Neratinib and Everolimus, Palbociclib, or Trametinib in Treating Participants With Refractory and Advanced or Metastatic Solid Tumors With EGFR Mutation/Amplification, HER2 Mutation/Amplification, or HER3/4 Mutation or KRAS Mutation

1. Is the biology right?

• Somatic driver evidence: yes · EGFR, ERBB4 in clear cell adenocarcinoma

  Rule: Open Targets has somatic-mutation evidence for the target in this cancer. Source: Open Targets: EGFR in clear cell adenocarcinoma, 2026-11-11

  Published context: 2.3× relative success for targets with somatic (IntOGen) support in oncology (Minikel et al., Nature 2024, drug programs to 2023). A ratio between groups, not a probability for this program; mostly phase 2 to 3.
• Human genetic evidence: yes · EGFR: somatic; ERBB4: somatic

  Rule: Any germline or somatic human genetic evidence for the target in this cancer, counted apart from animal-model and literature evidence. Source: Open Targets: EGFR in clear cell adenocarcinoma, 2026-11-11

  Published context: 2.6× relative probability of success, phase 1 to launch, with human genetic support (Minikel et al., Nature 2024, drug programs to 2023). All therapy areas, mostly germline evidence; not a probability for this program.
• Pediatric target: yes · EGFR, ERBB2, CCND1, CDK6, CDK4, MAP2K2, MAP2K1 on the FDA list

  Rule: Target is on FDA's Pediatric Molecular Target List (relevant targets); membership alone neither requires nor waives a study. Source: FDA Pediatric Molecular Target List (Listed as February 2026 on the FDA Pediatric Oncology page; the file served is 9.7.22_the_relevant_molecular_target_list.xlsx, whose Summary of Changes sheet is headed 'SEPTEMBER 2022 UPDATE' (footnote date 2022-09-01)), 2026-11-11
• Haematologic cancer: no · Solid tumour

  Rule: From the indication, or the registry conditions when no indication matches. Source: ClinicalTrials.gov NCT03065387, 2026-11-11

  Published context: Likelihood of approval from phase 1: 7.5% haematologic vs 4.6% solid (BIO / Informa / QLS 2021, 2011–2020). Population-level, not a prediction.

• FKBP1A (via Everolimus): Open Targets has no association between FKBP1A and clear cell adenocarcinoma. · Open Targets: FKBP1A in clear cell adenocarcinoma
• EGFR (via Neratinib): Evidence types in clear cell adenocarcinoma: literature, somatic_mutation; literature listed separately from human genetics. Datasources: cancer_gene_census, europepmc. · Open Targets: EGFR in clear cell adenocarcinoma
• ERBB2 (via Neratinib): Evidence types in clear cell adenocarcinoma: literature; literature listed separately from human genetics. Datasources: europepmc. · Open Targets: ERBB2 in clear cell adenocarcinoma
• ERBB4 (via Neratinib): Evidence types in clear cell adenocarcinoma: literature, somatic_mutation; literature listed separately from human genetics. Datasources: cancer_gene_census, europepmc. · Open Targets: ERBB4 in clear cell adenocarcinoma
• CCND1 (via Palbociclib): Evidence types in clear cell adenocarcinoma: literature; literature listed separately from human genetics. Datasources: europepmc. · Open Targets: CCND1 in clear cell adenocarcinoma
• CDK6 (via Palbociclib): Open Targets has no association between CDK6 and clear cell adenocarcinoma. · Open Targets: CDK6 in clear cell adenocarcinoma
• CDK4 (via Palbociclib): Evidence types in clear cell adenocarcinoma: literature; literature listed separately from human genetics. Datasources: europepmc. · Open Targets: CDK4 in clear cell adenocarcinoma
• MAP2K2 (via Trametinib): Open Targets has no association between MAP2K2 and clear cell adenocarcinoma. · Open Targets: MAP2K2 in clear cell adenocarcinoma
• MAP2K1 (via Trametinib): Evidence types in clear cell adenocarcinoma: literature; literature listed separately from human genetics. Datasources: europepmc. · Open Targets: MAP2K1 in clear cell adenocarcinoma

• Not loaded on this app yet: Normal-tissue expression in vital organs. Source: Human Protein Atlas (ticket 36).
• Not loaded on this app yet: Pan-essential in cell lines. Source: DepMap (ticket 36).
• Not loaded on this app yet: Approved drug on this target. Source: Drugs@FDA (ticket 30).

2. Can the result be trusted?

• Randomised: no · Non-randomised

  Rule: Registry allocation field. Source: ClinicalTrials.gov NCT03065387, 2026-11-11
• Small denominator: no · 84 enrolled; each patient moves a rate by 100 ÷ 84 = 1.2 points

  Rule: Enrolment under 30; the arithmetic is shown, not a benchmark. Source: ClinicalTrials.gov NCT03065387, 2026-11-11
• Primary endpoint is overall survival: no · Maximum tolerated dose (MTD) of neratinib when given in combination with everolimus, palbociclib, or trametinib

  Rule: A registered primary outcome measure names overall survival. Source: ClinicalTrials.gov NCT03065387, 2026-11-11

  Published context: Non-OS primary endpoint: odds ratio 2.79 for a positive phase 3 (Otsuka 2021, 400 phase 3 oncology trials, to 2020). Shown with the next figure: a surrogate is easier to hit, and often a weak guide to survival.

  Published context: 52% of surrogate-to-OS correlations are low (Prasad 2015, published to 2014). Shown with the figure above.
• Results overdue: no · Primary completion 2026-04-23, 6 months ago; within 12 months

  Rule: Primary completion (actual) more than 12 months ago and no results posted to the registry. Source: ClinicalTrials.gov NCT03065387, 2026-11-11

• Not loaded on this app yet: Treated and evaluable counts, assessor, confirmed response, follow-up and data cutoff. Source: Readout extraction (ticket 32).
• Not loaded on this app yet: Primary endpoint changed between registry versions. Source: Registry versions in the store (ticket 32).

