Amivantamab in 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是一種新型的全人源雙特異性抗體，其靶點包括表皮生長因子受體(EGFR)和MET。目前在CHRYSALIS研究(NCT02609776)中，正在探索將其作為非小細胞肺癌(NSCLC)的單藥治療。將該藥用於曾接受鉑化療的EGFR外顯子20插入疾病患者，已獲得突破性治療。考慮到amivantamab的雙特異性，研究人員正在探索它在可用MET療法以及使用MET後無效的，MET外顯子14跳躍性(METex14)突變患者中的作用。(MET-2隊列)。我們取得了了amivantamab在met驅動的非小細胞肺癌中的活性的早期結果。

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是一項正在進行的amivantamab在晚期NSCLC患者中的1期劑量遞增/劑量擴大研究。對於病情進展或目前的護理標準下降的METex14非小細胞肺癌患者，采用2期推薦劑量(RP2D) ，即：第1周期每周1050 mg (1400 mg≥80 kg)，之後每周兩次。研究者使用RECIST v1.1評估反應。

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 2021 JTO 16(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.

結果：

截至2021年3月29日，16例METex14 NSCLC患者接受了amivantamab的2期推薦劑量治療。中位年齡為70歲(55-75歲)，69%為女性，中位既往治療線為2人(0-10歲)，包括既往使用克唑替尼(n=3)、卡馬替尼(n=1)、替波替尼(n=2)和抗met抗體(n=1)。9例患者至少進行了1次基線後疾病評估，7例正在等待首次疾病評估；13人仍在接受治療。在9例可評價療效的患者中均觀察到抗腫瘤活性，其中4例確診為部分療效，包括既往接受過抗met治療的患者(圖)。4例應答者中有3例持續治療(6.0-6.6個月)，1例在12個月後停止治療。安全性與此前報道的amivantamab在RP2D中的經驗一致(Sabari 2021 JTO 16(3):S108-109)。6%的患者產生了必須減少劑量或停藥的副作用。

在此前接受MET酪氨酸激酶抑製劑(TKI)治療的7例患者中，基線ctDNA顯示有2例患者存在潛在的耐藥機製：其中1例患者出現PIK3CA突變，另1例患者出現CDK4和EGFR擴增，其他患者可能出現繼發性MET突變(A1251V)。5例患者未發現MET TKI耐藥性改變。

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.

結論：

該報告提供了amivantamab在met驅動的NSCLC中的活性的第一個證據，除了之前報道的抗EGFR活性，其餘與它的雙特異性作用機製一致。MET-2隊列的登記正在進行中，報告中將包括最新的數據。