Alpelisib

仿單連結:中文仿單

<<2020/5/5 大腸直腸癌即時照護網>>

Alpelisib（開發代碼BYL719；商標名Piqray）

是諾華公司出售的一種藥物，是一種α特異性 PI3K 抑製劑(Phosphatidylinositol 3-Kinase α-Selective Inhibition ) 

它於2019年5月在美國被批准用於醫療。

目前它在大腸直腸癌並沒有直接的臨床三期試驗使用，但是在早期臨床試驗第一期的研究中，有些病人是屬於大腸直腸癌，有些人似乎可以獲得穩定病情的效果。

PI3KCA (encoding the catalytic p110a subunit of PI3K)突變，在大腸直腸癌 (18%) 是常常發生的事情，但是有突變跟這個藥物是否能夠有效使用，還是需要大規模的臨床試驗才能獲得證實。

目前說，只能夠使用在對標準藥物沒有效果的病人，當作是一種似恩慈的使用。

臨床醫師並不能夠保證療效及安全，但是當病人沒有其它更適合的治療選擇的時候，或許是一個參考的藥物之一。

根據 J Clin Oncol. 2018 May 1;36(13):1291-1299.  

疾病控制率 34.3% 

疾病反應率 5.7%

常見的副作用包括

高血糖，腎臟問題，腹瀉，皮疹，低血細胞，肝臟問題，胰腺炎，嘔吐和脫髮。

以下是參考資料

 

 

We report a first-in-human study, to our knowledge, evaluating the safety, MTD, and preliminary efficacy of single-agent alpelisib,a potent and highly specific p110a inhibitor, in patients with PIK3CA-altered tumors. Alpelisib demonstrated a favorable safety profile up to the MTDs of 400 mg once daily and 150 mg twicedaily. At equivalent total daily doses (400 mg once daily and 200 mg

twice daily), the once-daily regimen was better tolerated. Overall,single-agent alpelisib demonstrated a wide therapeutic window,with significant pharmacodynamic effects and disease stabilization at $ 180 mg once daily, and objective activity at $ 270 mg once daily, both well below the MTD of 400 mg once daily. On the basis of improved tolerability and similar efficacy compared with 400 mg

once daily, 300 mg once daily was selected as the dose in the phaseIII trial of fulvestrantwith or without alpelisib (SOLAR-1; ClinicalTrials.gov identifier: NCT02437318).

最後 能耐受約 80% 劑量

J Clin Oncol. 2018 May 1;36(13):1291-1299.  

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

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 a (PI3Ka)–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 PI3Ka inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors.