Overview
The incidence of gastric cancer has decreased substantially in the United States and Western Europe over the past several decades.1–4 However, gastric cancer still constitutes a major global health problem, especially in East Asian countries.5,6 Globally, there were more than 968,000 new cases, resulting in approximately 660,000 deaths in 2022, making gastric cancer the fifth most frequently diagnosed cancer and the fifth leading cause of cancer-related deaths in the world.7,8 The global incidence of gastric cancer shows wide geographic variation, with a 15-to 20-fold difference between high- and low-incidence regions.1 The highest gastric cancer incidence rates occur in Northeast Asia, South and Central America, and Eastern Europe.5,6 Rates are particularly high in Japan and Korea, where gastric cancer is the most commonly diagnosed cancer in males, and in China, where gastric cancer is a leading cause of cancer-related mortality.5,6,9 In contrast, gastric cancer is one of the least commonly diagnosed cancers in Western Europe, sub-Saharan Africa, Australia, and North America.6 Based on SEER data for 2024, gastric cancer is the 15th most commonly diagnosed cancer and the 15th leading cause of cancer-related death in the United States.4 In the United States for 2025, an estimated 30,300 people are to be diagnosed and 10,780 people are expected to die of this disease.10 Despite overall declining rates, evidence suggests that the incidence of early-onset gastric cancer may be rising in the United States and other western countries.11,12 A recent global meta-analysis suggests factors that may contribute to risk of early-onset gastric cancer include family history, Helicobacter pylori (H pylori) infection, and diet.13
Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location (cardia/proximal or noncardia/distal) and histologic type (diffuse or intestinal).3 The diffuse type, which is characterized by poorly differentiated and discohesive tumor cells with a signet-ring or nonsignet-ring morphology diffusely infiltrating the gastric wall in a desmoplastic stroma, is more prevalent in low-risk areas and is mostly associated with heritable genetic abnormalities.3,9,14–16 The intestinal type, which tends to form a mass lesion and is characterized by variably differentiated tumor cells arranged in a tubular or glandular pattern with scattered goblet cells present, occurs more frequently in high-risk areas and accounts for most of the geographic variation seen with this disease. Intestinal type gastric cancer is often related to environmental factors such as H pylori infection, tobacco smoking, high salt intake, and other dietary factors.2,3,9,14–16 However, the role of alcohol as a risk factor for gastric cancer is without consensus. Although the results of several meta-analyses have shown no appreciable association between light or moderate alcohol consumption and gastric cancer risk, they showed a positive association between heavy alcohol use and gastric cancer, particularly noncardia gastric cancer.17–20
A dramatic shift in the type and location of upper gastrointestinal tract tumors has occurred in North America and Europe.2,21,22 There has been a marked decline in intestinal type gastric cancers of the distal stomach in North American and Western European countries over the past several decades, mainly due to enhanced access to clean drinking water, improved food preservation, an average diet with low promotion of gastric cancer, and H pylori eradication.1,3,16,23 However, incidence rates of diffuse type gastric cancer of the proximal stomach are rising.1,3,23 The etiology of this increase remains elusive and may be multifactorial. In contrast to the incidence trends in high income countries, tumors of the distal stomach continue to predominate in low and middle income countries.23 Gastric cancer generally carries a poor prognosis since it is often diagnosed at an advanced stage. In Japan and South Korea, where population screening is performed widely, early detection often results in improved outcomes.1,6 In the United States, survival rates from gastric cancer remain poor because early detection continues to pose a major challenge for health care professionals.
Overview of Treatment Guidelines
The comprehensive care of patients with gastric cancer requires expertise in several disciplines, including surgical oncology, medical oncology, radiation oncology, gastroenterology, radiology, and pathology. In addition, the presence of nutritional services, social workers, nurses, palliative care specialists, and other supporting disciplines is also desirable.24 Hence, the panel believes in an infrastructure that encourages multidisciplinary treatment decision-making by members of all disciplines caring for patients with gastric cancer. The recommendations made by the multidisciplinary team may be considered advisory to the primary group of treating physicians. See “Principles of Multidisciplinary Team Approach for Esophagogastric Cancers” in the full algorithm (available at NCCN.org) for more information.
Workup
Newly diagnosed patients should receive a complete history and physical examination, CBC, comprehensive chemistry profile, and esophagogastroduodenoscopy with biopsy of the primary tumor (Figures 1 and 2). CT scan (with oral and intravenous contrast) of the chest, abdomen, and pelvis should also be performed. FDG-PET/CT evaluation from skull base to midthigh is recommended for locally advanced or metastatic disease or if clinically indicated. However, this may not be appropriate for T1 disease. Endoscopic ultrasound is recommended if early-stage disease is suspected or if early-stage versus locally advanced disease needs to be determined (preferred). Endoscopic resection (ER) is essential for the accurate staging of early-stage cancers (T1a or T1b). Early-stage cancers can best be diagnosed by ER. ER may also be therapeutic for early-stage disease. Biopsy of metastatic disease should be performed as clinically indicated. Assessment of Siewert tumor type should also be included as part of the initial workup in all patients with esophagogastric junction (EGJ) adenocarcinoma.25,26
GAST-1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 5; 10.6004/jnccn.2025.0022
GAST-1A. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 5; 10.6004/jnccn.2025.0022
Universal testing for microsatellite instability (MSI) status by PCR/next-generation sequencing (NGS) or mismatch repair (MMR) status by immunohistochemistry (IHC) is recommended in all newly diagnosed patients. HER2, programmed death ligand 1 (PD-L1), and claudin 18 isoform 2 (CLDN18.2) testing are recommended at the time of diagnosis if advanced/metastatic disease is documented or suspected. NGS should be considered via a validated assay. See “Principles of Pathologic Review and Biomarker Testing” (next page) for more information.
