BRAF-MEK-inhibitor

BRAF-MEK 阻害薬

一行要約

BRAF V600E 変異 (NSCLC 腺癌の約 1-2%) を標的とする BRAF inhibitor + MEK inhibitor 併用療法で、NSCLC では Dabrafenib + Trametinib が Planchard et al. LancetOncol 2016 (BRF113928 2L+ ORR 63.2%) と Planchard et al. LancetOncol 2017 (1L cohort ORR 64%) で承認根拠を確立した。Melanoma での BRAF 単剤 paradoxical MAPK activation (Hatzivassiliou et al. Nature 2013) の教訓から BRAF + MEK 併用が標準化、NSCLC でも基本骨格は同一。Class II/III BRAF (K601E / D594G 等) には BRAF inhibitor 無効で、Yao et al. Nature 2017 が class III は upstream RAS 依存性で MEK / ERK 阻害感受性であることを示した。

メンバー比較表

薬剤	種別	製品名	標的	主要適応	NSCLC データ
Dabrafenib	BRAF inhibitor	Tafinlar	BRAF V600E	NSCLC, Melanoma	BRF113928: ORR 64% (+Trametinib)
Trametinib	MEK inhibitor	Mekinist	MEK1/2	NSCLC, Melanoma	Dabrafenib 併用パートナー
Vemurafenib	BRAF inhibitor	Zelboraf	BRAF V600E	Melanoma	NSCLC basket trial (VE-BASKET)
Encorafenib	BRAF inhibitor	Braftovi	BRAF V600E	CRC, Melanoma	NSCLC PHAROS (+Binimetinib)
Binimetinib	MEK inhibitor	Mektovi	MEK1/2	Melanoma	Encorafenib 併用パートナー
Selumetinib	MEK inhibitor	Koselugo	MEK1/2	NF1 plexiform	NSCLC SELECT 試験 (不成功)

メカニズム

BRAF V600E mutation: RAS-RAF-MEK-ERK (MAPK) pathway の構成的活性化。V600E は activation segment の glutamic acid 置換により、RAS-GTP 非依存的に BRAF kinase が恒常活性化 (class I)。class II (K601E、L597 等) は dimerization 依存、class III (D594、G469E 等) は kinase-impaired で upstream RAS に依存 (Yao et al. Nature 2017)。

BRAF 阻害薬: V600E mutant BRAF monomer に選択的結合 → kinase 活性抑制。WT BRAF では paradoxical ERK activation (RAF dimerization 誘導) → BRAF 単剤で secondary skin cancer リスク。conformation-based の薬剤選択性は Mayrhofer et al. ProcNatlAcadSciUSA 2020 が autoinhibitory conformation profiling で予測可能であることを示した。NSCLC での BRAF oncogene dependence は Lin et al. ProcNatlAcadSciUSA 2014 が分子決定因子を mapping。

MEK 阻害薬: MEK1/2 の allosteric inhibitor → ERK 活性化を直接抑制。BRAF 阻害薬による paradoxical activation を打消し、BRAF+MEK 併用で deeper / longer response を達成。Hatzivassiliou et al. Nature 2013 が MEK inhibitor の binding mode が BRAF-driven vs KRAS-driven 腫瘍での efficacy 差を決定することを示した。

耐性機構:

• MAPK pathway reactivation (MEK1/2 mutation、BRAF amplification、NRAS mutation)。BRAF V600E brain tumor で secondary BRAF 変異が耐性を獲得することは Wang et al. CancerDiscov 2018 が記載
• Bypass pathway (PI3K-AKT activation、Tolcher et al. ClinCancerRes 2015 が RAS-driven で AKT+MEK 同時阻害の rationale を提示)
• BRAF splicing variants (V600E exon skip → truncated form が dimerize)
• LKB1 / STK11 loss 文脈で MEK 感受性が変動 — Wang et al. ClinCancerRes 2018 が KRAS-mutant LKB1-loss NSCLC での trametinib + RT 増感を実証

主要エビデンス

NSCLC V600E

• BRF113928 2L+ cohort: Planchard et al. LancetOncol 2016 が Dabrafenib + Trametinib NSCLC V600E 2L+、ORR 63.2%、mPFS 9.7 mo → FDA 承認根拠
• BRF113928 1L cohort: Planchard et al. LancetOncol 2017 が 1L NSCLC V600E、ORR 64%、mPFS 10.9 mo、OS 24.6 mo → 1L 適応拡大
• NSCLC BRAF non-V600 / V600: Mazieres et al. AnnOncol 2020 が NSCLC で V600 群と non-V600 群を直接比較、V600 群で Vemurafenib 効果あり、non-V600 では限定的
• NSCLC BRAF 自然歴: Marchetti et al. JClinOncol 2011 / Paik et al. JClinOncol 2011 / Cardarella et al. ClinCancerRes 2013 が BRAF V600E 肺腺癌の clinical / pathologic feature を整理 (女性・前喫煙者にやや多い、histology は粘液性 / micropapillary 増加)
• 日本のガイダンス: 「肺がん患者における BRAF 遺伝子変異検査の手引き」(日本肺癌学会) が国内 BRAF 検査 / 治療指針

