Combined PIK3CA and FGFR inhibition with alpelisib and infigratinib in patients with PIK3CA-mutant solid tumors, with or without FGFR alterations Journal Article
| Authors: | Hyman, D. M.; Tran, B.; Paz-Ares, L.; Machiels, J. P.; Schellens, J. H.; Bedard, P. L.; Campone, M.; Cassier, P. A.; Sarantopoulos, J.; Vaishampayan, U.; Chugh, R.; Mahipal, A.; Lockhart, A. C.; Sessa, C.; Zander, T.; Ng, M.; Curigliano, G.; Bendiske, J.; Chen, X.; Choudhury, S.; Graus-Porta, D.; Lewis, N.; Garcia, J. M. P.; de Miguel-Luken, M. J. |
| Article Title: | Combined PIK3CA and FGFR inhibition with alpelisib and infigratinib in patients with PIK3CA-mutant solid tumors, with or without FGFR alterations |
| 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 PI3Kα 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. © 2019 by American Society of Clinical Oncology. |
| Keywords: | adult; controlled study; treatment response; middle aged; unclassified drug; gene sequence; major clinical study; constipation; fatigue; advanced cancer; cancer combination chemotherapy; diarrhea; drug dose reduction; drug safety; drug withdrawal; recommended drug dose; side effect; unspecified side effect; conference paper; cancer patient; controlled clinical trial; multiple cycle treatment; breast cancer; anemia; mucosa inflammation; nausea; stomatitis; thrombocytopenia; vomiting; genotype; creatinine; creatinine blood level; phosphatidylinositol 3 kinase; asthenia; fever; hyperglycemia; rash; alanine aminotransferase; aspartate aminotransferase; maculopapular rash; drug accumulation; multicenter study; xerostomia; maximum tolerated dose; drug half life; drug dose increase; amylase blood level; hand foot syndrome; triacylglycerol lipase blood level; dry eye; dry skin; alopecia; amylase; blurred vision; dysgeusia; triacylglycerol lipase; decreased appetite; fibroblast growth factor receptor; hyperphosphatemia; body weight disorder; human; male; female; priority journal; alpelisib; infigratinib; treatment interruption; solid malignant neoplasm; pik3ca protein; maximum concentration; alanine aminotransferase level; aspartate aminotransferase level |
| Journal Title: | JCO Precision Oncology |
| ISSN: | 2473-4284 |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2019-10-16 |
| Start Page: | 3 |
| Language: | English |
| DOI: | 10.1200/po.19.00221 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Conference Paper -- Export Date: 1 July 2020 -- Source: Scopus |
