PRACTICE AID Practice Guidelines: Gastric Cancer1 Unresectable locally advanced, locally recurrent, or metastatic disease Performance Status Karnofsky PS ≥60% or Karnofsky PS <60% or ECOG PS ≤2 ECOG PS ≥3 Perform HER2, PD-L1, MSI by PCR/MMR by ICH testing (if not done previously) if metastatic adenocarcinoma is documented or suspected HER2 All Others Trastuzumab First·Line Therapy Best t • Add to first-line • Two-drug cytotoxic regimens are supportive chemotherapy for preferred because of lower toxicity care HER2 overexpressing • Three-drug cytotoxic regimens should metastatic be reserved for medically fit patients adenocarcinoma with good PS and access to frequent • Combination with toxicity evaluation fluoropyrimidine and • Oxaliplatin is generally preferred over platinum agentsa cisplatin due to lower toxicity • Not recommended for Palliative Managemen use with anthracyclines Preferred Regimens • Fluoropyrimidine (fluorouracil or capecitabine) and oxaliplatinb • Fluoropyrimidine (fluorouracil or capecitabine) and cisplatinb Access the activity, “Optimizing Precision Medicine in Gastric Cancer Care: Essential Guidance on Translating Scientific Advances With Novel HER2-Targeted Therapies and Other Agents Into Current Clinical Practice,” at PeerView.com/VBJ40 PRACTICE AID Practice Guidelines: Gastric Cancer1 Systemic Therapy for Unresectable Locally Advanced, Recurrent, or Metastatic Disease (When Local Therapy Is Not Indicated) Second-Line and Subsequent Therapy Second-Line Therapy NCCN Category Ramucirumab + paclitaxel 1 Docetaxel 1 Paclitaxel 1 Preferred Regimens lrinotecan 1 Fluorouracil + irinotecan 2A Pembrolizumab (MSI-H or dMMR tumors)c 2A Ramucirumab 1 lrinotecan + cisplatin 2A Other Recommended Entrectinib or larotrectinib (NTRK gene fusion–positive tumors) 2A Regimens Docetaxel + irinotecan 2B Nivolumabd N/A Useful in Certain Fluorouracil + irinotecan + ramucirumab 2B Circumstances Third-Line Therapy Category Trifluridine/tipiracil 1 Pembrolizumab (MSI-H or dMMR tumors)c 2A Preferred Regimens Pembrolizumab (gastric adenocarcinoma with PD-L1 expression 2A levels by CPS ≥1)e Nivolumabd N/A a NCCN Category 1 in combination with cisplatin, Category 2A in combination with other platinum agents. b Category 2A. c Approved for use in the US and Japan. d Approved for use in Japan only. e Approved for use in the US only. CPS: combined positive score; dMMR: deficient mismatch repair; ECOG: Eastern Cooperative Oncology Group; ICH: International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; MMR: mismatch repair; MSI: microsatellite instability; MSI-H: MSI-high; NCCN: National Comprehensive Cancer Network; PCR: polymerase chain reaction; PD-L1: programmed death-ligand 1; PS: performance status. 1. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Access the activity, “Optimizing Precision Medicine in Gastric Cancer Care: Essential Guidance on Translating Scientific Advances With Novel HER2-Targeted Therapies and Other Agents Into Current Clinical Practice,” at PeerView.com/VBJ40 PRACTICE AID NCCN’s Principles of Pathologic Review and Biomarker Testing1 lmmunohistochemical Criteria for Scoring HER2 Expression in Gastric Cancer Surgical Specimen Biopsy Specimen HER2 Overexpression Expression Pattern, Expression Pattern, Assessment lmmunohistochemistry lmmunohistochemistry No reactivity or No reactivity or no 0 membranous reactivity membranous reactivity Negative in <10% of cancer cells in any cancer cell Cluster of five or more cancer Faint or barely perceptible cells with a faint or barely membranous reactivity in perceptible membranous 1+ ≥10% of cancer cells; Negative reactivity irrespective of cells are reactive only in percentage of cancer cells part of their membrane positive Cluster of five or more cancer cells with a weak Weak to moderate complete, to moderate complete, basolateral, or lateral 2+ basolateral, or lateral Equivocal membranous reactivity in membranous reactivity ≥10% of cancer cells irrespective of percentage of cancer cells positive Cluster of five or more cancer cells with a strong Strong complete, basolateral, complete, basolateral, or lateral membranous 3+ or lateral membranous Positive reactivity in ≥10% of reactivity irrespective of cancer cells percentage of cancer cells positive Access the activity, “Optimizing Precision Medicine in Gastric Cancer Care: Essential Guidance on Translating Scientific Advances With Novel HER2-Targeted Therapies and Other Agents Into Current Clinical Practice,” at PeerView.com/VBJ40 PRACTICE AID NCCN’s Principles of Pathologic Review and Biomarker Testing1 Microsatellite Instability (MSI) or Mismatch Repair (MMR) Testing • Used for locally advanced, recurrent, or metastatic gastric