背景：TAPUR 是一項Ⅱ期籃式研究，評估商業上可買到的靶向藥物對伴有基因組改變的晚期癌症患者的抗腫瘤活性。結果在一組具有 ERBB2 或 ERBB3 擴增的 UC 患者中，報告了經 P+T 治療的過度表達或突變。

Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of UC pts with ERBB2 or ERBB3 amplification, overexpression or mutation treated with P+T are reported.

方法：符合條件的患者有晚期 UC、無標準治療方案、可測量的疾病、ecogps0-2 和足夠的器官功能。基因組測試是在經過認證的、CAP 認證的選定實驗室進行的。與 P+T 匹配的患者有 UC 伴 ERBB2 或 ERBB3擴增或過表達或預先指定的 ERBB2 突變。推薦劑量為 P，初始劑量為 840 毫克靜脈注射（靜脈注射）超過60 分鍾（m），然後 420 毫克靜脈注射超過 30-60 米每 3 周（wks），和 T，初始劑量為 8 毫克/千克靜脈注射超過 90 米，然後 6 毫克/千克靜脈注射超過 30-60 米每 3 周，直到疾病進展。Simon 2 階段設計測試無效疾病控製（DC）-定義為部分（PR），完全緩解（CR）或 16 周以上穩定疾病（SD 16+）-比率為 15%對35%（冪=0.85；a=0.10）。如果第 1 階段的 10 個點中有 2 個點有 DC，則再注冊 18 個點。如果 28 分中有7 分有直流電，則拒絕零直流電費率。次要終點是無進展生存期（PFS）、總生存期（OS）和安全性。

Methods: Eligible pts had advanced UC, no standard treatment options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts matched to P+T had UC with ERBB2 or ERBB3 amplification or overexpression or a pre-specified ERBB2 mutation. Recommended dosing was P at an initial dose of 840 mg intravenously (IV) over 60 minutes (m), then 420 mg IV over 30-60 m every 3 weeks (wks), and T at an initial dose of 8 mg/kg IV over 90 m, then 6 mg/kg IV over 30-60 m every 3 wks until disease progression. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety.

結果：2017 年 8 月至 2019 年 11 月，28 名女性患者入選；所有患者的療效和毒性均可評估。人口統計和結果總結在下表中。22 例有 ERBB2 擴增（21 例）或過表達（1 例）；4 例有 ERBB2 基因突變；1 例有ERBB3 擴增；1 例腫瘤同時存在 ERBB2 擴增和突變。在 ERBB2 擴增的患者中觀察到 2 例 PR 和 7 例 SD16+，在一例僅發生 ERBB2V8421 突變（未擴增）的患者中觀察到 1 例 SD16+，客觀有效率（OR）分別為 37%（95%CI，21%-50%）和 7.1%（95%CI，0.8%-24%）。1 例患者出現 3 級肌無力，至少可能與 P+T 有關。

Results: Twenty-eight female pts were enrolled from August 2017 to November 2019; all pts were evaluable for efficacy and toxicity. Demographics and outcomes are summarized in Table. Twenty-two pts had tumors with ERBB2 amplification (21) or overexpression (1); 4 tumors had ERBB2 mutations; 1 tumor had ERBB3 amplification; 1 tumor had both an ERBB2 amplification and mutation. Two PR and 7 SD16+ were observed in pts with ERBB2 amplification, and 1 SD16+ was observed in a pt with ERBB2 V8421 mutation only (no amplification) for DC and objective response (OR) rates of 37% (95% CI, 21% to 50%) and 7.1% (95% CI, 0.8% to 24%), respectively. One pt experienced grade 3 muscle weakness at least possibly related to P+T.

結論：P+T 在經過大量預處理的具有 ERBB2 擴增或某些突變的 UC 患者中顯示出抗腫瘤活性。有必要進行額外的研究以證實 P+T 在該患者中的療效。

Conclusions: P+T demonstrated evidence of anti-tumor activity in heavily pre-treated UC pts with ERBB2 amplification or certain mutations. Additional study is warranted to confirm the efficacy of P+T in this pt population.