Fore Biotherapeutics · Regulatory · plixorafenib (PLX120-03 / FORTE)

DLGNT & PXA — Clinical-Development Summary, Citation-Gap Analysis & References

Source: "Patient Story Boards — Sub B, A1 CNS, PLX120-03" (M. Winkler, 03 Aug 2026) Prepared: 06 Aug 2026 Classification: Internal — Confidential 📖 GlossaryDLGNT, PXA, MAPK, methylation class & 40 more →

About this format — supports CTD Module 2.5.1

This is a disease-background reference, and its role in a marketing application is to be the evidence base behind Section 2.5.1, Product Development Rationale — the opening section of the Module 2.5 Clinical Overview under ICH M4E(R2). 2.5.1 must identify the disease and population, summarise current therapy and its limitations, state the unmet medical need, and give the scientific rationale linking mechanism to need.

2.5.1 itself is short and argumentative; it cannot carry this level of detail, but every figure it uses has to be traceable to something that can. That is what this document is. The consolidated rationale drawing on it lives at 2.5.1 Product Development Rationale.

2.5.1 Product Development Rationale ← evidence base: this document citation register2.7.3 Efficacy2.7.4 Safety
⚠ Decision support — not medical or regulatory advice. References verified against PubMed; medical + regulatory HITL review required before any external use.

1 · Document summary

An 8-slide disease-characterization reference for the two BRAF/MAPK-driven CNS tumor types in scope for the plixorafenib program. Disease background only — no trial or patient data. Each tumor follows one structure: description → localization → imaging → epidemiology → genetics → grading → WHO diagnostic criteria → a practical diagnostic checklist.

DLGNT — Diffuse Leptomeningeal Glioneuronal Tumor

PXA — Pleomorphic Xanthoastrocytoma

Through-line: both tumors are MAPK-pathway-driven (KIAA1549::BRAF fusion in DLGNT; BRAF-V600E in PXA) — the mechanistic rationale for a pan-RAF / paradox-breaker like plixorafenib. The deck stops at disease characterization; it does not yet connect these profiles to the drug, the treatment landscape, or the PLX120-03/FORTE trial.

2 · Citation-gap analysis

Claims on the slides checked against the deck's citation docs and resolved against the RWE literature search, with each resolving source pinned to its exact location in the primary document. Filled a primary source now exists · Resolved the claim is settled against a verified source · Discrepancy the number/source doesn't match · Clarify wording/denominator · Additive nothing to correct — content the deck lacks · Contradiction two primary sources disagree. Click Details on any row for the deeper explanation.

