On July 14, 2026, the U.S. Food and Drug Administration (FDA) approved gedatolisib (Revtorpyk, Celcuity Inc.) in combination with fulvestrant, with or without palbociclib, for adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who do not harbor a PIK3CA mutation and have progressed on or after at least one line of endocrine therapy in the metastatic setting. This marks the first targeted therapy approval specifically for PIK3CA wild-type HR+/HER2− advanced breast cancer, addressing a population historically lacking approved molecularly directed options.

Clinical Takeaway

Gedatolisib plus fulvestrant, with or without palbociclib, demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) compared with fulvestrant alone in patients with PIK3CA wild-type HR+/HER2− locally advanced or metastatic breast cancer following prior endocrine therapy. The approval expands treatment options for a molecularly defined subset of patients who have not benefited from PI3K-targeted agents reserved for PIK3CA-mutant disease.

Drug Profile & Mechanism

  • Drug name: Gedatolisib (brand name: Revtorpyk)
  • Developer: Celcuity Inc.
  • Drug class: PI3K/mTOR pathway inhibitor (pan-PI3K/mTOR inhibitor)
  • Administration: Intravenous infusion over 30 minutes, administered once weekly on Days 1, 8, and 15 of every 28-day cycle
  • Recommended dose: 180 mg IV per infusion
  • Treatment duration: Until disease progression or unacceptable toxicity
  • Combination partners: Fulvestrant (with or without palbociclib); refer to individual prescribing information for fulvestrant and palbociclib dosing

Target Population

  • Tumor type: HR-positive, HER2-negative locally advanced (inoperable) or metastatic breast cancer
  • Biomarker requirement: No PIK3CA mutation detected (PIK3CA wild-type)
  • Prior therapy requirement: Progression on or after at least one line of endocrine therapy in the metastatic setting
  • Patient population: Adult patients

Study Design

  • Trial name: VIKTORIA-1 (NCT05501886), Study 1
  • Design: Open-label, randomized, multicenter trial
  • Enrollment: 392 adults with locally advanced (inoperable) or metastatic HR-positive, HER2-negative breast cancer
  • Randomization: 1:1:1 across three arms:
  • Arm A:
    • Gedatolisib + fulvestrant + palbociclib
  • Arm B:
    • Gedatolisib + fulvestrant
  • Arm C (control):
    • Fulvestrant alone

Patients received treatment until disease progression or unacceptable toxicity. This review was conducted under the FDA’s Real-Time Oncology Review (RTOR) program and utilized the Assessment Aid, a voluntary applicant submission to facilitate FDA evaluation.

Endpoints

  • Primary endpoint: Progression-free survival (PFS) by blinded independent central review (BICR), assessed per RECIST v1.1, comparing Arm A vs. Arm C and Arm B vs. Arm C
  • Secondary endpoints: Overall survival (OS), objective response rate (ORR), and duration of response (DoR)

Efficacy Outcomes

  • Progression-Free Survival — Arm A vs. Arm C:
    • Median PFS: 9.3 months (95% CI: 7.2–16.6) in Arm A vs. 2.0 months (95% CI: 1.8–2.3) in Arm C
    • Hazard ratio: 0.24 (95% CI: 0.17–0.35); p < 0.0001
    • Representing a 76% reduction in the risk of disease progression or death with gedatolisib + fulvestrant + palbociclib vs. fulvestrant alone
  • Progression-Free Survival — Arm B vs. Arm C:
    • Median PFS: 7.4 months (95% CI: 5.5–9.9) in Arm B vs. 2.0 months (95% CI: 1.8–2.3) in Arm C
    • Hazard ratio: 0.33 (95% CI: 0.24–0.48); p < 0.0001
    • Representing a 67% reduction in the risk of disease progression or death with gedatolisib + fulvestrant vs. fulvestrant alone
  • Objective Response Rate (ORR) in patients with measurable disease:
    • Arm A: 32% (95% CI: 23–40)
    • Arm B: 28% (95% CI: 20–38)
    • Arm C: 1% (95% CI: 0–5)
  • Median Duration of Response (DoR):
    • Arm A: 17.5 months (95% CI: 8.8–Not Estimatable (NE))
    • Arm B: 12.0 months (95% CI: 8.1–NE)
    • Arm C: Not estimable (95% CI: NE–NE)
  • Overall Survival (OS): Data were immature at the time of PFS analysis, with only 25% deaths recorded in the overall population; OS follow-up is ongoing.

Safety

The prescribing information for gedatolisib (Revtorpyk) includes the following warnings and precautions:

  • Stomatitis: Monitor for oral mucositis; dose modifications may be required
  • Dermatologic adverse reactions: Skin toxicities have been reported; monitor and manage accordingly
  • Hyperglycemia: As a PI3K/mTOR pathway inhibitor, gedatolisib carries a risk of elevated blood glucose; monitor fasting blood glucose and manage with antihyperglycemic agents as needed
  • Embryo-fetal toxicity: Gedatolisib can cause fetal harm; advise patients of reproductive potential to use effective contraception during treatment and for an appropriate period after the last dose

Healthcare professionals are encouraged to report serious adverse events to the FDA MedWatch Reporting System at 1-800-FDA-1088. Full prescribing information will be available on Drugs@FDA.

Key Clinical Implications

✔ PIK3CA testing is now essential for all patients with HR+/HER2− advanced breast cancer progressing on endocrine therapy, as this approval is specifically restricted to the PIK3CA wild-type population — a group that does not benefit from existing PIK3CA inhibitors such as alpelisib or inavolisib.

✔ Gedatolisib offers two approved combination options — with fulvestrant alone (Arm B) or with fulvestrant plus palbociclib (Arm A) — giving clinicians flexibility based on prior CDK4/6 inhibitor exposure, tolerability considerations, and patient performance status.

✔ The magnitude of PFS benefit is clinically substantial: the gedatolisib + fulvestrant + palbociclib triplet reduced the hazard of progression or death by 76% versus fulvestrant alone, with a median PFS improvement of 7.3 months (9.3 vs. 2.0 months).

✔ Response durability was notable, with a median DoR of 17.5 months in the triplet arm, suggesting that responses, when achieved, are sustained — a clinically meaningful finding in a heavily pretreated population.

✔ Proactive monitoring for class-effect toxicities is warranted, including stomatitis, dermatologic reactions, and hyperglycemia, consistent with the PI3K/mTOR inhibitor drug class. Baseline glucose management and oral care protocols should be established prior to treatment initiation.

✔ Overall survival data remain immature at the time of approval; continued follow-up from VIKTORIA-1 will be critical to characterizing the full survival benefit of gedatolisib-based regimens in this population.

Bottom Line

The FDA approval of gedatolisib (Revtorpyk) in combination with fulvestrant, with or without palbociclib, represents a landmark advance for patients with PIK3CA wild-type HR+/HER2− locally advanced or metastatic breast cancer — a population that, until now, lacked an approved molecularly targeted therapy. Supported by compelling PFS data and durable response rates from the VIKTORIA-1 trial, this regimen is poised to become a new standard-of-care option for eligible patients progressing after endocrine therapy. Accurate PIK3CA biomarker testing will be critical to identify appropriate candidates and optimize treatment sequencing in this indication.

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