NCCN’s Principles of Pathologic Review and Biomarker Testing Full abbreviations, accreditation, and disclosure information available at PeerView.com/PXC40 lmmunohistochemical Criteria for Scoring HER2 Expression in Gastrointestinal Cancer1 HER2 Surgical Specimen Expression Biopsy Specimen Expression Overexpression Pattern, lmmunohistochemistry Pattern, lmmunohistochemistry Assessment No reactivity or membranous No reactivity or no membranous 0 reactivity in <10% Negative reactivity in any cancer cell of cancer cells Faint or barely perceptible Cluster of ≥5 cancer cells with a faint membranous reactivity in ≥10% of or barely perceptible membranous 1+ Negative cancer cells; cells are reactive only reactivity irrespective of percentage in part of their membrane of cancer cells positive Cluster of ≥5 cancer cells with Weak to moderate complete, a weak to moderate complete, basolateral, or lateral 2+ basolateral, or lateral membranous Equivocal membranous reactivity in ≥10% of reactivity irrespective of percentage cancer cells of cancer cells positive Cluster of five or more cancer cells Strong complete, basolateral, or with a strong complete, basolateral, 3+ lateral membranous reactivity in or lateral membranous reactivity Positive ≥10% of cancer cells irrespective of percentage of cancer cells positive Perform ISH to determine if cancer cells are ISH-negative or ISH-positive NCCN’s Principles of Pathologic Review and Biomarker Testing Full abbreviations, accreditation, and disclosure information available at PeerView.com/PXC40 Microsatellite Instability (MSI) or Mismatch Repair (MMR) Testing1 • 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 of MSI-H) MMR • Loss of nuclear expression of one or more MMR Interpretation proteins: deficient mismatch repair • Refer patients with MSI-H or dMMR tumors to a genetics counselor for further assessment • Microsatellite stable (MSS) • 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-High (MSI-H) – ≥30% of the markers exhibit instability – 2 or more of the 5 NCI or mono-nucleotide markers exhibit instability NCCN’s Principles of Pathologic Review and Biomarker Testing Full abbreviations, accreditation, and disclosure information available at PeerView.com/PXC40 PD-L1 Testing1 • 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 immuno-histochemical assay using anti–PD-L1 antibodies for the detection of PD-L1 protein in FFPE tissues from gastric adenocarcinoma Assessment of • A minimum of 100 tumor cells must be present in PD-L1 Protein the PD-L1–stained slide for the specimen to be Expression considered adequate for PD-L1 evaluation in Gastric • A specimen is considered to have PD-L1 expression if Cancers 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 NCCN’s Principles of Pathologic Review and Biomarker Testing Full abbreviations, accreditation, and disclosure information available at PeerView.com/PXC40 Colon Cancer2 KRAS, NRAS, • All patients with metastatic colorectal cancer should and BRAF have tumor tissue genotyped for RAS (KRAS and Mutation NRAS) and BRAF mutations individually or as part of Testing an NGS panel Microsatellite Instability • Universal MMR or MSI testing is recommended in all or Mismatch newly diagnosed patients with colon cancer Repair Testing • Diagnostic testing is via immunohistochemistry, FISH, or NGS • Positive by immunohistochemistry is defined as: 3+ staining in more than 50% of tumor cells – 3+ staining is defined as an intense membrane staining HER2 Testing that can be circumferential, basolateral, or lateral – Reflex those with a 2+ HER2 score to FISH testing » Positive when the HER2:CEP17 ratio is ≥2 in more than 50% of tumor cells • Anti-HER2 therapy is only indicated in HER2-amplified tumors that are also RAS and BRAF wild type • NTRK fusions are extremely rare in colorectal carcinomas NTRK Fusions • Methods for detecting NTRK fusions are IHC, FISH, DNA-based NGS, and RNA-based NGS 1. National Comprehensive Cancer Network Clinical Practice Guidelines. Gastric Cancer. Version 3.2020 https://www.nccn.org/professionals/physician_gls/pdf/gastric_blocks.pdf. 2. National Comprehensive Cancer Network Clinical Practice