Reviewer-driven revisions (10–11 Aug 2026): three rows were re-cut after SME review on this page. The sex-ratio row moved Discrepancy → Resolved (the figure was right; the citation was wrong). The prognosis row moved Clarify → Additive (the slides make no prognosis claim, so there was nothing to correct). The 1q gain row gained a non-independence caveat (shared senior authorship and probable patient overlap between the two disagreeing studies). Each row carries the attribution inline.
Claim (location)StatusResolving source (exact location)Action
PXA — "18 of 19 tumors" homozygous CDKN2A/B (slide 6) Filled Phillips 2019, Brain Pathol 29(1):85–96 (PMID 30051528; PMC7837273) — states 95% (18/19) homozygous CDKN2A/B deletion; CDKN2A biallelic in all 19. Results §"Somatic variants and copy number alterations"; landscape in Fig 1; per-tumor CNAs in Suppl. Table S5. Add Phillips 2019 to PXA citations; render as "95% (18/19)" to match the source (94.7% is the exact quotient).
PXA — "up to 94% CDKN2A/B" (slide 6) Filled Same Phillips 2019 (95%, 18/19). Large-series anchor: Dampier 2025, Neurooncol Adv 7(1):vdaf089 (PMID 40735274; PMC12305539) — CDKN2A/B homozygous deletion 406/469 (87%). Results §"mcPXA Tumors Harbor Key Genomic Changes…"; Fig 1B. State the frequency as a range (~87–95% across series) and add Dampier 2025 (n=469) as the large-cohort anchor.
PXA — "mean age 26.3 y" (slide 6) Clarify Primary anchor: Giannini 1999, Cancer 85(9):2033–45 (PMID 10223246) — mean age 26±16 y (n=71). Abstract, p. 2033 (full text paywalled — no interior page asserted). The exact "26.3" was attributed to Mahajan 2022, Lab Invest 102(7):670–81 (PMID 35031693) — could not be verified (paywalled; "26.3" absent from the abstract). Cite Giannini 1999 (26±16 y) as primary and use "≈26 years." Do not cite "26.3" until the Mahajan full text confirms it.
PXA — "anaplasia ~31% at diagnosis," attributed to Brain Pathol 2015;25(5):575-86 (slide 6) Resolved Ida 2015, Brain Pathol 25(5):575–86 (PMID 25318587; PMC4400218) — anaplasia in 33 of 74 (= 44.6%, calculated; paper text: "33 cases"). Results §Clinicopathologic features + Table 2; "31 pediatric" is in the Abstract & Table 1 ("31 [42%]"). Cleaner "at-diagnosis" anchor: Vaubel 2021, Brain Pathol 31(1):20–32 (PMID 32619305; PMC8018001) — A-PXA 14/67 (~21%) at primary diagnosis (Abstract p. 20 + Results §"Patient cohort characteristics"; Fig 1 / Suppl. Table S1). Correct the deck: overall anaplasia 33/74 (44.6%); at primary diagnosis ~21% (Vaubel). Remove the ambiguous "~31%."
DLGNT — "M:F ratio 1.6:1" (slide 2) Resolved Jiang 2022, Front Oncol 12:970076 (PMID 36185310) — systematic review, 145 pediatric patients across 43 studies: "male predominance was observed in the overall sample (male/female: 1.7/1)." Results §Demographics. Adults: de los Reyes-Nabhan 2024, Case Rep Oncol 17(1):337–43 (PMID 38404404) — 34 pooled adult cases, "M:F = 1.43:1." The figure is right; the citation was wrong. 1.6:1 is a pooled-literature number and is not reproducible from Rodriguez 2012 alone (24 M : 12 F = 2:1). Re-anchor to Jiang 2022 and state: "Male predominance, M:F ≈ 1.7:1 (pooled pediatric literature, n=145 across 43 series)." Preferred, since it shows the spread: "≈1.7:1 pooled; 2–2.75:1 in single-center series." Keep Rodriguez 2012 for the entity description, 1p deletion and anaplastic progression — not for sex ratio.
DLGNT — "25 (81%) of 31 patients in the largest reported cohort" (slide 2) Clarify Rodriguez 2012 (PMID 22941225) — total cohort is 36; the 81% is "25 of 31" evaluable for a discrete intraparenchymal lesion. Abstract, p. 627. State both denominators: 36 total; 25/31 (81%) evaluable for intraparenchymal disease.
PXA slides overall — specific stats with no matching citation (citation doc lists only WHO 2021 + Louis 2021) Filled Primary sources now supplied in §3: Phillips 2019, Giannini 1999, Ida 2015, Vaubel 2021, Dampier 2025 (+ Schindler 2011, Weber 2007, Ma 2018). The WHO 2021 / Louis 2021 references support classification only, not the epidemiologic/molecular stats. Rebuild the PXA citation doc from these primary sources.
DLGNT — prognosis absent from the slides Additive Mikkelsen 2025, Acta Neuropathol 150(1):18 (PMID 40788548; PMC12339613; n=30) — 5-yr OS 83.3% ± 8.8, 5-yr PFS 15.9% ± 8.0, median time to progression 21.5 mo. Abstract + Results §"Patient outcomes"; Fig 3a. Nothing to correct — content to add. The slides make no prognosis claim; an earlier draft of this row read an "implied indolent" framing into that silence, which the deck does not support (M. Winkler, 10 Aug 2026). Add a prognosis line: high OS with low PFS — most patients alive at 5 years, most progressed. Carry n=30 with the figures and note these are on-therapy outcomes, not natural history. See the 1q row for how much independent weight this cohort can bear.
DLGNT — 1q gain presented as an adverse prognostic marker (slide 3) Contradiction Chiang 2022, Acta Neuropathol 144(6):1185–87 (PMID 36175668; PMC9637611; n=32) — 1q gain associated with inferior PFS/OS (Fig 1c PFS / 1e OS). Not confirmed by Mikkelsen 2025 (PMID 40788548; PMC12339613; n=30) — 1q gain NOT prognostically significant (Results §"Patient outcomes"; Fig 3e,f).
Not independent cohorts: all four Chiang 2022 authors (Chiang, Moreira, Li, Furtado) are on Mikkelsen 2025, with Chiang as senior author. Mikkelsen is multi-institutional (25 affiliations; US, Lebanon, Brazil) — "Twelve patients were treated at St. Jude…, 16 at other institutions in the United States, one in Brazil, and one in Lebanon" — so up to ~12 of 30 may overlap Chiang's series. Neither paper states whether any patients were previously reported.		 Present 1q gain as unsettled, not as a settled adverse marker — and carry both n's on the face of the claim. Do not present these as two independent cohorts disagreeing: shared senior authorship and probable patient overlap mean the evidence must not be double-counted. Most accurate framing: "unresolved — the more recent, broader multi-institutional cohort did not confirm the association." Establishing true overlap requires the authors. (Caveat added per J. Jang, 11 Aug 2026.)

