Amivantamab

Amivantamab (アミバンタマブ)

一行要約

EGFR×MET bispecific IgG1 抗体 (Rybrevant)。Fc-mediated trogocytosis / ADCC による immune-directed killing を含む三重作用機序で、EGFR exon 20 insertion (従来 TKI 耐性) に初の有効薬として承認 (Park et al. JClinOncol 2021 CHRYSALIS: ORR 40%)。PAPILLON (Zhou et al. NEnglJMed 2023: exon 20 ins 1L PFS HR 0.40) で 1L 標準を確立し、MARIPOSA (Cho et al. NEnglJMed 2024: + lazertinib vs osimertinib 1L PFS HR 0.70, 23.7 vs 16.6 mo) で EGFR common mutation 1L でも osimertinib 超えを実証。MARIPOSA-2 で post-osimertinib にも有効 (PFS HR 0.48)。Yun et al. CancerDiscov 2020 が前臨床で receptor downregulation + ADCC + lysosomal degradation の triple MOA を体系的に実証。皮下投与製剤 (PALOMA-3) により IRR 軽減・投与利便性向上。VTE リスク管理が実臨床での key issue。

主要試験

試験	相	対象	N	主要結果	Reference
CHRYSALIS	I	Exon 20 ins post-Pt	81	ORR 40%, mPFS 8.3 mo, mDOR 11.1 mo	Park et al. JClinOncol 2021
PAPILLON	III	Exon 20 ins 1L	308	PFS HR 0.40 (11.4 vs 6.7 mo)	Zhou NEJM 2023
MARIPOSA	III	EGFR del19/L858R 1L	1,074	PFS HR 0.70 (23.7 vs 16.6 mo)	Cho NEJM 2024
MARIPOSA-2	III	Post-osimertinib	657	PFS HR 0.48 (triplet)	Passaro AnnOncol 2024
CHRYSALIS-2	I/II	Post-osimertinib various	—	ORR 36% (amivantamab + lazertinib)	—
PALOMA-3	III	SC vs IV bioequivalence	—	SC bioequivalent, IRR reduced	—

主要エビデンス

CHRYSALIS (Exon 20 insertion — 初承認根拠)

• Park et al. JClinOncol 2021: 多施設 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。RP2D: 1,050 mg (≥80 kg: 1,400 mg) q1w×4 → q2w
• Historical benchmark との比較: Exon 20 ins の post-platinum ORR は historical 23% (単剤 chemo) → amivantamab の 40% は約 2 倍。mOS 22.8 mo は exon 20 ins NSCLC の historical OS (約16 mo) を有意に上回る
• Exon 20 ins variant 非依存性: 100 種以上の多様な insertion variant (A767_V769dup, V769_D770ins, D770_N771ins 等) に一貫した activity → 細胞外ドメイン結合のため kinase domain 構造変異に非依存
• TKI 前治療歴と活性: TKI 前治療例 (62%) でも ORR 40% → prior TKI failure が amivantamab 活性に影響しない

PAPILLON (Exon 20 insertion 1L standard)

• Zhou NEJM 2023: Phase III randomized (N=308)。Amivantamab + carboplatin/pemetrexed vs chemo alone、exon 20 ins 1L。PFS HR 0.40 (11.4 vs 6.7 mo) — exon 20 ins 初の phase III positive trial
• ORR: Amivantamab + chemo 73% vs chemo 47% → absolute ORR difference 26%
• Post-progression crossover: Chemo arm の大半が PD 後に amivantamab を受領 → OS analysis は crossover dilution を考慮
• 臨床的意義: Exon 20 ins 1L treatment の paradigm を「chemo only」から「amivantamab + chemo」に変革。Mobocertinib (TKI approach) の開発中止と対照的に、bispecific antibody approach の勝利

MARIPOSA (EGFR common mutation 1L — Osimertinib 超え)

• Cho NEJM 2024: Phase III randomized (N=1,074)。Amivantamab + lazertinib vs osimertinib vs lazertinib 単剤、EGFR del19/L858R 1L。PFS HR 0.70 (23.7 vs 16.6 mo) — osimertinib 単剤を 1L で上回った初の Phase III
• Hazard 解析: HR 0.70 は 30% risk reduction。Subgroup (del19, L858R, brain mets あり/なし) で一貫した benefit
• Lazertinib 併用の根拠: 3rd-gen EGFR-TKI (T790M / activating mutation 選択的、CNS 透過良好) による intracellular kinase 阻害 + amivantamab extracellular / immune 攻撃 → dual blockade + MET bypass 阻害。Osimertinib 単剤では MET amp 耐性が 15-20% に出現 → amivantamab の MET 阻害で pre-emptive 耐性抑制
• OS maturity pending: PFS primary endpoint は positive だが OS data は immature → OS 優越確認が amivantamab + lazertinib の standard of care 確立に必要
• Toxicity trade-off: PFS 延長の代償として VTE リスク増加 + IRR + rash/paronychia → benefit-risk は patient selection dependent

