A phase I study of alpelisib in combination with trastuzumab and LJM716 in patients with PIK3CA-mutated HER2-positive metastatic breast cancer Journal Article
| Authors: | Jhaveri, K.; Drago, J. Z.; Shah, P. D.; Wang, R.; Pareja, F.; Ratzon, F.; Iasonos, A.; Patil, S.; Rosen, N.; Fornier, M. N.; Sklarin, N. T.; Chandarlapaty, S.; Modi, S. |
| Article Title: | 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 (HER2þ) 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 1⁄4 6), hypokalemia (n 1⁄4 3), abnormal liver enzymes (n 1⁄4 3), hyperglycemia (n 1⁄4 2), mucositis (n 1⁄4 2), and elevated lipase (n 1⁄4 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 1⁄4 5), hypokalemia (n 1⁄4 3), and hypomagnesemia (n 1⁄4 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 HER2þ MBC. © 2021 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 27 |
| Issue: | 14 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2021-07-15 |
| Start Page: | 3867 |
| End Page: | 3875 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-21-0047 |
| PUBMED: | 33947692 |
| PROVIDER: | scopus |
| PMCID: | PMC8282678 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 August 2021 -- Source: Scopus |
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