Active IDO1 Inhibitor is Well Tolerated in Advanced Tumors
The IDO1 inhibitor BMS-986205 had "best-in-class" activity as demonstrated by kynurenine reductions and IDO1 inhibition for patients with advanced tumors in a phase 1/2a study, according to lead investigator Lillian L. Siu, M.D., at the 2017 AACR Annual Meeting.
"BMS-986205 is fulfilling the criteria for being a best in class IDO1 inhibitor, it is potent and selective," said Siu, senior medical oncologist at Princess Margaret Cancer Centre. "The once-daily dosing exceeds the IC90 target concentrations. We see kynurenine reduction that is greater than reported with previous IDO1 inhibitors."
In preclinical studies, BMS-986205 showed potent and selective inhibition of IDO1 without significantly blocking IDO2 and TDO. BMS-986205 was also found to restore human T cell proliferation in dendritic cells while lowering levels of the immunosuppressive metabolite kynurenine. These pharmacokinetic studies also supported the exploration of a daily dose of BMS-986205.
For the phase 1/2a study, BMS-986205 was escalated from 25 mg to 200 mg daily across several previously treated advanced malignancies. The median age of patients was 58 years, and approximately 40 percent were males. The ECOG performance status was 0 and 1 and most patients had stage 4 disease (approximately 80 percent).
Single-agent oral BMS-986205 was administered once daily for a two-week lead in period followed by the addition of nivolumab at 240 mg intravenously every two weeks. Expansion cohorts were opened for patients with cervical, squamous cell carcinoma of the head and neck (SCCHN), and bladder cancer.
A high level of BMS-986205 inhibitory concentration of IDO1 was seen in the plasma with the 25-mg dose, which exceeded whole blood IC50 levels. The IC90 levels were exceeded by the 50-mg dose, with higher doses showing even higher concentrations. With the increased BMS-986205 concentration levels, there was a rapid reduction in serum kynurenine, with a ≥60 percent reduction in mean levels observed with both the 100 mg and 200 mg doses. Whole blood ex vivo assays showed ≥90 percent inhibition of kynurenine with the ≥50 mg dose.
This drop in the metabolite was greater than previously reported with the IDO1 inhibitor epacadostat, noted Siu. The average percentage drop in kynurenine levels with epacadostat was near 50 percent, with all patients reaching normal levels across doses.
In samples from 13 patients treated with BMS-986205, pretreatment and on-treatment tests showed significant kynurenine intratumoral reduction. This drop was seen even in those with high pretreatment levels across all dose levels. The decline in kynurenine levels ranged from 27 percent to 89 percent for those treated with the 200-mg dose. In the 100-mg dose arm, there was a 100 percent reduction in kynurenine levels.
A single dose-limiting toxicity was experienced by patients in each the 100 and the 200 mg doses. These consisted of grade 3 autoimmune hepatitis leading to treatment discontinuation at the 100 dose and grade 3 anemia that led to dose reduction in the 200-mg arm. The maximum tolerated dose was not reached.
The most common treatment emergent adverse events (TRAEs) during the lead in period for single-agent BMS-986205 (n = 44) were fatigue (18.2 percent), nausea (18.2 percent), decreased appetite (13.6 percent), and vomiting (6.8 percent). For the combination (n = 44), the most common TRAEs were decreased appetite (18.2 percent), fatigue (13.6 percent), nausea (9.1 percent), vomiting (9.1 percent), and diarrhea (6.8 percent). Across the full study (N = 55), the most common TRAEs were decreased appetite (20 percent), fatigue (12.7 percent), nausea (12.7 percent), diarrhea (9.1 percent), and vomiting (9.1 percent).
"There were no grade 3 events with BMS-986205 in the monotherapy lead in, and there were no grade 4 or 5 events with the monotherapy or combination," said Siu. "Overall, the combination has been very tolerated."
Limited data for clinical efficacy were presented. In scans for a patient with SCCHN previously treated with two platinum-based regimens, the combination of BMS-986205 and nivolumab led to a 63 percent reduction in target lesion size by day 52 which continued to the data cutoff at day 107. In a patient with clear cell renal cell carcinoma pretreated with pazopanib, there was a 42 percent reduction in target lesion size.
In another example of response, Siu showed scans from a patient with triple-negative breast cancer who received eight prior therapies. In this example, the combination led to a 48 percent reduction in target lesion size by day 50. Tumor reduction was maintained out to 155 days, which was the time of the data cutoff in February 2017.
"Data suggest that BMS-986205 fulfills characteristics of a best-in-class IDO1 inhibitor and support its further evaluation in combination for patients with advanced cancer," concluded Siu. The phase 1/2 study continues to enroll participants (NCT02658890).