Watch out, metastatic ER+/HER2- breast cancer. There’s a new targeted agent in town.
On Tuesday, the U.S. Food and Drug Administration approved the drug gedatolisib, a multi-targeted kinase inhibitor capable of squelching numerous parts of a key signaling pathway often co-opted by cancer to drive tumor growth and treatment resistance in patients.
Made by the Minneapolis-based biotech firm Celcuity, the new drug ― dubbed Revtorpyk ― is designed to be used in combination with the anti-hormone drug fulvestrant, with or without a targeted CDK4/6 inhibitor, in patients with estrogen-receptor-positive or ER+/HER2-negative locally advanced or metastatic breast cancer, or mBC. The ER+/HER2- subtype is found in 60% to 70% of all mBC patients.
Sara Hurvitz, MD, senior vice president and director of Fred Hutch Cancer Center’s Clinical Research Division, led the multicenter VIKTORIA-1 trial, which generated buzz when she shared results from Study 1 at the 2025 European Society for Medical Oncology (ESMO) meeting, recently published in the Journal of Clinical Oncology. Hurvitz shared trial results of VIKTORIA-1 Study 2 at the annual American Society of Clinical Oncology (ASCO) meeting last month.
Built as two parallel studies under one giant umbrella, VIKTORIA-1 was launched to evaluate the new agent’s potential in inhibiting multiple parts of the PAM, or PI3K/AKT/mTOR, pathway.
Trial participants in Study 1, which enrolled patients without a mutation in the gene for PI3K, were separated into three groups. Patients given the “doublet” treatment received gedatolisib with fulvestrant; those given the “triplet” treatment received gedatolisib and fulvestrant plus the targeted CDK4/6 inhibitor palbociclib, or Ibrance. Another arm of the trial had patients just take fulvestrant alone. All participants receiving the new agent showed significantly improved progression-free survival compared with standard of care.
At the time, Hurvitz called the finding “statistically significant and clinically meaningful” and a “potential new standard of care.”
Now that the FDA has granted approval, that new standard is underway.
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“The exciting thing about this study is really for the first time we’ve shown that an inhibitor that targets multiple parts of the PAM pathway and completely shuts it down is tolerable for patients,” said Hurvitz, who holds the Smith Family Endowed Chair in Women’s Health. “To my knowledge, there hasn't been a drug that’s made it through late phase that hits so many components of the pathway.”
What’s so special about this pathway?
The PAM, or PI3K/AKT/mTOR, pathway is sort of a master control center, one of 10 tiny intracellular signaling networks that regulate vital cellular functions like growth, proliferation, survival and metabolism. Unfortunately, it’s also a pathway that commonly goes sideways in cancer, driving tumor progression and treatment resistance through overactive PI3K, AKT or mTOR proteins. Half of all solid tumors are driven by overactivation or dysregulation of the PAM pathway.
Hurvitz, who called it “a really complex pathway,” said it’s been implicated in resistance to CDK4/6 inhibitors and endocrine or anti-hormone therapy, both pillars of ER+/HER2- breast cancer treatment.
“We have multiple inhibitors that hit one part of that pathway,” Hurvitz said. “And the benefit of those inhibitors has been muted. They help for a little bit, then resistance develops. And there have been attempts in the past to hit multiple parts of the pathway to prevent resistance from developing. But those were too toxic.”
Gedatolisib, she said, hits multiple targets within the PAM pathway ― and does so without putting patients through a slew of debilitating side effects.
“It’s less toxic than the agents we have available,” she said. “And it’s also demonstrated improved efficacy compared to the standard of care.”
Currently, approved PI3K inhibitors are used in breast cancers with a PIK3CA mutation. But gedatolisib, she said, works whether the patient’s tumor has a PIK3CA mutation or not.
“That makes it quite unique,” Hurvitz said. “We only have one other drug that targets this pathway (everolimus, which inhibits mTOR) that doesn’t require that mutation for efficacy.”
According to the FDA, gedatolisib (aka Revtorpyk) is approved for patients without the PIK3CA mutation, so many more patients will be eligible to receive and potentially benefit from the new drug.
“A PIK3CA mutation is a somatic mutation that occurs in about 40% of patients with ER+ metastatic breast cancer,” she said. “It is usually not acquired; if it’s there at the beginning, it'll be there throughout the disease. For 60% of patients not to be eligible for a therapy because it requires a mutation is kind of a big miss.”
The newly approved agent is designed for ER+/HER2- locally advanced or metastatic breast cancer patients whose disease has progressed after being on at least one line of endocrine therapy in the metastatic setting.
Patients with ER+/HER2- mBC traditionally receive treatments designed to target three signaling pathways shown to drive cancer growth. The estrogen-fueled pathway is targeted by anti-hormone agents (think Tamoxifen, Anastrozole or Fulvestrant) and the cyclin D1-CDK4/6-dependent pathway, which drives cell division, is targeted by a handful of CDK4/6 inhibitors such as Ibrance, Kisqali and Verzenio.