Melanoma での paradigm 確立

• Combination foundation: NSCLC 試験は Melanoma で確立された COMBI-d / COMBI-v paradigm (Dabrafenib + Trametinib) を延長したもの
• ctDNA 動態: Syeda et al. LancetOncol 2021 が advanced melanoma で BRAF-MEK 治療下の ctDNA dynamics を解析、early ctDNA clearance が深い response と関連
• Intermittent dosing: Algazi et al. NatMed 2020 が continuous vs intermittent BRAF-MEK 阻害を直接比較、intermittent では PFS 短縮 → continuous dosing が支持される
• IO vs BRAF-MEK 1L: Atkins et al. JClinOncol 2023 DREAMseq trial が BRAF-mutant melanoma で Nivo+Ipi → Dab+Tram の sequence が逆順より OS 良好を示した landmark — NSCLC の sequencing 議論にも示唆

機構 / Class III / 耐性

• Class III BRAF: Yao et al. Nature 2017 が class III BRAF は upstream RAS 依存で、SHP2 / RTK 阻害が rationale
• Brain tumor secondary mutation: Wang et al. CancerDiscov 2018 が secondary BRAF 変異による RAF inhibitor 耐性
• EGFR-TKI 耐性 BRAF: Shi et al. ClinCancerRes 2017 が osimertinib 耐性で MEK/ERK-dependent BIM/MCL1 degradation を modulate、Ercan et al. CancerDiscov 2012 が ERK reactivation を EGFR-TKI 耐性 driver と同定、Minari et al. JThoracOncol 2018 が osimertinib 1L 治療下で BRAF V600E + MET amp の concurrent emergence を症例報告
• NF1 loss → MEK sensitivity: deBruin et al. CancerDiscov 2014 が NF1 loss-induced MAPK reactivation の EGFR-TKI 耐性 mechanism

臨床位置づけ

• NSCLC BRAF V600E 1L/2L+: Dabrafenib + Trametinib が標準 (NCCN Category 2A)。Planchard et al. LancetOncol 2016 / Planchard et al. LancetOncol 2017 ベース
• IO との sequencing: BRAF V600E は PD-L1 発現様々、TMB は中等度 → IO+chemo vs BRAF-MEK の最適順序未確立。Melanoma では DREAMseq (Atkins et al. JClinOncol 2023) が IO 先行優位を示した
• Non-V600E BRAF: Class II (K601E 等) / Class III BRAF mutation には BRAF 阻害薬単剤無効 → MEK 阻害薬単剤 or SHP2 併用、RAS upstream 阻害が検討 (Yao et al. Nature 2017)
• Melanoma: Dabrafenib+Trametinib / Encorafenib+Binimetinib が標準、IO との sequencing が主要課題
• NSCLC における頻度: V600E は全 NSCLC の 1-2%、非喫煙者にやや多い (Paik et al. JClinOncol 2011)

Open Questions

• IO+chemo vs BRAF-MEK の 1L 最適 sequencing: V600E NSCLC で prospective 比較なし、Melanoma DREAMseq (Atkins et al. JClinOncol 2023) の IO 先行優位が NSCLC でも該当するか
• Non-V600E BRAF mutation: Class II/III BRAF への有効戦略 (SHP2 併用、ERK 阻害薬、pan-RAF 阻害薬) — Yao et al. Nature 2017 の preclinical を臨床へ
• BRAF-MEK 後の耐性戦略: 次治療としての IO efficacy、re-challenge 可能性、ctDNA-based monitoring (Melanoma での Syeda et al. LancetOncol 2021 アプローチを NSCLC へ)
• Combination with IO: BRAF-MEK + anti-PD-1 の肝毒性 (Melanoma KEYNOTE-022 で示唆) と efficacy のバランス
• EGFR-TKI 耐性 BRAF V600E: osimertinib 耐性で BRAF V600E が 1-3% に出現 (Minari et al. JThoracOncol 2018) → osimertinib + Dab+Tram triplet の臨床的妥当性

