EGFR-MET-bispecific

EGFR-MET 二重特異性抗体

一行要約

EGFR と MET の両方の細胞外ドメインに同時結合する bispecific antibody class。代表薬 Amivantamab (Rybrevant) は EGFR exon 20 insertion (CHRYSALIS: ORR 40% → Park et al. JClinOncol 2021) で初承認後、PAPILLON (exon 20 ins 1L: PFS HR 0.40)、MARIPOSA (EGFR del19/L858R 1L + lazertinib vs osimertinib: PFS HR 0.70, 23.7 vs 16.6 mo) で急速に適応拡大。三重作用機序 — (1) EGFR/MET receptor downregulation + lysosomal degradation、(2) downstream signal suppression、(3) Fc-mediated ADCC / trogocytosis (Yun et al. CancerDiscov 2020) — により従来の EGFR-TKI 単剤を超える multi-modal anti-tumor activity を発揮。Lazertinib (3rd-gen EGFR-TKI) との intracellular + extracellular dual blockade + MET bypass 阻害が combination の科学的根拠。Post-osimertinib (MARIPOSA-2: PFS HR 0.48) でも有効性を示し、EGFR-mutant NSCLC の全 treatment line に展開。VTE リスク増加と IRR が key management issue。皮下投与製剤 (PALOMA-3) で IRR 軽減・利便性向上。

メンバー比較表

薬剤	製品名	構造	標的	主要試験	投与経路	承認状況
Amivantamab	Rybrevant	Bispecific IgG1 (EGFR × MET) low-fucose Fc	EGFR ECD domain III + MET SEMA domain	CHRYSALIS, MARIPOSA, PAPILLON, MARIPOSA-2	IV → SC 製剤承認	FDA 承認 (exon 20 ins / EGFR-mut 1L)

※ Lazertinib は併用パートナーの 3rd-gen EGFR-TKI であり本 class のメンバーではない。他社 EGFR×MET bispecific (zanidatamab-like programs) は開発初期段階

主要エビデンス

CHRYSALIS (Exon 20 insertion 2L+ — 初承認)

• Park et al. JClinOncol 2021: Phase I dose-expansion。Exon 20 ins post-platinum (N=81) で ORR 40% (CR 4%, PR 36%)、mDOR 11.1 mo、mPFS 8.3 mo、mOS 22.8 mo → 2021 年 FDA accelerated approval
• Significance: 100+ variants ある exon 20 ins 全般に活性 — 細胞外ドメイン結合のため kinase domain 構造に非依存。既存 EGFR-TKI (osimertinib 含む) の exon 20 ins に対する ORR 0-9% と対照的
• RP2D: 1,050 mg (≥80 kg: 1,400 mg) IV q1w×4 → q2w。First dose に step-up infusion protocol

PAPILLON (Exon 20 insertion 1L standard)

• Zhou NEJM 2023: Phase III (N=308)。Amivantamab + carboplatin/pemetrexed vs chemo alone。PFS HR 0.40 (11.4 vs 6.7 mo) 、ORR 73% vs 47%。Exon 20 ins 初の positive Phase III → 1L standard 確立
• Mobocertinib (TKI approach) の開発中止 (efficacy insufficient + WT EGFR toxicity) と対照的に、bispecific antibody approach が exon 20 ins 治療の winning modality として定着

MARIPOSA (EGFR common mutation 1L — Osimertinib superiority)

• Cho NEJM 2024: Phase III (N=1,074)。Amivantamab + lazertinib vs osimertinib vs lazertinib alone。PFS HR 0.70 (23.7 vs 16.6 mo) — osimertinib 単剤を 1L で初めて上回った Phase III
• Dual blockade rationale: Lazertinib (intracellular EGFR kinase 阻害 + CNS 透過) + amivantamab (extracellular EGFR blocking + MET blocking + immune killing)。Osimertinib 単剤では MET amp 耐性 (15-20%) が major resistance → amivantamab の MET arm で pre-emptive suppression
• Trade-off: PFS superiority vs VTE 増加 (37% vs 9%)、IRR、rash → benefit-risk は patient selection dependent。OS data maturity 待ち

MARIPOSA-2 (Post-osimertinib rescue)

• Passaro AnnOncol 2024: Phase III (N=657)。Post-osimertinib で amivantamab + chemo ± lazertinib vs chemo。Triplet PFS HR 0.48、doublet HR 0.54
• Osimertinib 耐性 mechanism (MET amp / C797S / histologic transformation) に対し mechanism-agnostic approach — amivantamab の dual EGFR+MET targeting + immune MOA が heterogeneous resistance に broad activity

