Gedatolisib, Fulvestrant, and Palbociclib Triplet Under Investigation in HR+/HER2– Breast Cancer

The combination of gedatolisib and fulvestrant (Faslodex) with or without palbociclib (Ibrance) is under evaluation in the phase 3 VIKTORIA-1 trial (NCT05501886) for the treatment of patients with PIK3CA-mutated or wild-type hormone receptor (HR)–positive/HER2-negative breast cancer who have previously progressed on first-line therapy with a CDK4/6 inhibitor and a non-steroidal aromatase inhibitor, according to a poster presentation at the 2023 AACR Annual Meeting.^1,2

The primary end point of the open-label, randomized, two-part clinical trial is progression-free survival (PFS) assessed by blinded independent central review per RECIST v1.1. Overall survival (OS), safety and tolerability, overall response rate (ORR), duration of response, time to response, clinical benefit rate, quality of life, and pharmacokinetics will serve as secondary end points.

“Patients with metastatic HR-positive/HER2-negative breast cancer have good options of therapy, [with] the first line typically [involving] endocrine therapy in combination with a CDK4/6 inhibitor, which has improved overall outcomes significantly,” Heather Han, MD, said in an interview with OncLive^®. “However, most patients progress after initial first-line treatment. Resistance to CDK4/6 inhibitors, as well as to endocrine therapy, has been a major issue in this patient population.”

Han is research director and a medical oncologist in the Department of Breast Oncology at Moffitt Cancer Center in Tampa, Florida.

“There has been a major need to determine a better treatment, either up-front or at [disease] progression, to tackle these resistance issues,” Han added.

Gedatolisib plus palbociclib and endocrine therapy was previously investigated in patients with HR-positive/HER2-negative advanced breast cancer in a phase 1b trial (NCT02684032). Updated findings presented at the 2022 San Antonio Breast Cancer Symposium showed that among 94 patients evaluable for response across 4 dose-expansion arms experienced an ORR of 62%.³ In patients treated with the phase 3 dosing schedule, those in the first-line setting had a median PFS that was not yet reached, and those in the second-line setting had a median PFS of 12.9 months. Efficacy was observed irrespective of PIK3CA mutational status.

The combination of gedatolisib, fulvestrant, and palbociclib was well tolerated, and treatment-emergent adverse effects (AEs) were manageable. Only 1 patient (4%) who received the phase 3 dosing schedule discontinued treatment due to an AE. There was a low incidence of grade 3/4 AEs typically associated with PI3K/mTOR inhibitors, including hyperglycemia (7%), diarrhea (6%), and increased aspartate aminotransferase/alanine transaminase (4%). No instances of grade 3/4 colitis were reported.

“Gedatolisib is a [small molecule], dual inhibitor of the PI3K/mTORpathway. This medication has been studied extensively for this subset of patients in the prior phase 1 study in combination with endocrine therapy—either with fulvestrant or [letrozole [Femara]—and with palbociclib. [Data from] the prior phase 1 study and dose expansion showed great tolerability and great response rates. Based on this phase 1 study, this registrational phase 3 study was designed,” Han expanded.

VIKTORIA-1 is enrolling patients at least 18 years of age with confirmed metastatic or locally advanced HR-positive/HER2-negative breast cancer who previously progressed during or after treatment with a CDK4/6 inhibitor and a non-steroidal aromatase inhibitor.^1,2 Patients also need an adequate archival or fresh tumor specimen to analyze for PIK3CA mutations, and testing is being conducted by a central lab using an FDA-approved test. Radiologically evaluable disease per RECIST v1.1 criteria and adequate bone marrow, hepatic, renal, and coagulation function are also required.

Key exclusion criteria include prior treatment with PI3K, AKT, or mTOR inhibitors; prior chemotherapy for advanced disease; more than 2 prior lines of endocrine therapy (a selective estrogen receptor degrader other than fulvestrant is permitted); bone-only disease with no soft tissue component; or a history of drug-induced pneumonitis or interstitial lung disease.

The study is being broken into 2 parts, based on PIK3CA mutational status. Those with PIK3CA wild-type disease will be randomly assigned 1:1:1 to receive gedatolisib plus palbociclib and fulvestrant (arm A); gedatolisib plus fulvestrant (arm B); or fulvestrant alone (arm C). Those harboring PIK3CA mutations will be randomly assigned 3:3:1 to receive gedatolisib plus palbociclib and fulvestrant (arm D); alpelisib (Piqray) plus fulvestrant (arm E); or gedatolisib plus fulvestrant (arm F).

In the PIK3CA wild-type portion of the study, the primary end point of PFS will be evaluated for arm A vs arm C and arm B vs arm C. PFS for arm A vs arm B will be a secondary end point.

The PIK3CA-mutant portion of the study will examine PFS between arms D and E as the primary end point, and PFS for arm D vs arm F will be a secondary end point.

The study is expected to enroll approximately 701 patients, including 351 with PIK3CA wild-type disease and 350 with PIK3CA-mutated disease. The primary completion date is expected to occur in the second half of 2024.

“Despite success with first-line treatment with a CDK4/6 inhibitor and endocrine therapy for patients with HR-positive/HER2-negative advanced breast cancer, we need [better treatments in the] second line and beyond for this patient population, as resistance is a real issue. I urge you to enroll patients on this trial so we can determine if this triplet combination could potentially restore sensitivity to CDK4/6 inhibitors and prevent adaptive activation of the PI3K/mTOR pathway [during] initial first-line treatment,” Han concluded.

References

1. Hurvitz SA, André F, Cristofanilli F, et al. A phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1). Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL.
2. Hurvitz SA, André F, Cristofanilli F, et al. A Phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/ HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1). Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract OT3-26-02.
3. Wesolowski R, Rugo H, Stringer-Reasor E, et al. Updated results of a phase 1b study of gedatolisib plus palbociclib and endocrine therapy in women with hormone receptor positive advanced breast cancer: subgroup analysis by PIK3CA mutation status. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract PD13-05.