Practice Guidelines: Gastric Cancer1

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

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

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

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 + paclitaxel + ramucirumab

Antiangiogenesis + PARP Inhibitor + Immunotherapy PARP + Antiangiogenesis (RiME) NCT03008278 Phase 1/2 NCT03995017 Recruiting 49 participants Recruiting 61 participants Olaparib + ramucirumab Ramucirumab + rucaparib ± nivolumab

Immunotherapy + Antiangiogenesis Phase 1 NCT02572687 Active (114), not recruiting Ramucirumab + durvalumab

Immunotherapy and Combinations

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

Phase 2

Immunotherapy + Monoclonal Antibody Immunotherapy + DKK1 Neutralizing Antibody + CTX NCT04099641 NCT04363801: DisTinGuish Recruiting 80 participants Not yet recruiting (72) Bavituximab + pembrolizumab DKN-01 + tislelizumab ± CTX

Immunotherapy + PARP Inhibitor Immunotherapy Combinations PD-1 + CTLA-4 Inhibition Phase 1/2 NCT02734004: MEDIOLA NCT03281369 NCT04202601 Active, not recruiting (427) Recruiting 410 participants Recruiting 80 participants Durvalumab + olaparib Atezolizumab + various combinations Sintilimab + IBI310

TKI + PD-L1 Inhibitor NCT03539822: CAMILLA Phase 1 Recruiting 30 participants Cabozantinib + durvalumab

Other Therapies and Strategies

PARP Inhibitor FGFR Inhibitor NCT03427814: PARALLEL 303 NCT03694522: FIGHT Active, not recruiting (540) Recruiting 548 participants BGB-290 vs placebo Bemarituzumab + CTX Phase 3 Claudin 18.2-Positive Claudin 18.2-Positive NCT03653507: GLOW NCT03504397: SPOTLIGHT Recruiting 500 participants Recruiting 550 participants Zolbetuximab + CTX + placebo Zolbetuximab + CTX + placebo

AKT Small Molecule Inhibitor NCT01896531 Active (154), not recruiting Ipatasertib + CTX Claudin 18.2-positive NCT03505320: ILUSTRO Phase 2 Recruiting 112 participants FGFR Inhibitor Zolbetuximab + pembrolizumab + CTX NCT04189445 Not yet recruiting (115) Futibatinib

CTX Platform Combo NCT03368963 Phase 1/2 Recruiting 64 participants Trifluridine/tipiracil + nanoliposomal irinotecan

ADC: antibody–drug conjugates; CPI: checkpoint inhibitor; CTLA-4: cytotoxic T-lymphocyte–associated protein 4; CTX: chemotherapy; FGFR: fibroblast growth factor receptor; PARP: poly ADP-ribose polymerase; PD-1: programmed cell death protein 1; PD-L1: programmed cell death ligand 1. 1. https://clinicaltrials.gov. 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