前臨床 MOA の体系的実証

• Yun et al. CancerDiscov 2020: 5 種 exon 20 ins Ba/F3 + PDC 3 例 + organoid 2 例 + xenograft で活性実証。Triple MOA:

1. Receptor downregulation: 30 min で EGFR 約50% 減少。Lysosome 依存的 degradation (bafilomycin で rescue)
2. Signal suppression: pEGFR / pMET / pAKT / pERK / pS6 包括的抑制 (TKI は downstream bypass されるが amivantamab は完全抑制)
3. ADCC / trogocytosis: PBMC 共培養で dose-dependent killing + IFNγ。Xenograft で macrophage / NK 浸潤増加

• Poziotinib (exon 20 ins TKI) との in vivo 比較: 同等 efficacy で amivantamab は重篤 skin toxicity / 体重減少なし → tolerability advantage

皮下投与製剤 (PALOMA-3)

• SC amivantamab: rHuPH20 co-formulation。IV に対する bioequivalence 確認。IRR 約65% (IV 初回) → 約15% (SC)。投与時間 5 min vs 4-5 hr → 外来利便性大幅向上

メカニズム

Bispecific IgG1 抗体の分子構造

Amivantamab は controlled Fab-arm exchange 技術で製造された fully human bispecific IgG1:

• Arm 1 (EGFR) : EGFR extracellular domain III に binding。Cetuximab と同一 domain を target だが独自 epitope → cetuximab-resistant EGFR ECD mutation (S492R 等) との cross-resistance は partial
• Arm 2 (MET) : MET SEMA domain に binding。Onartuzumab (one-armed anti-MET) 類似の binding site
• Fc region: Low-fucose engineering → FcγRIIIa (NK cell / macrophage) への enhanced affinity → ADCC / trogocytosis 増強。IgG1 subclass → complement activation (CDC) は minor

三重作用機序の詳細

1. Receptor Downregulation / Lysosomal Degradation:

• Bispecific binding → EGFR-MET hetero-crosslinking → receptor clustering
• Clustering → accelerated internalization → endosome → lysosome pathway
• Lysosomal protease による EGFR / MET protein degradation → cell surface expression 消失
• TKI とは根本的に異なる: TKI は kinase 活性を阻害するが receptor は surface に残存 → feedback upregulation 可能。Amivantamab は receptor 自体を除去
• Kinetics: 30 min で EGFR 約50% loss、72 h で 約40-45% 残存 (continuous exposure)

2. Downstream Signal Suppression:

• EGFR ligand (EGF/TGFα) blocking + MET ligand (HGF) blocking
• Receptor level でのシグナル遮断 → pAKT / pERK / pS6 の包括的抑制
• Exon 20 ins 特有の problem: TKI は pEGFR を partial に抑制できても、αC-helix lock により downstream bypass が active → amivantamab は receptor degradation で bypass 不可能に

3. Fc-mediated Immune Effector Function:

• ADCC: NK cell FcγRIIIa binding → granzyme B / perforin release → target cell apoptosis
• Trogocytosis: Macrophage が antibody-coated tumor cell membrane patch を active に strip → membrane integrity disruption → cell death。完全 phagocytosis 不要で低 E:T ratio でも effective
• ADCP (Antibody-Dependent Cellular Phagocytosis) : M1 macrophage による whole cell phagocytosis
• Immune MOA の臨床的重要性: TKI-resistant clone (TP53 変異 / downstream bypass) でも immune killing は signal-independent に effective → heterogeneous resistance population に対する broad activity

Lazertinib 併用の科学的根拠

Lazertinib (YH25448) は 3rd-generation EGFR-TKI:

• Selectivity: EGFR activating mutation (del19 / L858R) + T790M に選択的。WT EGFR に低活性 → skin / GI toxicity 軽減
• CNS penetration: 高い BBB 透過性 (brain/plasma ratio high) → 脳転移制御は lazertinib が主に担当 (amivantamab は antibody のため CNS 移行限定的)
• Combination rationale:

Level	Lazertinib	Amivantamab	Combined effect
EGFR kinase (intracellular)	◎ 阻害	—	ATP-competitive inhibition
EGFR receptor (extracellular)	—	◎ degradation	Surface receptor 消失
MET pathway	—	◎ blocking + degradation	MET bypass prevention
Immune killing	—	◎ ADCC / trogocytosis	TKI-resistant clone 排除
CNS	◎ high penetration	△ limited	Brain mets control
Skin/GI toxicity	低 (WT EGFR sparing)	中 (ECD binding)	Additive but manageable

Exon 20 Insertion への Activity の構造的根拠

EGFR exon 20 insertions (>100 variants: A767_V769dup, V769_D770ins, D770_N771ins, H773_V774ins 等) :

