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Experts theorize that because resistance to PI3K inhibitors often involves downstream AKT activation, subsequent use of an AKT inhibitor is logical. However, re-challenging the pathway with a PI3K/mTOR agent like getatolisib after an AKT inhibitor has already failed is seen as less rational based on pathway biology.
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The VICTORIA-1 trial showed an unprecedented benefit for the gedatolisib triplet, with a hazard ratio of 0.24 in PIK3CA wild-type patients. The dramatic improvement suggests that PAM pathway activation is a dominant resistance mechanism even without a PIK3CA mutation, opening a new treatment avenue.
Next-generation mutant-specific PI3K inhibitors could lead to complex biomarker requirements. A future drug label might require a PIK3CA mutation for eligibility but simultaneously exclude patients who also have downstream PTEN or AKT alterations, which can confer resistance.
Despite alpelisib directly targeting the upstream PIK3CA mutation, clinicians have almost completely shifted to the downstream AKT inhibitor capivasertib in the second-line setting. This practical decision is driven by capivasertib's significantly better side effect profile and ease of management.
Retrospective analysis of the BOLERO-2 trial revealed that the mTOR inhibitor everolimus benefits patients irrespective of their PI3K mutation status. This challenges the assumption that pathway-targeted therapies are only effective when a specific mutation is present, suggesting broader mechanisms of action.
Data from older studies suggests that PI3K inhibitors and mTOR inhibitors (like everolimus) have distinct mechanisms and may not be cross-resistant. This allows clinicians to confidently sequence these agents, for example using everolimus after progression on a PI3K or AKT inhibitor, providing more lines of targeted therapy.
When patients progress on PI3K/AKT inhibitors like CAPF assertive, resistance is not primarily driven by new mutations within the PI3K pathway. In one trial, only 6% of patients developed such alterations. This suggests resistance mechanisms involve the activation of other signaling pathways, a key consideration for developing future combination therapies.
The IV drug gedatolisib, which inhibits the entire PI3K/AKT/mTOR pathway, is highly effective even in patients *without* PIK3CA mutations. This suggests pathway activation is not solely mutation-driven and creates a new option for a biomarker-negative patient group.
The VICTORIA-1 trial found that gedatolisib, a pan-PI3K/mTOR inhibitor, significantly improves progression-free survival in patients with PIK3CA *wild-type* tumors after CDK4/6 inhibitor progression. This is a crucial finding for a patient group lacking clear targeted options and broadens the utility of targeting the PI3K pathway beyond just mutated tumors.
The VICTORIA-1 trial demonstrated remarkable efficacy for the getatolisib/palbociclib/fulvestrant triplet in patients *without* PIK3CA mutations. Its ability to nearly quadruple median PFS versus fulvestrant alone (9.3 vs 2.6 months) in this wild-type population addresses a major unmet need, as these patients previously lacked effective targeted therapies in the PI3K/mTOR pathway.
Preclinical data suggests tumors with PTEN loss develop a heightened dependence on the mTOR pathway. This provides a strong biological rationale for selecting an mTOR inhibitor, like getatolisib, over an AKT or PI3K inhibitor in this specific patient subpopulation for potentially better efficacy.