Bristol-Myer says 'encouraging response observed' for Opdivo plus BMS-986205
Bristol-Myers Squibb Company announced updated results for Opdivo plus BMS-986205, a selective, once-daily oral indoleamine 2,3-dioxygenase 1 inhibitor from the ongoing Phase 1/2a dose escalation and expansion study, CA017-003. In the dose escalation phase, the maximum tolerated dose of BMS-986205 in combination with Opdivo was 200 mg. Based on safety and pharmacodynamic data, the recommended dose for further study was determined to be 100 mg. In the dose expansion phase, findings for anti-tumor activity were reported in two cohorts - heavily pre-treated bladder and cervical cancer patients. In the bladder cancer cohort, the objective response rate and disease control rate were 32% and 44%, respectively. In the cervical cancer cohort, the ORR was 14% and DCR was 64%. The study also measured ORR by PD-L1 expression levels; in patients who express PD-L1 greater than or equal to1%, ORR was 46% and 25% in the bladder and cervical cancer cohorts, respectively. In patients who express PD-L1 less than1%, ORR was 22% in the bladder cancer cohort; no response was observed in cervical cancer patients. Response was observed regardless of prior lines of therapy. IDO1 is an enzyme that breaks down tryptophan, an essential amino acid which fuels cytotoxic T cells, to help regulate the immune system and avoid an over-response to threats. Some tumors express excessive amounts of IDO1 and deplete tryptophan, resulting in kynurenine production, which starves T cells of their fuel and prevents the immune system from responding appropriately to the cancer. Preclinical studies evaluating BMS-986205 suggest that targeting the IDO1 pathway in combination with other possible complementary immune pathways has the potential to more effectively activate the anti-tumor response. Early clinical data also show anti-PD-1 therapy may upregulate IDO1 expression in patients. The primary objectives of the dose escalation study are to establish the safety, tolerability, dose-limiting toxicity and maximum tolerated dose, maximum administered dose or alternate dose; BMS-986205 doses from 25 to 400 mg once-daily were evaluated in combination with Opdivo given 240 mg every two weeks. The secondary objectives in the dose escalation phase include pharmacokinetics, pharmacodynamics, immunogenicity and preliminary anti-tumor activity. The primary objective of the dose expansion phase is to investigate preliminary anti-tumor activity, as well as safety and tolerability with BMS-986205 in combination with Opdivo. In this portion of the study, patients received BMS-986205 100 or 200 mg orally QD in combination with Opdivo 240 mg intravenously every two weeks, or 480 mg intravenously every four weeks. The study evaluated potency of BMS-986205 by measuring serum kynurenine, an immune-modulating metabolite produced by the IDO1 enzyme that potentially allows cancer cells to escape the immune response. In addition to the anti-tumor activity data presented at SITC, additional results included evidence of increased kynurenine inhibition in the blood, with 56% inhibition achieved at the 100 mg dose selected for further evaluation. Kynurenine was also evaluated in pre- and on-treatment tumor samples, with reductions of up to 100% noted. Proliferating CD8 positive T cells were also increased in the paired tumor samples from a range of tumor types, providing evidence of immunomodulation within the tumor microenvironment by an IDO1 inhibitor in combination with a PD-1 inhibitor. Across doses from 25 to 400 mg of BMS-986205 in combination with Opdivo, treatment-related Grade 3/4 toxicities occurred in 11% of patients. Those occurring in two or more participants included increased AST, increased ALT, anemia, autoimmune hepatitis, fatigue, pneumonitis, hepatitis, hyponatremia, hypophosphatemia and increased lipase. In the study, 1.4% of patients were discontinued due to study-drug toxicity.