Eganelisib/Nivolumab Elicits Promising Responses, PFS Benefit in Metastatic Urothelial Cancer

The addition of eganelisib (IPI-549) to nivolumab (Opdivo) was found to elicit encouraging responses and improve progression-free survival (PFS) compared with single-agent nivolumab in patients with platinum-refractory, immunotherapy-naïve, advanced, metastatic urothelial cancer, according to an update from the phase 2 MARIO-275 (NCT03980041).¹

The independent data monitoring committee for the trial reported a favorable risk/benefit profile for the combination once the dose was reduced from 40-mg once daily to 30-mg once daily to decrease the reversible liver enzyme elevations that had been observed in the first IDMC meeting scheduled.

Infinity Pharmaceuticals, the developer of the investigational PI3K-gamma inhibitor, completed an assessment of 49 participants enrolled to the study and results indicated that treatment with the doublet resulted in a promising responses rate and a benefit in PFS, even in those who had low levels of PD-L1 expression. Moreover, the regimen was found to have an acceptable safety profile.

Data from the trial will be presented at an upcoming medical meeting in Q1 2021.

“The MARIO-275 study provided Infinity with important insights to shape the future of eganelisib in urothelial cancer,” Adelene Perkins, chief executive officer and chair of Infinity Pharmaceuticals, stated in a press release. “The data from the 49 patients enrolled in the study are very encouraging. The combination was well tolerated at the 30-mg dose of eganelisib and provided patient benefit relative to the placebo controlled arm on important response rate and PFS measures, particularly in urothelial cancer patients with low levels of PD-L1 expression who respond poorly to checkpoint inhibitors alone.”

In the multinational, prospective, randomized, active-controlled phase 2 trial, investigators set out to examine the safety and efficacy of eganelisib plus nivolumab compared with nivolumab alone.²

To be eligible for enrollment, patients had to be checkpoint inhibitor naïve, have advanced urothelial cancer, and have experienced disease progression or recurrence following treatment with a platinum-based chemotherapy. They also needed to have measurable disease per RECIST v1.1 criteria and an ECOG performance status of 0-1. If they had active brain metastases or leptomeningeal metastases, a serious or uncontrolled medical disorder that could interfere with study treatment, or a prior malignancy that was active within the prior 3 years, they were excluded.

In the trial, participants were randomized 2:1 to receive intravenous (IV) nivolumab at a dose of 480 mg every 4 weeks plus oral eganelisib at a dose of 40 mg once daily or IV nivolumab at a dose of 480 mg every 4 weeks plus placebo.

Based on these data, the pharmaceutical company is in the process of planning the launch of a new registration-enabling trial; enrollment for MARIO-275 will not be re-opened.

Previously, data from the phase 2 MARIO-3 trial were presented during the 2020 San Antonio Breast Cancer Symposium and showed that all evaluable patients with locally advanced or metastatic triple-negative breast cancer (TNBC) who received the frontline combination of eganelisib, atezolizumab (Tecentriq), and nab-paclitaxel (Abraxane) experienced tumor reduction.³ Moreover, 69.2% of evaluable patients reported objective responses to the triplet, regardless of PD-L1 status.

A total of 60 patients were enrolled to the trial. To be eligible for participation, patients needed to have unresectable locally advanced or metastatic TNBC, measurable disease, and an ECOG performance status of 0-1. Patients could not have received previous systemic therapy for advanced disease.

In the safety run-in, investigators examined the safety of oral eganelisib delivered at a daily dose of 30 mg, IV nab-paclitaxel at a dose of 100 mg/m2 given on days 1, 8, and 15, and IV atezolizumab at a dose of 840 mg delivered on days 1 and 15. Treatment was administrated in 28-day cycles. In the expansion phase of the trial, investigators sought to enroll a total of 60 participants: 30 with PD-L1 negativity, and 30 with PD-L1 positivity.

The primary efficacy end point of the trial was confirmed complete response (CR) rate in accordance with RECIST v1.1 criteria, while secondary end points comprised overall response rate (ORR) and safety.

Additional results showed that among a total of 13 patients, the CR rate with the regimen was 7.7%, the partial response rate was 61.5%, the stable disease (SD) rate was 23.1%, and 7.7% of patients experienced disease progression. In the PD-L1–positive subgroup (n = 5), the CR rate with the triplet was 20.0% and the PR rate was 80.0%; here, the ORR was 100%. In the PD-L1–negative subgroup (n = 8), the PR rate was 50.0%, the SD rate was 37.5%, and 12.5% of patients progressed; the ORR in this group was 50.0%.

Regarding safety, the most frequently reported treatment-emergent toxicities reported in all patients included nausea (64.3%), alopecia (57.1%), rash maculo-papular (42.9%), diarrhea (35.7%), decreased neutrophil count (35.7%), increased alanine aminotransferase (35.7%), and increased aspartate aminotransferase (28.6%).

In March 2020, the FDA granted a fast track designation to eganelisib for use with nivolumab in patients with advanced urothelial cancer.

References

1. Infinity Pharmaceuticals provides update for eganelisib in patients with metastatic urothelial cancer. News release. Infinity Pharmaceuticals, Inc. January 6, 2021. Accessed January 7, 2021. http://bit.ly/3osKWeu.
2. Study to evaluate the efficacy/safety of IPI-549 in combination with nivolumab in patients with advanced urothelial carcinoma (MARIO-275). ClinicalTrials.gov. Updated December 7, 2020. Accessed January 7, 2021. https://clinicaltrials.gov/ct2/show/NCT03980041.
3. Hamilton E, Lee A, Swart R, et al. MARIO-3 phase II study initial data evaluating an novel triplet combination of eganelisib (IPI-549), atezolizumab (atezo), and nab-paclitaxel (nab-pac) as first-line (1L) therapy for locally advanced or metastatic triple-negative breast cancer (TNBC). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. http://bit.ly/3bj67f2.