MARIPOSA-2 (Post-osimertinib rescue)

• Passaro AnnOncol 2024: Phase III (N=657)。Osimertinib 耐性 NSCLC で amivantamab + chemo ± lazertinib vs chemo。Triplet PFS HR 0.48、doublet PFS HR 0.54 → osimertinib 後の新 standard 候補
• Osimertinib 耐性 landscape での positioning: Osimertinib 後の acquired resistance mechanisms (MET amp 約15%, C797S 約7%, histologic transformation 約5%) の multiple pathways に対し、amivantamab の dual EGFR+MET targeting + immune MOA が broad coverage
• MET-TKI との比較: Osimertinib + MET-TKI (capmatinib / tepotinib) は MET amp-specific。Amivantamab は MET amp 以外の耐性にも activity → mechanism-agnostic approach

前臨床 MOA (Trogocytosis / ADCC / Receptor Degradation)

• Yun et al. CancerDiscov 2020: 5 種 Exon 20 ins Ba/F3 細胞 + PDC + organoid + xenograft で systematic に活性を実証
• Triple mechanism of action:

1. Receptor downregulation / lysosomal degradation: Amivantamab 結合 → EGFR/MET の receptor crosslinking → internalization → lysosomal pathway での protein degradation。30 分で EGFR 量 約50% 低下、72 h で 40-45% 残存。Bafilomycin A1 で degradation 阻止 → lysosome 依存を確認
2. Downstream signal suppression: pEGFR / pMET / pAKT / pERK / pS6 の包括的抑制。従来 TKI (gefitinib / osimertinib) は exon 20 ins で pEGFR を部分的に抑制できても downstream (pAKT / pERK) が bypass される → amivantamab は receptor level で blocking するため downstream suppression が完全
3. Fc-mediated immune effector function: IgG1 Fc → ADCC (NK cell granzyme/perforin) + trogocytosis (macrophage が tumor membrane を strip)。PBMC 共培養で用量依存的殺傷 + IFNγ産生。Xenograft 内で macrophage / NK cell 浸潤増加

• TKI-resistant 腫瘍への immune MOA の重要性: TP53 変異等で downstream bypass が active な場合でも、immune effector function (ADCC / trogocytosis) は signal bypass に非依存 → TKI に完全耐性の腫瘍にも immune killing が effective

皮下投与製剤 (SC Amivantamab)

• PALOMA-3: SC amivantamab の IV に対する bioequivalence を Phase III で確認
• IRR 軽減: IV 初回 IRR 約65% → SC では大幅軽減 (約15%)。投与時間 5 min (SC) vs 4-5 hr (IV 初回)
• 臨床的利便性: 外来投与の feasibility 向上、chair time 短縮、patient preference で SC が preferred
• Hyaluronidase co-formulation: rHuPH20 により皮下組織での分散性向上 → 2 mL volume に高濃度 amivantamab を充填

メカニズム

Bispecific IgG1 抗体の構造

Amivantamab は fully human bispecific IgG1 antibody で以下の structural features:

• EGFR-binding arm: EGFR extracellular domain III に結合 (cetuximab と同一 domain)。Ligand (EGF / TGFα) blocking + receptor dimerization 阻害
• MET-binding arm: MET extracellular SEMA domain に結合。HGF blocking + MET homodimerization 阻害
• IgG1 Fc region: Low-fucose Fc engineering → enhanced FcγRIIIa binding → ADCC / ADCP (antibody-dependent cellular phagocytosis) / trogocytosis の増強

Exon 20 Insertion への Activity の構造的根拠

EGFR exon 20 insertion mutations (100+ variants) は kinase domain の C-helix / loop region に in-frame insertion を生じ:

• C-helix を active conformation に固定 → constitutive kinase 活性化
• αC-β4 loop の空間的制約 → osimertinib / gefitinib の binding pocket に steric hindrance → TKI IC50 が 10-100 倍上昇
• Amivantamab の解決策: 細胞外ドメイン結合のため kinase domain 構造に完全に非依存 → どの exon 20 ins variant でも EGFR ECD は intact → 一貫した binding / activity

Trogocytosis (免疫学的新規機序)

Trogocytosis は effector cell (macrophage / monocyte) が target cell membrane の一部を「噛み取る」process:

