Bristol-Myers Squibb announced encouraging results of combining Opdivo (nivolumab) with the investigational IDO1 Inhibitor, BMS-986205, in patients with advanced cancers and heavily treated with other therapies.
The data stems from the company’s ongoing CA017-003 Phase 1/2a study (NCT02658890), which is recruiting participants.
The presentation, titled “Preliminary antitumor and immunomodulatory activity of BMS‐986205, an optimized indoleamine 2,3‐dioxygenase 1 (IDO1) inhibitor, in combination with nivolumab in patients with advanced cancers,” was delivered during a late-breaking session at the Society for Immunotherapy of Cancer (SITC) 32nd Annual Meeting.
Some tumors, in an attempt to prevent an attack by the immune system, increase the expression of indoleamine-2,3-dioxygenase, or IDO. This depletes an important “fuel” of T-cells (vital cells of the immune system) called tryptophan.
Preclinical studies suggested that inhibiting IDO, coupled with other types of immunotherapy such as Opdivo (a checkpoint inhibitor targeting the PD-1 molecule). could boost the anti-tumor response.
The CA017-003 study had a first phase where researchers tested escalating doses and determined that the maximum tolerated dose of BMS-986205, combined with Opdivo, was 200 mg.
After reviewing data for the therapy’s pharmacodynamics (how a drug behaves in the body) they decided to proceed into expansion studies with a 100 mg dose.
In the dose expansion phase, researchers found that the therapy at 100 mg had anti-tumor activity in two groups of patients – heavily pre-treated bladder (25 patients) and cervical cancer patients (22 patients).
In the bladder group, the objective response rate (ORR) was 32 percent (eight patients out of 25) and the disease control rate (DCR), or the proportion of patients who achieved at least stable disease, was 44 percent (11 of 25 patients).
In the cervical cancer cohort, ORR was 14 percent (3 of 22 patients) and DCR was 64 percent (14 of 22 patients).
Researchers then analyzed patients’ responses, based on their PD-L1 levels. PD-L1 acts as a type of “off switch” and keeps immune cells from attacking tumor cells. High PD-L1 levels often are used as predictors of Opdivo response.
Patients who express PD-L1 levels above 1 percent showed an ORR of 46 percent and 25 percent in the bladder and cervical cancer groups, respectively.
In those expressing PD-L1 below 1 percent, ORR was 22 percent in the bladder cancer group. However, no response was detected in the bladder cancer patents.
These results suggest that the combined therapy is more effective in tumors with higher expression of PD-L1.
Also, researchers observed that the new combo led to an increase in the number of cytotoxic T-cells (capable of killing tumor cells) and decreased kynurenine production, a sign that they were targeting IOD-expressing tumor cells. Overall, these data suggest that the therapy is modulating the tumor immune response and making it more permissive to attack.
“The preliminary response observed with BMS-986205 plus nivolumab in this study adds to our understanding of this combination, and together with the increases in tumor CD8 positive T cells and decreases in kynurenine, suggests a potent effect, which warrants further investigation across advanced cancers,” Jason Luke, MD, study investigator and assistant professor of medicine at the University of Chicago, said in a press release.
“We are urgently pursuing transformative research to better understand tumor evasion mechanisms to help inform potential new treatment options for patients with advanced cancers,” added Mark Rutstein, development lead, IDO, Bristol-Myers Squibb. “BMS-986205 has shown encouraging characteristics, including potent and selective inhibition of IDO1, as well as pharmacokinetic data that support once-daily dosing. We look forward to additional data from this study.”