• C-helix / αC-β4 loop への in-frame insertion → C-helix active conformation 固定 → constitutive kinase activation
• Insertion により TKI binding pocket に steric hindrance → osimertinib IC50 10-100 倍上昇 → clinical inefficacy
• Amivantamab 解決策: 細胞外ドメイン (ECD domain III) は exon 20 ins で 全く影響されない → どの variant でも一貫した binding → kinase domain 構造に完全非依存の activity

耐性機序 (EGFR-MET bispecific 後)

Acquired resistance (emerging data) :

• EGFR ectodomain mutation (S492R analog) → amivantamab binding epitope disruption
• MET ectodomain mutation → MET arm efficacy 低下
• FcγR downregulation / TME immunosuppression → immune MOA 減弱
• Off-target bypass: KRAS / BRAF / PIK3CA activation、histologic transformation
• EMT (mesenchymal phenotype → EGFR dependency loss + immune evasion)

VTE (Venous Thromboembolism) の機序:

• MARIPOSA amivantamab+lazertinib 群 VTE 37% vs osimertinib 9%
• 推定: MET 阻害 → endothelial HGF signaling 障害 → prothrombotic phenotype / EGFR 阻害 → tissue factor upregulation / antibody-immune complex → coagulation activation
• 管理: Prophylactic anticoagulation (LMWH / DOAC) protocol amendment で義務化

臨床位置づけ

EGFR-mutant NSCLC での治療 algorithm

Setting	Standard	EGFR-MET bispecific の役割
Exon 20 ins 1L	Amivantamab + chemo	PAPILLON: PFS HR 0.40 — clear 1L standard
Exon 20 ins 2L+	Amivantamab monotherapy	CHRYSALIS: ORR 40%
Common mut 1L	Osimertinib or Ami+Laz	MARIPOSA: PFS HR 0.70 — new option (VTE trade-off)
Post-osimertinib	Amivantamab + chemo	MARIPOSA-2: PFS HR 0.48 — mechanism-agnostic
Post-osi (MET amp)	Ami+chemo or Osi+MET-TKI	Both valid; ami has broader coverage

MET-TKI (Capmatinib / Tepotinib) との比較

• MET-TKI + osimertinib: MET amplification-specific。SAVANNAH / TATTON data で ORR 約30-40% (MET amp confirmed)
• Amivantamab approach: MET amp に加え non-MET 耐性にも activity (immune MOA + EGFR ECD targeting) → mechanism 不問の broader utility
• 棲み分け: Rebiopsy で MET amp confirmed → 両方有効。MET amp 不明 / 非 MET → amivantamab preferred。CNS 主体 → MET-TKI (small molecule CNS 透過) advantage

毒性 profile と管理

AE	頻度 (MARIPOSA)	管理
IRR	65% (IV), 約15% (SC)	Step-up infusion + premedication。SC 製剤推奨
Skin rash / paronychia	40-50% / 30-40%	EGFR class effect。Prophylactic doxycycline + moisturizer
VTE	37%	Prophylactic anticoagulation 必須
Peripheral edema	20-30%	MET class effect
Hypoalbuminemia	20%	Monitoring + nutritional support

Open Questions

• MARIPOSA OS data: PFS superiority (HR 0.70) が OS に translate するか。VTE-related mortality が OS benefit を dilute する懸念
• SC vs IV の long-term outcome equivalence: SC 製剤の convenience が adherence 向上 → effectiveness improvement に繋がるか
• Optimal 1L choice (EGFR common mutation) : Amivantamab+lazertinib vs osimertinib の選択は VTE risk / CNS burden / patient preference で individualize。Predictive biomarker (MET expression? circulating markers?) の開発
• Post-amivantamab acquired resistance landscape: EGFR ECD mutation / MET ECD mutation / immune escape の prevalence。4th-gen strategies
• Beyond NSCLC expansion: CRC (OrigAMI-1) / head and neck / pancreatic cancer での EGFR×MET dependency の探索
• Combination beyond lazertinib: Amivantamab + IO (checkpoint inhibitor) / amivantamab + ADC の feasibility
• VTE prevention optimization: Anticoagulant 種類・期間・patient selection。VTE risk prediction score の開発

重要論文 Top 10

1. Cho et al. NEnglJMed 2024 MARIPOSA — Amivantamab+Lazertinib 1L > Osimertinib — PFS HR 0.70
2. Zhou et al. NEnglJMed 2023 PAPILLON — Exon 20 ins 1L paradigm shift — PFS HR 0.40
3. ★★★★★ Park et al. JClinOncol 2021 — CHRYSALIS pivotal — 初の Exon 20 ins 承認
4. Passaro 2024 MARIPOSA-2 — Post-Osi rescue — PFS HR 0.48
5. ★★★★ Yun et al. CancerDiscov 2020 — Triple MOA 前臨床実証

