MARIPOSA

一行要約

未治療 EGFR+ (ex19del / L858R) NSCLC における Amivantamab (EGFR×MET bispecific) + Lazertinib (3rd-gen EGFR-TKI) vs Osimertinib の phase III。PFS HR 0.70 (23.7 vs 16.6 mo) で有意に改善し、bispecific antibody + TKI による 1L EGFR+ NSCLC paradigm shift の可能性を示した。

試験デザイン

• 対象: Stage IIIB/IV or recurrent NSCLC、EGFR ex19del or L858R、未治療、N=1074 (2:2:1)
• 群 A (n=429) : Amivantamab 1400/1750mg IV + Lazertinib 240mg PO daily
• 群 B (n=429) : Osimertinib 80mg PO daily
• 群 C (n=216) : Lazertinib 240mg PO daily (exploratory)
• 層別化: 変異タイプ (ex19del vs L858R)、人種 (Asian vs non-Asian)、脳転移有無
• Primary endpoint: Amivantamab+Lazertinib (群 A) vs Osimertinib (群 B) の PFS

主要結果

• PFS (primary, 群 A vs 群 B) : HR 0.70 (95% CI 0.58–0.85, p<0.001)、median 23.7 vs 16.6 mo
• PFS (Lazertinib 単独 vs Osimertinib) : HR 1.00 — Lazertinib 単独は Osimertinib と同等
• ORR: 群 A 86% vs 群 B 85% (差軽微)
• DoR: 群 A 25.8 mo vs 群 B 16.8 mo
• OS: 初回解析で immature (trend あり、formal significance 未達)
• 安全性: 群 A で Grade ≥3 AE 75% vs 群 B 43%。Infusion-related reaction (IRR) 64%、皮疹 80% (EGFR on-target)、VTE (血栓塞栓症) 11% vs 4% が注目。治療中止率 10% vs 3%

臨床的意義

• Osimertinib 超えの 1L PFS: FLAURA 以降の 1L EGFR+ standard に初めて PFS で superiority を示した試験
• Bispecific + TKI paradigm: EGFR×MET bispecific による dual pathway blockade で MET bypass resistance を先制的に抑制するコンセプト
• 毒性とのトレードオフ: PFS 7 mo 改善 vs Grade ≥3 AE 倍増・VTE リスク・IRR — benefit-risk balance の議論が active
• FLAURA2 との競合: Osimertinib+化療 (FLAURA2, PFS HR 0.62) vs Amivantamab+Lazertinib の間接比較が注目点
• 皮下投与 (SC) の開発: Amivantamab SC 製剤 (PALOMA-3) で IRR 軽減・利便性向上

Open Questions

• OS maturation: PFS gain が OS に translate するか。Cross-over 影響と VTE 関連死亡の balance
• VTE リスク管理: 予防的抗凝固療法の prospective 評価が必要
• MARIPOSA vs FLAURA2 の head-to-head: Bispecific+TKI vs TKI+化療 の直接比較は planning されていない
• Amivantamab SC の real-world 運用: IRR 軽減と通院回数削減の実臨床 impact
• EGFR-C797S-resistance / MET bypass 後の salvage: 1L combo 後の resistance pattern と treatment options

重要論文 Top 10

1. Cho et al. NEnglJMed 2024 — MARIPOSA primary publication、PFS HR 0.70
2. ★★★★★ Soria et al. NEnglJMed 2018 — FLAURA—Osimertinib 1L standard (MARIPOSA の comparator)
3. ★★★★★ Janne et al. NEnglJMed 2026 — FLAURA2 (Osimertinib+chemo, PFS HR 0.62) —競合レジメン
4. Park et al. — CHRYSALIS-2 (Amivantamab+Lazertinib, Osimertinib 耐性) —後方ライン
5. Yun et al. — Amivantamab (JNJ-61186372) phase I —EGFR×MET bispecific の first-in-human

関連エンティティ・概念

• EGFR-MET-bispecific — Amivantamab
• EGFR-TKI — Lazertinib / Osimertinib
• EGFR — Driver gene
• MET — Bypass resistance target (Amivantamab の co-target)
• FLAURA — 1L Osimertinib (MARIPOSA comparator)
• EGFR-C797S-resistance — Osimertinib on-target resistance
• TATTON / SAVANNAH — MET bypass combination の先行知見

関連論文

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

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

Clinical-NSCLC-EGFR

• Yun et al. CancerDiscov 2020 — Antitumor activity of amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in diverse models of EGFR exon 20
• 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,
• 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
• 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
• 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
• Jia et al. Nature 2016 — Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors

合成 (Outputs)

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