Pemetrexed

一行要約

Multi-target antifolate antimetabolite (TS / DHFR / GARFT triple-target inhibitor)。非扁平 NSCLC で platinum との doublet 1L、PARAMOUNT で continuation maintenance 標準化、悪性胸膜中皮腫 1L で cisplatin 併用標準を 20 年超維持し、KEYNOTE-189 chemo backbone として IO 時代でも引き続き central role を担う。Squamous NSCLC では TS 高発現で効果劣る (むしろ harm) → histology-specific chemotherapy paradigm の歴史的代表例。Folate / B12 supplementation で骨髄抑制を抑え docetaxel と比較し tolerability に優れる (Hanna et al. JClinOncol 2004)。

主要エビデンス

Advanced NSCLC 1L histology-specific paradigm (JMDB)

Scagliotti et al. JClinOncol 2008 (JMDB、1725 例) が cisplatin + pemetrexed vs cisplatin + gemcitabine 1L NSCLC を比較し、非扁平 NSCLC で OS 11.0 vs 10.1 ヶ月 (HR 0.84)、特に adenocarcinoma / large cell carcinoma で benefit を示し、対照的に扁平上皮では gemcitabine が優位という histology-driven 戦略を確立した。これにより「全 NSCLC 一律治療」から「histology-specific selection」へ paradigm shift。

Maintenance therapy (PARAMOUNT)

Ciuleanu et al. Lancet 2009 (switch maintenance) が non-pemetrexed induction 後の pemetrexed maintenance で OS benefit を示した後、Paz-Ares et al. LancetOncol 2012 (PARAMOUNT、continuation maintenance) が cisplatin + pemetrexed 4 cycles 後の pemetrexed continuation で PFS HR 0.62 を示し、Paz-Ares et al. JClinOncol 2013 で OS benefit (13.9 vs 11.0 ヶ月、HR 0.78) を確認、現代 maintenance paradigm を確立した。Bevacizumab combination の継続 maintenance は Patel et al. JClinOncol 2013 (PointBreak、carbo/pemetrexed/bev → pem/bev maintenance vs carbo/pac/bev → bev maintenance) で OS 等価性を示し、Ramalingam et al. JClinOncol 2019 (ECOG ACRIN 5508) で pemetrexed 単剤 / bevacizumab 単剤 / pemetrexed + bevacizumab の 3 群比較、bev 単剤と pem + bev は同等 OS で combo の上乗せを否定した。

IO + chemo backbone (KEYNOTE-189)

Gandhi et al. NEnglJMed 2018 が pembrolizumab + carboplatin/pemetrexed → pembrolizumab + pemetrexed maintenance vs placebo + chemo で OS HR 0.49 を達成し、非扁平 NSCLC 1L IO + chemo の global standard を確立。Pemetrexed maintenance を IO maintenance と並行して継続するのが現代 paradigm。扁平 NSCLC は Paz-Ares et al. JThoracOncol 2020 (KEYNOTE-407、carbo + (nab-)paclitaxel) が標準で、pemetrexed は使用されない (histology-specific が IO 時代でも維持)。

2L NSCLC (vs Docetaxel)

Hanna et al. JClinOncol 2004 が pemetrexed vs docetaxel 2L NSCLC で OS 非劣性 (8.3 vs 7.9 ヶ月)、骨髄抑制軽減 (grade 3-4 neutropenia 5.3% vs 40.2%) を示し、非扁平 NSCLC 2L の選択肢として確立。1L pemetrexed 普及で 2L での適用機会は減少したが、IO 後 2L の選択肢として残存。

Mesothelioma 1L (Vogelzang)

Vogelzang et al. JClinOncol 2023 (cisplatin + pemetrexed vs cisplatin alone、448 例) が悪性胸膜中皮腫 1L で OS 12.1 vs 9.3 ヶ月 (HR 0.77)、ORR 41% vs 17% を示し、20 年超の standard を確立。Dual IO (Baas et al. Lancet 2021、CheckMate 743) が non-epithelioid 中皮腫で nivo/ipi の OS benefit を示したが、epithelioid 型では化療 backbone (cisplatin/pemetrexed) が依然 first choice。