Nutritional assessment and counseling as well as smoking cessation advice, counseling, and pharmacotherapy (as indicated) are recommended for all patients. The guidelines also recommend screening for family history of gastric cancers. See “Hereditary Cancer Predisposition Syndromes Associated with Gastric Cancer” in the full Discussion section (at NCCN.org). Testing/screening for H pylori and genetic testing should be considered as needed. The panel recommends testing for H pylori infection and to eradicate in all patients with early gastric cancer, if positive. If testing is positive, recommendations should be discussed with family members as appropriate. For close family members, H pylori testing should be recommended, and genetic testing should be performed as needed.
Initial workup enables patients to be classified into 3 clinical stage groups:
• Localized cancer (stages cTis or cT1a)
• Locoregional cancer (stages cT1b–cT4a; cM0, Any N)
• Metastatic cancer (stage cT4b; cM1)
Additional Evaluation
Additional evaluations are warranted to assess a patient’s medical condition, their ability to tolerate major surgery, and the feasibility of resection. These evaluations may include pulmonary function studies, cardiac testing, and nutritional assessment. Laparoscopy with assessment of cytology with or without biopsies is recommended to evaluate for peritoneal spread when considering local therapy for patients who are medically fit with stage cT1b or higher potentially resectable locoregional disease. Laparoscopy with cytology can be considered for patients who are medically fit with surgically unresectable disease. It is not indicated if a palliative resection is planned.
Additional evaluation enables patients with locoregional cancer to be further classified into the following groups:
• Medically fit with potentially resectable disease
• Medically fit with surgically unresectable disease
• Non-surgical candidates (medically unable to tolerate major surgery or medically fit but declined surgery)
Principles of Pathologic Review and Biomarker Testing
Pathologic review and biomarker testing play important roles in the diagnosis, classification, and molecular characterization of gastric cancer. Classification based on histologic subtype and molecular features helps improve early diagnosis and has implications for therapy. An accumulation of genetic aberrations occurs during gastric carcinogenesis, resulting in overexpression of growth factors and/or receptors, loss of certain tumor suppressor genes, alterations in the cell cycle, and changes in the DNA repair and damage response.27,28 Genome instability, which includes increased chromosomal instability and MSI, is often associated with some of these changes and can contribute to tumorigenesis.28–30 Additionally, MSI-H in gastric tumors is frequently associated with an increase in immune checkpoint ligand expression.30–32 A genomic stable subtype has also been identified by The Cancer Genome Atlas data.27 Characterization of these alterations and pathways has enabled the application of molecular pathology to aid in the diagnosis, classification, and treatment of gastric cancer.
Principles of Pathologic Review
A specific diagnosis of gastric adenocarcinoma should be established for staging and treatment purposes. Subclassification of gastric adenocarcinoma as intestinal or diffuse type may have implications for therapy since intestinal type tumors are more likely to be HER2 overexpression positive (see subsequent section). In addition to the histologic type, the pathology report (regardless of the specimen type) should include specifics about tumor invasion and pathologic grade, which are required for staging. Universal testing for MSI by PCR/NGS or MMR deficiency by IHC is recommended in all newly diagnosed patients. The pathology report of endoscopic mucosal resection (EMR) specimens should include an assessment of lymphovascular invasion, depth of tumor invasion, tumor diameter, and the status of mucosal and deep margins. Pathology reports of gastrectomy specimens should also document the location of the tumor midpoint in relationship to the EGJ, whether the tumor crosses the EGJ, the lymph node status, and the number of lymph nodes recovered (≥16). In patients who undergo gastrectomy after treatment with chemoradiation for unresectable gastric cancer, and without grossly obvious residual tumor, the tumor site should be thoroughly sampled to detect microscopic residual disease. The pathology report should include all these elements plus an assessment of treatment effect.
Principles of Biomarker Testing
Presently, IHC and/or molecular testing for HER2/ERBB2 overexpression/amplification, MSI or MMR status, PD-L1 expression, CLDN18.2 positivity, tumor mutational burden-high (TMB-H) status, NTRK gene fusion, RET gene fusion, and BRAF V600E mutation are implicated in the clinical management of advanced gastric cancer. IHC, in situ hybridization (ISH), or targeted PCR is preferred to evaluate biomarkers. However, a validated NGS assay performed in a CLIA-approved laboratory may be considered later in the clinical course of a patient with sufficient tumor tissue available. NGS can assess several mutations and other molecular events simultaneously. Specific recommendations for HER2, PD-L1, MSI/MMR status, and CLDN18.2 are outlined in the following sections. The biomarkers that will define additional subsets are expected to grow.
