86 Gedatolisib, a Multitarget PI3K/AKT/mTOR (PAM) Inhibitor, Plus Fulvestrant With or Without Palbociclib for Second-Line (2L) Treatment of Patients With HR+/HER2–/PIK3CA-Wild Type (WT) Advanced Breast Cancer (ABC): Updated Results From VIKTORIA-1

Background

The PAM pathway drives breast cancer growth and mediates resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i). Combining PAM inhibition with ET plus CDK4/6i after progression may restore sensitivity, and ideally, would provide clinical benefit independent of direct PI3K-pathway alterations. Gedatolisib, a highly potent multitarget inhibitor of all class I PI3K isoforms plus mTORC1 and mTORC2, comprehensively blocks PAM regardless of PIK3CA status. The phase 3 VIKTORIA-1 trial was designed to evaluate the safety and efficacy of gedatolisib-based therapy in patients with hormone receptor-positive (HR+)/HER2-negative (HER2–) advanced breast cancer that progressed during or after standard therapy. Patients are enrolled to study 1 or study 2 based on PIK3CA status (wild type [WT] vs mutated, respectively). Herein, we present updated subgroup, safety, and quality of life (QOL) data.

Methods

This randomized, open-label, phase 3 trial enrolled patients with HR+/HER2– advanced breast cancer that progressed on/after CDK4/6i plus nonsteroidal aromatase inhibitor and had radiologically evaluable disease (per RECIST v1.1), no prior chemotherapy for advanced breast cancer, and no prior PAMi. Study 1 patients were randomized to gedatolisib plus palbociclib plus fulvestrant (triplet), gedatolisib plus fulvestrant (doublet), or fulvestrant alone, stratified by visceral metastasis, time to radiological disease progression (TTP) on immediate prior therapy, and geographic region. Treatment was given in 28-day cycles of gedatolisib 180 mg IV weekly for 3 weeks on/1 week off; palbociclib 125 mg by mouth daily for 21 days; fulvestrant 500 mg intramuscularly every 2 weeks (cycle 1) then every 4 weeks.

Results

As previously reported, study 1 met its co-primary end points, demonstrating statistically and clinically meaningful progression-free survival (PFS) prolongations with gedatolisib (median PFS, 9.3 vs 2.0 months for triplet vs fulvestrant [HR, 0.24; 95% CI, 0.17-0.35; P < .0001] and 7.4 vs 2.0 months for doublet vs fulvestrant [HR, 0.33; 95% CI, 0.24-0.48; P < .0001]). Expanded subgroup analyses showed benefit regardless of TTP on immediate prior therapy (> 6, > 12, > 18, and > 24 months) and in bone-only disease. Median time to onset of treatment-related stomatitis was generally within the first treatment week. Median time to improvement from worst grade was generally within 2 weeks. Comparing baseline and end-of-treatment HbA1c levels, gedatolisib did not produce clinically relevant hyperglycemia. QOL assessed by EQ-5D- 5L showed notable improvements in median time to deterioration for the gedatolisib arms compared with fulvestrant. EQ-5D-5L scores remained stable with gedatolisib from cycles 1 through 8. With fulvestrant, notable declines began at cycle 6 and remained below baseline at cycle 8.

Conclusions

These data support gedatolisib combination therapy as a potential new standard of care for the second-line treatment of patients with HR+/HER2– PIK3CA WT advanced breast cancer.