Adjuvant 非扁平 NSCLC

Kenmotsu et al. JClinOncol 2020 (JIPANG) が完全切除後 stage II–IIIA 非扁平 NSCLC で cisplatin + pemetrexed vs cisplatin + vinorelbine を比較し、両群同等 RFS / OS で毒性は pemetrexed 有利を示し、JCOG 主導の日本人エビデンスとして adjuvant 非扁平 NSCLC の選択肢を拡大した。

メカニズム

葉酸代謝経路の multi-target antimetabolite:

1. Thymidylate synthase (TS): dUMP → dTMP の還元的メチル化を阻害 → DNA 合成停止 (primary target、最も強力)
2. Dihydrofolate reductase (DHFR): DHF → THF を阻害 → 葉酸 cofactor 枯渇
3. GARFT (glycinamide ribonucleotide formyltransferase): purine de novo 合成阻害 (GAR → FGAR の formyl transfer 阻害)

細胞内で folylpolyglutamate synthetase (FPGS) により polyglutamate 化されて細胞内停留・活性増強。

Histology selectivity (pemetrexed の最大特徴) :

• 非扁平 NSCLC (adenocarcinoma) : TS 低発現 → pemetrexed 高感受性
• 扁平 NSCLC: TS 高発現 → pemetrexed 低効果 (Scagliotti et al. JClinOncol 2008 のサブ解析で扁平群は OS HR 1.23 と inverse benefit)
• Mesothelioma: TS 低発現 → 高感受性

MTAP-loss biomarker: MTAP 欠失 (9p21.3、CDKN2A 周辺で頻繁に co-deletion) 細胞は purine salvage 低下で pemetrexed 高感受性、近年 PRMT5 阻害との synthetic lethality でも注目。

毒性管理:

• Folate (葉酸 1 mg/day) + B12 (vitamin B12 1000 µg q9wk) supplementation 必須 (骨髄抑制軽減)
• Steroid pre-medication (dexamethasone 4 mg bid × 3 days、皮疹軽減)
• 腎機能 (CrCl) で dose adjustment、CrCl <45 mL/min は禁忌相当

臨床位置づけ

• 非扁平 NSCLC 1L: Carboplatin/cisplatin + pemetrexed が 1L IO + chemo backbone (KEYNOTE-189 / IMpower150 / IMpower130) として universal、IO maintenance と pemetrexed maintenance を並行継続
• 非扁平 NSCLC maintenance: PARAMOUNT に基づく continuation pemetrexed が standard
• 非扁平 NSCLC 2L: 1L pemetrexed-naive 例で docetaxel に対する選択肢、IO 後の 2L 化療として再評価
• Adjuvant 非扁平 NSCLC: JIPANG で cisplatin + pemetrexed が cisplatin + vinorelbine と同等で毒性有利
• 悪性胸膜中皮腫 1L: Cisplatin + pemetrexed が epithelioid 型 standard、non-epithelioid では nivo/ipi 競合
• Squamous NSCLC: 効果劣るため 使用しない (histology-specific 原則)
• Thymic carcinoma / atypical carcinoid: pemetrexed 単剤で活性報告あり (standard chemo limited 領域)

Open Questions

• PD-L1 ≥50% での pembro 単剤 vs pembro + pemetrexed: backbone 必要性の患者層別化 (KEYNOTE-024 vs KEYNOTE-189 cross-trial)
• Pemetrexed maintenance duration: long-responder で 5 yrs+ 持続 vs 中止の RCT
• MTAP-loss biomarker 個別化: 9p21 co-deletion を用いた pemetrexed / PRMT5 阻害の predictive marker 開発
• Mesothelioma 現代治療 selection: dual IO (CheckMate-743) vs cisplatin/pemetrexed の histology / biomarker driven 選択
• 腎機能低下例: CrCl 30–45 mL/min での dose 調整 PK study が乏しい

重要論文 Top 10

1. ★★★★★ Scagliotti et al. JClinOncol 2008 — JMDB — histology-specific paradigm 確立
2. ★★★★★ Vogelzang et al. JClinOncol 2023 — Mesothelioma 1L 標準化
3. ★★★★ Paz-Ares et al. LancetOncol 2012 — PARAMOUNT — continuation maintenance
4. ★★★★★ Gandhi et al. NEnglJMed 2018 — KEYNOTE-189 — IO+chemo backbone
5. ★★★★ Hanna et al. JClinOncol 2004 — Pemetrexed vs docetaxel 2L