Assessment of HER2 Overexpression
Overexpression of the HER2 protein or amplification of the ERBB2 gene has been implicated in the development of gastric adenocarcinoma.33 However, unlike in breast cancer, the prognostic significance of HER2 status in gastric cancer is unclear. Some studies suggest that HER2 positivity is associated with poor prognosis34–39 and others have shown that it is not an independent prognostic factor of patient outcome, except in a very small subgroup of patients with intestinal histology.40–42 Although further studies are needed to assess the prognostic significance of HER2 status in gastric cancer, the addition of HER2 monoclonal antibodies to chemotherapy regimens is a promising treatment option for patients with HER2 overexpression-positive disease.43
The reported rates of HER2 positivity in patients with gastric cancer range from 12% to 23%.34,35,41,42,44,45 HER2 positivity also varies with the histologic subtype (intestinal more than diffuse) and tumor grade (moderately differentiated more than poorly differentiated).35,39,41,42,44 HER2 positivity is reported in ≤20% of European and US patients with metastatic gastric cancer with significantly higher rates seen in patients with intestinal histology (33% vs 8% for diffuse/mixed histology; P=.001).41 In the United States population, the reported HER2 positivity rate in gastric cancer is 12% and is more often identified in the intestinal subtype than the diffuse subtype (19% and 6%, respectively).42 The HER-EAGLE study, which examined the HER2 positivity rate in a large multinational population of nearly 5,000 patients with gastric or EGJ adenocarcinoma, reported that 14.2% of samples were HER2 overexpression positive.46 HER2 positivity was significantly higher in males versus females, in EGJ tumors versus stomach tumors, and in intestinal subtypes versus diffuse subtypes. In the ToGA trial, which evaluated the addition of trastuzumab to chemotherapy in patients with HER2 overexpression-positive advanced gastric or EGJ cancers, HER2 positivity rates were 32.2%, 21.4%, 31.8%, and 6.1%, respectively, in patients with EGJ adenocarcinoma, gastric adenocarcinoma, intestinal gastric adenocarcinoma, and diffuse gastric adenocarcinoma.47,48 Therefore, subclassification of gastric adenocarcinomas as intestinal or diffuse type may have implications for therapy.
HER2 testing is recommended for all patients with gastric cancer at the time of diagnosis if advanced/metastatic disease is documented or suspected. In concordance with HER2 testing guidelines from the College of American Pathologists, the American Society for Clinical Pathology, and ASCO,49 the NCCN Guidelines for Gastric Cancer recommend using IHC and, if needed, ISH techniques to assess HER2 status in gastric cancer. As stated previously, IHC/ISH/targeted PCR is preferred, followed by NGS later in the clinical course as appropriate. Repeat biomarker testing may be considered at clinical or radiologic progression of advanced or metastatic disease.
IHC evaluates the membranous immunostaining of tumor cells, including the intensity and extent of staining and the percentage of immunoreactive tumor cells, with scores ranging from 0 (negative) to 3+ (positive). In 2008, Hofmann et al50refined this 4-tiered scoring system to assess HER2 status in gastric cancer by using a cut-off of ≥10% immunoreactive tumor cells.48 In a subsequent validation study (n=447 prospective diagnostic gastric cancer specimens), this scoring system was found to be reproducible between different pathologists.51 This modified HER2 scoring system is therefore recommended by the panel. A score of 0 (membranous reactivity in <10% of cancer cells) or 1+ (faint membranous reactivity in ≥10% of cancer cells) is considered HER2-negative.49 A score of 2+ (weak to moderate membranous reactivity in ≥10% of cancer cells) is considered equivocal and should be additionally examined using fluorescence in situ hybridization (FISH) or other ISH methods. FISH/ISH results are expressed as the ratio between the number of copies of the ERBB2 gene and the number of chromosome 17 centromeres (CEP17) within the nucleus counted in at least 20 cancer cells (ERBB2:CEP17). Alternatively, FISH/ISH results may be given as the average ERBB2 copy number per cell. Cases that have an IHC score of 3+ (strong membranous reactivity in ≥10% of cancer cells)49 or an IHC score of 2+ and are FISH/ISH positive (ERBB2:CEP17 ratio ≥2 or average ERBB2 copy number ≥6 signals/cell) are considered HER2 overexpression positive. Positive (3+) or negative (0 or 1+) HER2 IHC results do not require further ISH testing. See “Principles of Pathologic Review and Biomarker Testing: Assessment of Overexpression or Amplification of HER2 in Gastric Cancer” (Table 3 in the full algorithm, at NCCN.org) for more information.
MSI and/or MMR Testing
It is well-established that MSI-H or dMMR can occur in various malignancies. Microsatellites are mutational hotspots, and loss of functional MMR facilitates elevated mutation events at these sites.29 Prevalence of MSI-H/dMMR in gastric cancer can vary depending on factors including disease stage, sex and age, histologic type, and tumor location. Specifically, MSI-H/dMMR status is associated with earlier stage, ≥68 years of age, intestinal subtype, and if the tumor is in the distal stomach.27,30,52–55 Analysis of gastric adenocarcinoma data from The Cancer Genome Atlas showed an incidence of 22% for MSI-H tumors.27 Similarly, a pan-cancer whole-exome sequencing analysis of numerous tumor-normal pairs from both The Cancer Genome Atlas and the Therapeutically Applicable Research to Generate Effective Treatments project reported an incidence of 19% in MSI-H/dMMR in gastric tumors.56 Better prognosis has been reported with MSI-H/dMMR gastric tumors compared with microsatellite stable/MMR-proficient tumors,52,53,57 including for those with MSI-H/dMMR who receive immunotherapy.58,59
Universal testing for MSI by PCR/NGS or MMR by IHC should be performed for all newly diagnosed patients with gastric cancer. PCR/NGS for MSI and IHC for MMR proteins measure different biologic effects caused by dMMR function. MSI status of the tumor can be assessed by PCR to determine shifts in validated microsatellite markers (eg, mononucleotide repeats BAT25, BAT26, MONO27, NR21, NR24).60 MMR deficiency is evaluated by IHC to assess nuclear expression of proteins involved in DNA MMR (ie, MLH1, MSH2, MSH6, PMS2).61 Testing is performed on formalin-fixed, paraffin-embedded (FFPE) tissue and results are interpreted as MSI-H or dMMR in accordance with CAP DNA Mismatch Repair Biomarker Reporting Guidelines.62 Testing should be performed only in CLIA-approved laboratories. Patients with MSI-H or dMMR tumors should be referred to a genetics counselor for further assessment in the appropriate clinical context.
