Phosphatidylinositol 3-Kinase α–Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study

Abstract

Purpose We report the first-in-human phase Ia study to our knowledge (ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)–selective inhibitor. Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor–positive/human epidermal growth factor receptor 2–negative breast cancer received alpelisib 400 mg once daily. Results One hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation. Objective tumor responses were observed at doses ≥ 270 mg once daily; overall response rate was 6.0% (n = 8; one patient with endometrial cancer had a complete response, and seven patients with cervical, breast, endometrial, colon, and rectal cancers had partial responses). Stable disease was achieved in 70 (52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%. In patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative breast cancer, median progression-free survival was 5.5 months. Frequently mutated genes (≥ 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%). Conclusion Alpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3Kα inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors.

PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression

“…PI3Kα inhibitors have shown improved clinical outcome in estrogen receptor (ER)-positive and PIK3CA mutant breast cancers that have elevated PI3K signaling (Juric et al, 2017, 2018), but not all tumors are sensitive to these inhibitors. We have observed a highly uniform adaptive tumor response to PI3K inhibitors that is characterized by an increase in ER-dependent transcription, which mediates therapeutic resistance (Bosch et al, 2015).…”

A controlled trial of HNSCC patient‐derived xenografts reveals broad efficacy of PI3Kα inhibition in controlling tumor growth

“…Our study addresses the translational gap that presently exists between preclinical studies of PI3K inhibition and clinical efficacy of these agents for HNSCC patients. PI3K targeting by BYL719 has already been shown to be disease‐stabilizing in humans, supporting the potential of this drug in a restricted time window to avoid the acquisition of resistance . Moving forwards, we suggest PI3K‐targeted agents be examined for their fit into clinical usage in the neoadjuvant setting, ahead of surgical management.…”

“…Therefore, while our PDX clinical trial suggests that PI3Kα inhibition alone is likely insufficient to induce complete or partial responses, it highlights perhaps the optimal implementation approach for BYL719 in HNSCC: as a stabilizing neoadjuvant therapy, effective across most tumor genotypes. In support of this observation, the first in‐human study of BYL719 in solid tumors (including HNSCC) found that the majority of patients experienced disease stabilization from treatment, rather than partial or complete tumor regression . As all PDX models were derived from surgical specimens and all but two specimens were from primary HNSCC, the use of PI3Kα inhibition as a neoadjuvant therapy may be best suited for primary HSNCC cases undergoing initial surgery, in order to prevent progression while waiting for treatment.…”

Inhibition of the α-Subunit of Phosphoinositide 3-Kinase in Heart Increases Late Sodium Current and Is Arrhythmogenic

“…The present data lead to a prediction that inhibitors of PI3Kα will prolong QT while inhibitors of other isoforms may not (assuming no interaction with IKr) and that the QT prolongation would not be addressed appropriated during pre-clinical testing. To date, clinical trials have not reported systematically collected QT intervals in large numbers of drug-exposed subjects (Juric et al, 2017;Juric et al, 2018).…”

“…The final version may differ from this version. , and idelalisib are inhibitors of PI3K-α (Juric et al, 2018;Park and Kim, 2018), -β (Mao et al, 2017), -γ (Jin et al, 2014) and -δ (Jin et al, 2016) subunits respectively, and BKM120…”