Guidelines. Colon Cancer. NCCN Answer Blocks™. Version 4.2020. https://www.nccn.org/professionals/physician_gls/pdf/colon_blocks.pdf. Gastric and Colorectal Cancer: Current Treatment Algorithms and Select Clinical Trials Full abbreviations, accreditation, and disclosure information available at PeerView.com/PXC40 The Evolving Treatment Algorithm With Targeted Agents for Advanced Gastric Cancer1 If progression and PS 0-1, second-line treatment: ramucirumab-based, irinotecan, paclitaxel, or clinical trial ECOG/PS 0-1 If progression and PS first-line treatment: 0-1, third-line treatment: platinum + trifluridine/tipiracil or fluoropyrimidine ± clinical trial trastuzumab (if HER2+) If progression and PS If CPS ≥1, third-line 0-1 and MSI-H tumor, treatment: New diagnosis of GC second-line treatment: pembrolizumab PS, blood analysis, pembrolizumab physical examination, If HER2-positive pathology report with and received prior HER2 status trastuzumab-based regimen: newly FDA approved T-DXd ECOG PS >2 Best supportive care Gastric and Colorectal Cancer: Current Treatment Algorithms and Select Clinical Trials Full abbreviations, accreditation, and disclosure information available at PeerView.com/PXC40 Diagnosis of Advanced/Metastatic Colorectal Cancer2,3 Identify patient characteristics according to performance status, comorbidities, age, previous adjuvant treatment, quality of life, acceptance of toxicities, and patient preferences Unfit for intensive treatment: FP + anti-EGFR (if RAS wt) Totally unfit: Fit patients FP + bev Best supportive care Dose-adjusted doublet CT Treatment Goal: Cure Second Step Surgery ± CT in “clearly resectable” metastases Focus on treatment goals Preoperative CT in “potentially resectable disease” according to resectability of MDT metastases, sites of metastases, pattern of progression, and Treatment Goal: Disease Control tumor burden Best combination of CT ± surgery ± locoregional treatments in oligometastatic disease Third Step Evaluate disease characteristics according to primary tumor location (left vs right) and molecular profile (RAS/BRAF status, MSI status and HER2 overexpression, NTRK rearrangements) Trastuzumab + (pertuzumab or lapatinib) and trastuzumab deruxtecan are recommended by the NCCN guidelines as initial therapy for patients with HER2-amplified and BRAF wild-type, advanced CRC, who are not appropriate for intensive therapy Gastric and Colorectal Cancer: Current Treatment Algorithms and Select Clinical Trials Full abbreviations, accreditation, and disclosure information available at PeerView.com/PXC40 HER2+ Gastric Cancer4 PD-1 Inhibitor + Monoclonal Antibody + CTX NCT03615326: KEYNOTE-811 Phase 3 Recruiting 732 participants Pembrolizumab + trastuzumab + CTX Monoclonal Antibody ± PD-1 Inhibitor ± CTX ± Dual CPI NCT04082364: MAHOGANY Phase 2/3 Recruiting 850 participants Margetuximab +/- INCMGA00012 +/- CTX +/- MGD013 +/- trastuzumab ADC ADC CTLA-4 Inhibitor or CTX + PD-1 Inhibitor + NCT03556345 NCT04014075: DESTINY-Gastric02 Monoclonal Antibody Active (127), not recruiting Recruiting 72 participants NCT03409848: INTEGA RC48-ADC Trastuzumab deruxtecan Active (97), not recruiting 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) Zanidatamab + CTX vs physician's choice ADC + PD-L1 Inhibitor + CTX Monoclonal Antibody + PD-1 Inhibitor Bispecific Antibody + PD-1 Inhibitor + CTX NCT04379596: DESTINY-Gastric03 NCT02689284 NCT04276493 Phase 1b/2 Recruiting 220 participants Active (95), not recruiting Recruiting 50 participants Trastuzumab deruxtecan ± durvalumab ± CTX Margetuximab + pembrolizumab Zanidatamab + tislelizumab + CTX ADC + PD-1 Inhibitor NCT04280341 Phase 1 Not yet recruiting (50) RC48-ADC + JS001 Gastric and Colorectal Cancer: Current Treatment Algorithms and Select Clinical Trials Full abbreviations, accreditation, and disclosure information available at PeerView.com/PXC40 Immunotherapy and Combinations for Gastric Cancer4 Immunotherapy + CTX Immunotherapy + CTX Immunotherapy + CTX Phase 3 NCT03745170: ORIENT-16 NCT03675737: KEYNOTE-859 NCT03221426: KEYNOTE-585 Recruiting 650 participants Recruiting 1,542 participants Recruiting 1,000 participants