FDA Approves Gedatolisib for Advanced Breast Cancer

Treatment can initially control hormone-driven breast cancer for months or years, but the tumour often adapts and begins to grow again. A new option is now available in the United States for some patients at this stage: the FDA has approved gedatolisib, a drug that blocks several components of a major cancer-cell signalling system at once.

Marketed as Revtorpyk, gedatolisib is approved in combination with fulvestrant, with or without palbociclib. The indication covers adults with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer in which no PIK3CA mutation has been detected, following progression on or after at least one line of endocrine therapy in the metastatic setting.

The decision was based on the phase III VIKTORIA-1 trial. The results do not show that the drug cures metastatic disease, and it is not yet established that it extends overall survival. They do, however, show a substantial increase in the time patients lived without their cancer progressing.

Three approaches after treatment resistance

The trial enrolled 392 people with HR-positive, HER2-negative advanced breast cancer without a detected PIK3CA mutation. Their disease had already progressed during or after treatment with a CDK4/6 inhibitor combined with a nonsteroidal aromatase inhibitor.

Participants were randomly assigned in roughly equal numbers to three groups. One received gedatolisib, fulvestrant and palbociclib. A second received gedatolisib and fulvestrant. The control group received fulvestrant alone.

Fulvestrant blocks the oestrogen receptor that drives most cancers of this type. Palbociclib inhibits CDK4 and CDK6, proteins that help cells enter the division cycle. Gedatolisib targets a third system: the PI3K/AKT/mTOR pathway, which regulates cellular growth, metabolism and survival.

This pathway can be viewed as a branching chain of signals telling a cell to keep growing. In cancer, it can become overactive and help the tumour escape endocrine treatment and CDK4/6 inhibition. Gedatolisib inhibits all four class I PI3K isoforms as well as the mTORC1 and mTORC2 complexes, blocking several points in the pathway rather than a single component.

Nine months without progression instead of two

After a median follow-up of 10.1 months, median progression-free survival was 9.3 months with the three-drug regimen and 7.4 months with gedatolisib plus fulvestrant. It was 2.0 months with fulvestrant alone.

The hazard ratio for progression or death was 0.24 for the triplet and 0.33 for the doublet compared with fulvestrant. These correspond to relative reductions of 76% and 67% in the rate of progression or death during follow-up. They should not be interpreted as meaning that every individual patient’s risk fell by exactly those percentages.

A confirmed objective response was recorded in 31.5% of participants receiving the triplet and 28.3% receiving the doublet, compared with 1% in the fulvestrant group. Median response duration was 17.5 months and 12.0 months in the two gedatolisib groups.

Overall survival data were still immature at the primary analysis. Ninety-nine of the 392 participants had died, and neither comparison had crossed the stringent prespecified boundary for statistical significance. It therefore remains uncertain whether gedatolisib prolongs life overall.

Benefit must be weighed against toxicity

The most frequent adverse effect attributed to gedatolisib was stomatitis, including inflammation and ulcers in the mouth. It occurred in 69.2% of participants receiving the triplet and 56.9% receiving the doublet. Grade 3 stomatitis affected 19.2% and 12.3%, respectively.

Neutropenia was particularly common when palbociclib was included. Grade 3 or 4 neutropenia occurred in 62.3% of the triplet group, compared with 0.8% of the doublet group. Investigators also attributed two deaths to treatment: one from pneumonia and one from hepatic failure.

Despite these events, treatment-related toxicity led to discontinuation in 2.3% of participants receiving the triplet and 3.1% receiving the doublet. Grade 3 hyperglycaemia, a recognised effect of several drugs targeting this pathway, occurred in 2.3% of each gedatolisib group.

The FDA has required an additional randomised trial to characterise tolerability at the approved dose, including severe stomatitis and adverse events leading to dose reductions or interruptions. Follow-up for overall survival is also continuing.

VIKTORIA-1 has other limitations. Fulvestrant alone served as the control, although additional post-CDK4/6 treatment options are now used in many countries. People with uncontrolled diabetes, immediately life-threatening visceral disease or poor performance status were excluded, so the findings cannot automatically be applied to every patient with metastatic breast cancer. The trial was also funded by the drug’s manufacturer, which participated in its design, analysis and publication.

Even with these qualifications, the result is important for patients whose tumours lack a detectable PIK3CA mutation. Several earlier drugs targeting this signalling system have been used mainly in molecularly selected cancers. VIKTORIA-1 showed that broad inhibition of the PI3K/AKT/mTOR pathway can produce clinically meaningful activity even without a detected PIK3CA mutation. That finding has now moved beyond an experimental trial and become an FDA-approved treatment option, although careful toxicity management and longer follow-up remain essential.