Adding Eganelisib to Standard of Care Therapy Shows Promise in Frontline TNBC

For patients with metastatic triple-negative breast cancer (TNBC), a combined regimen of eganelisib (IPI-549) to atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) may lead to long-term progression-free survival (PFS) benefits when administered in the frontline setting, according to updated findings from the phase 2 MARIO-3 trial (NCT03961698).¹

At a median follow-up of 10.0 months (range, 8.1-14.2), the 1-year PFS rate in the intention-to-treat (ITT) population (n = 57) enrolled to the trial was 36.0% (95% CI, 23.7%-49.3%). In the phase 3 IMpassion130 trial (NCT02425891), which compared atezolizumab plus nab-paclitaxel with nab-paclitaxel alone, the PFS rate at 1 year with the investigative regimen was 23.7% (95% CI, 19.6%-27.9%) in the ITT population (n = 451); this translates to a 52% relative improvement with the eganelisib regimen.

In the PD-L1–positive population (n = 18) of MARIO-3, the 1-year PFS rate with the eganelisib triplet was 37.5% (95% CI, 16.8%-60.9%) compared with the IMpassion130 benchmark (n = 185) of 29.1% (95% CI, 22.2%-36.1%), which translated to a 29% relative improvement. In the PD-L1–negative population (n = 35) of MARIO-3, the 1-year PFS rate was 34.7% (95% CI, 19.6%-51.6%).

“Given our goal of improving long-term patient outcomes, we are particularly pleased to see that the addition of eganelisib to standard-of-care therapy showed benefit in the 1-year PFS rate in MARIO-3, regardless of PD-L1 status,” Robert Illaria, Jr., MD, chief medical officer of Infinity Pharmaceuticals, Inc., stated in a press release.

The prospective, multi-arm, multicenter, open-label combination cohort study enrolled patients with metastatic or locally advanced, histologically documented TNBC who were at least 18 years of age, had at least 1 measurable lesion, an ECOG performance status of 0 or 1, a life expectancy of at least 12 weeks, and acceptable hematologic and organ function at baseline.²

Patients who had a history of or currently active brain or leptomeningeal metastases were excluded. Other exclusion criteria included having significant cardiovascular disease, having undergone a major surgical procedure within 4 weeks before enrollment, active tuberculosis, and uncontrolled pleural effusion, pericardial effusion, or ascites in need of recurrent drainage procedures, among others.

Study participants received oral eganelisib at a daily dose of 20 mg, 30 mg, or 40 mg in combination with intravenous (IV) atezolizumab at 840 mg on days 1 and 15 of each 28-day cycle and IV nab-paclitaxel at 100 mg/m2 on days 1, 8, and 15 of each 28-day cycle.³

The primary outcome measure for the trial is complete response (CR) rate, and secondary outcome measures included safety, objective response rate (ORR), time to complete remission, time to response, duration of complete remission, duration of response (DOR), PFS, and pharmacokinetics, among others.³

Previous data from the trial were presented at the 2021 San Antonio Breast Cancer Symposium and had a data cutoff date of October 2, 2021. At a median follow-up of 9.9 months, 92.8% of 14 evaluable patients with PD-L1–positive tumors experienced tumor reduction; this was also true for 85.2% of the 27 evaluable patients with PD-L1–negative tumors.⁴

At this time point, the disease control rate (DCR) was 92.8% in those with the PD-L1–positive tumors vs 81.4% in those with PD-L1–negative tumors; the CR rates were 14.3% and 0%, respectively. Moreover, the median PFS was 11.0 months and 7.3 months, respectively.

Additional updated data showed that in the PD-L1–positive populations of MARIO-3 and IMpassion130, the ORRs were 66.7% and 58.9%, respectively. The median DOR was 11.7 months (95% CI, 1.8–not applicable [NA]) vs 8.5 months (95% CI, 7.3-9.7), respectively; the median PFS was 6.4 months (95% CI, 3.6-NA) vs 7.5 months (95% CI, 6.7-9.5), respectively.

In the PD-L1–negative populations of MARIO-3 and IMpassion130, the ORR were 54.3% vs 54.0%, respectively. The median DOR was 7.4 months (95% CI, 3.7-NA) vs not reported, respectively; the median PFS was 7.3 months (95% CI, 5.2-13.3) vs 5.6 months (95% CI, 5.5-7.3), respectively.

No new safety signals were observed during the extended period on treatment with the triplet regimen, and the safety profile of the regimen continued to be in line with what was expected for all 3 drugs.

The most common treatment-related toxicities reported in 10% or more of all treated patients (n = 62), included fatigue (all-grade, 48.4%; grade 3 or higher, 6.5%), skin adverse effects (46.8%; 11.3%), nausea (45.2%; 0%), hepatic toxicities (38.7%; 24.2%), diarrhea (29.0%; 4.8%), alopecia (25.8%; 0%), neutropenia toxicities (25.8%; 14.5%), vomiting (21.0%; 1.6%), pyrexia (16.1%; 0%), peripheral neuropathy (30.6%; 11.3%), stomatitis (14.5%; 0%), decreased appetite (12.9%; 0%), headache (12.9%; 0%), decreased weight (11.3%; 1.6%), dysgeusia (11.3%; 0%), and constipation (11.3%; 0%).

Seventy-four percent of patients remain on treatment with eganelisib vs 81% of patients who received the doublet on IMpassion130.

“These data reinforce the positive 2-year landmark overall survival [OS] data from MARIO-275 [NCT03980041] in second-line urothelial cancer, also regardless of PD-L1 status, and the encouraging PFS observed in checkpoint inhibitor–refractory squamous cell cancer of the head and neck in our MARIO-1 study [NCT03980041], which all support the potential of eganelisib to improve long-term outcomes for patients,” Illaria added.

References

1. Infinity Pharmaceuticals provides MARIO-3 update in patients with front line metastatic triple negative breast cancer suggesting potential long-term patient benefit of eganelisib. News release. Infinity Pharmaceuticals, Inc. November 14, 2022. Accessed November 15, 2022. http://bit.ly/3X2lAFP
2. About the MARIO 3 study. Infinity Pharmaceuticals, Inc. website. Accessed November 15, 2022. http://bit.ly/3UPeYsy
3. Evaluation of IPI-549 combined with front-line treatment in pts with triple-negative breast cancer or renal cell carcinoma (MARIO-3) (MARIO-3). ClinicalTrials.gov. Updated April 4, 2022. Accessed November 15, 2022. https://clinicaltrials.gov/ct2/show/NCT03961698
4. Encouraging updated data from phase 2 MARIO-3 TNBC trial presented at 2021 San Antonio Breast Cancer Symposium. News release. Infinity Pharmaceuticals, Inc. December 10, 2021. Accessed November 15, 2022. http://bit.ly/3TGVWnb