Background

Deregulation of the PI3K signalling pathway is frequent in squamous cell carcinoma of the head and neck (SCCHN) and may be implicated in radioresistance. We report on the results from a phase I 3 + 3 dose escalation study of alpelisib, a class I α-specific PI3K inhibitor in combination with concurrent cisplatin-based chemoradiation (CRT) in patients with locoregionally advanced SCCHN (LA-SCCHN).

Methods

Eligible patients had previously untreated LA-SCCHN and were candidates for CRT. The primary objective was to evaluate safety and determine the recommended phase II dose (RP2D). Alpelisib was given orally once daily at two dose levels: 200 mg and 250 mg. CRT consisted of cisplatin 100 mg/m² IV every three weeks and standard fractionation radiotherapy (IMRT) 70 Gy in 35 fractions.

Results

Nine patients were enrolled (six alpelisib 200 mg, three 250 mg). Oropharynx was the primary site in all patients (seven p16-positive; five T1-2N2M0, four T3-4N2-3M0 [AJCC 7th edition]). All patients completed CRT within seven weeks. Grade 3 alpelisib-related toxicities occurred in four patients. No dose-limiting toxicity (DLT) was observed at 200 mg among three DLT-evaluable patients. Two of two DLT-evaluable patients treated at 250 mg experienced DLTs (inability to complete ≥75% alpelisib secondary to radiation dermatitis and febrile neutropenia). Thus, RP2D was declared at 200 mg. After median follow-up of 39.7 months, two patients developed pulmonary metastases despite locoregional control. Three-year overall survival was 77.8% (95% CI 36.5%–93.9%).

Conclusion

Alpelisib at 200 mg has a manageable safety profile in combination with cisplatin-based CRT in LA-SCCHN.

中文翻译：

---

alpelisib与顺铂同步放化疗联合治疗局部局部晚期头颈部鳞状细胞癌的I期试验。

背景

PI3K信号通路的失调在头颈部鳞状细胞癌（SCCHN）中很常见，可能与放射抗性有关。我们报告了局部局部晚期SCCHN（LA-SCCHN）患者alpelisib的I 3 + 3期剂量递增研究的结果，alpelisib是I类α特异性PI3K抑制剂联合顺铂同步放化疗（CRT）。

方法

符合条件的患者以前未接受过LA-SCCHN的治疗，并且可能接受CRT治疗。主要目的是评估安全性并确定推荐的II期剂量（RP2D）。每天口服一次Alpelisib，分为两种剂量：200 mg和250 mg。CRT由每三周100 mg / m ²的顺铂和70 Gy的标准分级放疗（IMRT）分为35个部分组成。

结果

招募了九名患者（六名alpelisib 200毫克，三名250毫克）。口咽是所有患者的主要部位（七个p16阳性；五个T1-2N2M0，四个T3-4N2-3M0 [AJCC第7版]）。所有患者在7周内完成了CRT。4名患者发生了3级与alpelisib相关的毒性反应。在三例可评估DLT的患者中，在200 mg剂量下未观察到剂量限制性毒性（DLT）。在接受250 mg治疗的2位DLT可评估患者中，有2位经历了DLT（由于放射性皮炎和发热性中性粒细胞减少症，继发性阿尔培利西不能完成≥75％）。因此，宣称RP2D为200mg。中位随访39.7个月后，尽管有局部区域控制，两名患者仍发生了肺转移。三年总生存率为77.8％（95％CI 36.5％–93.9％）。

结论

在LA-SCCHN中，与200 mg的Alpelisib结合以顺铂为基础的CRT具有可控的安全性。