Phase I study of alpelisib (BYL719), an α‐specific PI3K inhibitor, in Japanese patients with advanced solid tumors

Abstract

This phase I study aimed to determine tolerability and preliminary efficacy of single‐agent alpelisib (BYL719) in Japanese patients with advanced solid malignancies. The primary objective of the study was to estimate the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of oral alpelisib in patients with advanced solid tumors who had progressed despite standard therapy. The expansion part included patients with PIK3CA mutation/amplification; safety, preliminary efficacy, pharmacokinetic (PK)/pharmacodynamic profile, and food effect on the PK profile of alpelisib at the MTD/RP2D were determined. Oral alpelisib was given as a single agent on a continuous 28‐day treatment cycle once daily. Overall, 33 patients received alpelisib. Dose‐limiting toxicities were observed in 2 patients in the escalation part (at 400 mg/day) and 1 patient in the expansion part (at 350 mg/day). The RP2D of alpelisib was determined as 350 mg/day based on overall safety profile in the dose escalation part and previous data from a Western population; the MTD was not determined. The most common all‐grade treatment‐suspected adverse events were hyperglycemia and maculopapular rash (48.5% each) and diarrhea (45.5%). The PK of alpelisib in the Japanese population was similar to that reported in the Western population. The overall response rate, disease control rate, and median progression‐free survival at 350 mg/day were 3%, 57.6%, and 3.4 months, respectively. Alpelisib as single agent showed a favorable safety profile and encouraging preliminary efficacy in Japanese patients with advanced solid tumors.

Strategies to Overcome Failures in T-Cell Immunotherapies by Targeting PI3K-δ and –γ

“…In many solid tumor malignancies, including breast cancer, lung, head and neck cancer, and melanoma, increased activity within the PI3K pathway occurs through activating mutations and gene amplifications in PIK3CA (PI3K-a), or loss of expression of the PI3K tumor suppressor, PTEN (8)(9)(10)(11)(12)(13)(14)(15). Efforts to develop pan-PI3K inhibitors into successful anticancer therapy have been stymied by low response rates to PI3K inhibitors and significant toxicities (16)(17)(18)(19)(20)(21)(22)(23). Unlike the use of PI3K inhibitors in solid tumor malignancies, the antitumor effects of PI3K inhibition in lymphoid malignancies are not dependent on gene mutations, amplifications, or deletions within the PI3K pathway.…”

IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer

“…To date, agents that block the PI3K pathway have shown modest effects as monotherapy in PIK3CA amplified/mutated solid tumor patients, including in HNC [ 27 , 32 , 33 , 35 , 81 , 82 ]. Therefore, it is important to identify compounds that synergize with isiPI3K for treating cancer patients [ 58 , 59 , 75 , 83 , 84 , 85 , 86 ].…”

“…Alpelisib (BYL719) is an FDA-approved isiPI3K [ 30 ] that binds the p110 alpha subunit of PI3K and is inducing tumor growth arrest in PIK3CA altered solid cancers, including in HNC HPV− [ 23 , 29 , 31 , 32 , 33 ]. A similar anti-tumor response to a different isiPI3K, taselisib (GDC0032, a beta-sparing PI3K inhibitor), was observed in phase 1b clinical trials [ 34 , 35 ].…”

Targeting phosphatidylinositol 3‐kinase gamma (PI3Kγ): Discovery and development of its selective inhibitors

“…Compared with Ofatumumab, Duvelisib showed improved progression‐free survival and overall response rate in those patients for whom chemo‐immunotherapy was not suitable, which may promote the development of PI3Kγ inhibitors. Recently, in May 2019, Alpelisib (BYL‐719), a PI3Kα‐specific inhibitor, was launched onto the market 68,69 . All of these achievements highlight the greater clinical significance of PI3K isoform‐specific inhibitors compared to nonspecific inhibitors.…”