (yellow) is the difference between the observed objective response rate (ORR) for a combination and the estimated ORR from the Bliss equation. Z can be positive or negative. C, The regression plot (solid line) describes the association between the Bliss-estimated ORR based on independent contributions and the ORR of combinations determined in clinical trials. The dashed lines indicate 95% prediction intervals, and the dots represent individual trials. D, The histogram describes the frequency distribution of Z scores beyond the ORRs estimated by the Bliss model for combination efficacy.

Figure 4.. Programmed Cell Death 1 Checkpoint Pathway Combination Regimens Activity With Estimated Combination Outcome

Trials on the x-axis are identified in eTable 4 in the Supplement. Orthogonal combinations (ie, chemotherapies and targeted therapies) vs immune synergy combinations (ie, the tumor microenvironment [TME], adaptive immunity, and innate immunity) are shown.

Figure 5.. Combination Dynamics of Combinations

Columns indicate the observed objective response rate (ORR) for the combination therapies. Squares indicate the monotherapy ORRs for the identified programmed cell death 1 (PD-1) checkpoint inhibitors; triangles, the monotherapy ORR for the identified combination agent; and orange lines, the Bliss estimated ORR. Whiskers indicate SEs, which were not reported in all trials. The distance between the line and column represents the Z score, which can be positive or negative. The columns, squares, triangles, and orange lines all use the y-axis ORR scale. Individual trials are identified on the x-axis and in eTable 5 in the Supplement. CTLA-4 indicates cytotoxic T-lymphocyte–associated protein 4; IDO, indoleamine 2,3-dioxygenase; VEGF, vascular endothelial growth factor; and VEGFR, vascular endothelial growth factor receptor.