PD-L1 Testing
Binding of the programmed cell death protein 1 (PD-1) receptor by its ligand PD-L1 is a critical immune checkpoint blockade that negatively affects T cell function and proliferation. Tumor cells can express PD-L1 and exploit PD-1/L1 binding to facilitate immune evasion, tumor growth/survival, and moderate activity of different immune cell types and signaling.63–65 This makes PD-1/L1 a valuable target, and PD-1/L1 inhibitors have emerged as beneficial therapeutic options for certain patients (see “Targeted Therapies,” page 181).
PD-L1 expression has been frequently observed in the intestinal subtype,66–68 although some studies have not observed a significant association with histologic subtype.69 PD-L1 is reportedly associated with MSI-H and Epstein-Barr virus positivity in gastric tumors.27,66,67,69,70 The prognostic significance of PD-L1 in gastric cancer remains unclear. This may be due to different factors such as PD-L1 testing variability or small sample size. Currently, some studies suggest a significant favorable association with survival outcomes,59,67,68 while others showed an unfavorable or no relationship between PD-L1 and survival.69,71
PD-L1 testing may be considered on locally advanced, recurrent, or metastatic gastric cancers in patients who are candidates for treatment with PD-1 inhibitors. A companion diagnostic test should be used to identify patients for treatment with PD-1 inhibitors. The companion diagnostic test is a qualitative IHC assay using anti-PD-L1 antibodies for the detection of PD-L1 protein levels in FFPE tumor tissue. A minimum of 100 tumor cells must be present in the PD-L1–stained slide for the specimen to be adequately evaluated. Combined positive score (CPS) is determined by the number of PD-L1–stained cells (ie, tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells evaluated, multiplied by 100. A specimen is considered to have PD-L1 expression if the CPS is ≥1. PD-L1 testing should be performed only in CLIA-approved laboratories. Tumor proportion score and tumor area positivity score are also considered and reported in some trials, but they are not included in these Guidelines.
Claudin 18 Isoform 2
CLDN18.2 is a tight junction transmembrane protein that is typically expressed in normal gastric epithelia and is retained during malignant transformation.72,73 CLDN18.2-positive tumors represent 24%–38% of advanced gastric and EGJ adenocarcinomas.74–77 However, due to variations in detection methods, assays used, and differing definitions of CLDN18.2 positivity, the percentage of CLDN18.2-positive tumors can vary across the literature.78 CLDN18.2 expression has been observed in intestinal-type gastric tumors, but is more commonly seen in the diffuse subtype.74,75,77,79 CLDN18.2 positivity has been shown independent of other established molecular subtypes (eg, dMMR, HER2 status) and PD-L1.75–77 Association between CLDN18.2 and Epstein-Barr virus status is unclear, as certain studies have reported a significant correlation between the two,74,75 while another study reported no significance.76
Changes in tumor cell adhesion and polarity expose the normally inaccessible CLDN18.2 protein, which makes it a unique molecular target.80,81 Testing is recommended for untreated patients who have unresectable locally advanced, recurrent, or metastatic gastric adenocarcinoma and for whom zolbetuximab is being considered. Tumors are considered CLDN18.2 positive if ≥75% of viable tumor cells demonstrate moderate to strong membranous CLDN18.2 staining (2+ or 3+ intensity) by a qualitative IHC assay for FFPE tumor tissue.72,82
Liquid Biopsy
The genomic alterations of solid cancers may be identified by evaluating circulating tumor DNA in the blood, hence a form of “liquid biopsy.”37,83 The detection of mutations/alterations or fusions in DNA shed from gastric carcinomas can identify targetable alterations or the evolution of clones with altered treatment response profiles. In one study, a complete or partial response to immunotherapy was experienced by 63% of patients with advanced gastric carcinoma who tested positive for MSI by cell-free DNA analysis.83 In another study that analyzed the genomic alterations of 55 patients with advanced gastroesophageal adenocarcinomas using NGS performed on plasma-derived circulating tumor DNA, 69% of patients had one or more characterized alterations theoretically targetable by a US FDA–approved agent (on or off label).37 Therefore, when limited tissue is available or for patients who have advanced or metastatic gastric cancer who are not able to undergo a traditional biopsy, testing using a validated NGS-based comprehensive genomic profiling assay performed in a CLIA-approved laboratory may be considered. A negative result should be interpreted with caution, because this does not exclude the presence of a tumor.
Peritoneal Carcinoma as Only Disease
For many patients with locally advanced or metastatic gastric cancer, there is a high risk of peritoneal disease, which confers a poor prognosis. The blood-peritoneal barrier presents challenges in effectively treating the disease.84,85 For selected patients with only peritoneal metastatic disease, see “Peritoneal Carcinoma As Only Disease” (Figure 3) for panel recommendations. Briefly, after workup (if not previously done), selected patients should be given systemic therapy for a minimum of 3 months. Before considering further therapy, patients should undergo restaging. Multidisciplinary discussion is then recommended for patients with low peritoneal cancer index (PCI) (≤10), improved or stable disease, and no metastasis/extraperitoneal disease to determine status for cytoreduction. Regardless of whether complete or incomplete cytoreduction is predicted, these patients have the option of clinical trial participation or continuing systemic therapy. Only patients who are likely to have complete cytoreduction of all visible nodes/plaques have the option of gastrectomy with cytoreductive surgery and intraperitoneal chemotherapy (IC)/hyperthermic intraperitoneal chemotherapy (HIPEC). For patients with high PCI (>10) and disease progression or extraperitoneal disease, the panel recommends systemic therapy, clinical trial participation, or best supportive care.