3 · References

In deck already cited  ·  New added by this literature search. PMIDs link to PubMed; identifiers verified against primary sources.

3.1 · DLGNT

  1. In deck Rodriguez FJ, et al. Disseminated oligodendroglial-like leptomeningeal tumor of childhood. Acta Neuropathol. 2012;124(5):627–641. PMID 22941225. Original entity description (n=36, 24 M : 12 F); 1p deletion; anaplastic progression 8/36 (22%).
  2. In deck Deng MY, et al. Molecularly defined DLGNT comprises two subgroups with distinct clinical and genetic features. Acta Neuropathol. 2018;136(2):239–253. PMID 29766299. Defines MC-1 vs MC-2 (5-yr OS 100% vs 43%); universal 1p loss; MAPK/ERK activation 80% (KIAA1549::BRAF most frequent).
  3. In deck Chiang J, et al. Prognostic significance of chromosome arm 1q gain and methylation class in DLGNT. Acta Neuropathol. 2022;144(6):1185–1187. PMID 36175668. 1q gain = independent adverse prognosticator (n=32). Not confirmed by Mikkelsen 2025 — and the two are not independent: all four authors here are also on Mikkelsen 2025, with Chiang as senior author.
  4. In deck Lee C, et al. DLGNT: a systematic review highlighting molecular heterogeneity and survival outcome. Cancers (Basel). 2026;18(6):912. DOI 10.3390/cancers18060912. Pooled IPD review; predominantly pediatric; resection trends to longer PFS/OS.
  5. In deck WHO Classification of Tumours Editorial Board. Central Nervous System Tumours, 5th ed. IARC; 2021. Formalizes DLGNT as a distinct glioneuronal entity + molecular criteria.
  6. New Mikkelsen MK, et al. DLGNT: a comprehensive clinical and molecular analysis. Acta Neuropathol. 2025;150(1):18. PMID 40788548. Largest recent integrated cohort (n=30; multi-institutional — 12 at St. Jude, 16 other US, 1 Brazil, 1 Lebanon). KIAA1549::BRAF 96%; 22 M : 8 F; 5-yr OS 83.3%±8.8 vs 5-yr PFS 15.9%±8.0; 1q gain not prognostic. Shares its four senior authors with Chiang 2022 — treat as non-independent.
  7. New Jiang H, et al. Clinical progression, pathological characteristics, and radiological findings in children with diffuse leptomeningeal glioneuronal tumors: a systematic review. Front Oncol. 2022;12:970076. PMID 36185310. Sex-ratio anchor — 145 pediatric patients pooled from 43 studies; "male/female: 1.7/1"; median age 5 y. Pooled published cases (publication bias; pediatric-only).
  8. New de los Reyes-Nabhan NK, et al. Diffuse leptomeningeal glioneuronal tumor in adults: case report and literature review. Case Rep Oncol. 2024;17(1):337–343. PMID 38404404. Adult sex-ratio anchor — 34 pooled published adult cases, "M:F = 1.43:1," mean age 35.6 y (19–62).
  9. New Manoharan N, et al. DLGNT in children: the emerging role of genomic analysis. Acta Neuropathol Commun. 2021;9(1):147. PMID 34493325. Pediatric genomic series; MAPK/ERK up to 80%.
  10. New Messiaen J, et al. Patient-derived models from a metastatic pediatric DLGNT with KIAA1549::BRAF fusion. Acta Neuropathol. 2022;144(3):585–588. PMID 36107235. First DLGNT cell line + xenograft; enables preclinical MAPK-targeted testing.
  11. New Chun BM, et al. Response to a novel type II RAF inhibitor in DLGNT with BRAF fusion. The Oncologist. 2025;30(5):oyaf093. PMID 40377441. Case report — KIAA1549::BRAF DLGNT; response to tovorafenib (type II RAF). Most on-point targeted-therapy precedent.
  12. New Castellano-Damaso S, et al. Continuous response on reduced-dose trametinib in relapsed disseminated KIAA1549-BRAF pLGG. Front Oncol. 2024;14:1381354. PMID 38846974. Case + review — MEK-inhibitor durability/tolerability.
  13. New Selt F, et al. Response to trametinib in progressive pediatric low-grade glioma. J Neurooncol. 2020;149(3):499–510. PMID 33026636. Trametinib series incl. KIAA1549-BRAF fusion; high on-therapy control, off-treatment rebound.

