Eganelisib Combination Therapies Demonstrate Promising Survival Benefit in Advanced Urothelial Carcinoma and TNBC


Novel eganelisib shows survival-extending potential in patients with triple-negative breast and bladder cancers.

Eganelisib (IPI-549) has demonstrated a promising survival benefit in combination with nivolumab (Opdivo) for patients with advanced urothelial carcinoma and in combination with atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) in patients with locally advanced or metastatic triple-negative breast cancer (TNBC), according to updated findings from the phase 2 MARIO-275 (NCT03980041) and MARIO-3 trials (NCT03961698) announced by Infinity Pharmaceuticals, Inc.1

In MARIO-275—which evaluated the combination in a population of patients with platinum-refractory, immunotherapy-naïve advanced urothelial carcinoma—the eganelisib plus nivolumab combination yielded a median overall survival (OS) of 15.4 months (95% CI, 6.2–not evaluable [NE]) vs 7.9 months (95% CI, 2.3-NE) with single-agent nivolumab in the intent-to-treat (ITT) population (HR, 0.62; 95% CI, 0.28-1.36). At 1 year, 59% of patients in the ITT population who received eganelisib/nivolumab were alive compared with 32% of patients in the control arm.

“The promising survival benefit was noted after over a year of following MARIO-275 patients versus the control arm as well as compared to historical trials including CheckMate 275 [NCT02387996], particularly given the magnitude of the unmet need in [second-line urothelial carcinoma], including in the PD-L1–negative patient population,” Brian Schwartz, MD, consulting chief physician at Infinity Pharmaceuticals, said in a press release. “We believe overall survival represents a key registrational end point, and given these exciting new OS data, we are exploring the optimal study design for a potential registration study and expect to provide a program update by the end of 2021.”

Moreover, findings from MARIO-3—which evaluated the triplet combination of eganelisib plus atezolizumab and nab-paclitaxel in the frontline setting for patients with unresectable locally advanced or metastatic TNBC—indicated that 86.8% of patients experienced tumor reduction. In total, investigators reported that those with PD-L1–negative (n = 23) and -positive (n = 12) tumors had a disease control rate (DCR) of 78.2% and 91.7%, respectively, as well as a DCR of 84.2% for all patients (n = 38).

Additionally, patients with PD-L1–negative tumors experienced an extended median progression-free survival (PFS) vs benchmark data for atezolizumab and nab-paclitaxel alone, having increased from 5.6 months to 7.3 months (95% CI, 3.5-not available [NA]). Patients with PD-L1–positive tumors experienced a similar increase from 7.5 months to 11.2 months (95% CI, 5.3-11.2). Median PFS extended from 7.2 to 7.4 months (95% CI, 5.3-NA) in the ITT population.

“The emerging progression-free survival data from MARIO-3 are very encouraging and suggest that the impressive disease control rate observed, regardless of PD-L1 status, is translating to a benefit in progression-free survival. These results are consistent with the results from MARIO-275, which show the similar translation of disease control into a meaningful survival benefit for patients. For patients with TNBC, the potential to extend progression-free survival, regardless of PD-L1 status, would be a transformational breakthrough. We are on track to complete enrollment by year end, and with the majority of patients still on treatment, look forward to presenting additional, more mature data at that time,” lead study author Erika Hamilton, MD, director of the Breast Cancer and Gynecologic Cancer Research Program at Tennessee Oncology, noted.

As of June 2020, 49 patients had enrolled on the MARIO-275 trial. Forty-three patients had enrolled on the MARIO-3 trial, 38 of whom were evaluable

Other findings from the MARIO-275 trial indicated that patients with PD-L1–negative tumors within the ITT population had a median OS of 15.4 months (95% CI, 4.7-NE) after being treated with the combination vs 7.9 months (95% CI, 1.9-NE) in the control arm (HR, 0.60; 95% CI, 0.21-1.71); this translates to a 40% lower chance of death with the combination. Over half (54%) of patients with PD-L1–negative tumors who received the combination were alive at 1 year vs 17% in the control arm.

Patients enrolled on the MARIO-3 trial who had PD-L1–negative tumors and received the triplet regimen had a partial response (PR) rate of 47.8% and 30.4% had stable disease. Moreover, those with PD-L1–positive tumors had a complete response (CR) rate of 16.7%, a PR rate of 50%, and 28.9% achieved stable disease. The overall patient population achieved a CR rate of 5.3%, a PR rate of 50%, and a stable disease rate of 28.9%.

The most common treatment-emergent adverse effects (TEAE) that were noted on the MARIO-275 trial included pyrexia (33.3%), decreased appetite (30.3%), pruritus (27.3%), and asthenia (27.3%). The most common grade 3 or higher TEAE were disease progression (27.3%), anemia (12.1%), and hepatic AEs including hepatotoxicity (15.2%), increased alanine aminotransferase (12.1%), and increased aspartate aminotransferase (AST; 12.1%) with no Hy’s Law. No patient experienced grade 5 hepatic AEs.

Moreover, no new safety signals were reported with the MARIO-3 regimen. The most common any-grade TEAEs were nausea (51.2%), fatigue (48.8%), alopecia (32.6%), diarrhea (32.6%), and rash maculo-papular (30.2%). There were no reported cases of grade 5 hepatic AEs, although 1 patient permanently discontinued treatment due to elevated liver function.

Eganelisib is a first-in-class, selective PI3K-γ–inhibiting immuno-oncology agent that is being investigated across multiple indications.


Infinity Pharmaceuticals presents updated data from phase 2 MARIO-275 trial in urothelial cancer (UC) and phase 2 MARIO-3 trial in triple negative breast cancer (TNBC). News release. Infinity Pharmaceuticals. July 27, 2021. Accessed July 28, 2021.

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