1. Amivantamab が tumor EGFR/MET に結合 → FcγR を介して macrophage が engage
2. Macrophage が tumor cell membrane patch を active に strip → EGFR / MET / associated lipid raft の loss
3. Tumor cell は membrane integrity disruption → eventual death
4. 従来の ADCC / phagocytosis と異なり、完全な phagocytosis 不要 → low E:T ratio でも effective

臨床的意義: MARIPOSA の circulating immune cell analysis で amivantamab 投与後に trogocytosis marker 上昇が response と相関 → trogocytosis が in vivo で寄与する evidence

Lazertinib 併用の Dual Blockade Rationale

Target level	Lazertinib	Amivantamab	組合せ効果
EGFR intracellular	T790M / activating mut 阻害	—	Kinase activity 抑制
EGFR extracellular	—	Ligand blocking + degradation	Receptor level 消失
MET	—	HGF blocking + degradation	Bypass resistance 予防
Immune killing	—	ADCC / trogocytosis	TKI-resistant clone 排除
CNS	◎ (高 BBB 透過)	△ (antibody: 低 CNS 移行)	CNS は lazertinib が cover

耐性機序 (Amivantamab 後)

On-target (EGFR ectodomain mutation) :

• EGFR S492R — cetuximab 耐性で知られる ECD mutation が amivantamab にも cross-resistance を示す可能性
• EGFR ECD structural change → amivantamab binding epitope の disruption

Off-target / bypass:

• KRAS / BRAF / PIK3CA activation → EGFR/MET 非依存的 downstream 活性化
• Histologic transformation (SCLC / squamous)
• EMT (mesenchymal phenotype → EGFR dependency の喪失)

Immune evasion:

• FcγR polymorphism → ADCC 活性の inter-individual variability
• TME immunosuppression → trogocytosis / ADCC efficacy の減弱
• MHC-I downregulation は amivantamab MOA に直接影響しない (antibody-mediated mechanism は MHC-independent)

VTE リスクの機序

• Amivantamab の VTE 増加 (MARIPOSA で amivantamab+lazertinib 群 37% vs osimertinib 群 9%) の mechanism は完全には解明されていない
• 推定機序: (1) MET 阻害 → endothelial dysfunction → prothrombotic state、(2) EGFR 阻害 → tissue factor upregulation、(3) antibody-immune complex → platelet / coagulation 活性化
• 管理: Prophylactic anticoagulation (LMWH / DOAC) 推奨。MARIPOSA protocol amendment で anticoagulation 義務化

臨床位置づけ

EGFR-mutant NSCLC Treatment Algorithm 2026

Setting	推奨	根拠
Exon 20 ins 1L	Amivantamab + chemo (PAPILLON)	PFS HR 0.40 — clear standard
Exon 20 ins 2L+	Amivantamab monotherapy (CHRYSALIS)	ORR 40%, mPFS 8.3 mo
Common mut (del19/L858R) 1L	Osimertinib or Amivantamab+Lazertinib (MARIPOSA)	PFS HR 0.70 favoring ami+laz, but VTE/toxicity trade-off
Post-osimertinib (any mechanism)	Amivantamab + chemo (MARIPOSA-2)	PFS HR 0.48 — mechanism-agnostic
Post-osimertinib (MET amp specific)	Amivantamab + chemo or Osi + MET-TKI	Both valid; amivantamab broader coverage

Amivantamab + Lazertinib vs Osimertinib 1L: 臨床判断

Amivantamab + Lazertinib を選択する状況:

• MET amplification co-occurrence / high MET expression (MET bypass prevention)
• 若年・good PS で aggressive treatment acceptable
• VTE 低リスク (BMI 正常、mobility 良好、no prior VTE)

Osimertinib を選択する状況:

• VTE ハイリスク (肥満、不動、prior VTE)
• CNS 転移主体 (osimertinib の CNS 透過 > amivantamab)
• Toxicity tolerance 低い (高齢、併存症多数)
• 外来通院困難 (SC 製剤でも q2w 通院 vs osimertinib 経口 daily)

MET-TKI との棲���分け

状況	Amivantamab	MET-TKI + Osimertinib
Post-osi MET amp	◎ (MARIPOSA-2)	◎ (SAVANNAH / TATTON)
Post-osi non-MET amp	◎	×
1L MET amp prevention	◎ (MARIPOSA)	—
CNS 転移	△ (antibody CNS 透過低)	◎ (capmatinib CNS 活性)