3.2 · PXA

  1. In deck Louis DN, et al. The 2021 WHO Classification of Tumors of the CNS: a summary. Neuro-Oncol. 2021;23(8):1231–1251. PMID 34185076. Defines CNS WHO grade 2 vs 3 PXA (mitoses ≥5/10 HPF ± necrosis).
  2. New Phillips JJ, et al. The genetic landscape of anaplastic PXA. Brain Pathol. 2019;29(1):85–96. PMID 30051528. Source for "18 of 19" and "94%" CDKN2A/B; TERT in 47% of anaplastic PXA.
  3. New Giannini C, et al. Pleomorphic xanthoastrocytoma: what do we really know about it? Cancer. 1999;85(9):2033–2045. PMID 10223246. Primary "mean age ~26" anchor (26±16 y); mitotic index + resection = survival predictors.
  4. New Ida CM, et al. Pleomorphic xanthoastrocytoma: natural history and long-term follow-up. Brain Pathol. 2015;25(5):575–586. PMID 25318587. The deck's "anaplasia" reference — reports 44.6% (33/74), not 31% (reconcile).
  5. New Schindler G, et al. BRAF V600E mutation in 1,320 nervous-system tumors. Acta Neuropathol. 2011;121(3):397–405. PMID 21274720. Foundational BRAF-V600E frequency in PXA (~65–66%).
  6. New Weber RG, et al. Frequent CDKN2A/CDKN2B homozygous deletion in PXA. Oncogene. 2007;26(7):1088–1097. PMID 16909113. Original description of 9p21.3/CDKN2A-B deletion in PXA.
  7. New Ma C, et al. BRAF V600E, TERT, and IDH2 in PXA: a large case series. World Neurosurg. 2018;120:e1225–e1233. PMID 30240866. 55 cases; V600E tumors younger; TERT enriched in anaplastic.
  8. New Vaubel R, et al. Biology and grading of PXA. Brain Pathol. 2021;31(1):20–32. PMID 33368753. Authoritative grading/biology review (molecular vs histologic grade).
  9. New Mahajan S, et al. The evolution of PXA: genesis to molecular alterations and mimics. Lab Invest. 2022;102(7):670–681. PMID 35031693. Review; source of the "mean 26.3 / median 20.5 y" figure (secondary compilation).
  10. New Dampier CH, et al. Methylation-class PXA: analysis of 469 tumors. Neuro-Oncol Adv. 2025;7(1):vdaf089. DOI 10.1093/noajnl/vdaf089. Largest methylation-class series; V600E 86%, CDKN2A/B del 87%, TERT 22%.

