背景：EGFR-MET 雙特異性抗體阿米萬他抗和第三代酪氨酸激酶抑製劑拉澤替尼聯合單純治療和奧西美替尼（奧西）複發患者(pts)聯合 EGFRm NSCLC（ChoAnnOncol2020；31：S813）。我們提供了老年複發患者的組合的更新結果，包括對反應的潛在生物標記的分析。

Background: Preliminary efficacy was observed with the combination of amivantamab, an EGFR-MET bispecific antibody, and lazertinib, a 3rd-generation tyrosine kinase inhibitor, in both treatment-naïve and osimertinib (osi)-relapsed patients (pts) with EGFRm NSCLC (Cho Ann Oncol 2020;31:S813). We present updated results of the combination in osi-relapsed pts, including an analysis of potential biomarkers of response.

方法：將有 EGFR 外顯子 19 缺失或 L858R 突變 NSCLC 的患者，納入正在進行的聯合研究（NCT02609776）。前瞻性收集預處理腫瘤活檢和 ctDNA，患者接受 1050/1400mg 阿米萬他抗 240mg 拉澤替尼，以評估老年複發人群的安全性和療效。研究者根據 RECIST 第 1.1 版對反應進行了評估。通過下一代 ctDNA 或腫瘤活檢(生物標記物陽性[pos])鑒定的 EGFR/MET的奧西替尼抗性突變或擴增，以豐富反應。免疫組化學(IHC)染色 EGFR 和 MET 表達也被探索作為潛在的生物標誌物。

Methods: Pts with EGFR exon 19 deletion or L858R mutation NSCLC, who had progressed on osi without intervening chemotherapy, were enrolled in the combination cohort of the ongoing CHRYSALIS study (NCT02609776). With pre-treatment tumor biopsies and ctDNA collected prospectively, pts received the combination dose of 1050/1400 mg amivantamab + 240 mg lazertinib to assess safety and efficacy in the osi-relapsed population. Response was assessed by investigator per RECIST v1.1. Osi-resistance mutations or amplifications in EGFR/MET identified by next-generation sequencing (NGS) in either ctDNA or tumor biopsy (biomarker-positive [pos]), were evaluated for enriching response. Immunohistochemistry (IHC) staining for EGFR and MET expression was also explored as a potential biomarker for response.

結果：在 45 例老年複發患者中，36%（95%CI，22-51）有確認應答（1 例完全反應，15例部分反應[PR]）。中位數隨訪 8.2 個月（1.0-11.8），20/45 的患者（44%）仍在接受治療。隨著 11/16 患者（69%）持續反應（2.6-9.6 個月），未達到反應持續時間中值(NR)。無進展生存率中位數(mPFS)為 4.9 個月（95%置信區間為 3.7-8.3）。共有 44/45 分通過 ctDNA 評估， 29/45 的患者由腫瘤 NGS 評估。基因檢測發現了 17 個生物標記點，其中 8 例（47%）有反應。在剩下的 28 個患者中，有 8 個患者（29%）做出了回應。在這 28 例患者中，18 例具有未知的選擇性抵抗機製（8PR），10 例具有非 EGFR/MET 抵抗機製（無應答）。生物標記物點和剩餘點的 mPFS（95%CI）分別為 6.7 個月（3.4-NR）和 4.1 個月（1.4-9.5）。20 名對 EGFR和 9/10（90%）IHC 高（EGFRMETH 評分>400）患者進行 IHC 測試，而 1/10 IHC 低患者對治療有反應。

Results: Of the 45 osi-relapsed pts, 36% (95% CI, 22–51) had a confirmed response (1 complete response and 15 partial responses [PR]). At a median follow-up of 8.2 mo (1.0–11.8), 20/45 pts (44%) remain on treatment. With 11/16 pts (69%) continuing in response (2.6–9.6+ mo), median duration of response has not been reached (NR). The median progression-free survival (mPFS) was 4.9 mo (95% CI, 3.7–8.3). In total, 44/45 pts were evaluable by ctDNA and 29/45 by tumor NGS. Genetic testing identified 17 biomarker-pos pts, of whom 8 (47%) responded. Of the remaining 28 pts, 8 (29%) responded. Among these 28 pts, 18 had unknown mechanisms of osi-resistance (8 PR) and 10 had non-EGFR/MET mechanisms of resistance identified (none responded). The mPFS (95% CI) for biomarker-pos and remaining pts was 6.7 mo (3.4–NR) and 4.1 mo (1.4–9.5), respectively. Adequate tissue was available for 20 pts to perform IHC testing for EGFR and MET–9/10 (90%) IHC high (combined EGFR+MET H score>400) pts responded to treatment, while 1/10 IHC low pts responded to treatment.

結論：阿米萬他馬抗和拉澤替尼聯合治療對 36%沒有化療的患者有反應。在這些患者中，遺傳性 EGFR 和基於 MET 的抗性生物標記確定了一組更有可能對阿米萬他馬抗和拉澤替尼有反應的患者，盡管其他缺乏已識別的抗性標記的患者也有反應。基於 IHC 的方法可能會確定最有可能受益於組合方案的患者，但有必要進行進一步的調查。

Conclusions: Treatment with the combination of amivantamab and lazertinib yielded responses in 36% of chemotherapy-naïve pts who progressed on osi. Among these pts, genetic EGFR and MET-based biomarkers of resistance identified a subgroup of pts more likely to respond to amivantamab and lazertinib, although additional pts lacking identified resistance markers also responded. An IHC-based approach may identify pts most likely to benefit from the combination regimen, but further investigation is warranted.