Patient
VERIFIED-ESOPHAGEAL-L2-ESOPH_METASTATIC_2L_HER2_POSIT · Algorithm: ALGO-ESOPH-2L
Clinical significance of mutations (ESCAT)
Tumor-board context — the engine does not use these tiers to rank tracks
| Biomarker | Variant | ESCAT | Evidence | Clinical significance | Drugs | Sources |
|---|
| BIO-HER2-SOLID | amplification / overexpression — IHC 3+ or (IHC 2+ + ISH amplified) using gastric Hofmann 2008 criteria; ~10-30% of esophageal/GEJ adenocarcinoma | IA | - SRC-NCCN-ESOPHAGEAL-2025
- SRC-ESMO-ESOPHAGEAL-2024
Evidence cited from clinical guidelines; per-source evidence levels not yet structured. See Phase-2-of-CIViC-pivot for re-cite roadmap. | HER2-positive esophageal/GEJ adenocarcinoma scored by gastric criteria: trastuzumab + chemotherapy is preferred 1L (cross-referenced from ToGA / KEYNOTE-811) per SRC-NCCN-ESOPHAGEAL-2025, SRC-ESMO-ESOPHAGEAL-2024. Pembrolizumab + trastuzumab + fluoropyrimidine/platinum is FDA-approved for HER2+ PD-L1 CPS≥1 metastatic GEJ adenocarcinoma (KEYNOTE-811). Trastuzumab deruxtecan is FDA-approved 2L+ for HER2-positive advanced gastric/GEJ adenocarcinoma (DESTINY-Gastric01 includes Siewert types). Squamous-cell esophageal carcinoma is HER2-negative as a rule and is not in scope for HER2-directed therapy. | trastuzumab + fluoropyrimidine + platinum (1L per SRC-NCCN-ESOPHAGEAL-2025, SRC-ESMO-ESOPHAGEAL-2024)
pembrolizumab + trastuzumab + fluoropyrimidine + platinum (1L HER2+ PD-L1 CPS≥1 GEJ adenocarcinoma per SRC-NCCN-ESOPHAGEAL-2025)
trastuzumab deruxtecan (2L+ per SRC-NCCN-ESOPHAGEAL-2025) | - SRC-NCCN-ESOPHAGEAL-2025
- SRC-ESMO-ESOPHAGEAL-2024
|
Primary current-line option
- Indication
- IND-ESOPH-METASTATIC-2L-HER2-POSITIVE-T-DXD
- Regimen
- Trastuzumab deruxtecan (T-DXd) — 2L+ HER2+ gastric (DESTINY-Gastric01)
- Drugs + NSZU
- Trastuzumab deruxtecan (T-DXd) (DRUG-TRASTUZUMAB-DERUXTECAN) 6.4 mg/kg · IV q3 weeks until progression / unacceptable toxicity · IV ⚠ NSZU — not for this indication
- Reason
- Primary current-line option selected by ALGO-ESOPH-2L at step 10.
Other current-line alternatives (2 tracks)
Same treatment line; review when biomarker, access, contraindication, or patient-context assumptions change.
- Indication
- IND-ESOPH-METASTATIC-2L-NIVO-SQUAMOUS
- Regimen
- Nivolumab monotherapy — 2L esophageal squamous (ATTRACTION-3)
- Drugs + NSZU
- Nivolumab (DRUG-NIVOLUMAB) 240 mg IV q2w (alternatively 480 mg IV q4w) · IV until progression / unacceptable toxicity / max 2 years · IV ⚠ NSZU — not for this indication
- Hard contraindications
- CI-PEMBROLIZUMAB-AUTOIMMUNE
- Reason
- Current-line alternative presented for HCP consideration
- Indication
- IND-ESOPH-METASTATIC-2L-PEMBRO-CPS10
- Regimen
- Pembrolizumab monotherapy — 2L esophageal PD-L1 CPS ≥10 (KEYNOTE-181)
- Drugs + NSZU
- Pembrolizumab (DRUG-PEMBROLIZUMAB) 200 mg IV q3w OR 400 mg IV q6w · IV until progression / unacceptable toxicity / max 35 cycles (~2 years) · IV ⚠ NSZU — not for this indication
- Hard contraindications
- CI-PEMBROLIZUMAB-AUTOIMMUNE
- Reason
- Current-line alternative presented for HCP consideration
Pre-treatment investigations
Investigations before treatment start · critical / standard / desired · merged across tracks
| ID | Name | Priority | Category | Where to order | Needed for |
|---|
| TEST-CBC | Complete Blood Count with Differential | Critical | lab | — | all tracks |
| TEST-CMP | Comprehensive Metabolic Panel | Critical | lab | — | all tracks |
| TEST-CT-CHEST-ABDOMEN-PELVIS | CT chest + abdomen + pelvis with IV contrast | Critical | imaging | — | all tracks |
| TEST-HER2-IHC-FISH | HER2 IHC + reflex FISH on tumor | Critical | — | CSD Lab ✓ (code TBC) | aggressive |
| TEST-ECHO | Echocardiography | Standard | imaging | — | aggressive |
Red flags — PRO / CONTRA aggressive
PRO-AGGRESSIVE
Triggers that push toward the aggressive track
- Patient with active or incompletely controlled pre-existing autoimmune or inflammatory disease (sarcoidosis, rheumatoid arthritis, IBD, SLE, autoimmune hepatitis, inflammatory myopathy, myasthenia gravis, or similar) is considered for immune checkpoint inhibitor (ICI) therapy — elevated risk of immune-related adverse events (irAE) flare or de-novo grade 3-4 irAE. Requires specialist (rheumatology / pulmonology / gastroenterology) pre-treatment review; prefer lower-irAE-burden backbone when options exist (pembrolizumab mono > ipilimumab+nivolumab).