毒性管理の実践

AE	頻度	Grade 3+	管理
IRR (IV 初回)	65%	3%	Step-up infusion rate + premedication (diphenhydramine + dexamethasone + acetaminophen)。SC 製剤で 約15% に軽減
Skin rash	40-50%	5%	EGFR 阻害 class effect。Prophylactic doxycycline + moisturizer
Paronychia	30-40%	2%	Antiseptic soaks、early podiatry referral
Peripheral edema	20-30%	2%	MET 阻害 class effect。Compression stockings
VTE	37% (MARIPOSA)	15%	Prophylactic anticoagulation 必須 (LMWH / DOAC)。D-dimer monitoring
Hypoalbuminemia	20%	3%	MET pathway → hepatocyte function? Nutritional support

Colorectal Cancer への展開 (Beyond NSCLC)

• Oberstein et al. JClinOncol 2026: OrigAMI-1 Phase Ib/II — RAS/BRAF wild-type chemo-refractory mCRC で amivantamab 単剤 ORR / DCR を報告。EGFR-driven CRC での cetuximab alternative / post-cetuximab option として探索中
• Pan-cancer EGFR/MET 依存腫瘍への basket expansion の可能性

Open Questions

• MARIPOSA OS confirmation: PFS HR 0.70 は positive だが OS 優越性が確認されるまで amivantamab + lazertinib 1L の standard of care 確立は incomplete。OS data maturity 2025-2026 予定
• VTE リスクの長期安全性: Prophylactic anticoagulation の至適期間・種類 (LMWH vs DOAC)。VTE risk prediction model の開発。Anticoagulation の bleeding risk との balance (特に brain mets 患者)
• SC vs IV の実臨床 outcome: SC 製剤の利便性・IRR 軽減が adherence / real-world effectiveness に translate するか。SC の bioavailability variability (肥満 / 浮腫患者)
• Amivantamab 後の耐性 landscape: EGFR ectodomain mutation / immune evasion / bypass pathway の頻度と pattern。Post-amivantamab salvage strategy (osimertinib re-challenge? 4th-gen EGFR-TKI?)
• Biomarker-driven patient selection: EGFR / MET expression level / EGFR ligand level / FcγR polymorphism と response の correlation。Benefit が全員均等か、responder 群が同定可能か
• CNS 活性の limitation: Antibody の BBB 透過は限定的 → CNS 転移主体の患者では lazertinib (CNS 透過良好) が carrier。Amivantamab 自体の CNS efficacy data の蓄積が必要
• Optimal sequencing (EGFR common mutation) : 1L osimertinib → 2L amivantamab + chemo vs 1L amivantamab + lazertinib → 2L? Lifetime outcome (total PFS / OS) の比較。Sequential strategy の clinical trial design

重要論文 Top 10

1. Cho NEJM 2024 (MARIPOSA) — 1L EGFR-mut: Ami+Laz > Osi — paradigm shift
2. Zhou — PAPILLON — Exon 20 ins 1L standard 確立 — PFS HR 0.40
3. Passaro — MARIPOSA-2 — Post-Osi rescue — PFS HR 0.48
4. ★★★★★ Park et al. JClinOncol 2021 — CHRYSALIS: 初の Exon 20 ins 承認薬
5. ★★★★ Yun et al. CancerDiscov 2020 — Triple MOA 前臨床実証 (receptor degradation + signal + ADCC)

関連エンティティ

• Drug class: EGFR-MET-bispecific
• 標的遺伝子: EGFR, MET
• 併用薬: Lazertinib (3rd-gen EGFR-TKI), Platinum-chemotherapy, Pemetrexed
• 競合: Osimertinib (1L comparator), MET-TKI (post-osi MET amp), Mobocertinib (exon 20 ins, 開発中止)
• 試験: MARIPOSA, PAPILLON, MARIPOSA-2, CHRYSALIS
• Concept: EGFR-TKI-resistance, T790M-and-sequential-EGFR-TKI, C797S-resistance
• 関連 class: anti-EGFR-antibody (cetuximab — 同一 ECD 結合 domain)
• 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 42 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-Others

• Oberstein et al. JClinOncol 2026 — Amivantamab monotherapy in chemorefractory RASBRAF wild-type metastatic colorectal cancer results from OrigAMI-1, an
• Chen et al. JImmunotherCancer 2026 — Targeting CD74 may mitigate immune-escape features and enhance BCMA CAR-T activity in preclinical models of

Clinical-NSCLC-Driver negative

• Shiraishi et al. LungCancer 2026 — Final overall survival analysis of the APPLE study atezolizumab and platinum-pemetrexed with or without bevacizumab for

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

• Leonetti et al. BrJCancer 2019 — Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer
• Passiglia et al. Cancer 2026 — Amivantamab in advanced non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations
• 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
• 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
• Ramalingam et al. JClinOncol 2018 — Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer
• 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…