3.3 · Therapeutic context (RAF/BRAF-targeted therapy & plixorafenib)

  1. New de la Fuente M, et al. Safety & efficacy of plixorafenib (FORE8394/PLX8394) in BRAF-altered primary CNS tumors [TRLS-02]. Neuro-Oncology. 2024;26(Suppl 4). NCT02428712. Single-arm trial (abstract) — CNS-specific: 9 evaluable MAPKi-naïve V600 PCNST, ORR 67%, mDOR 13.9 mo. Published abstract — distinct from the embargoed internal SNO-2026 reinterpretation.
  2. New de la Fuente MI, et al. FORE8394 in advanced solid and CNS tumors: phase 1/2a results. J Clin Oncol. 2023;41(16_suppl):3006. NCT02428712. Single-arm trial (abstract) — V600 MAPKi-naïve PR 39%, mDOR 32 mo.
  3. New Rosen E, et al. FORTE: a phase 2 master protocol assessing plixorafenib for BRAF-altered cancers. J Clin Oncol. 2025;43(16_suppl):TPS2091. NCT05503797. Trial-in-progress — the registrational path (this is the FORTE / PLX120-03 program).
  4. New Kilburn LB, et al. Type II RAF inhibitor tovorafenib in R/R pediatric low-grade glioma: FIREFLY-1. Nat Med. 2024;30(1):207–217. PMID 37978284. NCT04775485. Pivotal single-arm — ORR 67%, mDOR 16.6 mo; closest competitive benchmark in BRAF-altered pLGG.
  5. New Singh S, et al. FDA Approval Summary: tovorafenib for R/R BRAF-altered pediatric LGG. Clin Cancer Res. 2025;31(8):1383–1389. PMID 39808502. Regulatory basis of the accelerated approval (first therapy for pLGG with BRAF fusions).
  6. New Bouffet E, et al. Dabrafenib plus trametinib in pediatric glioma with BRAF V600 mutations. N Engl J Med. 2023;389(12):1108–1120. PMID 37733309. NCT02684058. Pivotal RCT — first-line dab+tram vs chemo in pLGG (V600 only; inactive against fusions).
  7. New Hargrave DR, et al. Dabrafenib plus trametinib in R/R BRAF V600 pediatric high-grade glioma. J Clin Oncol. 2023;41(33):5174–5183. PMID 37643378. Single-arm phase 2 — ORR 56%, mDOR 22.2 mo.
  8. New Wen PY, et al. Dabrafenib plus trametinib in BRAF V600E low- and high-grade glioma (ROAR). Lancet Oncol. 2022;23(1):53–64. PMID 34838156. Basket trial incl. PXA histology.
  9. New Kaley T, et al. BRAF inhibition in BRAF-V600 gliomas: VE-BASKET. J Clin Oncol. 2018;36(35):3477–3484. PMID 30351999. Vemurafenib; PXA subset ~7 pts (1 CR, 2 PR). Verify PXA subset counts before external use.
  10. New Brown NF, et al. Dabrafenib in BRAF-V600 anaplastic PXA. CNS Oncol. 2017;6(1):5–6. PMID 27781490. Case report — verify page/PMID in reference manager.
  11. New Chamberlain MC. Salvage BRAF inhibitors for recurrent PXA: a retrospective case series. J Neurooncol. 2013;114(2):237–240. PMID 23756727. Case series — vemurafenib n=4 (1 PR, 2 SD); type-I BRAFi limitations.

4 · Positioning note (for the program)

Type I vs type II / paradox-breaker is the through-line. Dabrafenib (type I) works in BRAF-V600 disease but is inactive against BRAF fusions (KIAA1549::BRAF — the dominant driver in pLGG and DLGNT). Tovorafenib (type II) and plixorafenib (paradox-breaker, active against both fusions and V600) cover the fusion space. DLGNT-specific targeted-therapy evidence is single-case-level (Chun 2025) — a genuine white-space plixorafenib's fusion activity addresses. The competitive bar to beat is tovorafenib/FIREFLY-1 (ORR ~51–67%, mDOR ~14–17 mo).

5 · Second pass — broader sources

Extended beyond PubMed to ClinicalTrials.gov, ASCO / SNO / ISPNO / AACR conference proceedings, FDA / EMA regulatory sources, and Google Scholar / open-web grey literature. Items marked ✓ were verified against a primary source; items marked ⚠ are real but need a manual primary-source pull before external/investor use (agency & conference publisher pages blocked automated fetch, and the session web-search budget capped mid-run).