Pre-existing autoimmune disease is present in ~10-15% of patients eligible for ICI therapy; historically excluded from pivotal trials. Real-world data (Abdel-Wahab 2018, 3557 pts) shows 55% experienced irAE flare and ~29% required…
RF-ACTIVE-AUTOIMMUNE-DISEASE-ICI-RISKSRC-SITC-ICI-IRAEMANAGEMENT-2021SRC-ESMO-ICI-TOXICITY-2022 - Frailty profile precluding CROSS / FLOT / definitive CRT in esophageal: ECOG ≥3, OR (age ≥75 + Charlson ≥3), OR composite (age ≥70 + albumin <3.0 + ≥10% weight loss + sarcopenia). Triggers definitive RT-only (palliative-intent), best-supportive-care with palliative stenting + nutrition optimization.
Esophageal cancer disproportionately affects older patients; pre-CROSS nutrition optimization (PEG/J-tube) often required. Frail elderly: hypofractionated RT 30-40 Gy palliative + stenting for dysphagia control.
RF-ESOPH-FRAILTY-AGESRC-NCCN-ESOPHAGEAL-2025SRC-ESMO-ESOPHAGEAL-2024 - Severe dysphagia with weight loss / aspiration risk in esophageal cancer: inability to swallow saliva, recurrent aspiration pneumonia, >10% weight loss in 3 months, OR malignant tracheoesophageal fistula. Mandates urgent palliative intervention (stenting OR dilation OR diversion) BEFORE any definitive systemic / RT therapy.
Self-expandable esophageal stent OR endoscopic dilation OR PEG/J-tube for nutritional support. Tracheoesophageal fistula precludes RT (worsens fistula) — covered stent + chemo only. Severe weight loss pre-CROSS predicts poor tolerance —…
RF-ESOPH-SEVERE-DYSPHAGIA-ASPIRATIONSRC-NCCN-ESOPHAGEAL-2025SRC-ESMO-ESOPHAGEAL-2024 - Fit performance status (ECOG 0-1): patient is fully active or restricted in physically strenuous activity but ambulatory and able to carry out light work. Eligible for full-dose chemotherapy and intensive regimens (CHOEP, BEACOPP-escalated, HD-MTX, ASCT consolidation, CAR-T).
Pan-disease eligibility gate. ECOG 0-1 is the canonical entry criterion for intensified regimens across DLBCL (CHOEP-21 in age ≤60 with elevated LDH per German High-Grade NHL Study Group), Hodgkin (BEACOPP-escalated), Burkitt…
RF-FITNESS-ECOG-FITSRC-NCCN-BCELL-2025SRC-ESMO-DLBCL-2024
CONTRA-AGGRESSIVE
Hard contraindications to escalation
- Pembrolizumab (and other PD-1/PD-L1 inhibitors) augment T-cell responses; in patients with active autoimmunity or post-transplant immunosuppression, this can precipitate severe organ-specific flares (colitis, hepatitis, pneumonitis, transplant rejection) that may be fatal or require transplant loss.
CI-PEMBROLIZUMAB-AUTOIMMUNE
What NOT to do
Explicit prohibitive rules, each grounded in a regimen / supportive care / contraindication entity
Aggressive plan (IND-ESOPH-METASTATIC-2L-HER2-POSITIVE-T-DXD)
- Do NOT use in squamous-cell esoph carcinoma (ESCC) — DG-01/04 and ToGA did not enroll ESCC, HER2 amplification rare.
