Can Gedatolisib Go Beyond Breast Cancer?

Half a century of searching along the PI3K/mTOR pathway and a new drug

On 14 July 2026, the US Food and Drug Administration (FDA) approved gedatolisib (Revtorpyk) for hormone receptor-positive, HER2-negative advanced breast cancer without a PIK3CA mutation (FDA product information; supporting study VIKTORIA-1, Journal of Clinical Oncology 2026). The drug simultaneously inhibits all four class I subtypes of PI3K and both mTOR complexes. Early-phase data also exist in prostate, uterine and ovarian cancers. However, these data remain a source of hope rather than evidence.

Why is this issue important?

The PI3K/AKT/mTOR pathway is one of the main routes governing the cell's growth, nutrition and survival signals. It is among the signaling pathways most commonly disrupted in cancer: a mutation in pathway genes (PIK3CA), loss of a suppressor gene (PTEN) or overactivity is common in breast, prostate, uterine, ovarian, lung and head and neck cancers. Drugs targeting the pathway have therefore been developed for more than 20 years, but much of the journey has been filled with failures.

The problem has two sides. First, when a single pathway node is shut down, the cell reactivates the signal through another route using feedback loops. Second, this pathway is also central to insulin and blood sugar balance; drugs that strongly inhibit the pathway reach dose limits because of severe hyperglycemia, rash and mouth sores. Gedatolisib tries a different answer to these two problems: shutting down the pathway at three points at once and giving the drug intravenously, intermittently.

We discussed its place in breast cancer in our article on 2026 PI3K inhibitors , and the overall picture of breast cancer treatment in our article on what has changed since 2020 . This article has a different focus: where did gedatolisib come from, why is it different and what has it shown outside breast cancer?

What is gedatolisib, and how does it work?

Gedatolisib is an intravenously administered targeted drug that inhibits the PI3K/AKT/mTOR pathway governing cell growth at three points. It inhibits all four class I subtypes of the PI3K enzyme (alpha, beta, gamma, delta) and both mTOR complexes (mTORC1 and mTORC2) together. In July 2026, the FDA approved its use in HR+/HER2- advanced breast cancer without a PIK3CA mutation with fulvestrant, with palbociclib or without palbociclib.

Laboratory data show the drug's potency. In the 2010 study that first described it, gedatolisib inhibited PI3Kα at 0,4 nanomolar and mTOR at 1,6 nanomolar; it was similarly potent (0,6 nanomolar) against the H1047R and E545K mutant PI3Kα forms common in breast cancer. In a laboratory study published by the company, gedatolisib was effective in breast cancer cell lines regardless of PIK3CA or PTEN status, and the concentration needed to inhibit growth was much lower than for alpelisib, capivasertib and everolimus. These data come from cell culture; they do not demonstrate superiority in patients.

Intravenous and intermittent administration is also a deliberate choice: the drug was developed intravenously because it did not enter the bloodstream when taken orally in mice. The recommended dose is 180 mg; it is given as a 30-minute infusion on days 1, 8 and 15 of a 28-day cycle, with a half-life of approximately 36 hours. The VIKTORIA-1 authors suggest that this difference between approximately 3 intravenous doses per month and daily oral drugs may explain the lower frequency of hyperglycemia. This is a hypothesis, not a proven mechanism.

From Easter Island soil to 2026 approval: historical context

Gedatolisib's story actually begins with a soil sample. A substance obtained from a bacterium in soil collected from Easter Island (Rapa Nui) in 1964-65 was isolated by Surendra Sehgal at Ayerst laboratories in 1972 and named rapamycin after the island. The protein targeted by rapamycin was later called the "mammalian target of rapamycin," or mTOR. During the same years, Lewis Cantley and colleagues identified the PI3K enzyme. A study published in Science in 2004 showed that the PIK3CA gene is frequently mutated in many cancers, bringing the pathway to the center of drug development.

Why did previous "dual-action" drugs fail?

The idea of inhibiting PI3K and mTOR together is not new. Many dual inhibitors were developed before gedatolisib; none received approval. Their shared problem was that these orally and continuously administered drugs could not be tolerated at an effective dose because of high blood sugar, rash and mouth sores.

Single-node drugs also had their own problems. In breast cancer, buparlisib (BELLE-2/3), pictilisib and taselisib (SANDPIPER), which inhibit all PI3K subtypes, were not approved because of side effects. In blood cancers, some indications for PI3K delta inhibitors were withdrawn in 2022-2023 because of adverse overall survival signals and toxicity. This history requires viewing gedatolisib's results with both hope and caution.

What did it show in breast cancer?

VIKTORIA-1 was conducted after progression following treatment with a CDK4/6 inhibitor and aromatase inhibitor in HR+/HER2- advanced breast cancer as a phase 3 study. In the cohort of 392 patients without a PIK3CA mutation, gedatolisib + palbociclib + fulvestrant (triplet) and gedatolisib + fulvestrant (doublet) were compared with fulvestrant alone. In the cohort of 362 patients with a PIK3CA mutation, the comparator arm was alpelisib + fulvestrant. The study is noteworthy because it tested the drug in two different biological groups, with and without PIK3CA mutations, together.

