Amivantamabin Non-small Cell Lung Cancer (NSCLC) with MET Exon 14 Skipping (METex14) Mutation: Initial Results from CHRYSALIS

Introduction

Amivantamab, a novel, fully human bispecific antibody targeting both the epidermal growth factor receptor (EGFR) and MET, is being explored as a monotherapy in non-small cell lung cancer (NSCLC) within the CHRYSALIS study (NCT02609776), and has received Breakthrough Therapy Designation for the treatment of patients with EGFR exon 20 insertion disease, after prior treatment with platinum chemotherapy. Given the bispecific nature of amivantamab, its role in patients with MET exon 14 skipping (METex14) mutations is being explored (MET-2 cohort) in patients both naïve to and refractory to other available MET therapy. We present early results demonstrating amivantamab activity in MET-driven NSCLC.

摘要

Amivantamab是一种新型的全人源双特异性抗体，其靶点包括表皮生长因子受体(EGFR)和MET。目前在CHRYSALIS研究(NCT02609776)中，正在探索将其作为非小细胞肺癌(NSCLC)的单药治疗。将该药用于曾接受铂化疗的EGFR外显子20插入疾病患者，已获得突破性治疗。考虑到amivantamab的双特异性，研究人员正在探索它在可用MET疗法以及使用MET后无效的，MET外显子14跳跃性(METex14)突变患者中的作用。(MET-2队列)。我们取得了了amivantamab在met驱动的非小细胞肺癌中的活性的早期结果。

Methods

CHRYSALIS is an ongoing phase 1 dose escalation/dose expansion study of amivantamab in patients with advanced NSCLC.

Patients with METex14 NSCLC whose disease progressed on or who declined current standard of care were treated at the recommended phase 2 dose (RP2D) of 1050 mg (1400 mg ≥80 kg) weekly in cycle 1 and biweekly thereafter. Response was assessed by the investigator using RECIST v1.1.

研究方法

CHRYSALIS是一项正在进行的amivantamab在晚期NSCLC患者中的1期剂量递增/剂量扩大研究。对于病情进展或目前的护理标准下降的METex14非小细胞肺癌患者，采用2期推荐剂量(RP2D) ，即：第1周期每周1050 mg (1400 mg≥80 kg)，之后每周两次。研究者使用RECIST v1.1评估反应。

Results

As of 29 Mar 2021, 16 patients with METex14 NSCLC had received amivantamab at the RP2D. Median age was 70 (range, 55–75), 69% were women, and median prior lines of therapy were 2 (range, 0–10), including prior treatment with crizotinib (n=3), capmatinib (n=1), tepotinib (n=2), and anti-MET antibody (n=1). Nine patients had at least 1 postbaseline disease assessment,

7 are pending first disease assessment; 13 remain on treatment. Antitumor activity was observed in each of the 9 response-evaluable patients, with 4 confirmed partial responses, including patients with prior anti-MET therapy (Figure). Three of the 4 responders remain on treatment (6.0–6.6+ months) with ongoing responses, and 1 discontinued after 12 months. The safety profile was consistent with previously reported experience of amivantamab at the RP2D (Sabari 2021JTO16(3):S108-109). Treatment-related adverse events leading to dose reduction or discontinuation occurred in 6% of patients, each.

Among 7 patients who received prior MET tyrosine kinase inhibitor (TKI), baseline ctDNA demonstrated 2 patients with potential resistance mechanisms: PIK3CA mutation in one, and CDK4 and EGFR amplifications and a possible secondary MET mutation (A1251V) in the other. Five patients had no identified MET TKI resistance alteration.

结果：

截至2021年3月29日，16例METex14 NSCLC患者接受了amivantamab的2期推荐剂量治疗。中位年龄为70岁(55-75岁)，69%为女性，中位既往治疗线为2人(0-10岁)，包括既往使用克唑替尼(n=3)、卡马替尼(n=1)、替波替尼(n=2)和抗met抗体(n=1)。9例患者至少进行了1次基线后疾病评估，7例正在等待首次疾病评估；13人仍在接受治疗。在9例可评价疗效的患者中均观察到抗肿瘤活性，其中4例确诊为部分疗效，包括既往接受过抗met治疗的患者(图)。4例应答者中有3例持续治疗(6.0-6.6个月)，1例在12个月后停止治疗。安全性与此前报道的amivantamab在RP2D中的经验一致(Sabari 2021 JTO 16(3):S108-109)。6%的患者产生了必须减少剂量或停药的副作用。

在此前接受MET酪氨酸激酶抑制剂(TKI)治疗的7例患者中，基线ctDNA显示有2例患者存在潜在的耐药机制：其中1例患者出现PIK3CA突变，另1例患者出现CDK4和EGFR扩增，其他患者可能出现继发性MET突变(A1251V)。5例患者未发现MET TKI耐药性改变。

Conclusion

This report provides first evidence of amivantamab activity in MET-driven NSCLC, in addition to its previously reported anti-EGFR activity, consistent with its bispecific mechanism of action. Enrollment into MET-2 cohort is ongoing, and presentation will include updated data.

结论：

该报告提供了amivantamab在met驱动的NSCLC中的活性的第一个证据，除了之前报道的抗EGFR活性，其余与它的双特异性作用机制一致。MET-2队列的登记正在进行中，报告中将包括最新的数据。