- Do NOT skip baseline + serial HRCT chest — ILD ~13.9% (DG-04), predominantly G1-2 but historically ~1% fatal.
- Do NOT continue at suspicion of pneumonitis — immediate hold + pulmonologist + corticosteroids.
- Do NOT prescribe without HER2 reconfirmation on fresh biopsy when feasible — HER2 loss after 1L common (~30%).
- Do NOT prescribe at baseline LVEF <50% — cardiotoxicity of trastuzumab-based conjugates.
- Do NOT skip prophylactic high-emetogenic antiemetics — T-DXd HEC.
- Do NOT confirm the plan without verified funding pathway — NSZU 2026 does NOT cover T-DXd for gastric/esoph indications.
Standard plan (IND-ESOPH-METASTATIC-2L-NIVO-SQUAMOUS)
- Do not prescribe in active autoimmune disease (lupus, IBD, untreated thyroiditis G3+) — irAE will progress uncontrollably.
- Do not continue through Grade ≥3 irAE without permanent discontinuation consideration.
- Do not ignore ICI-pneumonitis at the onset of dyspnea / cough — HRCT + corticosteroids.
- Do not use at ECOG ≥3 — benefit of ICI in frail population not established; consider best-supportive-care.
- Do not use after 1L ICI-exposure — no data on reuse; consider cytotoxic alternative.
- Do not confirm the plan without verified funding pathway — NSZU 2026 does NOT cover nivolumab for esophagus.
Aggressive plan (IND-ESOPH-METASTATIC-2L-PEMBRO-CPS10)
- Do not prescribe without PD-L1 CPS testing — efficacy limited to CPS ≥10 subgroup.
- Do not prescribe in active autoimmune disease — irAE will progress.
- Do not continue through Grade ≥3 irAE without permanent discontinuation consideration.
- Do not use at ECOG ≥3 — benefit of ICI in frail population not established.
- Do not use after 1L ICI-exposure (KEYNOTE-590) — no data on reuse.
- Do not confirm the plan without verified funding pathway — NSZU 2026 does NOT cover pembrolizumab for esophagus.
Timeline
Treatment timeline — derived from regimen + monitoring schedule
Aggressive plan
Induction · Trastuzumab deruxtecan (T-DXd) — 2L+ HER2+ gastric (DESTINY-Gastric01)
21-day cycles × Until progression or unacceptable toxicity
Standard plan
Induction · Nivolumab monotherapy — 2L esophageal squamous (ATTRACTION-3)
14-day cycles × Until progression / unacceptable toxicity / max 2 years
Aggressive plan
Induction · Pembrolizumab monotherapy — 2L esophageal PD-L1 CPS ≥10 (KEYNOTE-181)
21-day cycles × Until progression / unacceptable toxicity / max 35 cycles
MDT brief
Discussion questions (2, 0 blocking)
OQ-LDH-CURRENT
What is the current LDH? Marker of tumor burden and transformation.
LDH is part of the prognostic indices of indolent lymphomas.
→ hematologist
OQ-BIOMARKER-PDL1-CPS
What is the status of PD-L1 Combined Positive Score (CPS) (BIO-PDL1-CPS)? It is required by track(s): IND-ESOPH-METASTATIC-2L-PEMBRO-CPS10. Expected value: CPS ≥10 (22C3 assay).
A treatment-track biomarker requirement is missing from the patient profile; the MDT should verify the test result, method, specimen, and date before relying on this option.
→ pathologist
MDT talk tree (3 steps)
| # | Owner | Topic | Action |
|---|
| 1 | hematologist | Staging / disease burden | What is the current LDH? Marker of tumor burden and transformation. |
| 2 | pathologist | Biomarker status | What is the status of PD-L1 Combined Positive Score (CPS) (BIO-PDL1-CPS)? It is required by track(s): IND-ESOPH-METASTATIC-2L-PEMBRO-CPS10. Expected value: CPS ≥10 (22C3 assay). |
| 3 | clinical_pharmacist | Specialist review | Chemoimmunotherapy regimen — drug-drug interactions, dose adjustments, premedication. |
Skills (recommended) — for consideration (1)
Data quality
Usable with caveats. No critical default-track gap was found, but the MDT should review the listed caveats before final sign-off.
