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IDO Plus PD-1 Inhibitor Combo Sparks Responses in Bladder and Cervical Cancers

Anita T. Shaffer @Shaffer1
Published: Sunday, Nov 12, 2017

Jason J. Luke, MD, FACP
Jason J. Luke, MD, FACP
The combination of nivolumab (Opdivo), a PD-1 inhibitor, and BMS-986205, a novel IDO inhibitor, generated promising response rates without increasing adverse effects in patients with advanced cervical or bladder cancers in an early-phase clinical trial that helps fuel growing interest in regimens that target the 2 immune checkpoint pathways.

The dual immunotherapy regimen resulted in an objective response rate (ORR) of 32.0% (95% CI, 14.9%-53.5%) among 25 evaluable patients with bladder cancer and 13.6% (95% CI, 2.9%-34.9%) among 22 patients with cervical cancer who were treated during the expansion stage of an ongoing phase I/IIa dose-escalation study (CA017-003), according to findings presented at the SITC 32nd Annual Meeting.1 All responses were partial responses (PRs).

The disease control rate (DCR), which consists of ORR and stable disease, was 44.0% (95% CI, 24.4%-65.1%) in the bladder cancer group and 63.6% (95% CI, 40.7%-82.8%) in the cervical cancer group. Among patients with PD-L1 expression levels ≥1%, the ORR increased to 46.2% in the bladder cancer cohort and 25.0% for the cervical cancer group. The DCR rates among PD-L1–positive patients were 61.5% in the bladder cancer group and 75.0% in the cervical cancer cohort.

Jason J. Luke, MD, lead investigator on the study, said the response rates elicited by the combination therapy exceed those seen for anti–PD-1 monotherapy in bladder cancer, where the historical response rates are 15% to 20%. For those with cervical cancer, he noted that responses were similar to those seen in patients with less extensive disease, who are more likely to respond than the participants in this study.

Notably, Luke, an assistant professor of medicine at the University of Chicago Medical Center, said the combination did not increase toxicities beyond those adverse effects that have been seen with nivolumab monotherapy. He said grade 3 or 4 treatment-related adverse events (TRAEs) were reported in 11% of patients who received the combination therapy and that no deaths related to TRAEs were observed.

If the dual checkpoint blockade strategy proves successful in larger trials, it would represent an important clinical advance. “There is the potential for the combination of IDO inhibitor and PD-1 to replace PD-1 monotherapy in almost every indication,” Luke said in an interview with OncLive.

“Based on our understanding of the biology, blocking those 2 together should universally be better than blocking PD-1 alone and, if that’s the case and there’s no increase in side effects, then obviously that’s advantageous for patients,” he said. “. . . That sets a new baseline for combination therapies moving into the future,” he added.

As research into the immune system has expanded, IDO has emerged as the second most important anticancer checkpoint target after the PD-1/PD-L1 pathway, said Luke. During his presentation, Luke said prior studies have shown that IDO1 expression in tumors is associated with a decrease in immune cell tumor infiltration, an increase in regulatory T cells, and poor patient prognosis. Specifically, IDO1 enzymes deplete tryptophan, resulting in the increased production of immunosuppressive kynurenine.

“The IDO pathway is an important immunosuppressant pathway that is upregulated in the context of a productive interferon gamma–associated tumor microenvironment,” Luke said in the interview. “We initially thought of that as PD-L1 alone but we’re learning that most often when PD-L1 gets upregulated IDO gets upregulated as well and can act as a secondary immunologic or metabolic checkpoint to slow down T cells, even if you block PD-1.”

In their study, Luke and colleagues evaluated BMS-986205, which is administered orally, at once-daily doses of 25 mg, 50 mg, 100 mg, 200 mg, and 400 mg. Patients received BMS-986205 monotherapy for a 2-week lead-in period, followed by daily BMS-986205 plus nivolumab at either 240 every 2 weeks (including the bladder and cervical cancer cohorts) or 480 mg every 4 weeks. The primary objectives were to assess safety, tolerability, dose-limiting toxicities, and appropriate dose level. After analyzing the findings, investigators are recommending a BMS-986205 dose of 100 mg daily for phase II testing.

The trial was open to patients with advanced solid tumors that have progressed following at least 1 standard regimen, including prior checkpoint inhibitors or T-cell–targeting agents. In all, 289 patients were treated in 5 dose-escalation and expansion cohorts as of data cutoffs on September 14 and October 13.

In his SITC presentation, Luke discussed results for the patients in the bladder and cervical cancer cohorts. The bladder cancer group consisted of 26 patients, including 1 patient without a posttreatment tumor assessment who was not included in the efficacy data. The median age was 66 years (range, 48-79), approximately 85% were male, about 42% had received 2 or more prior systemic regimens, and nearly 58% had an ECOG performance score of 1. The cervical cancer cohort consisted of 22 patients with a median age of 53 years (range, 33-67). More than 50% had received 2 or more prior systemic regimens and nearly 64% had an ECOG score of 1.

In addition to the efficacy measures, investigators also analyzed key indicators of immune response. They found that the dual regimen reduced intratumoral kynurenine across all doses following treatment, including in samples with relatively high pretreatment levels. The reduction was approximately 60% in serum kynurenine levels with BMS-986205 at the 100-mg dose level. Additionally, treatment with the 2 drugs was associated with an increase in Ki67-positive and CD8-positive antitumor T cells in the majority of samples tested.

In terms of toxicities, Luke reported TRAEs for all 268 patients who received at least 1 dose of the 2-drug combination. TRAEs of any grade were reported in 53.5% of patients, including grade 3 events in 10.5% and grade 4 in 0.7%. The most commonly reported TRAEs of any grade were fatigue (13.6%), nausea (11.5%), and decreased appetite (10.5%). Serious TRAEs of any grade affected 5.6% of patients, including 4.5% with grade 3 and 4 events. TRAEs of any grade leading to discontinuation affected 7% of patients.

For the entire study population, the median duration of therapy was 7.5 weeks (95% CI, 0-47) for BMS-986205 and 8.0 weeks (95% CI, 2-50) for nivolumab. Approximately 47% of the patients remain on the study; only 4 patients (1.4%) discontinued treatment due to study drug toxicity. Other reasons for discontinuation include disease progression (37.4%) and an adverse event unrelated to the study drug (6.2%).
References
  1. Luke JJ, Gelmon K, Pachynski RK, et al. 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. Presented at: 32nd Annual Meeting of the Society for Immunotherapy of Cancer; November 9-12, 2017; National Harbor, MD. Abstract O41.
  2. Moon YW, Hajjar J, Hwu P, Naing A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J Immunother Cancer. 2015;3:51. doi: 10.1186/s40425-015-0094-9.
  3. Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R. Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res. 2011;17(22):6985-6991. doi: 10.1158/1078-0432.CCR-11-1331.

 





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