GAST-10. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 5; 10.6004/jnccn.2025.0022
Intraperitoneal Chemotherapy/Hyperthermic Intraperitoneal Chemotherapy
Only case reports and small series are available to support the use of IC/HIPEC/pressurized intraperitoneal aerosolized chemotherapy (PIPAC) in resectable gastric tumors. The HIPEC procedure involves the continuous circulation of a heated sterile chemotherapy–containing solution throughout the peritoneal cavity after cytoreductive surgery. HIPEC enables the infusion of high doses of chemotherapy directly into the abdominal cavity, where traditional methods of chemotherapy cannot effectively reach. Similarly, PIPAC is the introduction of chemotherapy directly to the abdomen but via aerosol. Note that PIPAC is considered investigational and should only be performed in the context of a clinical trial. Therefore, the focus of this section is on HIPEC and the panel’s recommendations.
HIPEC can potentially improve long-term outcomes and provide more treatment options for certain patients with advanced gastric cancer. This technique is currently under investigation in clinical trials. In the CYTO-CHIP study, which included 277 patients with peritoneal metastases from gastric cancer who underwent cytoreductive surgery with HIPEC (n=180) or cytoreductive surgery alone (n=97), the addition of HIPEC improved overall survival (OS) and recurrence-free survival, without increasing morbidity or mortality.86 However, the median PCI remained higher in the HIPEC group following treatment. Therefore, cytoreductive surgery with HIPEC may be effective for strictly selected patients with limited peritoneal metastases.
In a phase II trial, 20 patients with gastric adenocarcinoma and positive peritoneal cytology or carcinomatosis who had completed systemic chemotherapy and laparoscopic HIPEC underwent cytoreduction, gastrectomy, and HIPEC. The 90-day morbidity and mortality rates were 70% and 0%, respectively. A median OS of 16.1 months was observed from the time of cytoreduction, gastrectomy, and HIPEC. The OS rates for 1, 2, and 3 years from the diagnosis of metastatic disease were 90%, 50%, and 28%, respectively.87 In a phase III trial, 68 patients with gastric cancer and peritoneal carcinomatosis were randomized to receive cytoreductive surgery alone or cytoreductive surgery with HIPEC.88 At a median follow-up of 32 months, death occurred in 97% of cases in the surgery alone group and 85% of cases in the surgery plus HIPEC group. The median survival was 6.5 months and 11 months, respectively (P=.046). Four patients (11.7%) in the surgery alone group and 5 (14.7%) in the HIPEC group developed serious adverse events (AEs) (P=.839). Multivariate analysis found that the addition of HIPEC to cytoreductive surgery is an independent predictor for better survival.
A recent phase III trial, GASTRIPEC-I, investigated cytoreductive surgery with and without HIPEC after preoperative chemotherapy in patients with gastric or EGJ cancers and peritoneal metastasis. No significant differences were observed in OS between the 2 approaches (hazard ratio [HR], 0.72; P=.1647).89 Median progression-free survival (PFS) (7.1 vs 3.5 months; P=.0472) and other distant metastasis-free survival (10.2 vs 9.2 months; P=.0286) were improved with the addition of HIPEC. Of note, some patients were excluded from further treatment and complete cytoreduction after initial preoperative chemotherapy due to disease progression, among other causes, and almost half had a PCI of ≥7.89 Additionally, an ongoing Dutch study, PERISCOPE II, is investigating gastrectomy followed by cytoreductive surgery plus HIPEC versus systemic treatment in resectable cT3–cT4 gastric cancer with limited peritoneal carcinoma (PCI<7). The primary endpoint is OS and secondary endpoints are PFS, toxicity, and quality of life.90
Due to limited evidence and a lack of randomized clinical trials to support the use of these methods in resectable tumors, the panel recommends that IC/HIPEC should be pursued only in select circumstances and after multidisciplinary discussion. Any patient considered for IC/HIPEC should undergo pretreatment evaluation as described in the algorithm for those with documented peritoneal carcinoma as the only disease. This includes staging with chest/abdomen/pelvis CT, diagnostic laparoscopy with washings for PCI and/or cytology-positive disease evaluation, and consideration of a PET scan to rule out distant metastases. For certain patients with PCI ≤10 and who are candidates for complete cytoreduction, IC/HIPEC in conjunction with cytoreductive surgery is an option. For certain patients with PCI>10, IC/HIPEC may be considered in a clinical trial. All treatment decisions should be made in the context of a multidisciplinary tumor board.
Unresectable Locally Advanced, Recurrent, or Metastatic Disease
When locoregional recurrence develops after prior therapy, the clinician should determine whether surgery is an appropriate option. Surgery should be considered in patients who are medically fit with isolated resectable recurrences. Palliative management, which may include chemoradiation (only if locally unresectable and not previously received), systemic therapy, and/or best supportive care, is recommended for patients with unresectable or metastatic recurrence (Figure 4). If not done previously, HER2, PD-L1, CLDN18.2, and MSI/MMR testing should be performed. NGS should be considered via a validated assay.
GAST-9. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 5; 10.6004/jnccn.2025.0022
Management of unresectable or metastatic disease may include either systemic therapy and/or chemoradiation, with the goal of providing symptom relief and delaying progression and should incorporate symptom-directed best supportive care (See “Palliative/Best Supportive Care” in the full Discussion, available at NCCN.org). The decision to offer palliative/best supportive care alone or with systemic therapy is dependent on the patient’s performance status. The ECOG Performance Status Scale (ECOG PS) and the Karnofsky Performance Status Scale (KPS) are commonly used to assess the performance status of patients with cancer.91–93 Patients with higher ECOG PS scores are considered to have worse performance status while lower KPS scores are associated with worse survival for most serious illnesses. Patients with a KPS score <60% or an ECOG PS score ≥3 should be offered palliative/best supportive care only. Systemic therapy or chemoradiation (only if locally unresectable and not previously received) can be offered in addition to palliative/best supportive care for patients with better performance status (KPS score of ≥60% or ECOG PS score ≤2).
