Abstract TS2-2: Clinical development of inhibitors of the PI3K pathway

Abstract

The activation of the PI3K-AKT-mTOR pathway as a mechanism of resistance to different breast cancer treatments has been well described for years at the preclinical level. This observation, together with the high frequency of alterations of this pathway in patients with breast tumors (especially in the luminal subtype such as PI3KCA mutations, loss of PTEN function or AKT mutations) makes this pathway a highly desirable in inhibiting the growth of these tumor types. The first clinical evidence that inhibition of the PI3K-AKT-mTOR pathway leads to increased progression-free survival in metastatic breast cancer came from the BOLERO-2 trial with the mTORC1-targeting agent everolimus, the only PI3K-AKT-mTOR pathway inhibitor approved to date in breast cancer. Potentially better drugs have subsequently been developed and tested. PI3K inhibitors were designed to potentiate the inhibition of the pathway to optimize treatment efficacy and improve the toxicity profile. The first to be developed were the pan-PI3K inhibitors buparlisib and pictilisib. Results from pivotal clinical studies combining fulvestrant demonstrated increased efficacy but at the cost of increased toxicity that was considered clinically unacceptable. None of them consequently eceived approval for breast cancer treatment. It was hoped that Isoform-specific PI3K inhibitors (alpha or beta-sparing) would improve the toxicity profile and increase efficacy, especially in patients with molecular alterations in the PI3K-AKT-mTOR pathway. We are now witnessing interesting times for these drugs since we have seen the results of the two phase III studies with specific pathway inhibitors, taselisib and alpelisib. During this session we will carefully review the results of both studies in terms of efficacy and toxicity profile as well as those from other phase I-II clinical trials with these and other agents. Representing the main challenges in the future, we still have to determine the best strategy to select those patients who will likely derive greater benefit from these therapies as well as establish the context in which they are most effective, taking into account the mechanisms of resistance that PI3K inhibitors can overcome or those that emerge during treatment with these drugs. Citation Format: Saura Manich C. Clinical development of inhibitors of the PI3K pathway [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr TS2-2.