Ibrilatazar Plus Chemotherapy Elicits Promising Activity in Recurrent Endometrial Cancer

Alessandro Santin, MD

Combining the AKT/mTOR inhibitor and autophagy inducer ibrilatazar (ABTL0812) with paclitaxel/carboplatin led to encouraging efficacy in patients with advanced/recurrent endometrial cancer.^1,2

Findings from the phase 1/2 ENDOLUNG trial (NCT03366480) published in BMC Cancer showed that patients in the efficacy-evaluable population (n = 38) achieved an overall response rate (ORR) of 65.8% (95% CI, 52.0%-78.9%); this was comprised of a 13.2% complete response rate. The median duration of response (DOR) was 7.4 months (95% CI, 6.3-10.8). Additionally, 34.2% of patients experienced stable disease and the disease-control rate was 100%.¹

“The PI3K pathway is almost universally altered in endometrial cancer and thus represents a very interesting target. Ibrilatazar is the first PI3K inhibitor demonstrating encouraging activity and [an] excellent [adverse] effect [AE] profile in the capsule form now available”, Alexandra Leary, MD, PhD, of Gustave Roussy in Paris, France, said in a news release.²

Further, patients experienced a median overall survival of 23.6 months (95% CI, 6.4-not determined) and the median progression-free survival (PFS) was 9.8 months (95% CI, 6.6-10.6).1

Examining ENDOLUNG Enrollment and Dose Examination

The open-label ENDOLUNG study evaluated the first-in-class oral agent ibrilatazar plus paclitaxel/carboplatin in patients with histologically confirmed advanced or recurrent endometrial cancer. The phase 1 portion of the trial, a 3 + 3 de-escalation followed by an expansion cohort, also examined the regimen in patients with advanced squamous non–small cell lung cancer (NSCLC). Patients were enrolled at 9 academic institutions in Spain and France from November 2016 to February 2020. Those with carcinosarcoma and uterine sarcoma were excluded from the study.

Additional exclusion criteria noted patients could not have symptomatic brain metastases or gastrointestinal abnormalities. They were also not permitted to have received a prior PI3K/AKT/mTOR pathway inhibitor and adjuvant chemotherapy or radiotherapy less than 6 months before inclusion.

The starting dose of the 100 mg/mL oral solution was 1300 mg administered 3 times a day and de-scalation dose levels in phase 1 were 1000, 650, and 500 mg administered 3 times daily. Investigators noted that intrapatient de-escalation was not permitted. Ibrilatazar was administered 1 week before the first cycle of chemotherapy and continued until disease progression, unacceptable toxicity, withdrawal of informed consent, or investigator’s decision.

The primary end point of phase 1 was safety and tolerability, and the secondary end point was determining the recommended phase 2 dose (RP2D). In phase 2, the primary end point was ORR; PFS, DOR, and pharmacokinetics served as secondary end points.

Patients with endometrial cancer who were enrolled in phase 1 were also included in the evaluation of phase 2. Those in phase 2 of the trial (n = 51) had a median age of 69 years (range, 48-82), an ECOG performance status of 0 (n = 23) or 1 (n = 28), and were from Spain (n = 31) or France (n = 20). Most patients had recurrent disease (78.4%) and endometrioid histology (74.0%).

Safety in the Phase 1 and 2 Portions of the Study

In phase 1, one patient with endometrial cancer experienced a dose-limiting toxicity (DLT) of grade 4 neutropenia when treated at the 1300-mg dose level. In the expansion cohort, 1 DLT of grade 3 neutropenia occurred in a patient with NSCLC. The RP2D of ibrilatazar was determined to be 1300 mg given 3 times a day.

The safety population included the 51 patients enrolled in both portions of the study; 10 patients did not achieve the primary efficacy end point, and 3 experienced very low dose intensity, so these patients were not included in the per-protocol efficacy analysis group.

Patients experienced AEs that were serious (25.5%), grade 3 (66.7%), and grade 4 (17.6%) when treated with ibrilatazar plus chemotherapy. AEs led to discontinuation of therapy in 11.8% of patients and no patients died due to an AE. Grade 4 neutropenia (15.7%) also occurred. Grade 3 toxicities included neutropenia (31.4%), anemia (5.9%), thrombocytopenia (3.9%), nausea (3.9%), peripheral neuropathy (3.9%), decreased appetite (3.9%), diarrhea (3.9%), lymphopenia (2.0%), asthenia (2.0%), vomiting (2.0%), neurotoxicity (2.0%), and dysgeusia (2.0%).

Investigators noted that given the safety profile and efficacy of the combination, further confirmation in prospective randomized trials is warranted.

“Ibrilatazar, when administered in combination with chemotherapy and subsequently as maintenance therapy, has shown a median survival of over 9 months in advanced endometrial cancer. These results are highly promising. If confirmed in a randomized study, ibrilatazar could become a treatment alternative for this complex disease,” Alejandro Pérez-Fidalgo, MD, PhD, of Clinic University Hospital in Valencia, Spain, said in the news release.2

References

1. Leary A, Estévez-García P, Sabatier R, et al. ENDOLUNG trial. A phase 1/2 study of the Akt/mTOR inhibitor and autophagy inducer ibrilatazar (ABTL0812) in combination with paclitaxel/carboplatin in patients with advanced/recurrent endometrial cancer. BMC Cancer. 2024;24(1):876. doi:10.1186/s12885-024-12501-5
2. IBRILATAZAR (ABTL0812) from AbilityPharma increases chemotherapy effectiveness by 40% in patients with endometrial cancer. News release. Biospace. September 9, 2024. Accessed September 11, 2024. https://www.biospace.com/press-releases/ibrilatazar-abtl0812-from-abilitypharma-increases-chemotherapy-effectiveness-by-40-in-patients-with-endometrial-cancer