Dataset Information

A Phase I Study of Alpelisib in Combination with Trastuzumab and LJM716 in Patients with PIK3CA-Mutated HER2-Positive Metastatic Breast Cancer.

ABSTRACT:

Purpose

Activating mutations in PIK3CA promote resistance to HER2-targeted therapy in breast cancer; however, inhibition of PI3K alone leads to escape via feedback upregulation of HER3. Combined inhibition of HER2, HER3, and PI3K overcomes this mechanism preclinically.

Patients and methods

This phase I study investigated the MTD of alpelisib given in combination with trastuzumab and LJM716 (a HER3-targeted antibody) in patients with PIK3CA-mutant HER2-positive (HER2⁺) metastatic breast cancer (MBC) using the continual reassessment method. Secondary analyses included efficacy and exploratory correlative studies.

Results

Ten patients were treated initially with daily alpelisib (arm A). Grade ≥3 adverse events seen in ≥2 patients included diarrhea (n = 6), hypokalemia (n = 3), abnormal liver enzymes (n = 3), hyperglycemia (n = 2), mucositis (n = 2), and elevated lipase (n = 2). The MTD of alpelisib in arm A was 250 mg daily. This prompted the opening of arm B in which 11 patients received intermittently dosed alpelisib. Grade ≥3 adverse events seen in ≥2 patients included diarrhea (n = 5), hypokalemia (n = 3), and hypomagnesemia (n = 2). The MTD of alpelisib in arm B was 350 mg given 4 days on, 3 days off. Among 17 patients assessed, 1 had a partial response, 14 had stable disease, and 2 had disease progression at best response. Five patients had stable disease for >30 weeks. mRNA profiling of pre- and on-treatment tissue demonstrated PIK3CA target engagement by alpelisib via induction of downstream signaling and feedback pathways.

Conclusions

Combination treatment with alpelisib, trastuzumab, and LJM716 was limited by gastrointestinal toxicity. Further efforts are warranted to target the PI3K pathway in HER2⁺ MBC.

SUBMITTER: Jhaveri K

PROVIDER: S-EPMC8282678 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

A Phase I Study of Alpelisib in Combination with Trastuzumab and LJM716 in Patients with <i>PIK3CA</i>-Mutated HER2-Positive Metastatic Breast Cancer.

Jhaveri Komal K Drago Joshua Z JZ Shah Payal Deepak PD Wang Rui R Pareja Fresia F Ratzon Fanni F Iasonos Alexia A Patil Sujata S Rosen Neal N Fornier Monica N MN Sklarin Nancy T NT Chandarlapaty Sarat S Modi Shanu S

Clinical cancer research : an official journal of the American Association for Cancer Research 20210504 14

<h4>Purpose</h4>Activating mutations in <i>PIK3CA</i> promote resistance to HER2-targeted therapy in breast cancer; however, inhibition of PI3K alone leads to escape via feedback upregulation of HER3. Combined inhibition of HER2, HER3, and PI3K overcomes this mechanism preclinically.<h4>Patients and methods</h4>This phase I study investigated the MTD of alpelisib given in combination with trastuzumab and LJM716 (a HER3-targeted antibody) in patients with <i>PIK3CA</i>-mutant HER2-positive (HER2< ...[more]

PMID: 33947692

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