Results of the PIK3CA mutant cohort were presented as a conference abstract at ASCO 2026; the company submitted a supplemental application to the FDA for this group in August 2026. Overall survival data are not yet mature in either cohort. The VIKTORIA-2 study comparing against ribociclib in the first line is ongoing. In the phase 1b study, the response rate with first-line gedatolisib + palbociclib + hormone therapy was reported as 85,2%, and median progression-free survival as 48,4 months; this is a small, single-arm group.

Side effects: blood sugar and mouth sores

Gedatolisib's most notable feature is the lower frequency of hyperglycemia, the best-known problem with PI3K drugs. In the PIK3CA mutant cohort, this was compared directly with alpelisib within the same study. Mouth sores (stomatitis) are the most common side effect; the product information requires steroid mouthwash 4 times daily for the first 8 weeks. We also use this approach with everolimus; we described the details in our article on everolimus and dexamethasone mouthwash .

The figures from the two sources differ, and it is important to know both. The hyperglycemia rate in the article (9-12%) represents cases reported as side effects. In the FDA product information, laboratory-measured increases in fasting blood sugar occur in 46-57%, but grade 3 increases in only 0,9-1,8%. Similarly, drug-related treatment discontinuation is 2,3-3,1% in the article, while discontinuation due to any side effect is 9-12% in the product information. We discussed the relationship between cancer and blood sugar in our articles on cancer and diabetes and does sugar feed cancer? .

Gedatolisib beyond breast cancer: which cancers has it been tested in?

Before focusing on breast cancer, gedatolisib was tested in many tumor types during the Pfizer period. All these studies are phase 1 or phase 2; most are small and single-arm. Nevertheless, they contain important clues about which tumors' pathways respond to the drug. We explained what phase 1 and phase 2 studies mean in our article on phase 1 clinical trials .

Prostate cancer: the most active program

The only active development program outside breast cancer is in prostate cancer. In prostate cancer, the androgen receptor pathway and PI3K pathway work like two signaling routes that balance each other; inhibiting one can activate the other. Adding a PI3K pathway drug to hormonal treatment is therefore a rational target. Previously, another dual inhibitor, samotolisib, had also shown a signal with enzalutamide in a randomized phase 1b/2 study but did not proceed to phase 3.

In CELC-G-201, men previously treated with an androgen receptor inhibitor and with castration-resistant disease, 38 in total, received gedatolisib (120 or 180 mg) and darolutamide. At month 6, 67% of patients were being followed without radiographic progression; this rate was 74% in the low-dose arm. PSA response and tumor shrinkage rates have not yet been published. Mouth sores occurred in 44,7% (grade 3: 2,6%); there were no grade 4 or 5 drug-related side effects. The company reported that higher doses (240 and 300 mg) were being tested and that it would announce its prostate cancer strategy in the last quarter of 2026. You can find general prostate cancer treatment in this article .

Uterine and ovarian cancers

Cancers in women are among the tumors in which PI3K pathway abnormalities are common. Gedatolisib alone achieved a 16% response rate in recurrent endometrial cancer; however, the study was closed before proceeding to its second stage, and no biomarker predicting response was validated. A more striking signal came from clear cell ovarian cancer: with paclitaxel and carboplatin, responses were seen in 8 of 10 patients. However, some of these patients had not previously received chemotherapy; the proportion of responses attributable to gedatolisib versus chemotherapy therefore cannot be separated. Ovarian cancer has a clear cell subtype known to be relatively resistant to chemotherapy, so testing this signal in a randomized study would be valuable.

Colorectal cancer, lung and others

Efficacy with irinotecan in colorectal cancer remained very limited (response 4,7%). With a MEK inhibitor in KRAS- or BRAF-mutated tumors, the response was 11%; most responders again had cancers in women. Both patients who responded in the first phase 1 study had PTEN loss. In lung (non-small cell), bladder and head and neck cancers, responses were seen in combinations with chemotherapy or targeted drugs, but separate results for each tumor are limited. Results of studies with palbociclib in squamous cell lung, pancreatic and head and neck cancers and alone in acute myeloid leukemia have not been published.

Gedatolisib and CDK4/6 inhibitors: can they be used together outside breast cancer?

In breast cancer, gedatolisib gave the best result with the CDK4/6 inhibitor palbociclib. The rationale for this combination is not specific to breast cancer. Two pathways converge at the "checkpoint" that determines whether a cell divides: the PI3K/mTOR pathway increases production of cyclin D1, the protein that initiates the cell cycle; cyclin D1 then activates the CDK4/6 enzyme, inactivating the RB protein and pushing the cell toward division. The two drugs lock the same gate at two different points.