The complex PI3K/AKT/mTOR or PAM pathway, however, is currently targeted only by drugs that inhibit a single part of it, such as Piqray, a PI3K inhibitor; Truqap, an AKT inhibitor and Afinitor, which blocks the mTOR complex.
The unique design of VIKTORIA-1 allowed researchers to tease out how the new drug would respond in a number of different scenarios, including how it would perform with more than one therapy (endocrine plus CDK4/6 inhibitors) and how it would perform in those who had an unmutated or “wild type” PIK3CA gene. Additional VIKTORIA trials will see how the new drug performs with other CDK4/6 inhibitors and anti-hormone drugs, as well as how it performs in patients who have not received previous treatment.
Hurvitz was equally enthusiastic about the results of VIKTORIA-1 Study 2. This study, which enrolled patients with a PIK3CA tumor mutation, showed the gedatolisib triplet and doublet regimens significantly improved median progression-free survival compared to fulvestrant/Piqray.
“FDA approval may soon be expanded to these patients as well,” she said. “Both of the gedatolisib arms showed a substantially better outcome than just using fulvestrant alone. That was in Study 1. And then in Study 2, where it was just patients with PIK3CA tumor mutations, the triplet and doublet performed very similarly to one another. And they both did better than fulvestrant with alpelisib [Piqray], which is the standard PI3K inhibitor that was in the study.”
That’s the current standard of care for many metastatic breast cancer patients with ER+/HER2- tumors. And the new drug performed better.
“This drug hits all four isoforms of PI3 kinase class one and mTORC1 and mTORC2,” Hurvitz said. “We were all surprised when we saw the Phase 1 data. We’re like, ‘Wow, this looks really active, and it looks really tolerable,’ but you never know if in a larger patient population, it’s going to continue to hold water.”
Luckily for patients, the trial results did hold water.
VIKTORIA-1 Study 1 trial participants who received gedatolisib nearly doubled the amount of time they went without any kind of cancer progression. Those on the triplet regimen went 9.3 months before progression and those on the doublet regimen went 7.4 months. The control group, which received fulvestrant alone, had a median progression-free survival of two months.
And there were far fewer side effects.
Hurvitz said drugs that inhibit parts of the PI3K pathway often cause high blood sugar or hyperglycemia, because PI3K is involved in the way we metabolize glucose in the body.
“It's an on-target toxicity we expect to see,” she said. “We also see diarrhea and rash in a lot of patients. And what was sort of surprising to all of us was that we didn’t really see diarrhea. Around 1.5% of patients had it, but it was mild, grade 1 or 2 compared to approximately 40% all-grade diarrhea which is what you see with alpelisib.”
Hyperglycemia was also very low, she said, experienced by only 2.3% of participants, and there was no grade 3 hyperglycemia in the gedatolisib-fulvestrant arm at all. In contrast, she said, 55% to 60% of patients on alpelisib have hyperglycemia.
“The one side effect we saw that’s important to be aware of with this drug was stomatitis or mouth sores,” she said. “They occurred at a higher rate, so we did mandate in these studies that patients receive steroid mouthwash four times a day. They just swish and spit.”
Gedatolisib is an intravenous infusion designed to be given three times a month in combination with fulvestrant, an intramuscular injection given once a month, with or without Ibrance, a pill taken daily for three weeks followed by one week off. According to Celcuity, the drug should be launched by October.
― Dr. Sara Hurvitz, breast cancer oncologist and senior vice president and director of Fred Hutch’s Clinical Research Division
“Big, big change, big benefit,” Hurvitz said with regard to what this would mean for patients with metastatic breast cancer, which is treatable but still not curable.
“For patients with ER+/HER2- locally advanced or metastatic breast cancer, there is an urgent need for new treatment options that can meaningfully increase the likelihood of survival without disease progression or death,” Hurvitz said in the Celcuity news release. “With the approval of Revtorpyk, oncologists now have an effective new treatment option for these patients.”
Hurvitz went on to praise the altruistic patients who participated in VIKTORIA-1 and other clinical trials designed to create more effective, less-toxic therapies.
“It’s a time for tremendous hope with the amount of progress we’re making in breast oncology,” she said. “And the discoveries we’re making are in partnership with our patients, who are our colleagues. Without their willingness to volunteer and be part of a clinical trial, none of the progress made in the last five, 10, 20 years would have been made.”
“Clinical participation can sometimes help the clinical trial participant, but not always,” she said. “But it does allow science to move forward. It’s just a wonderful example of altruism.”
Diane Mapes is a senior editor and writer at Fred Hutch Cancer Center, who's written for NBC News, TODAY, CNN, MSN, Seattle Magazine and other publications. A breast cancer survivor and patient advocate, you can reach her at dmapes@fredhutch.org or doublewhammied.com / @double_whammied / @doublewhammied.bsky.social. Just diagnosed and need information and resources? Visit our Patient Care page.
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