The survival benefit of systemic therapy compared with palliative/best supportive care alone for patients with advanced gastric cancer has been demonstrated in several randomized trials.94–97 In an early comparison between chemotherapy and best supportive care versus best supportive care alone, OS (8 vs 5 months) and time to progression (5 vs 2 months) were longer in patients receiving chemotherapy in addition to best supportive care for advanced gastric cancer.94 More patients in the chemotherapy group (45%) had an improved or prolonged quality of life for a minimum of 4 months compared with those who received best supportive care alone (20%). In a randomized phase III study, the addition of second-line chemotherapy with irinotecan significantly prolonged OS compared with best supportive care alone in patients with metastatic or locally advanced gastric or EGJ adenocarcinoma (n=40).95 Median survival was 4 months in the irinotecan and best supportive care group compared with 2.4 months in the best supportive care alone group. However, the study was closed prematurely due to poor accrual. In a larger randomized trial (n=193), second-line chemotherapy with irinotecan (or docetaxel) was also found to significantly improve OS compared with best supportive care alone (5.1 vs 3.8 months) in patients with advanced gastric cancer.96 In another phase III randomized trial, the addition of docetaxel to best supportive care was associated with a survival benefit for patients with advanced adenocarcinoma of the esophagus (n=33), EGJ (n=59), or stomach (n=76) that had progressed on or within 6 months of treatment with platinum and fluoropyrimidine-based combination chemotherapy.97 After a median follow-up of 12 months, the median OS was 5.2 months for patients in the docetaxel and best supportive care group compared with 3.6 months for those in the best supportive care alone group (P=.01). Therefore, the addition of systemic therapy to best supportive care can improve the quality of life and may prolong survival in patients with advanced gastric cancer.
See “Principles of Systemic Therapy” (Figures 5 through 8) in the algorithm for a full list of specific regimens for unresectable locally advanced, recurrent, or metastatic disease. Some of the regimens and dosing schedules included in the guidelines are based on extrapolations from published literature and clinical practice.
GAST-F 1 of 20. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 5; 10.6004/jnccn.2025.0022
GAST-F 4 of 20. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 5; 10.6004/jnccn.2025.0022
GAST-F 4A of 20. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 5; 10.6004/jnccn.2025.0022
GAST-F 5 of 20. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 5; 10.6004/jnccn.2025.0022
Chemoradiation for Unresectable Disease
Chemoradiation alone may be offered to certain patients who are medically fit with unresectable disease and if not received previously. Since there are limited data in gastric cancer, the panel recommends extrapolation of fluorouracil-based chemoradiation regimens with proven efficacy in esophageal carcinoma. Preferred regimens in this setting include FOLFOX as well as fluorouracil and cisplatin. Another recommended regimen is fluoropyrimidine (fluorouracil or capecitabine) and paclitaxel (category 2B). Chemoradiation with either FOLFOX or fluorouracil and cisplatin were shown to be effective in a randomized phase III trial of patients with unresectable esophageal cancer.98 In a randomized phase III trial (PRODIGE5/ACCORD17), 267 patients with unresectable esophageal cancer or those medically unfit for surgery were randomized to receive chemoradiation with either FOLFOX or fluorouracil and cisplatin. The median PFS was 9.7 months in the FOLFOX group compared with 9.4 months in the fluorouracil and cisplatin group (P=.64). Although FOLFOX was not associated with a PFS benefit compared with fluorouracil and cisplatin, the investigators suggest that FOLFOX might be a more convenient option for patients who may not be candidates for surgery.98 A trial of patients with stage II–IV esophageal carcinoma confirmed the safety and efficacy of FOLFOX combined with radiation therapy with or without surgery.99 In the FFCD 9102 trial, survival was similar for patients with esophageal cancer receiving fluorouracil and cisplatin-based chemoradiation with or without surgery.100 Additionally, patients may receive a fluoropyrimidine combined with paclitaxel, which has proven efficacy in yielding a pathologic response in resectable gastric cancer.101 After primary treatment, patients should undergo restaging to determine whether surgery is an option. Surgery is preferred if appropriate for patients with resectable and medically operable disease after chemoradiation, while those found to still have unresectable or medically inoperable and/or metastatic disease should receive palliative management.
First-Line Therapy
Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic gastric cancer.94–97 First-line systemic therapy regimens with 2 cytotoxic drugs are preferred for patients with advanced disease because of their lower toxicity (Figure 5). The use of 3 cytotoxic drugs in a regimen should be reserved for patients who are medically fit with excellent PS and easy access to frequent toxicity evaluations.102 Oxaliplatin is generally preferred over cisplatin due to lower toxicity.
For HER2 overexpression-positive disease, the addition of trastuzumab to chemotherapy with or without pembrolizumab is a treatment option for certain patients in this setting (Figures 6 and 7). Preferred regimens for HER2 overexpression-negative disease include certain immune checkpoint inhibitors (ICIs) combined with fluoropyrimidine and platinum-based therapies. Specifically, an ICI should be added to first-line chemotherapy for patients with PD-L1 CPS ≥1. For MSI-H/dMMR tumors, treatment options also include certain ICIs. See “Targeted Therapies” (page 181) for more information and specific panel recommendations.
