FDA Grants IPI-549 and Nivolumab Combo Fast Track Designation for Urothelial Cancer

The FDA has granted a fast track designation a combination of novel selective PI3K-gamma inhibitor IPI-549 plus nivolumab for the treatment of patients with advanced urothelial cancer, according to a press release from developer Infinity Pharmaceuticals.

The FDA has granted a fast track designation a combination of novel selective PI3K-gamma inhibitor IPI-549 plus nivolumab (Opdivo) for the treatment of patients with advanced urothelial cancer, according to a press release from developer Infinity Pharmaceuticals.1

Following positive data seen in an ongoing phase I/Ib trial (MARIO-1; NCT02637531) of IPI-549 with or without nivolumab in patients with advanced solid tumors, patients are now being enrolled in a phase II trial (MARIO-275; NCT03980041) to assess the safety and efficacy of the combination specifically in patients with advanced urothelial carcinoma.

“Receiving Fast Track designation is an important recognition of the significant unmet need in advanced urothelial cancer and reflects the potential for IPI-549, in combination with Opdivo, to improve outcomes for these patients,” Adelene Perkins, CEO and chair of Infinity Pharmaceuticals, said in a statement. “A retrospective analysis of Bristol Myers Squibb’s CheckMate 275 accelerated approval study of Opdivo monotherapy in patients with urothelial cancer revealed an important association between high baseline levels of myeloid-derived suppressor cell (MDSC) and poor overall survival. These data, combined with our MARIO-1 data that showed IPI-549, both as a monotherapy and in combination with Opdivo treatment, is associated with a reduction in blood MDSC levels, inspired our MARIO-275 study with the goal of improving outcomes for [patients with] urothelial cancer.”

Preliminary findings from the phase I/Ib dose-escalation study were presented at the 2018 Society for Immunotherapy of Cancer Annual Meeting.2,3The combination demonstrated antitumor activity and an acceptable safety profile in patients not expected to respond to anti—PD-1 monotherapy.

For example, a patient with metastatic melanoma who had previously progressed on nivolumab achieved a partial response. This patient had an 86% reduction in MDSCs from baseline. Additionally, a patient with chemotherapy-resistant triple-negative breast cancer (TNBC) had a 26% reduction in tumor lesion size.

Eighty-two patients had been enrolled as of data cutoff, including 17 with TNBC, 11 with mesothelioma, 15 with melanoma, 12 with head and neck squamous cell carcinoma, 14 with high MDSCs, 5 with adrenocortical carcinoma, and 8 with non—small cell lung cancer. A majority of these patients were resistant to anti–PD-1/PD-L1 therapy and were being treated in the fourth-line setting. The findings covered 44 evaluable patients.

Fifteen patients achieved a best response of stable disease or better, which included a partial response in 1 patient.

The combination was considered well tolerated with mostly grade 1/2 adverse events (AEs) observed. Common treatment-related treatment-emergent AEs of any grade included rash in 24%, fatigue in 17%, aspartate aminotransferase increase (AST) in 14%, pyrexia in 14%, alanine aminotransferase increase (ALT) in 14%, and alkaline phosphatase increase ([ALP], 12%). The common grade ≥3 treatment-related treatment-emergent AEs were rash (11%), AST increase (9%), ALP increase (7%), and ALT increase (5%).

Four percent of patients discontinued treatment due to treatment-related toxicities, but no treatment-related deaths were reported.

The trial is ongoing with 129 patients expected to be enrolled across the different tumor type cohorts.

The MARIO-275 trial is a multicenter, randomized, double-blind, active-controlled phase II trial of the combination of IPI-549 and nivolumab versus nivolumab alone in patients with advanced urothelial carcinoma who have never had exposure to immune checkpoint inhibition therapy and have progressed on or recurred after treatment with platinum-based chemotherapy.

In the trial, about 160 patients are expected to be enrolled and randomized to either the combination or monotherapy arm. In the combination arm, IPI-549 will be administered orally once daily at 40 mg with intravenous nivolumab given every 4 weeks at 480 mg.

The primary end point of the trial is objective response rate by RECIST v1.1 criteria, and key secondary end points include time to response, duration of response, and progression-free survival. The study will also be observing changes in thyroid-stimulating hormone levels, electrocardiograms, ECOG performance status, temperature, pulse rate, respiration rate, and blood pressure from baseline.

IPI-549 is also being studied in combination with frontline atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) in patients with TNBC and in combination with bevacizumab (Avastin) in patients with renal cell carcinoma in the phase II MARIO-3 trial (NCT03961698).


  1. Infinity Receives Fast Track Designation for IPI-549 in Combination with the Checkpoint Inhibitor Opdivo for the Treatment of Advanced Urothelial Cancer [press release]. Cambridge, MA: Infinity Pharmaceuticals, Inc; March 25, 2020. https://bwnews.pr/2QNqtlM. Accessed March 25, 2020.
  2. Chmielowski B, Sullivan RJ, Postow M, et al. The first clinical/translational data from the expansion cohorts of a Ph1/1b Study of IPI-549, a tumor macrophage-reprogramming small molecule, in combination with nivolumab in advanced solid tumors. Presented at: 33rd Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer; November 7-11, 2018; Washington, DC. Abstract P716.
  3. Infinity Reports Clinical and Translational Data from Expansion Cohorts of MARIO‑1 Phase 1b Study of IPI-549 in Combination with Opdivo® (nivolumab) at SITC's 33rd Annual Meeting [press release]. Cambridge, MA: Infinity Pharmaceuticals, Inc; November 10, 2018.https://prn.to/2UiJiPZ. Accessed March 25, 2020.
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