5.1 · Regulatory (FDA / EMA)

  1. New Plixorafenib — FDA designations: ✓ Fast Track (Sep 2022, BRAF Class 1/2); ✓ Orphan Drug (Mar 2023, primary brain & CNS malignancies); ✓ Breakthrough Therapy (1 Apr 2026, adult BRAF-V600E high-grade glioma — "first BTD for a targeted therapy in HGG"). ⚠ No Rare-Pediatric-Disease designation and no EMA designation found — flag: program is positioned pediatric, but the BTD is adult HGG.
  2. New Tovorafenib (OJEMDA): ✓ FDA accelerated approval 23 Apr 2024 — pediatric LGG with BRAF fusion/rearrangement or V600 (ORR 51%, mDOR 13.8 mo; FIREFLY-1). ✓ EMA conditional MA 22 Apr 2026 (Ipsen; same indication; confirmatory FIREFLY-2). FDA-approval summary Singh 2025 already cited; the EMA CMA + verbatim labels are new.
  3. New Dabrafenib + trametinib: ✓ FDA pediatric LGG BRAF-V600E (16 Mar 2023; ORR 46.6% vs 10.8%); ✓ EMA Finlee/Spexotras (15 Nov 2023, with an explicit pediatric HGG V600E indication); ✓ FDA tissue-agnostic BRAF-V600E solid tumors (22 Jun 2022) — the histology-agnostic template.
  4. New Pathway precedents: RACE for Children Act (BRAF is on FDA's pediatric molecular-target list); tissue-agnostic framework; Rare-Pediatric-Disease designation + priority-review voucher (⚠ program authorization sunset ~Dec 2024, reauthorization pending — verify); EMA PIP mandatory + conditional-MA criteria. Vemurafenib has no CNS/glioma indication (melanoma/ECD only).

5.2 · Clinical trials (ClinicalTrials.gov)

  1. New Plixorafenib: FORTE NCT05503797 (Ph2 pivotal, recruiting — Sub-A BRAF-fusion CNS, Sub-B V600E glioma/glioneuronal, ≥8 y); NCT02428712 (Ph1/2a, completed); NCT06610682 — plixorafenib ± retifanlimab, CSF-ctDNA endpoint, V600E glioma (Johns Hopkins). DLGNT/PXA captured molecularly, not by histology name.
  2. New Tovorafenib: FIREFLY-1 NCT04775485; FIREFLY-2/LOGGIC NCT05566795 (Ph3 front-line vs chemo); NCT07206849 (HGG/DIPG expansion); combos (vinblastine NCT06381570), craniopharyngioma NCT05465174, LCH NCT05828069, EAP NCT05760586.
  3. New Dab+tram: NCT02684058 (PXA explicitly named in eligibility); NCT03919071 (HGG, anaplastic PXA named); NCT03975829 (rollover).
  4. New Competitors in CNS: belvarafenib CNS Ph2 NCT07688356 (BRAF-altered brain tumors — closest CNS competitor; ⚠ investigator-initiated, 2025-registered); PF-07799933 NCT05355701 (Pfizer brain-penetrant pan-mutant BRAF ± binimetinib).
  5. White-space finding: no interventional RAF/MEK trial names DLGNT in eligibility (only a terminated CSF-ctDNA study, NCT05934630). PXA is named across dab+tram / MEK trials.

5.3 · Conference readouts — verify numbers before external use

  1. New ✓ Plixorafenib, SNO 2023 (CTNI-76): V600+ primary-CNS tumors n=10 — ORR 60% (6/10), HGG 67%, mPFS 34.1 mo (PMC10639671).
  2. ✓ Plixorafenib, SNO 2024 (TRLS-02) — n=113 incl. 5 children; V600E ORR 67%, mDOR 13.9 mo; no pediatric DLTs (PMC11182979). ✓ ASCO 2023 abstr 3006 (already cited). ⚠ AACR 2025 CT247 (FORTE design); AACR 2026 CT154 (V600 CRC ORR 8%).
  3. New ✓ Tovorafenib, SNO 2024 (CTNI-09): FIREFLY-1 drug-holiday — 24/26 stayed off-treatment (durability-after-stopping); NCOG-05 HRQoL stable. Nysom 2025 optic-pathway subgroup (PMID 39700439).
  4. ✓ Dab+tram, ASCO 2022 LBA2002 (LGG debut). ⚠ ASCO 2026 abstr 10031 — pediatric MAPKi long-term follow-up (numbers unverified).

