Gedatolisib Combinations Nearly Double PFS in PIK3CA-Mutant Breast Cancer

On July 14, 2026, the FDA approved gedatolisib (Revtorpyk) in combination with fulvestrant (Faslodex), with or without palbociclib (Ibrance), for adults with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer without a PIK3CA mutation, based on results from Study 1 of the phase 3 VIKTORIA-1 trial (NCT05501886).¹ Gedatolisib is the first agent to receive FDA approval that inhibits all 4 class I PI3K isoforms along with both mTORC1 and mTORC2.

Data presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting now extend the VIKTORIA-1 story to the trial's second cohort: patients with PIK3CA-mutant disease.² Celcuity, the drug's developer, has stated it plans to submit a supplemental new drug application in the third quarter of 2026 seeking to expand the indication to this population, based on these results.

In an interview, Sara Hurvitz, MD, senior vice president and director of the Clinical Research Division, professor in the Clinical Research Division, and Smith Family Endowed Chair in Women’s Health at Fred Hutch Cancer Center, discussed the design and key findings of the PIK3CA-mutant cohort of VIKTORIA-1, how the data compare with existing standard-of-care options, the regimen's safety and monitoring considerations, and what the results could mean for patients as gedatolisib moves toward a broader approval.

Targeted Oncology^TM: What are the main takeaways you would want colleagues to have from this presentation?

Sara Hurvitz, MD: VIKTORIA-1 is a large, phase 3, randomized, open-label trial conducted as 2 studies within 1. Both are testing gedatolisib, a potent inhibitor of the PI3K/AKT/mTOR pathway that hits all 4 class I PI3K isoforms as well as mTORC1 and mTORC2. Previous attempts to inhibit the pathway this comprehensively were limited by toxicity, so this is a fairly unique molecule. The first study, already reported and published, enrolled patients whose tumors were PIK3CA wild-type [and supported gedatolisib's recent FDA approval]. The data presented at ASCO 2026 come from the second study, which enrolled patients whose tumors were PIK3CA mutant. These patients were randomly assigned, in a 3:3:1 ratio, to a triplet of gedatolisib, palbociclib, and fulvestrant (n = 155); a doublet of gedatolisib and fulvestrant (n = 52), a smaller, exploratory arm; or alpelisib [Piqray] plus fulvestrant (n = 155), which was the standard of care for this population when the trial was designed. The primary end point was PFS for the triplet vs alpelisib plus fulvestrant.

The triplet showed a statistically significant and clinically meaningful improvement in PFS, with a median of 11.1 months versus the standard-of-care doublet—to our knowledge, the longest PFS reported in a phase 3 trial in this disease subtype after a CDK4/6 inhibitor—and a hazard ratio of 0.50, a 50% reduction in the risk of progression or death. The objective response rate with the triplet was 48.9%, also the highest reported in this population. In the exploratory analysis, the gedatolisib-fulvestrant doublet showed a very similar benefit, with a median PFS of 11.3 months and a hazard ratio of 0.51.

How do these efficacy results compare with the existing standard of care for this population?

One strength of VIKTORIA-1 is that it included an active standard-of-care comparator rather than fulvestrant alone, something few trials in this setting have done, and it gives us a direct, within-trial comparison. Looking at other studies for context: in EPIK-B5 [NCT05038735],³ which evaluated alpelisib plus fulvestrant in CDK4/6 inhibitor-pretreated, PIK3CA-mutant patients, the median PFS was around 7.4 months, lower than what we saw in VIKTORIA-1, though that was a smaller study with a somewhat different, less heavily pretreated population. In CAPItello-291 [NCT04305496], which evaluated capivasertib [Truqap] plus fulvestrant, the median PFS was around 5.5 months, which lines up closely with where our doublet arm falls.⁴ So from an efficacy standpoint, these results represent real progress. Just as important, though, is that we've substantially improved the toxicity profile, likely helped by gedatolisib's intravenous formulation—we're seeing much better outcomes in terms of GI side effects, hyperglycemia, and rash than with alpelisib.