The preferred regimens for HER2-negative disease also include a fluoropyrimidine (fluorouracil or capecitabine) combined with either oxaliplatin103–105 or cisplatin.103,106–108 A phase III trial conducted by the German Study Group compared treatment with fluorouracil and cisplatin to FOLFOX in patients (n=220) with previously untreated advanced adenocarcinoma of the stomach or EGJ.103 Results showed that FOLFOX (referred to as FLO) was associated with significantly less toxicity and showed a trend toward improved median PFS (5.8 vs 3.9 months; P=.77) compared with fluorouracil, leucovorin, and cisplatin (FLP).103 However, there was no significant difference in median OS (10.7 vs 8.8 months, respectively) between the 2 groups. FOLFOX resulted in significantly superior response rates (41.3% vs 16.7%; P=.12), time to treatment failure (5.4 vs 2.3 months; P<.001), PFS (6.0 vs 3.1 months; P=.029), and improved OS (13.9 vs 7.2 months) compared with FLP in patients >65 years (n=94). Therefore, FOLFOX offers reduced toxicity and similar efficacy compared with fluorouracil plus cisplatin and may also be associated with improved efficacy in older adult patients. The safety and efficacy of FOLFOX have also been demonstrated in other studies.104,109,110
Regimens combining a platinum agent with capecitabine have also been evaluated in several studies for patients with advanced gastric cancer.108,111,112 A phase III randomized trial (ML 17032) that evaluated the efficacy of combined capecitabine and cisplatin compared with fluorouracil and cisplatin found that capecitabine was noninferior to fluorouracil as first-line therapy in patients with advanced gastric cancer.108 Two phase II trials concluded that capecitabine in combination with oxaliplatin is active and well-tolerated as first-line therapy for advanced gastric cancer.111,112 Furthermore, results of a meta-analysis suggest that OS was superior in patients with advanced gastroesophageal cancer treated with capecitabine-based combinations compared with patients treated with fluorouracil-based combinations, although no significant difference in PFS between treatment groups was seen.113 Another meta-analysis reported that treatment with oxaliplatin-based regimens significantly improved the partial response rate, disease progression rate, and 1-year OS rate of patients with gastric cancer as compared with cisplatin-based regimens.114 Therefore, capecitabine and oxaliplatin is also a preferred regimen for first-line treatment of patients with advanced gastric cancers. The GO2 phase III trial demonstrated that a low-dose capecitabine and oxaliplatin regimen (60% of the standard dose) was noninferior in terms of PFS and resulted in significantly lower toxicities and better overall treatment utility in patients who are older and/or frail with advanced gastroesophageal cancers (n=514).115 Therefore, this low-dose regimen is recommended as an alternative to standard-dose capecitabine and oxaliplatin for patients who are older and/or frail with advanced or metastatic disease. See “Principles of Systemic Therapy—Regimens and Dosing Schedules” in the algorithm (available at NCCN.org) for recommended modifications to this regimen.
First-line treatment with irinotecan-based regimens has been explored extensively in clinical trials involving patients with advanced or metastatic gastroesophageal cancers.107,116–127 The results of a randomized phase III study comparing irinotecan and fluorouracil (FOLFIRI) to cisplatin and fluorouracil (CF) in patients with advanced gastric or EGJ adenocarcinoma (n=337) showed that FOLFIRI was noninferior to CF in terms of PFS, but not in terms of OS or time to progression.122 FOLFIRI was also associated with a more favorable safety profile. A phase III trial (French Intergroup Study) compared FOLFIRI with ECF as first-line treatment in patients (n=416) with advanced or metastatic gastric or EGJ adenocarcinoma.127 After a median follow-up of 31 months, median time to treatment failure was significantly longer with FOLFIRI than with ECF (5.1 vs 4.2 months; P=.008).127 However, there were no significant differences in median PFS (5.3 vs 5.8 months; P=.96), median OS (9.5 vs 9.7 months; P=.95), or response rate (39.2% vs 37.8%). Importantly, FOLFIRI was less toxic and better tolerated than ECF. Therefore, FOLFIRI may be recommended as an option for first-line therapy in patients with advanced or metastatic gastric cancer.
Docetaxel, cisplatin, and fluorouracil (DCF) has also demonstrated activity in patients with locally advanced or metastatic gastric cancer.128,129 An international phase III study (V325) that randomized 445 patients with untreated advanced gastric or EGJ cancer to receive either DCF or CF found that the addition of docetaxel to CF significantly improved time to progression, OS, and overall response rate (ORR).128 However, DCF was associated with increased toxicities including myelosuppression and infectious complications. Various modifications of the DCF regimen have demonstrated improved safety in clinical trials of patients with advanced gastric cancer compared with the DCF regimen evaluated in the V325 study.130–135 Therefore, due to concerns regarding toxicity, dose-modified DCF or other DCF modifications should be used as alternative options to the standard DCF regimen for first-line therapy.131,134,135 Other recommended regimens for first-line therapy include fluorouracil plus irinotecan,127 paclitaxel with either cisplatin or carboplatin,136–138 docetaxel with cisplatin,139,140 docetaxel plus oxaliplatin and fluorouracil,141 and single-agent fluoropyrimidine (fluorouracil or capecitabine),107,142,143 docetaxel,97,144 or paclitaxel.145,146
Second-Line and Subsequent Therapy
The selection of regimens for second-line or subsequent therapy is dependent on prior therapy and performance status (Figure 8). Ramucirumab plus paclitaxel,147 as well as single-agent docetaxel,97,144 paclitaxel,145,146,148 and irinotecan95,148–150 are category 1 preferred options for second-line or subsequent therapy. Fam-trastuzumab deruxtecan-nxki is an option for HER2 overexpression-positive adenocarcinoma. See “Targeted Therapies” (page 181) for more information on and specific recommendations for ramucirumab and fam-trastuzumab deruxtecan-nxki. In a randomized phase III trial (COUGAR-02) single-agent docetaxel was shown to significantly increase 12-month OS compared with active symptom control alone (5.2 vs 3.6 months, respectively; HR, 0.67; P=.01).97 A randomized phase III trial comparing second-line therapy with paclitaxel to irinotecan in patients with advanced gastric cancer found similar OS between the 2 groups (9.5 months in the paclitaxel group vs 8.4 months in the irinotecan group; HR, 1.13; P=.38).148
FOLFIRI is a preferred treatment option that can be safely used in the second-line setting if it was not previously used in first-line therapy.118,150–153 A phase II trial investigating the efficacy and toxicity of FOLFIRI in patients (n=40) with recurrent or metastatic gastric cancer reported an ORR of 29% and median OS of 6.4 months.153 Another phase II trial reported similar results with an ORR of 20% and OS of 6.7 months in patients with advanced gastric cancer (n=59) treated with FOLFIRI in the second-line setting.150 Additionally, FOLFIRI was shown to be an effective and safe treatment option in a cohort of patients with metastatic gastric or EGJ cancers refractory to docetaxel-based chemotherapy.151 In this study, the ORR was 22.8% and median PFS and OS were 3.8 and 6.2 months, respectively. The most common grade 3–4 toxicities were neutropenia (28.5%) and diarrhea (14.5%).