関連エンティティ・概念

• 関連遺伝子: EGFR, MET
• 関連 class: EGFR-TKI (Lazertinib / Osimertinib), MET-TKI (競合), anti-EGFR-antibody (Cetuximab 類似 ECD 結合)
• 関連概念: T790M-and-sequential-EGFR-TKI (耐性 context), C797S-resistance, EGFR-TKI-resistance
• 試験: CHRYSALIS / MARIPOSA / PAPILLON / MARIPOSA-2 / PALOMA-3
• ドメイン: lung-cancer-treatment, novel-cancer-modalities

関連論文

直近 30 件のみ表示中 (関連 33 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Brain metastasis

• Mavrikios et al. AnnOncol 2026 — Lung cancer brain metastases management at the dawn of personalized medicine are we ready to break the barriers

Basic-Oncogene and genetics

• Bhang et al. NatMed 2015 — Studying clonal dynamics in response to cancer therapy using high-complexity barcoding

Basic-Others

• Oberstein et al. JClinOncol 2026 — Amivantamab monotherapy in chemorefractory RASBRAF wild-type metastatic colorectal cancer results from OrigAMI-1, an

Clinical-NSCLC-Driver-Other

• Kropf-Sanchen et al. ClinLungCancer 2026 — A retrospective, multicenter analysis within the national network genomic medicine lung cancer in germany to detect RET
• Bylicki et al. OncoTargetsTher 2020 — Targeting the MET-signaling pathway in NSCLC

Clinical-NSCLC-EGFR

• Beau-Faller et al. AnnOncol 2014 — Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients a multicentre observational
• Passiglia et al. Cancer 2026 — Amivantamab in advanced non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations
• Janjigian et al. CancerDiscov 2014 — Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and
• Yun et al. CancerDiscov 2020 — Antitumor activity of amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in diverse models of EGFR exon 20
• Choudhury et al. ClinCancerRes 2021 — Response to standard therapies and comprehensive genomic analysis for patients with lung adenocarcinoma with EGFR exon
• Matikas et al. ClinLungCancer 2015 — Current and future approaches in the management of non-small-cell lung cancer patients with resistance to EGFR TKIs
• Kim et al. FrontOncol 2026 — Paired ctDNA analysis reveals diverse resistance mechanisms to mobocertinib in EGFR exon 20 insertion NSCLC
• HARMONi et al. JAMA 2026 — A-Bispecific antibody ivonescimab added to chemotherapy in EGFR-variant non-small cell lung cancer the HARMONi-A
• Park et al. JClinOncol 2021 — Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy initial
• Li et al. LancetOncol 2026 — Aumolertinib with or without chemotherapy in EGFR-mutated advanced non-small-cell lung cancer (AENEAS2) an open-label,
• OKane et al. LungCancer 2017 — Uncommon EGFR mutations in advanced non-small cell lung cancer
• Wang et al. LungCancer 2026 — Vebreltinib plus EGFR-TKI for EGFR-mutated NSCLC with MET-driven resistance A real-world study of chinese patients
• Mok et al. NEnglJMed 2017 — Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer
• Soria et al. NEnglJMed 2018 — Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer
• Ramalingam et al. NEnglJMed 2020 — Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC
• Zhou et al. NEnglJMed 2023 — Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions
• Cho et al. NEnglJMed 2024 — Amivantamab plus lazertinib in previously untreated EGFR-Mutated advanced NSCLC
• Yang et al. NEnglJMed 2025 — Overall survival with amivantamab-lazertinib in EGFR-Mutated advanced NSCLC
• Janne et al. NEnglJMed 2026 — Survival with osimertinib plus chemotherapy in EGFR-mutated advanced nsclc
• Zhou et al. NEnglJMed 2026 — First-line sunvozertinib in NSCLC with
• Blakely et al. NatGenet 2017 — Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers
• Zhao et al. NatRevClinOncol 2026 — Navigating the landscape of EGFR TKI resistance in EGFR-mutant NSCLC-mechanisms and evolving treatment approaches

Clinical-NSCLC-HER2

• Zhao et al. JThoracOncol 2020 — Conformational landscapes of HER2 exon 20 insertions explain their sensitivity to kinase inhibitors in lung
• Friedlaender et al. NatRevClinOncol 2022 — EGFR and HER2 exon 20 insertions in solid tumours from biology to treatment

Clinical-Others

• Mahmud et al. Oncologist 2026 — Biomarker testing patterns among patients newly diagnosed with metastatic non-small cell lung prostate and bladder ca…

合成 (Outputs)

• egfr-osimertinib-post-resistance-strategy
• egfr-uncommon-mutation-treatment-selection
• novel-modality-sequencing-driver-resistance