This rationale was demonstrated in the laboratory. In a study published in Cancer Cell in 2014, resistance to a PI3K inhibitor was linked to incomplete mTORC1 inhibition and persistence of cyclin D1; adding a CDK4/6 inhibitor overcame resistance. Subsequent studies showed that early adaptation to CDK4/6 inhibitors could be prevented with PI3K inhibitors and that inhibiting mTORC1/2 together stopped the cell cycle more profoundly and durably. Most of these studies were conducted in breast cancer models.

Are there clinical results outside breast cancer?

Short answer: No, not yet. The only clinical study testing gedatolisib and palbociclib together outside breast cancer is a phase 1 study at Dana-Farber Cancer Institute in squamous cell lung cancer, pancreatic cancer, head and neck cancer and other tumors dependent on the PI3K pathway (NCT03065062). Started in 2017, the study appears to have stopped enrolling patients (suspended), according to records; no safe dose, response rate or side effect data have been published to date, and the reason for suspension has not been disclosed.

There are some clues at the laboratory level:

• Colorectal cancer: In a study published in 2023, gedatolisib and palbociclib showed synergistic effects in all five colorectal cancer cell lines. This is interesting because clinically, gedatolisib had shown very limited efficacy with chemotherapy in colorectal cancer.
• Oral and head and neck cancers: In oral cavity squamous cell cancer models, PIK3CA-mutated tumors were shown to be resistant to palbociclib, while adding Pfizer's similar PI3K/mTOR inhibitor brought tumor growth under control. In tumor models obtained from patients with HPV-negative head and neck cancer, PI3K/AKT/mTOR inhibitors were among the drugs showing the strongest synergy with palbociclib.

What have similar combinations shown in other cancers?

Studies testing CDK4/6 inhibitors with PI3K/mTOR pathway drugs other than gedatolisib outside breast cancer provide the closest clinical clues. The most commonly used pair in these studies is ribociclib and the mTORC1 inhibitor everolimus:

This table provides two lessons. First, a rational mechanism does not guarantee clinical success: in neuroendocrine tumors, the combination was both ineffective and caused substantial bone marrow suppression. Second, drug interactions and tissue penetration matter: ribociclib increased everolimus levels, while everolimus did not sufficiently reach the brain tumor. Intravenous administration of gedatolisib and its inhibition of PI3K and mTORC2 in addition to mTORC1 may change some of these problems; however, there are still no clinical data demonstrating this outside breast cancer.

What distinguishes gedatolisib from other PI3K pathway drugs?

Perhaps gedatolisib's most important difference is that efficacy does not depend on a PIK3CA mutation. While other PI3K pathway drugs in breast cancer are given only to patients with pathway alterations, gedatolisib received approval in patients without a mutation. This means that patient selection in tumors outside breast cancer may also not depend on a genetic alteration. On the other hand, it means being unable to know "who will benefit" through a biomarker; there is no biomarker predicting response outside breast cancer yet. We discussed how tumors develop resistance to treatment in this article .

Frequently asked questions

What is gedatolisib?

Gedatolisib (Revtorpyk) is an intravenously administered targeted cancer drug that inhibits the PI3K/AKT/mTOR pathway governing cell growth at three points. In July 2026, the FDA approved its use with fulvestrant, with or without palbociclib, in hormone receptor-positive, HER2-negative advanced breast cancer without a PIK3CA mutation.

Is gedatolisib used outside breast cancer?

No, it is currently approved only in breast cancer. Promising signals were seen in early-phase studies in prostate, uterine and ovarian cancers; the most advanced program continues with darolutamide in prostate cancer. These uses should not enter routine treatment before being proven in randomized phase 3 studies.

Does gedatolisib raise blood sugar?

It can, but less than oral PI3K drugs. In VIKTORIA-1, hyperglycemia reported as a side effect ranged between 9-15%, versus 57,9% with alpelisib. Although increased fasting glucose was more common in laboratory measurements, grade 3 increases were below 2%.

Is gedatolisib available in Turkey?

We could not find information about authorization in Turkey. Off-label approval and procurement from abroad may be considered for unauthorized drugs; suitability is assessed according to the patient's condition and regulations.

Glossary

PI3K

Phosphoinositide 3-kinase; an enzyme family that transmits growth signals from the cell surface into the cell. Class I includes alpha, beta, gamma and delta subtypes.

mTOR

A kinase that regulates cell growth and protein production; it works as two complexes: mTORC1 and mTORC2.

PIK3CA

The gene encoding the alpha subtype of PI3K; frequently mutated in breast, uterine and other cancers.

PTEN

A tumor suppressor gene that restrains the PI3K pathway; its loss overactivates the pathway.

Dual inhibitor

A drug that inhibits two different points in the same pathway together.

IC50

The concentration of a drug required to halve the activity of its target enzyme; the lower the value, the more potent the drug.

Radiographic progression-free survival (rPFS)

The period during which disease does not progress on imaging; commonly used in prostate cancer studies.

Stomatitis

Sores and inflammation inside the mouth; a common side effect of PI3K/mTOR drugs.