- Biomarker coverage: 1/2 known (50%), 1 missing, 0 default-track gaps
- Unevaluated RedFlags: RF-ACHALASIA-ESOPHAGEAL-PREVENTION, RF-ACTIVE-AUTOIMMUNE-DISEASE-ICI-RISK, RF-BARRETTS-ESOPHAGUS-PREVENTION, RF-ESOPH-FRAILTY-AGE, RF-ESOPH-HIGH-RISK-BIOLOGY, RF-ESOPH-INFECTION-SCREENING, RF-ESOPH-SEVERE-DYSPHAGIA-ASPIRATION, RF-ESOPH-TRANSFORMATION-PROGRESSION, RF-ESOPHAGEAL-POST-CROSS-NON-PCR, RF-LIFESTYLE-ALCOHOL-CANCER-PREVENTION, RF-LIFESTYLE-HOT-BEVERAGES-PREVENTION, RF-LIFESTYLE-HOT-MATE-ESOPHAGEAL-PREVENTION, RF-LIFESTYLE-OBESITY-CANCER-PREVENTION, RF-LIFESTYLE-SMOKELESS-TOBACCO-PREVENTION, RF-OLIGOMET-DEFINITION
| Missing biomarker | Label | MDT owner | Default track | Required by | Next action |
|---|
BIO-PDL1-CPS | PD-L1 Combined Positive Score (CPS) | pathologist | no | IND-ESOPH-METASTATIC-2L-PEMBRO-CPS10 | Verify result, method, specimen, and report date before sign-off. Expected/constraint: CPS ≥10 (22C3 assay) |
Technical MDT skill metadata (1/16 activated in this plan)
All registered virtual specialists. ✓ — activated for this case; ○ — not activated (available for other clinical scenarios).
| Specialist | skill_id | Version | Last reviewed | Sign-offs | Domain |
|---|
| Cellular therapy specialist (CAR-T) | cellular_therapy_specialist | v0.1.0 | 2026-04-25 | 0 | cellular_therapy |
| Clinical pharmacist | clinical_pharmacist | v0.1.0 | 2026-04-25 | 0 | clinical_pharmacy |
| Hematologist / oncohematologist | hematologist | v0.1.0 | 2026-04-25 | 0 | hematology_oncology |
| Hematopathologist (lymphoma / leukemia / myeloma) | hematopathologist | v0.1.0 | 2026-04-25 | 0 | hematopathology |
| Infectious disease / hepatology | infectious_disease_hepatology | v0.1.0 | 2026-04-25 | 0 | infectious_diseases |
| Medical oncologist (solid-tumor chemotherapist) | medical_oncologist | v0.1.0 | 2026-04-25 | 0 | solid_oncology |
| Molecular geneticist / molecular oncologist | molecular_geneticist | v0.1.0 | 2026-04-25 | 0 | molecular_oncology |
| Palliative care | palliative_care | v0.1.0 | 2026-04-25 | 0 | palliative_care |
| Pathologist (general) | pathologist | v0.1.0 | 2026-04-25 | 0 | pathology |
| Primary care / family physician | primary_care | v0.1.0 | 2026-04-25 | 0 | primary_care |
| Psycho-oncologist | psychologist | v0.1.0 | 2026-04-25 | 0 | psychosocial |
| Radiation oncologist | radiation_oncologist | v0.1.0 | 2026-04-25 | 0 | radiation_oncology |
| Radiologist | radiologist | v0.1.0 | 2026-04-25 | 0 | diagnostic_imaging |
| Social worker / case manager | social_worker_case_manager | v0.1.0 | 2026-04-25 | 0 | psychosocial |
| Surgical oncologist | surgical_oncologist | v0.1.0 | 2026-04-25 | 0 | surgical_oncology |
| Transplant specialist (BMT) | transplant_specialist | v0.1.0 | 2026-04-25 | 0 | cellular_therapy |
Sources cited
- SRC-DESTINY-GASTRIC01-SHITARA-2020: Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer (2020)
- SRC-DESTINY-GASTRIC04-SHITARA-2025: Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer (2025)
- SRC-ESMO-ESOPHAGEAL-2024: ESMO Esophageal Cancer (2024)
- SRC-NCCN-ESOPHAGEAL-2025: NCCN Esophageal and EGJ Cancers (v.3.2025)
Experimental options (clinical trials)
Third plan track — open-enrollment trials from ClinicalTrials.gov. Render-time metadata; engine selection is not affected by this block (CHARTER §8.3). Last synced: 2026-07-15.