cancer in patients who are candidates for treatment with PD-1 inhibitors • Performed on formalin-fixed, paraffin -embedded (FFPE) tissue • Results interpreted as MSl-high (MSI-H) or mismatch repair-deficient (dMMR) in accordance with CAP DNA Mismatch Repair Biomarker Reporting Guidelines • Refer patients with MSI-H or dMMR tumors to a genetics counselor for further assessment • No loss of nuclear expression of MMR proteins: No evidence of deficient mismatch repair (low probability MMR of MSI-H) Interpretation • Loss of nuclear expression of one or more MMR proteins: deficient mismatch repair • MSI-stable (MSI-S) • MSI-low (MSI-L) - 1%-29% of markers exhibit instability - 1 of the 5 National Cancer Institute (NCI) or MSI mononucleotide markers exhibits instability Interpretation • MSI-H - ≥30% of the markers exhibit instability - 2 or more of the 5 NCI or mono-nucleotide markers exhibit instability Access the activity, “Optimizing Precision Medicine in Gastric Cancer Care: Essential Guidance on Translating Scientific Advances With Novel HER2-Targeted Therapies and Other Agents Into Current Clinical Practice,” at PeerView.com/VBJ40 PRACTICE AID NCCN’s Principles of Pathologic Review and Biomarker Testing1 PD-L1 Testing • Used for locally advanced, recurrent, or metastatic gastric carcinomas in patients who are candidates for treatment with PD-1 inhibitors • An FDA-approved companion diagnostic test for use on FFPE tissue is available as an aid in identifying patients for treatment with PD-1 inhibitors • Should be performed only in CLIA-approved laboratories • This is a qualitative immunohistochemical assay using anti–PD-L1 antibodies for the detection of PD-L1 protein in FFPE tissues from gastric adenocarcinoma • A minimum of 100 tumor cells must be present Assessment of in the PD-L1–stained slide for the specimen to be PD-L1 Protein considered adequate for PD-L1 evaluation Expression in • A specimen is considered to have PD-L1 expression Gastric Cancers if the combined positive score (CPS) ≥1 - CPS is the number of PD-L1 staining cells (ie, tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100 CAP: College of American Pathologists; CLIA: Clinical Laboratory Improvement Amendments; NCCN: National Comprehensive Cancer Network; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1. 1. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Access the activity, “Optimizing Precision Medicine in Gastric Cancer Care: Essential Guidance on Translating Scientific Advances With Novel HER2-Targeted Therapies and Other Agents Into Current Clinical Practice,” at PeerView.com/VBJ40 PRACTICE AID Selected Clinical Trials in Gastric Cancer1 HER2+ Gastric Cancer PD-1 Inhibitor + Monoclonal Antibody + CTX NCT03615326: KEYNOTE-811 Phase 3 Recruiting 732 participants Pembrolizumab + trastuzumab + CTX + placebo Monoclonal Antibody ± PD-1 Inhibitor ± CTX ± Dual CPI Antiangiogenesis + CTX NCT04082364: MAHOGANY NCT03081143: RAMIRIS Phase 2/3 Recruiting 850 participants Recruiting 429 participants Margetuximab + INCMGA00012 + CTX + MGD013 + trastuzumab Ramucirumab + FOLFIRI ADC ADC CTX or CTLA-4 Inhibitor + PD-1 Inhibitor + NCT03556345 NCT04014075: DESTINY-Gastric02 Monoclonal Antibody NCT03409848: INTEGA Active (127), not recruiting Recruiting 72 participants Recruiting 97 participants RC48-ADC Trastuzumab deruxtecan Ipilimumab or FOLFOX + nivolumab + trastuzumab Phase 2 ADC Bispecific Antibody + CTX NCT03329690: DESTINY-Gastric01 NCT03929666 Active (220), not recruiting Recruiting 115 participants Trastuzumab deruxtecan vs physician's choice (irinotecan or paclitaxel) ZW25 vs physician's choice ADC + PD-L1 Inhibitor + CTX Bispecific Antibody + PD-1 Inhibitor + CTX Monoclonal Antibody + PD-1 Inhibitor NCT04379596: DESTINY-Gastric03 NCT04276493 NCT02689284 Phase 1b/2 Not yet recruiting (220) Recruiting 50 participants Active (95), not recruiting Trastuzumab deruxtecan vs trastuzumab ZW25 + tislelizumab + CTX Margetuximab + pembrolizumab deruxtecan ± CTX ± durvalumab ADC + PD-1 Inhibitor NCT04280341 Phase 1 Not yet recruiting (50) RC48-ADC + JS001 Access the activity, “Optimizing Precision Medicine in Gastric Cancer Care: Essential Guidance on Translating Scientific Advances With Novel HER2-Targeted Therapies and Other Agents Into Current Clinical Practice,” at PeerView.com/VBJ40 PRACTICE AID Selected Clinical Trials in Gastric Cancer1 Antiangiogenesis Combinations Immunotherapy + Antiangiogenesis Immunotherapy + Antiangiogenesis CTX + Antiangiogenesis + CTX + CTX NCT03686488 Phase 2 NCT04069273: SEQUEL NCT03966118 Recruiting 25 participants Not yet recruiting (58) Recruiting 59 participants Trifluridine/tipiracil + ramucirumab Pembrolizumab + ramucirumab + paclitaxel Avelumab