5.4 · DLGNT — additional literature

  1. New ✓ Campanelli 2025, Acta Neuropathol Commun 13:208 (DOI 10.1186/s40478-025-02100-1). Highest-value new treatment reference — trametinib responses in DLGNT are real but not durable (all progressed < 2 y).
  2. New ✓ De Carli 2026 (Cancers 18(4):549); Witten 2024 (PMID 39073721); de los Reyes-Nabhan 2024 (PMID 38404404, adult onset); Torres-Rey 2023 (PMID 38034149, MMR / aggressive); Giantini Larsen 2023 SNO METB-07 (CSF cfDNA detected KIAA1549::BRAF 5/7).

5.5 · PXA — additional literature

  1. New ✓ Vaubel 2018 (PMID 28181325) — CDKN2A/B deletion the dominant recurrent CNA; ✓ Vizcaino 2024 (PMID 39042515) — CDKN2A homozygous deletion in >90% of PXA. Together these anchor the CDK4/6-inhibitor combination rationale (near-universal Rb-pathway lesion).
  2. New ✓ Vaubel 2021 (21% anaplastic at diagnosis; 5-yr OS 80.8% vs 47.6%); ✓ Zuo 2023 (PMID 37448517, high-grade PXA 5-yr OS 51.5%); ✓ Sullivan 2024 (grade-3 aggressive).
  3. New ✓ Rudà 2022 EANO/EURACAN/SNO guideline (PMID 35908833) positions BRAF/MEK inhibitors for BRAF-altered PXA; ✓ Kata 2022 (PMID 36351333, dab+tram series), Migliorini 2017 (PMID 28235815), Inoue 2024 (PMID 39640311).

5.6 · Competitive & resistance landscape

Class mechanism (the through-line, sharpened): type-I (dabrafenib, vemurafenib — V600 monomer only, paradoxically activates fusions) → type-II / pan-RAF (tovorafenib — dimers + V600) → paradox-breaker (plixorafenib — BRAF-dimer-selective, fusions + V600, monotherapy). Competitors: the pan-RAF pack (exarafenib/KIN-2787, naporafenib/LXH254, belvarafenib, lifirafenib) is anchored in NRAS melanoma, not CNS, and mostly needs a MEK partner. Watch-item: PF-07799933 (Pfizer) — a brain-penetrant pan-mutant BRAF on the same paradox-breaker thesis, with reported in-brain responses in RAF-refractory patients (Yaeger, Cancer Discov 2024, PMC11372368). Resistance: paradoxical MAPK activation (type-II solves it), CDKN2A/B loss (→ CDK4/6 combos), MAPK/dimer reactivation, and PK/CNS-exposure gating durability. Positioning: plixorafenib sits in a three-agent CNS-penetrant cohort (tovorafenib, plixorafenib, PF-07799933); its moat is dimer-selective fusion + V600 coverage as monotherapy, with proven in-brain exposure — best evidenced by the CSF-ctDNA study (NCT06610682).
Verification caveat (this pass): the session's automated web-search budget capped mid-run and several FDA/agency + ASCO/ISPNO publisher pages blocked automated fetch, so items flagged ⚠ above must be confirmed against the primary source before any external or investor-facing use. All ✓ items were fetched/verified (PubMed/PMC/ClinicalTrials.gov/EMA).
Fore Biotherapeutics — Regulatory · Internal & Confidential · prepared 06 Aug 2026 · second pass 07 Aug 2026.
Literature identified by an automated RWE PubMed search; PMIDs/DOIs verified against primary sources at time of preparation (DLGNT in-deck references cross-checked against the source abstracts in this folder). Two identifiers flagged for manual confirmation (VE-BASKET PXA subset; Brown 2017). Decision support only — medical + regulatory sign-off required before any external or investor-facing use. Select any text to leave an anchored comment.
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