Hormone receptor–positive, HER2-negative (HR+/HER2–) breast cancer is the most common subtype of the disease. Although endocrine therapy combined with CDK4/6 inhibitors is a widely used first-line treatment, resistance frequently develops in the advanced setting, resulting in disease progression. The PI3K–AKT–mTOR signaling pathway, which regulates key cellular processes such as growth and survival, has been implicated in driving resistance to endocrine therapy in some ER-positive tumors. 

Roche’s Ipatasertib (ITOVEBI), an oral AKT inhibitor, targets this pathway and may help overcome endocrine resistance by disrupting tumor cell proliferation and survival. The ITOVEBI-based regimen is approved in the United States, Switzerland, Canada, Australia, United Arab Emirates and China. In May 2025, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency gave it a favorable opinion. The European Commission is anticipated to make a final decision on approval soon. Other international health agencies are now reviewing data from the INAVO120 study [NCT04191499].

At ASCO 2025, Roche presented final results from the overall survival (OS) analysis of the phase III INAVO120 study. The ITOVEBI-based regimen showed a significant OS benefit of 34.0 months (95% CI: 28.4–44.8) versus 27.0 months (95% CI: 22.8–38.7) in the palbociclib and fulvestrant group (stratified hazard ratio [HR] = 0.67; 95% CI: 0.48–0.94; p = 0.0190 [boundary = 0.0469]). The advantage in delaying disease progression was sustained in the updated analysis, with median progression-free survival (PFS) reaching 17.2 months for the Itovebi regimen compared with 7.3 months for the comparator arm (stratified HR = 0.42; 95% CI: 0.32–0.55).

Additionally, the ITOVEBI-based regimen led to a statistically significant improvement in objective response rate (ORR)—the proportion of patients whose cancer completely disappeared or significantly shrank following treatment. Exploratory ad hoc analyses also indicated a notable delay in time to chemotherapy by roughly two years (stratified HR = 0.43; 95% CI: 0.30–0.60). At the time of the final OS analysis, no new safety concerns were identified, and the low rate of treatment discontinuation due to adverse events supported the regimen’s favorable tolerability profile.

KOL insights: 

“The landmark data for the inavolisib-based regimen showed not only a doubling in progression-free survival, but importantly that it extended lives and gave people more time without chemotherapy.” – Expert Opinion.

Conclusion:

Targeting the PI3K pathway has shown a survival benefit in HR-positive breast cancer. For the first time, a PI3K pathway-targeted drug has shown it can help people with this breast cancer subtype live longer. The PIK3CA mutation which is associated with a poor prognosis is found in approximately 40% of HR+ advanced breast cancers. In addition to doubling PFS, the inavolisib-based regimen's groundbreaking data also demonstrated that it improved survival and the duration that patients could avoid chemotherapy. With a stable safety profile and low discontinuation rates from adverse events, no new safety flags surfaced. The INAVO120 study has several notable limitations. First, while various CDK4/6 inhibitors are being investigated in other studies, such as MORPHEUS-pan Breast Cancer, palbociclib was the only one evaluated. Furthermore, just 1.2% of patients had previously taken adjuvant CDK4/6 inhibitors, and only 0.6% of the study group were Black or African American patients, indicating a major underrepresentation of these individuals. Subgroup analyses of OS were also limited by being based on a secondary endpoint, with small patient numbers and few OS events, leading to imprecise estimates and wide confidence intervals. 

Apart from INAVO120 study, ITOVEBI is currently being investigated in three additional company-sponsored phase III clinical studies [(INAVO121; NCT05646862 (combination with fulvestrant) , INAVO122; NCT05894239 (combination with pertuzumab plus trastuzumab), INAVO123; NCT06790693 (combination with CDK4/6 inhibitor and letrozole)] in PIK3CA-mutated locally advanced or metastatic breast cancer in various combinations.