| NCT | Title | Phase | Status | Sponsor | UA | Signals | Eligibility (excerpt) |
|---|
| NCT07109726 | A Phase 1/2 Trial of TER-2013 in Patients With Solid Tumors Harboring AKT/PI3K/PTEN Pathway Alterations | PHASE1 / PHASE2 | RECRUITING | — | Biomarker: unclear Surrogate endpoint only | |
| NCT05238922 | Study of INCB123667 in Subjects With Advanced Solid Tumors | PHASE1 | RECRUITING | — | Phase 1 only | |
| NCT05059444 | ORACLE: Observation of ResiduAl Cancer With Liquid Biopsy Evaluation | N/A | RECRUITING | — | — | |
| NCT06500052 | A Study of BL-M17D1 in Patients With Locally Advanced or Metastatic HER2 Positive/Lower Expression Gastrointestinal Cancer and Other Solid Tumors | PHASE1 | RECRUITING | — | Biomarker: enriched Phase 1 only Small N (<50) Single country | |
| NCT06293898 | Open Label Study to Evaluate BL-M07D1 in HER2 Expressing Malignant Solid Tumors | PHASE1 | RECRUITING | — | Biomarker: enriched Phase 1 only Single country | |
| NCT03740256 | Binary Oncolytic Adenovirus in Combination With HER2-Specific Autologous CAR VST, Advanced HER2 Positive Solid Tumors | PHASE1 | RECRUITING | — | Biomarker: enriched Phase 1 only Small N (<50) Single country | |
| NCT06760819 | A Study to Learn More About How Well Treatment With Sevabertinib (BAY 2927088) Tablets Works and How Safe it is in Participants Who Have a Solid Tumor With Mutations of the Human Epidermal Growth Factor Receptor 2 (HER2) | PHASE2 | RECRUITING | — | Biomarker: unclear Surrogate endpoint only | |
| NCT07124000 | DESTINY-PANTUMOUR04 | N/A | RECRUITING | — | Biomarker: enriched Surrogate endpoint only Single country | |
| NCT06695845 | A Phase 2 Study of Zanidatamab in Patients With HER2-expressing Tumors | PHASE2 | RECRUITING | — | Biomarker: enriched Surrogate endpoint only | |
| NCT07334119 | Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of MT-304 in Adults With Advanced HER2-Expressing Solid Tumors | PHASE1 | RECRUITING | — | Biomarker: unclear Phase 1 only Single country | |
Verify recruitment status directly with the trial site. ctgov data can lag behind current UA-site status.
Option availability in Ukraine
Per-track UA registration · NSZU · cost · access pathway. Render-time metadata; engine selection does not depend on these fields (CHARTER §8.3).
| Option | UA registration | NSZU | Cost orientation | Access pathway |
|---|
| Aggressive plan Trastuzumab deruxtecan (T-DXd) — 2L+ HER2+ gastric (DESTINY-Gastric01) (REG-TDXD-GASTRIC) | ✓ registered | ✓ covered | ₴-? — verify pathway | NSZU formulary |
| Standard plan Nivolumab monotherapy — 2L esophageal squamous (ATTRACTION-3) (REG-NIVO-MONO-ESOPH-2L) | ✓ registered | ✓ covered | ₴-? — verify pathway | NSZU formulary |
| Aggressive plan Pembrolizumab monotherapy — 2L esophageal PD-L1 CPS ≥10 (KEYNOTE-181) (REG-PEMBRO-MONO-ESOPH-2L) | ✓ registered | ✓ covered | ₴-? — verify pathway | NSZU formulary |
| Trial · NCT07109726 A Phase 1/2 Trial of TER-2013 in Patients With Solid Tumors Harboring AKT/PI3K/PTEN Pathway Alterations No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT05238922 Study of INCB123667 in Subjects With Advanced Solid Tumors No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT05059444 ORACLE: Observation of ResiduAl Cancer With Liquid Biopsy Evaluation No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT06500052 A Study of BL-M17D1 in Patients With Locally Advanced or Metastatic HER2 Positive/Lower Expression Gastrointestinal Cancer and Other Solid Tumors No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT06293898 Open Label Study to Evaluate BL-M07D1 in HER2 Expressing Malignant Solid Tumors No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT03740256 Binary Oncolytic Adenovirus in Combination With HER2-Specific Autologous CAR VST, Advanced HER2 Positive Solid Tumors No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT06760819 A Study to Learn More About How Well Treatment With Sevabertinib (BAY 2927088) Tablets Works and How Safe it is in Participants Who Have a Solid Tumor With Mutations of the Human Epidermal Growth Factor Receptor 2 (HER2) No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT07124000 DESTINY-PANTUMOUR04 No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT06695845 A Phase 2 Study of Zanidatamab in Patients With HER2-expressing Tumors No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
| Trial · NCT07334119 Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of MT-304 in Adults With Advanced HER2-Expressing Solid Tumors No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
Cost information is orientation. Verify with a specific pharmacy / foundation / trial site. Status updated: 2026-07-15.