The Phase 3 VIKTORIA-1 PIK3CA wild-type cohort reported a hazard ratio of 0.24 for the gedatolisib triplet (gedatolisib, fulvestrant, palbociclib) versus fulvestrant, with median PFS of 9.3 months versus 2.0 months. The gedatolisib doublet (gedatolisib, fulvestrant) achieved a hazard ratio of 0.33 with median PFS of 7.4 months versus 2.0 months. Both regimens were evaluated in HR+/HER2- advanced breast cancer patients without PIK3CA mutations.
Celcuity has completed an NDA submission to FDA for gedatolisib in HR+/HER2- advanced breast cancer under the Real-Time Oncology Review program, leveraging prior Breakthrough Therapy and Fast Track designations. The filing is anchored in the VIKTORIA-1 PIK3CA wild-type data; enrollment for the mutant cohort has completed, and a separate first-line Phase 3 (VIKTORIA-2) pairing gedatolisib with a CDK4/6 inhibitor and fulvestrant is ongoing.
Strategically, this is an attempt to redefine the post-CDK4/6 landscape for patients without PIK3CA mutations, a population with fewer targeted options than those eligible for alpelisib or capivasertib-based regimens. Gedatolisib’s multi-node inhibition of the PI3K/AKT/mTOR axis aims to sidestep the adaptive resistance seen with single-node inhibitors, positioning the drug as a potential backbone for doublet and triplet endocrine combinations. The tension is the comparator and regimen selection. Both readouts benchmark against fulvestrant alone, a control that underrepresents contemporary sequencing where elacestrant is used in ESR1-mutant disease and capivasertib is available for tumors harboring PI3K/AKT/PTEN alterations. The triplet’s outsized effect size will invite scrutiny of the contribution of continued CDK4/6 inhibition beyond progression, a strategy with mixed precedent. The doublet’s result, while less dramatic, offers a cleaner regulatory narrative for isolating gedatolisib’s effect.
For sites, the near-term impact is operational. If approved, treatment would likely require rapid genomic triage to confirm PIK3CA wild-type status and ongoing monitoring for PAM pathway class toxicities, intensifying glucose and metabolic management workflows already familiar from PI3K and mTOR agents. Sites running VIKTORIA-2 and other follow-ons can expect tighter screening-to-treatment cycles if RTOR compresses timelines and increases demand. For sponsors and CROs, the bar for PAM-pathway programs rises: future studies will need to justify comparator choices, clarify component contributions in combination regimens, and demonstrate tolerability that supports chronic endocrine backbones. Payers will focus on regimen selection (doublet versus triplet), total cost of care, and the incremental value of continuing CDK4/6 inhibitors beyond progression, especially given competing ADCs and SERDs reshaping later lines. Diagnostic vendors may see higher volume for reflex PIK3CA testing and more nuanced panel strategies to sequence ESR1 and PAM alterations in real time.
Next, watch whether FDA accepts the filing under RTOR and how it scopes the label: PIK3CA wild-type only, doublet and/or triplet, and any line-of-therapy constraints tied to prior CDK4/6 exposure. Briefing documents will be pivotal for safety granularity, dose modification rates, and subgroup performance by ESR1, AKT/PTEN status, and duration on prior CDK4/6. The mutant cohort and the first-line VIKTORIA-2 trial are the leverage points for label expansion and earlier positioning, but they will meet a tougher comparator environment as ADCs move up-line. Manufacturing readiness and regimen logistics will matter at launch, particularly if regulators favor the triplet. The core risk is whether the magnitude of PFS benefit against a lean control translates into regulatory comfort, clinician uptake, and durable real-world performance amid rapidly evolving standards.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
