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| Ref Type | Journal Article | ||||||||||||
| PMID | (29401002) | ||||||||||||
| Authors | Juric D, Rodon J, Tabernero J, Janku F, Burris HA, Schellens JHM, Middleton MR, Berlin J, Schuler M, Gil-Martin M, Rugo HS, Seggewiss-Bernhardt R, Huang A, Bootle D, Demanse D, Blumenstein L, Coughlin C, Quadt C, Baselga J | ||||||||||||
| Title | Phosphatidylinositol 3-Kinase α-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study. | ||||||||||||
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| Abstract Text | 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. | ||||||||||||
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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| PIK3CA mutant | colorectal cancer | sensitive | Alpelisib | Phase I | Actionable | In a Phase I trial, Alpelisib (BYL719) treatment resulted in a disease control rate of 34.3% (12/35, 0 complete response (CR), 2 partial response (PR), 10 stable disease (SD)), and a clinical benefit rate (CR+PR+SD>24 weeks) of 8.6% (3/35) in patients with colorectal cancer harboring PIK3CA mutations (PMID: 29401002; NCT01219699). | 29401002 |
| PIK3CA mutant | Advanced Solid Tumor | sensitive | Alpelisib | Phase I | Actionable | In a Phase I trial, Alpelisib (BYL719) demonstrated safety and efficacy in patients with advanced solid tumor harboring PIK3CA mutations, resulted in a disease control rate of 58.2% (78/134, 1 complete response (CR), 7 partial response (PR), 70 stable disease (SD)), and a clinical benefit rate (CR+PR+SD>24 weeks) of 15.7% (21/134) (PMID: 29401002; NCT01219699). | 29401002 |
| PIK3CA wild-type | Her2-receptor negative breast cancer | no benefit | Alpelisib | Phase I | Actionable | In a Phase I trial, Alpelisib (BYL719) treatment resulted in no clinical benefit in 4 patients with ER-positive, ERBB2 (HER2)-negative breast cancer harboring PIK3CA mutations (PMID: 29401002; NCT01219699). | 29401002 |
| PIK3CA mutant | cervical cancer | predicted - sensitive | Alpelisib | Case Reports/Case Series | Actionable | In a Phase I trial, Alpelisib (BYL719) treatment resulted in partial response in 3 patients with cervical cancer harboring PIK3CA mutations (PMID: 29401002; NCT01219699). | 29401002 |
| PIK3CA mutant | Her2-receptor negative breast cancer | sensitive | Alpelisib | Phase I | Actionable | In a Phase I trial, Alpelisib (BYL719) treatment resulted in a disease control rate of 60.9% (14/23, 0 complete response (CR), 1 partial response (PR), 13 stable disease (SD)), and a clinical benefit rate (CR+PR+SD>24 weeks) of 17.4% (4/23) in patients with ER-positive, ERBB2 (HER2)-negative breast cancer harboring PIK3CA mutations (PMID: 29401002; NCT01219699). | 29401002 |
| PIK3CA mutant | head and neck cancer | sensitive | Alpelisib | Phase I | Actionable | In a Phase I trial, Alpelisib (BYL719) treatment resulted in a disease control rate of 68.4% (13/19, 0 complete response (CR), 0 partial response (PR), 13 stable disease (SD)), and a clinical benefit rate (CR+PR+SD>24 weeks) of 10.5% (2/19) in patients with head and neck cancer harboring PIK3CA mutations (PMID: 29401002; NCT01219699). | 29401002 |
| PIK3CA mutant | endometrial cancer | sensitive | Alpelisib | Case Reports/Case Series | Actionable | In a Phase I trial, Alpelisib (BYL719) treatment resulted in 1 complete response and 1 partial response in patients with endometrial cancer harboring PIK3CA mutations (PMID: 29401002; NCT01219699). | 29401002 |