Abstract 1381: Impact of PI3K/mTOR inhibitors on the development of taxane resistance
Authors: Esplund Jayda Nicole , Xu Bing , Elsey Rachel J. , Messner Tobias , Williams Casey B. 
Published: July 2021

Background:Preclinical evidence suggests PI3K pathway activation is associated with resistance to taxane chemotherapy as well as that treatment with a PI3K or mTOR inhibitor concomitantly with paclitaxel may reduce the occurrence of taxane resistance. Data of alpelisib in combination with paclitaxel showed PR or SD in 14 out of 18 patients in the study who were previously treated with paclitaxel. A second early phase study showed a 67% ORR in heavily pretreated patients given PI3K and mTOR inhibitors in addition to paclitaxel for patients considered taxane resistant or refractory prior to study enrollment. Interestingly, a trial participant with metastatic breast cancer was effectively maintained on paclitaxel after participation in the trial had stopped. Therefore, the purpose of this analysis was to examine further whether taxane chemotherapy administered after the use of PI3K/mTOR inhibitors may reduce the development or impact of taxane resistance.

Methods: A retrospective analysis was performed on patients with breast and gynecologic cancers at Avera Cancer Institute. Patients who had an oncogenic PI3K pathway alteration and received at least one cycle of taxane chemotherapy followed by at least one dose of a PI3K or mTOR inhibitor were included. Descriptive statistics were used to determine primary and secondary outcomes. Clinical benefit was defined as the duration of time achieved with stable disease or remission from a treatment before a successive therapy was warranted. The primary outcome was defined as duration of clinical benefit achieved from each therapy. The secondary outcomes were defined as survival from date of diagnosis of metastatic disease or recurrence and reasons for discontinuation of targeted therapy.

Results: Thirty-six patients were eligible for inclusion in the analysis. PIK3CA E545K (n=7) and PIK3CA H1047R (n=10) were the most common mutations identified. Thirty-four patients received a median duration of benefit of 8 months from treatment with a PI3K or mTOR inhibitor. Twenty patients received paclitaxel after treatment with a PI3K or mTOR inhibitor and received a median duration of benefit of 6 months. Survival for evaluable patients was a median of 3.3 years, with 11 patients still alive. Main reasons for discontinuation of therapy were side effects, including rash, pneumonitis, acute kidney failure and mucositis, or progression in disease (n=20).

Conclusion: Some patients treated with PI3K or mTOR inhibitors received additional benefit from subsequent taxane therapy when considered to be resistant to taxane treatment. Several different regimens were used and in various orders; however, earlier use of PI3K or mTOR inhibitors with paclitaxel trended toward better patient outcomes with fewer lines of treatment. Adequately controlled and powered prospective studies are needed to determine a true relationship between PI3K and/or mTOR inhibitor therapy and re-initiation of taxane sensitivity.

Citation Format: Jayda Nicole Esplund, Bing Xu, Rachel J. Elsey, Tobias Messner, Casey B. Williams. Impact of PI3K/mTOR inhibitors on the development of taxane resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1381.