Background: Since the era of cytotoxic chemotherapy, the maximum tolerated dose (MTD) in a phase I trial has represented the recommended phase II dose and often the initial FDA-approved dose. This dosing recommendation stems from data that cytotoxic chemotherapy is most effective at the MTD. Unlike chemotherapy, immune checkpoint inhibitor therapy is not directly cytotoxic and harnesses the host immune system’s T cell to target tumor cell kill. Whether higher doses are associated with survival in immune checkpoint inhibitor phase I trials remains unknown. Purpose: To evaluate whether dose of immune checkpoint inhibitor administered in a phase I trial is associated with progression-free survival and overall survival. Methods: We analyzed clinical data from patients treated in phase I immune checkpoint inhibitor dose-escalation trials (anti-CTLA4 antibody and anti-PD1 trials) at the MD Anderson Center for Targeted Therapy. Patients were stratified into a low-dose (≤33% MTD), medium-dose (34-66% MTD), high-dose (67-100% MTD), or very-high-dose (≥101% MTD) group. Groups were compared for progression-free survival and overall survival. Results: Among 91 patients treated in a dose-escalation immune checkpoint inhibitor phase I trial (58 CTLA4- and 33 PD1-based) between January 2013 and November 2015, the median age was 59 years (range: 20-86 years) and 37 (41%) were females. The most common tumor types treated included renal cell carcinoma (n = 23; 25%), melanoma (n = 16; 18%), sarcoma (n = 10; 11%), gastrointestinal stromal tumors (n = 10; 11%), and non-small cell lung cancer (n = 4; 4%). Progression-free survival in the low-dose group (n=16) was 2.76 months (95% CI 1.48-NA), medium-dose group (n=21) was 2.76 months (95% CI 1.48-NA), high-dose group (n=36) was 2.46 months (95% CI 1.84-3.29), and very-high-dose group (n=17) was 3.68 months (95% CI 2.76-NA). Log rank p=0.22. Overall survival in the low-dose group was 6.18 months (95% CI 3.45-NA), medium-dose group was 17.05 months (95% CI 3.94-NA), high-dose group was 5.16 months (95% CI 4.24-7.62), and very-high-dose group was 7.49 months (95% CI 5.59-NA). Log rank p=0.0070. Conclusion: We identify that in this subset of patients treated in dose-escalation immune checkpoint inhibitor phase I trials, administration of higher dose is not associated with improved progression-free survival but is associated with improved overall survival. Evaluation of dose with immune-related adverse events and prospective examination in a larger subset of patients is ongoing. These data may have implications for optimizing the recommended phase II dose for immune checkpoint inhibitor therapy and may alleviate patient concerns when receiving lower doses in phase I dose-escalation studies.

Citation Format: Shiraj Sen, David S. Hong, Kenneth Hess, Funda Meric-Bernstam, Vivek Subbiah. Association of immune checkpoint inhibitor dose and survival in phase I clinical trials: is it time to redefine the recommended phase II dose [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A199.