Hyman, David M., Tran, Ben, Paz-Ares, Luis, Machiels, Jean-Pascal, Schellens, Jan H., Bedard, Philippe L., Campone, Mario, Cassier, Philippe A., Sarantopoulos, John, Vaishampayan, Ulka, Chugh, Rashmi, Mahipal, Amit, Lockhart, A. Craig, Sessa, Cristiana, Zander, Thomas, Ng, Matthew, Curigliano, Giuseppe ORCID: 0000-0003-1781-2518, Bendiske, Jennifer, Chen, Xueying, Choudhury, Somesh, Graus-Porta, Diana, Lewis, Nancy, Perez Garcia, Jose Manuel and Jose de Miguel-Luken, Maria (2019). Combined PIK3CA and FGFR Inhibition With Alpelisib and Infigratinib in Patients With PIK3CA-Mutant Solid Tumors, With or Without FGFR Alterations. JCO Precis. Oncol., 3. ALEXANDRIA: AMER SOC CLINICAL ONCOLOGY. ISSN 2473-4284

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Abstract

PURPOSE Concurrent PIK3CA mutations and fibroblast growth factor receptor (FGFR) alterations occur in multiple cancer types, including estrogen receptor-positive breast cancer, bladder cancer, and endometrial cancer. In this first-in-human combination trial, we explored safety and preliminary efficacy of combining the PI3K alpha selective inhibitor alpelisib with the FGFR1-4 selective inhibitor infigratinib. PATIENTS AND METHODS Patients with PIK3CA-mutant advanced solid tumors, with or without FGFR1-3 alterations, were enrolled in the dose escalation or one of three molecular-defined dose-expansion cohorts. The primary end point was the maximum tolerated dose. Secondary end points included safety, pharmacokinetics, and response. Archival tumor samples were sequenced to explore genomic correlates of response. RESULTS In combination, both agents were escalated to full, single-agent recommended doses (alpelisib, 300 mg per day continuously; infigratinib, 125 mg per day 3 weeks on followed by 1 week off). The toxicity profile of the combination was consistent with the established safety profile of each agent, although 71% of all patients required at least one treatment interruption or dose reduction. Molecularly selected dose expansions in breast cancer and other solid tumors harboring PIK3CA mutations, alone or in combination with FGFR alterations, identified sporadic responses, predominately in tumor types and genotypes previously defined to have sensitivity to these agents. CONCLUSION The combination of alpelisib and infigratinib can be administered at full single-agent doses, although the high rate of dose interruption or reduction suggests long-term tolerability may be challenging. In exploratory signal-seeking cohorts of patients harboring dual PIK3CA and FGFR1-3 alterations, no clear evidence of synergistic activity was observed. (C) 2019 by American Society of Clinical Oncology

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hyman, David M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tran, BenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paz-Ares, LuisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Machiels, Jean-PascalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schellens, Jan H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bedard, Philippe L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campone, MarioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cassier, Philippe A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sarantopoulos, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vaishampayan, UlkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chugh, RashmiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mahipal, AmitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lockhart, A. CraigUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sessa, CristianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ng, MatthewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Curigliano, GiuseppeUNSPECIFIEDorcid.org/0000-0003-1781-2518UNSPECIFIED
Bendiske, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, XueyingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Choudhury, SomeshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Graus-Porta, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lewis, NancyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perez Garcia, Jose ManuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jose de Miguel-Luken, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-130762
DOI: 10.1200/PO.19.00221
Journal or Publication Title: JCO Precis. Oncol.
Volume: 3
Date: 2019
Publisher: AMER SOC CLINICAL ONCOLOGY
Place of Publication: ALEXANDRIA
ISSN: 2473-4284
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENETIC ALTERATIONS; MEK INHIBITION; COMBINED BRAF; CANCER; DABRAFENIB; CRIZOTINIB; PATHWAY; BGJ398Multiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/13076

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