背景：晚期 EGFRm NSCLC 患者（患者）在 EGFR TKI 和鉑化療(PBC)失敗後的治療選擇有限。HER3-DXd 是一種抗體藥物偶軛物，由完全人類對 HER3 的單克隆抗體組成，通過四肽基可分裂連接器連接到拓撲異構酶 I 抑製劑有效載荷上。我們之前提供了 EGFR TKI 治療失敗後的 HER3-DXD 的療效/安全性數據（中位數隨訪，5.4 個月）。我們現在對接受推薦擴張劑量的患者（5.6mg/kg IV Q3W）進行延長隨訪。
Background: Patients (pts) with advanced EGFRm NSCLC have limited treatment options after failure of EGFR TKI and platinum-based chemotherapy (PBC). HER3-DXd is an antibody drug conjugate consisting of a fully human monoclonal antibody to HER3 attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. We previously presented efficacy/safety data (median follow-up, 5.4 mo) from an ongoing study of HER3-DXd in EGFRm NSCLC after failure of EGFR TKI therapy. We now present extended follow-up of pts receiving the recommended dose for expansion (5.6 mg/kg IV Q3W).
方法：本 Ph1 劑量增加/擴張研究包括局部晚期或轉移性 EGFRm NSCLC 患者及既往EGFR TKI 治療（NCT03260491）。允許對患者進行穩定的腦轉移(BM)。根據 RECISTv1.1，通過盲法獨立中心審查(BICR)確認主要終點為 ORR；次要終點包括 DOR、PFS 和安全性。
Methods: This Ph 1 dose-escalation/expansion study included pts with locally advanced or metastatic EGFRm NSCLC with prior EGFR TKI therapy (NCT03260491). Pts with stable brain metastases (BM) were allowed. The primary endpoint was confirmed ORR by blinded independent central review (BICR) per RECIST v1.1; secondary endpoints included DOR, PFS and safety.
結果：在數據截止（2020 年 9 月 24 日），57 名接受 HER3-DXd5.6mg/kg IV Q3W；中位數隨訪，10.2 個月(範圍，5.2-19.9 個月)。先前抗癌方案的中位數為 4（範圍，1-10）。100%有 EGFR TKI 前期（86%有奧西美替尼[OSI]），91%有 PBC 前期。47%的人有 BM 的病史。治療時間為 5.5 個月（範圍為 0.7-18.6 個月）；18 分治療（32%）。BICR 確認的 ORR 為 39%（22/57；95%置信區間，26.0%-52.4%；1CR、21PR、19SD），在開始 HER3-DXD 後 3 個月內出現 14/22 反應。DCR 為 72%(95%CI，58.5%-83.0%)。中值為 6.9 個月（95%置信區間， 3.1 個月-NE），而中值 PFS 為 8.2mm（95%，4.4-8.3 個月）。在 EGFR TKI 抗性的不同機製中觀察到抗腫瘤活性，包括那些與 HER3 無關的機製(EGFRC797S、MET 或 HER2 amp 和 BRAF 融合)。在既往 PBC 患者中，ORR 為 37%（19/52；95%CI，23.6%-51.0%）；在既往 OSI 和 PBC 患者中，ORR 為 39%（17/44；95%CI，24.4%-54.5%）。在可評估 HER3 表達的 43 個患者中，幾乎全部表達 HER3；中位膜的 IHC 的 H 評分指標中值為 180（範圍，2-280）。CR/PR患者的 H 評分指標中值（範圍；N）為 195（92-268；15），SD 為 180（4-280；15），PD為 126.5（2-251；6），患者為 180（36-180；7）。最常見的≥3 級不良事件(AE)為血小板減少（30%）、中性粒細胞減少（19%）和疲勞（14%）。中心判定的藥物相關間質性肺病共 4例（7%，1≥3 級[2%]，無 5 級）。6/57 的患者（11%）有與停止治療相關的不良事件（無因血小板減少所致）。
Results: At data cutoff (Sept 24, 2020), 57 pts were treated with HER3-DXd 5.6 mg/kg IV Q3W; median follow-up, 10.2 mo (range, 5.2-19.9 mo). Median number of prior anticancer regimens was 4 (range, 1-10). 100% had prior EGFR TKI (86% prior osimertinib [OSI]) and 91% had prior PBC. 47% had a history of BM. Median treatment duration was 5.5 mo (range, 0.7-18.6 mo); treatment was ongoing in 18 pts (32%). Confirmed ORR by BICR was 39% (22/57; 95% CI, 26.0%-52.4%; 1 CR, 21 PR, 19 SD) with 14/22 responses occurring within 3 mo of starting HER3-DXd. DCR was 72% (95% CI, 58.5%-83.0%). Median DOR was 6.9 mo (95% CI, 3.1 mo-NE), and median PFS was 8.2 mo (95% CI, 4.4-8.3 mo). Antitumor activity was observed across diverse mechanisms of EGFR TKI resistance, including those not directly related to HER3 (EGFR C797S, MET or HER2 amp, and BRAF fusion). Among pts with prior PBC, ORR was 37% (19/52; 95% CI, 23.6%-51.0%); in pts with prior OSI and PBC, ORR was 39% (17/44; 95% CI, 24.4%-54.5%). Among 43 pts evaluable for HER3 expression, nearly all expressed HER3; median membrane H-score by IHC was 180 (range, 2-280). Median H-score (range; N) was 195 (92-268; 15) in pts with CR/PR, 180 (4-280; 15) with SD, 126.5 (2-251; 6) with PD, and 180 (36-180; 7) in pts unevaluable for best overall response. The most common grade ≥3 adverse events (AEs) were thrombocytopenia (30%), neutropenia (19%), and fatigue (14%). Drug-related interstitial lung disease by central adjudication occurred in 4 pts (7%; 1 grade ≥3 [2%]; no grade 5). 6/57 pts (11%) had AEs associated with treatment discontinuation (none were due to thrombocytopenia).
結論：HER3-DXd 5.6mg/kg IV Q3W 在重預處理的轉移/局部高級 EGFRm NSCLC 中顯示了各種 EGFR TKI 抵抗機製的腫抗瘤活性。安全狀況與之前的報告一致。已啟動了對 EGFR TKI 和 PBC 失敗後的 EGFRmNSCLC 患者的 HER3-DXD 的 Ph2 研究（NCT04619004）。
Conclusions: HER3-DXd 5.6 mg/kg IV Q3W demonstrated antitumor activity across various EGFR TKI resistance mechanisms in heavily pretreated metastatic/locally advanced EGFRm NSCLC. The safety profile was consistent with previous reports. A Ph 2 study of HER3-DXd in pts with EGFRm NSCLC after failure of EGFR TKI and PBC has been initiated (NCT04619004).
