背景：EGFR-MET 双特异性抗体阿米万他抗和第三代酪氨酸激酶抑制剂拉泽替尼联合单纯治疗和奥西美替尼（奥西）复发患者(pts)联合 EGFRm NSCLC（ChoAnnOncol2020；31：S813）。我们提供了老年复发患者的组合的更新结果，包括对反应的潜在生物标记的分析。

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：将有 EGFR 外显子 19 缺失或 L858R 突变 NSCLC 的患者，纳入正在进行的联合研究（NCT02609776）。前瞻性收集预处理肿瘤活检和 ctDNA，患者接受 1050/1400mg 阿米万他抗 240mg 拉泽替尼，以评估老年复发人群的安全性和疗效。研究者根据 RECIST 第 1.1 版对反应进行了评估。通过下一代 ctDNA 或肿瘤活检(生物标记物阳性[pos])鉴定的 EGFR/MET的奥西替尼抗性突变或扩增，以丰富反应。免疫组化学(IHC)染色 EGFR 和 MET 表达也被探索作为潜在的生物标志物。

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.

结果：在 45 例老年复发患者中，36%（95%CI，22-51）有确认应答（1 例完全反应，15例部分反应[PR]）。中位数随访 8.2 个月（1.0-11.8），20/45 的患者（44%）仍在接受治疗。随着 11/16 患者（69%）持续反应（2.6-9.6 个月），未达到反应持续时间中值(NR)。无进展生存率中位数(mPFS)为 4.9 个月（95%置信区间为 3.7-8.3）。共有 44/45 分通过 ctDNA 评估， 29/45 的患者由肿瘤 NGS 评估。基因检测发现了 17 个生物标记点，其中 8 例（47%）有反应。在剩下的 28 个患者中，有 8 个患者（29%）做出了回应。在这 28 例患者中，18 例具有未知的选择性抵抗机制（8PR），10 例具有非 EGFR/MET 抵抗机制（无应答）。生物标记物点和剩余点的 mPFS（95%CI）分别为 6.7 个月（3.4-NR）和 4.1 个月（1.4-9.5）。20 名对 EGFR和 9/10（90%）IHC 高（EGFRMETH 评分>400）患者进行 IHC 测试，而 1/10 IHC 低患者对治疗有反应。

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.

结论：阿米万他马抗和拉泽替尼联合治疗对 36%没有化疗的患者有反应。在这些患者中，遗传性 EGFR 和基于 MET 的抗性生物标记确定了一组更有可能对阿米万他马抗和拉泽替尼有反应的患者，尽管其他缺乏已识别的抗性标记的患者也有反应。基于 IHC 的方法可能会确定最有可能受益于组合方案的患者，但有必要进行进一步的调查。

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.