重要論文 Top 10

1. Planchard et al. LancetOncol 2016 — BRF113928 — Dab+Tram NSCLC V600E pivotal、FDA 承認根拠
2. ★★★★★ Planchard et al. LancetOncol 2017 — BRF113928 1L cohort — 1L 適応拡大の根拠
3. ★★★★★ Yao et al. Nature 2017 — Class III BRAF の RAS 依存性 — 治療階層化
4. ★★★★ Hatzivassiliou et al. Nature 2013 — MEK inhibitor binding mode の機構基盤
5. ★★★★ Atkins et al. JClinOncol 2023 — DREAMseq — BRAF-mutant melanoma の IO 先行優位、NSCLC sequencing への示唆

関連エンティティ・概念

• 関連遺伝子: BRAF
• 関連 class: KRAS-G12C-inhibitor (同 MAPK pathway), SHP2-inhibitor (下流併用)
• 関連概念: MAPK-pathway-resistance (resistance context)
• 試験: BRF113928 / VE-BASKET / COMBI-d
• ドメイン: lung-cancer-treatment

関連論文

直近 30 件のみ表示中 (関連 99 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Brain metastasis

• Chen et al. FrontOncol 2026 — Stereotactic radiotherapy for brain metastases indications, dose fractionation, technological innovations, and evolving
• Weng et al. FrontOncol 2026 — Assessment of real-world surveillance strategies for patients undergoing systemic therapy for brain metastases

Basic-Immunotherapy

• Tang et al. CancerDiscov 2022 — Combined inhibition of SHP2 and CXCR12 promotes antitumor T-cell response in NSCLC
• Meric-Bernstam et al. Lancet 2021 — Enhancing anti-tumour efficacy with immunotherapy combinations

Basic-Liquid-biopsy

• Leighl et al. ClinCancerRes 2019 — Clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly
• Syeda et al. LancetOncol 2021 — Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib a

Basic-Neutrophil and myeloid cell

• Wan et al. NatCellBiol 2026 — Thy1+ cancer stem cells drive metastasis through a pseudohypoxic state shaped by neutrophil-derived mitochondria

Basic-Oncogene and genetics

• Johnson et al. CancerDiscov 2022 — Classification of KRAS-activating mutations and the implications for therapeutic intervention
• Mikubo et al. JThoracOncol 2021 — Mechanism of drug tolerant persister cancer cells the landscape and clinical implication for therapy
• Reiter et al. NatRevCancer 2019 — An analysis of genetic heterogeneity in untreated cancers
• Mayrhofer et al. ProcNatlAcadSciUSA 2020 — Mutation-oriented profiling of autoinhibitory kinase conformations predicts RAF inhibitor efficacies

Basic-Others

• Zhao et al. CancerCell 2020 — Large-scale characterization of drug responses of clinically relevant proteins in cancer cell lines
• Atkins et al. JClinOncol 2023 — Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced
• Algazi et al. NatMed 2020 — Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma a randomized phase 2 trial
• Lu et al. Nature 2026 — Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer
• Davalos et al. TrendsCancer 2026 — How DNA methylation predicts response to cancer therapies

Basic-Tumor microenvironment

• Remsing et al. SciSignal 2022 — IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung

Clinical-Epidemiology

• Thai et al. Lancet 2021 — Lung Cancer

Clinical-NSCLC-Driver negative

• Planchard et al. AnnOncol 2018 — Metastatic non-small cell lung cancer ESMO clinical practice guidelines for diagnosis, treatment and follow-up
• Dummer et al. JAMAOncol 2020 — Rationale for immune checkpoint inhibitors plus targeted therapy in metastatic melanoma A review
• Hu et al. JImmunotherCancer 2021 — Genomic profiles and their associations with TMB, PD-L1 expression, and immune cell infiltration landscapes in

Clinical-NSCLC-Driver-Other

• Mazieres et al. AnnOncol 2020 — Vemurafenib in non-small-cell lung cancer patients with BRAFV600 and BRAFnonV600 mutations
• Kim et al. Cell 2020 — Targeting KRAS(G12C) from inhibitory mechanism to modulation of antitumor effects in patients
• Jonna et al. ClinCancerRes 2019 — Detection of NRG1 gene fusions in solid tumors
• Skoulidis et al. NEnglJMed 2021 — Sotorasib for lung cancers with KRAS p.g12c mutation

Clinical-NSCLC-EGFR

• Asao et al. RespirInvestig 2019 — Resistance to molecularly targeted therapy in non-small-cell lung cancer

Clinical-Novel modalities

• Sarnaik et al. CancerCell 2024 — Tumor-infiltrating lymphocytes a new hope

Clinical-Others

• Cowzer et al. ClinCancerRes 2026 — Molecular and clinical determinants of targeted therapy treatment in biliary tract cancer
• Larkin et al. NEnglJMed 2019 — Five-year survival with combined nivolumab and ipilimumab in advanced melanoma

Clinical-Supportive care

• Griggs et al. JClinOncol 2021 — Appropriate systemic therapy dosing for obese adult patients with cancer ASCO guideline update