関連エンティティ

• 関連 class: Platinum-chemotherapy (doublet partner), PD-1-inhibitor (KEYNOTE-189 backbone), anti-VEGF-antibody (AVAPERL)
• 試験: JMDB / PARAMOUNT / AVAPERL / KEYNOTE-189
• ドメイン: lung-cancer-treatment

関連論文

直近 30 件のみ表示中 (関連 369 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
• Jiang et al. FrontOncol 2026 — Advances in ommaya reservoir-based intrathecal therapy for leptomeningeal metastasis from non-small cell lung cancer a
• Weng et al. FrontOncol 2026 — Assessment of real-world surveillance strategies for patients undergoing systemic therapy for brain metastases

Basic-Immunotherapy

• Gonzalez et al. JImmunotherCancer 2026 — Morning versus afternoon administration of immune checkpoint inhibitors in metastatic non-small-cell lung cancer

Basic-Liquid-biopsy

• Cai et al. JImmunotherCancer 2026 — Neoadjuvant camrelizumab plus chemotherapy in resectable stage IIIA-IIIB non-small cell lung cancer integrated
• Hartono et al. NatAging 2026 — Urinary detection of therapy-induced senescence and fibrosis using an injectable albumin-based nanoprobe

Basic-Oncogene and genetics

• Scaparone et al. CancerDiscov 2026 — EML4-ALK mediates resistance to KRAS G12C inhibition and induces an

Basic-Others

• Xu et al. CancerCell 2026 — Received 24 february 2026
• Winslow et al. CancerDiscov 2026 — A roadmap to transform lung cancer outcomes priorities in biology, therapeutic innovation, early detection, prevention
• Strohbehn et al. JCOOncolPract 2026 — Maintenance PemetrexedPembrolizumab versus pembrolizumab in non-small cell lung cancer A propensity score-weighted

Clinical-Mesothelioma

• Dungey et al. TrendsCancer 2026 — Mesothelioma a systemic therapy clinical trials snapshot

Clinical-NSCLC-Driver negative

• Shimizu et al. CancerSci 2026 — Atezolizumab + chemotherapy in older patients with lung cancer in japan
• DiFederico et al. JAMAOncol 2026 — PD-(l)1 inhibitor monotherapy vs chemoimmunotherapy
• Socinski et al. JAMAOncol 2026 — Tiragolumab plus atezolizumab and chemotherapy for advanced nonsquamous non-small cell lung cancer the phase 3
• Ulas et al. JImmunotherCancer 2026 — Rescue by radiotherapy and anti-CTLA4PD-1 after failure of anti-PD-1 therapy in patients with metastatic NSCLC the
• Shiraishi et al. LungCancer 2026 — Final overall survival analysis of the APPLE study atezolizumab and platinum-pemetrexed with or without bevacizumab for
• Huang et al. NatMed 2026 — Time-of-day immunochemotherapy in non-small cell lung cancer a randomized phase 3 trial
• Cengiz et al. SciRep 2026 — Comparison of flat-dose versus weight-based dose nivolumab treatment in NSCLC patients

Clinical-NSCLC-EGFR

• Passiglia et al. Cancer 2026 — Amivantamab in advanced non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations
• Niu et al. FrontImmunol 2026 — Efficacy and mechanisms of immune checkpoint inhibitors in late-stage EGFR-mutated non-small cell lung cancer following
• 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
• 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
• 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
• Zhao et al. NatRevClinOncol 2026 — Navigating the landscape of EGFR TKI resistance in EGFR-mutant NSCLC-mechanisms and evolving treatment approaches

Clinical-Others

• Zhu et al. IntJRadiatOncolBiolPhys 2026 — Low-dose SBRT-based radiotherapy followed by pembrolizumab and chemotherapy for potentially resectable NSCLC A phase ib
• Baramidze et al. JThoracOncol 2026 — Cemiplimab plus chemotherapy versus chemotherapy in advanced NSCLC 5-year results from phase 3 EMPOWER-lung 3 part 2

Clinical-SCLC

• Hao et al. CancerCommun(Lond) 2026 — Serplulimab plus chemotherapy, with or without HLX04, versus chemotherapy as first-line treatment for nonsquamous NSCLC