Does the safety profile call for any different monitoring compared with what oncologists already do?

Because the alpelisib-fulvestrant arm was included, regulatory discussions tied to alpelisib's label required an HbA1c cutoff of 6.4% for enrollment, and glucose monitoring was correspondingly more intensive for patients on that arm. In practice, I suspect we could treat patients with somewhat higher HbA1c, and studying gedatolisib's safety specifically in patients with diabetes, a substantial population, would be a worthwhile future study. I don't think we'll need the same intensity of glucose monitoring [in practice].

What we do need to watch for is stomatitis. All patients on this study received prophylactic steroid swish-and-spit mouthwash from the outset, and still, more than 60% had some degree of stomatitis, although with the doublet only 6% were grade 3, and we didn't see new events accumulate much after cycle 3. So it tends to happen early, and clinicians should monitor closely in the first two cycles, reinforce good oral care, and make sure patients know to report problems promptly.

What did you see in terms of treatment discontinuation between the triplet and the exploratory doublet arm?

Keeping in mind that the gedatolisib-fulvestrant doublet arm included only 52 patients vs 155 in the triplet, discontinuation due to an adverse event occurred in 4 patients in the triplet arm and 2 in the doublet arm, both treatment-related, compared with 13 patients in the alpelisib arm, 11 of which were treatment related. Relative dose intensity is another useful way to look at how much drug actually reached patients, and it was notably high for gedatolisib: 100% for the gedatolisib-fulvestrant doublet, compared with 81.7% for alpelisib. Palbociclib dose reductions for neutropenia did occur in the triplet, bringing its relative dose intensity to 93.3%, which is still quite strong for a three-drug regimen.

With gedatolisib now approved in the PIK3CA wild-type setting, what would an expanded approval in the PIK3CA-mutant population mean to you and to patients?

It's very exciting to think about having a regimen with a therapeutic index this much better, not only because of its efficacy but because of its tolerability. This is something I would want to offer my patients, and I think it also gives them real hope. Historically, single-agent endocrine therapy after a CDK4/6 inhibitor has offered a PFS on the order of 2 to 3 months, and even the doublet PI3K/AKT/mTOR pathway-targeted therapies we've had have generally landed around 5.5 months. What we're seeing with gedatolisib moves that needle substantially. I'm also looking forward to the overall survival data maturing, likely over the next year to year and a half, which will further inform how we sequence and choose among these doublet and triplet regimens in practice.

Read more about the FDA approval of gedatolisib in an interview with Erica Stringer-Reasor, MD.

REFERENCES

1. FDA approves gedatolisib with fulvestrant, with or without palbociclib, for HR-positive, HER2-negative locally advanced or metastatic breast cancer. News release. FDA. July 14, 2026. Accessed July 14, 2026. https://tinyurl.com/3bc988ps

2. 1. Hurvitz SA et al. A randomized, open-label, phase 3 study of gedatolisib + fulvestrant ± palbociclib vs standard of care in HR+/HER2−/PIK3CA-mutant (MT) advanced breast cancer (VIKTORIA-1 Study 2). J Clin Oncol. 44, 2026 (suppl 17; abstr LBA1008). doi: 10.1200/JCO.2026.44.17_suppl.LBA1008

3. Loizidis S, Michaelides D, Marcou Y, et al. Comparison Between Alpelisib Plus Endocrine Therapy and Everolimus Plus Endocrine Therapy After CDK4/6 Inhibitors Progression in Patients with PIK3CA-Mutant Metastatic Breast Cancer: A Single-Center Retrospective Study. Cancers (Basel). 2026 Jan 30;18(3):468. doi: 10.3390/cancers18030468. PMID: 41681940; PMCID: PMC12896634.

4. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023 Jun 1;388(22):2058-2070. doi: 10.1056/NEJMoa2214131. PMID: 37256976; PMCID: PMC11335038.