Abstract
The PI3Kα inhibitor alpelisib achieved a 58.2% disease control rate in PIK3CA-altered solid tumors.
Major finding: The PI3Kα inhibitor alpelisib achieved a 58.2% disease control rate in PIK3CA-altered solid tumors.
Concept: Selective PI3Kα inhibition may have a better safety profile than pan-PI3K inhibition.
Impact: Combination therapies including alpelisib may be beneficial for the treatment of PIK3CA-altered tumors.
Mutations or amplifications affecting PIK3CA, which encodes the catalytic p110α subunit of PI3K, occur frequently in a variety of solid tumor types and result in dysregulated PI3K/mTOR signaling. This suggests the potential for PI3K inhibitors in patients with cancer, but pan-PI3K inhibitors have exhibited limiting toxicities and modest clinical activity. Isoform-specific inhibitors might overcome the limitations of pan-PI3K inhibitors, and an oral, selective p110α inhibitor, alpelisib, has demonstrated antitumor activity in preclinical studies of PIK3CA-altered tumors. Juric and colleagues evaluated the safety and efficacy of single-agent alpelisib in patients with PIK3CA-altered advanced solid tumors in a phase I dose-escalation and dose-expansion study. In total, 134 patients were enrolled, 127 with PIK3CA-altered tumors and 7 patients with PIK3CA wild-type tumors. The primary objective was to determine the maximum tolerated or recommended phase II dose of alpelisib, and secondary objectives included evaluation of alpelisib safety and tolerability, and preliminary efficacy. The overall response rate was 6%, including a complete response in a patient with endometrial cancer, and 7 partial responses in patients with cervical, breast, endometrial, colon, or rectal cancer. In addition, 52.2% of patients achieved stable disease, for an overall disease control rate of 58.2%. Nine patients (13.2%) in the dose-escalation cohort experienced dose-limiting toxicities, and the maximum tolerated doses were determined to be 400 mg daily and 150 mg twice daily. Serious adverse events were experienced by 10.4% of patients, but overall alpelisib had a tolerable safety profile. Taken together, the results of this phase I trial suggest that alpelisib is tolerable and may have antitumor activity in patients with PIK3CA-altered tumors, supporting further investigation of alpelisib in combination with other agents for the treatment of PIK3CA-altered tumors.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
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