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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 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: -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 (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: 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 + ( or ) and 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 or FOLFOX + + 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 ± ± 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 Sintilimab + CTX Pembrolizumab + CTX Pembrolizumab + CTX

Immunotherapy + PARP + CTX Immunotherapy + PARP Inhibitor Immunotherapy + TKI NCT03579784 NCT04209686 NCT04164979 Recruiting 40 participants Not yet recruiting (36) Recruiting 20 participants Paclitaxel + olaparib then Paclitaxel + pembrolizumab + olaparib Pembrolizumab + durvalumab + olaparib + paclitaxel

Immunotherapy + Monoclonal Antibody Immunotherapy + DKK1 Neutralizing Antibody + CTX NCT04099641 NCT04363801: DisTinGuish Phase 2 Recruiting 80 participants Not yet recruiting (72) Pembrolizumab + bavituximab Tislelizumab + DKN-01 ± CTX

Immunotherapy + Antiangiogenesis + CTX Immunotherapy + Antiangiogenesis + CTX NCT04069273: SEQUEL NCT03966118 Not yet recruiting (58) Recruiting 59 participants Pembrolizumab + ramucirumab + paclitaxel + paclitaxel + ramucirumab

Immunotherapy + PARP Inhibitor Immunotherapy Combinations Antiangiogenesis + PARP Inhibitor + NCT02734004: MEDIOLA NCT03281369 Immunotherapy (RiME) Phase 1/2 Active, not recruiting (427) Recruiting 410 participants NCT03995017 Durvalumab + olaparib + various combinations Recruiting 61 participants Ramucirumab + rucaparib ± nivolumab

Immunotherapy + TKI Immunotherapy + Antiangiogenesis NCT03539822: CAMILLA NCT02572687 Phase 1 Recruiting 30 participants Active (114), not recruiting Durvalumab + cabozantinib Durvalumab + ramucirumab Gastric and Colorectal Cancer: Current Treatment Algorithms and Select Clinical Trials Full abbreviations, accreditation, and disclosure information available at PeerView.com/PXC40

Other Therapies and Strategies for Gastric Cancer4

Claudin 18.2-Positive + CTX Claudin 18.2-Positive + CTX NCT03653507: GLOW NCT03504397: SPOTLIGHT Phase 3 Recruiting 500 participants Recruiting 550 participants Zolbetuximab + CTX Zolbetuximab + CTX

FGFR Inhibitor Claudin 18.2-positive + PD-1 Inhibitor + CTX CTX + Antiangiogenesis Phase 2 NCT04189445 NCT03505320: ILUSTRO NCT03686488 Not yet recruiting (115) Recruiting 112 participants Recruiting 25 participants Futibatinib Zolbetuximab + pembrolizumab + CTX Trifluridine/tipiracil + ramucirumab

CTX Platform Combo PARP + Antiangiogenesis NCT03368963 NCT03008278 Phase 1/2 Recruiting 64 participants Recruiting 49 participants Trifluridine/tipiracil + nanoliposomal irinotecan Olaparib + ramucirumab Gastric and Colorectal Cancer: Current Treatment Algorithms and Select Clinical Trials Full abbreviations, accreditation, and disclosure information available at PeerView.com/PXC40

HER2-Expressing CRC4

ADC TKI + Monoclonal Antibody TKI + Monoclonal Antibody Phase 2 NCT03384940: DESTINY-CRC01 NCT03457896 NCT03043313 Active (90), not recruiting Recruiting 35 participants Recruiting 115 participants Trastuzumab deruxtecan + trastuzumab or + trastuzumab

Immunotherapy for CRC4

Anti-PD-1 + Anti-CTLA-4 ± CTX NCT04008030: CheckMate -8HW Phase 3 Recruiting 748 (MSI-H) participants Nivolumab ± ipilimumab or nivolumab + ipilimumab + physician’s choice CTX (oxaliplatin, leucovorin, fluorouracil, irinotecan, , or cetuximab)

Anti-PD-L1 + Anti-CTLA-4 + CTX Anti–PD-L1 + Yttrium-90 RadioEmbolization NCT03202758: MEDITREME NCT04108481: iRE-C Phase 1/2 Recruiting 48 participants Recruiting 18 (MSS) participants Durvalumab + tremelimumab + FOLFOX Durvalumab + Yttrium-90 radioembolization

Other Therapies for CRC4

PARP ± Anti-Angiogenesis BRAF inhibitor+ EGFR Inhibitor ± CTX NCT04456699: LYNK-003 NCT04607421: BREAKWATER Recruiting 525 participants Not yet recruiting (930) Olaparib ± bevacizumab + cetuximab ± CTX (oxaliplatin, irinotecan, leucovorin, fluorouracil, capecitabine, or bevacizumab) Phase 3 VEGFR Inhibitor + BSC CTX Platform CDK 4/6 Inhibitor NCT04322539: FRESCO-2 NCT03306394: PRECONNECT NCT04607668: PRESERVE1 Recruiting 522 participants Active (907), not recruiting Recruiting 296 participants Fruquintinib + BSC vs placebo + BSC Trifluridine/tipiracil hydrochloride

1. Adapted from Alsina M et al. ESMO Open. 2019;4(suppl 2):e000521. 2. De Falco V et al. ESMO Open. 2019;4(Suppl 2):e000813. 3. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. Version 4.2020. https://www.nccn.org/professionals/physician_gls/pdf/colon_blocks.pdf. 4. https://clinicaltrials.gov.