“We are pleased to share initial data from the trial of INCB001158 in MSS colorectal carcinoma that is refractory to standard therapies, a disease that has very low historical average response rates to checkpoint inhibitors such as pembrolizumab,” said
- The PD-(L)1-naïve MSS colorectal carcinoma (CRC) patient cohort has advanced to stage 2 of a Simon 2-stage design. Among 43 response-evaluable patients who had received a median of 3 prior therapies, 3 patients achieved a confirmed partial response (7%); the historical overall response rate is 0-1% in second- and third-line MSS CRC patients treated with checkpoint inhibitor therapies. Two of the three responders are ongoing at the time of data cutoff with a duration of response of 2.4+ and 7+ months respectively. The third responder had a duration of response of 6.7 months. The six month PFS rate for the cohort was 20%.
- Pharmacodynamic increases in total intratumoral CD8+ cells were seen post-treatment with INCB001158 + pembrolizumab in MSS CRC patients.
- The colorectal carcinoma monotherapy cohort has advanced to stage 2 of a Simon 2-stage design. Among 33 response-evaluable MSS CRC patients, one patient achieved a confirmed partial response (3%) and one patient achieved stable disease lasting seven months. Both patients had disease progression within six months on their immediately preceding line of therapy. The disease control rate for the monotherapy MSS CRC cohort was 27%.
- INCB001158 inhibited plasma arginase activity at all doses and induced dose-related increases in plasma arginine, including a mean three-fold increase at the recommended phase 2 dose of 100 mg bid.
- A total of 85 patients with advanced solid tumors were treated with INCB001158 as a monotherapy in doses of 50 to 150mg bid and were evaluable for safety. A maximum tolerated dose was not reached. Immune-related adverse events included one dose-limiting toxicity (DLT) each of Grade 2 malaise (at 150mg) and Grade 3 colitis (100mg). Clinically significant urea cycle inhibition was not seen.
- A total of 114 PD-(L)1-naïve and PD-(L)1 refractory patients were treated in INCB001158 in combination with pembrolizumab and evaluable for safety across multiple disease specific cohorts. The overall frequency and severity of immune related adverse events was consistent with the pembrolizumab safety profile.
About INCB001158 (CB-1158)
INCB001158 (CB-1158) is an investigational first-in-class, novel small molecule arginase inhibitor. Arginase is an enzyme that suppresses the immune-mediated destruction of tumors by depleting levels of a key amino acid, L-arginine, from the tumor microenvironment. A number of cell types in the tumor microenvironment, including myeloid-derived suppressor cells, macrophages, and neutrophils, can secrete arginase. L-arginine deprivation can act via nutrient sensor pathways to exert several suppressive effects on T-cell function, inhibiting proliferation, decreasing cytokine production, and diminishing expression of the T-cell receptor CD3ζ chain. Arginase activity may thus impair T-cell mediated anti-tumor responses. INCB001158 is being developed in a global collaboration with
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SOURCE: Calithera Biosciences, Incorporated
Source: Calithera Biosciences, Inc.