3. What must it beat?

• Not loaded on this app yet: Control-arm result and approved therapies for the same segment, with label links. Source: Drugs@FDA, FDA labels and readouts (tickets 30, 32).

4. Too crowded, or too late?

• Stopped on this target: 578 terminated, withdrawn or suspended trials of drugs against FKBP1A; 8 of the 200 most recent give no reason. Reasons are quoted as the registry gives them on the target page. · FKBP1A: what already stopped

• Not loaded on this app yet: Programs on the target by phase and months behind the leader. Source: Programs and Drugs@FDA (ticket 33).

5. Can it be approved, and stay approved?

• Single-country: yes · The only site is in United States

  Rule: All listed sites are in one country; the share of US sites is shown. Source: ClinicalTrials.gov NCT03065387, 2026-11-11
• EU paediatric investigation plan: yes · EMEA-001177-PIP02-20 (trametinib, Treatment of glioma): P: decision agreeing on a investigation plan, with or without partial waiver(s) and or deferral(s), 23 Oct 2020; compliance positive 27 Sept 2022; EMEA-002146-PIP01-17-M04 (Palbociclib, Treatment of Ewing sarcoma): PM: decision on the application for modification of an agreed PIP, 13 Apr 2022; EMEA-002783-PIP01-20 (neratinib, Treatment of breast cancer): W: decision granting a waiver in all age groups for all conditions or indications, 15 Jul 2020; EMEA-002146-PIP02-18 (Palbociclib, Treatment of breast malignant neoplasms): W: decision granting a waiver in all age groups for all conditions or indications, 3 Jan 2019; +6 more

  Rule: An EMA PIP decision (agreement, modification or waiver) lists the drug as its active substance, exact name. Source: EMA data download (dated snapshot), 2026-11-11
• EU orphan designation: yes · EU/3/10/764 expired 4 Aug 2010: Treatment of tuberous sclerosis; EU/3/20/2374 positive 9 Dec 2020: Treatment of glioma; EU/3/07/488 withdrawn 14 Nov 2007: Treatment of gastro-entero-pancreatic neuroendocrine tumours; EU/3/11/894 withdrawn 30 Aug 2011: Treatment of gastric cancer; +1 more

  Rule: An EU orphan designation lists the drug as its active substance (exact name) or belongs to a medicine that does; withdrawn and expired designations are listed with their status. Source: EMA data download (dated snapshot), 2026-11-11
• Authorised in the EU: yes · Palbociclib Viatris: authorised since 19 Jun 2026; Afinitor: authorised since 2 Aug 2009; Mekinist: authorised since 30 Jun 2014; Spexotras: authorised since 5 Jan 2024, orphan medicine; +3 more

  Rule: An EMA medicine record lists the drug as its active substance or INN, exact name; national-only authorisations are not in this file. Source: EMA data download (dated snapshot), 2026-11-11
• FDA orphan designation: not published · FDA's orphan designation database turns away automated requests, so this app does not read it; search it by hand at the link

  Rule: Would be: an FDA orphan designation names the drug. Source: FDA orphan designations search
• FDA pediatric oncology approval: yes · Everolimus [Afinitor] &, 29 Oct 2010: Adult and pediatric patients aged 1 year and older with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected; Trametinib [Mekinist], 31 Aug 2023: In combination with dabrafenib, for the treatment of adult and pediatric patients 1 year of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options; Trametinib [Mekinist], 16 Mar 2023: In combination with dabrafenib, for the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy

  Rule: FDA's Pediatric Oncology Drug Approvals table names the drug. Source: FDA Pediatric Oncology Drug Approvals (content current as of 2026-03-03), 2026-11-11
• Registered studies open to children: yes · 153 interventional studies of Everolimus, Neratinib, Palbociclib, Trametinib include patients under 18; 60 are recruiting, not yet recruiting or active

  Rule: The registry's age group includes Child (birth to 17 years), which also counts studies that set no minimum age. Source: ClinicalTrials.gov search, 2026-11-11

• Caveat: Site counts are not patients per country, and trials registered only outside ClinicalTrials.gov are not covered. Where the sites are is a fact about the record, not a judgement of its quality.
• Rare pediatric disease voucher: FDA, content current as of 29 Apr 2026: “As of February 3, 2026, enactment of the Consolidated Appropriations Act, 2026, the rare pediatric disease PRV program will sunset after September 30, 2029. FDA may not award any PRVs under this program after September 30, 2029.” Voucher sale prices are not shown here; they appear only as company-reported news. · FDA: Rare Pediatric Disease Designation and Priority Review Voucher Programs

• Not loaded on this app yet: Precedent approvals for target, modality and endpoint; accelerated-approval status. Source: Drugs@FDA and FDA accelerated-approval tables (ticket 30).

6. Can the sponsor finish?

• Sponsor: M.D. Anderson Cancer Center (academic or other) · ClinicalTrials.gov NCT03065387
• principal investigator: Sarina A Piha-Paul, M.D. Anderson Cancer Center · Person page

• Not loaded on this app yet: Filed cash, quarterly spend and the runway arithmetic. Source: SEC XBRL company facts (ticket 37).
• Not loaded on this app yet: Sponsor's completed vs stopped oncology trials and results-reporting record. Source: Registry, by company (ticket 37).

What public data cannot tell you

Public records cannot show: sales forecasts; a probability of success for this asset; full deal terms and net prices; FDA designations and action dates before approval (shown only as company-reported); clinical holds unless the company disclosed them; manufacturing; patents on unapproved drugs; whether preclinical findings have been replicated.