The trifluridine and tipiracil regimen was approved by the FDA in 2019 for previously treated recurrent or metastatic gastric and EGJ adenocarcinoma, based on results from the global phase III TAGS trial, in which 507 patients with heavily pretreated metastatic gastric or EGJ cancer were randomized 2:1 to receive trifluridine and tipiracil plus best supportive care (n=337) or placebo plus best supportive care (n=170).154 This study reported an improvement in median OS by 2.1 months (5.7 vs 3.6 months) with the trifluridine and tipiracil regimen compared with placebo (HR, 0.69; 95% CI, 0.56–0.85; P=.0003). PFS was significantly longer in the trifluridine and tipiracil group (2.0 vs 1.8 months; HR, 0.57; 95% CI, 0.47–0.70; P<.0001).154,155 The efficacy benefits of trifluridine and tipiracil were observed regardless of whether the patient had undergone previous gastrectomy.156 The most frequently reported grade 3–4 toxicities were neutropenia (38%), leukopenia (21%), anemia (19%), and lymphocytopenia (19%).154 Patients ≥65 years had a higher incidence of moderate renal impairment compared with the overall study population (31% vs 17%).155 In the trifluridine and tipiracil arm versus the placebo arm, the ORR was 4.5% versus 2.1%, respectively, and the disease control rate was 44.1% versus 14.5%.154 However, trifluridine and tipiracil produced substantial grade 3–4 toxicities. Therefore, this treatment should be considered for a very select population of patients with low-volume gastric cancer who have minimal or no symptoms and the ability to swallow pills. Trifluridine and tipiracil is recommended as a preferred category 1 treatment option for patients with recurrent or metastatic gastric cancer in the third-line or subsequent setting.
Other recommended regimens for second-line or subsequent therapy include single-agent ramucirumab (category 1),157 irinotecan and cisplatin,104,158 ramucirumab combined with irinotecan159 or FOLFIRI,160 and irinotecan and docetaxel (category 2B).161 Options that are useful in certain circumstances include pembrolizumab,61,162,163 nivolumab and ipilimumab,164 or dostarlimab-gxly165 for MSI-H/dMMR tumors; pembrolizumab for TMB-H (≥10 mutations/megabase) tumors166; entrectinib, larotrectinib, or repotrectinib for NTRK gene fusion-positive tumors167–169; dabrafenib and trametinib for BRAF V600E-mutated tumors170; and selpercatinib for RET gene fusion-positive tumors.171 See “Targeted Therapies” (next section) for more information on these agents.
Targeted Therapies
At present, several targeted therapeutic agents, including HER2-directed therapies, ICIs, and various kinase inhibitors have been approved by the FDA for advanced gastric cancer. See “Principles of Biomarker Testing” (page 172) for details on testing recommendations.
Trastuzumab
The ToGA trial was the first randomized prospective phase III trial that evaluated the efficacy and safety of trastuzumab in patients with HER2 overexpression-positive advanced gastric or EGJ adenocarcinoma.48 In this trial, 594 patients with HER2 overexpression-positive, locally advanced, recurrent, or metastatic gastric or EGJ adenocarcinoma were randomized to receive trastuzumab plus chemotherapy (cisplatin plus fluorouracil or capecitabine) or chemotherapy alone.48 The majority of patients had gastric cancer (80% in the trastuzumab group and 83% in the chemotherapy group). Median follow-up was 19 months and 17 months, respectively, in the 2 groups. Results showed significant improvement in median OS with the addition of trastuzumab to chemotherapy in patients with HER2 overexpression-positive disease (13.8 vs 11 months, respectively; P=.046). This study established trastuzumab in combination with cisplatin and a fluoropyrimidine as a treatment option for patients with HER2 overexpression-positive advanced gastroesophageal adenocarcinoma. In a posthoc subgroup analysis, the addition of trastuzumab to chemotherapy further improved OS in patients whose tumors were IHC 2+ and FISH positive or IHC 3+ (n=446; 16 vs 11.8 months; HR, 0.65) compared with those with tumors that were IHC 0 or 1+ and FISH positive (n=131; 10 vs 8.7 months; HR, 1.07).
The phase II HERXO trial assessed the combination of trastuzumab with capecitabine and oxaliplatin in the first-line treatment of patients with HER2 overexpression-positive advanced gastric or EGJ adenocarcinoma (n=45).172 At a median follow-up of 13.7 months, PFS and OS were 7.1 and 13.8 months, respectively, and 8.9%, 37.8%, and 31.1% of patients achieved a CR, partial response, and stable disease. The most frequently reported grade 3 or higher AEs were diarrhea (26.6%), fatigue (15.5%), nausea (20%), and vomiting (13.3%). In a retrospective study of 34 patients with HER2 overexpression-positive metastatic gastric or EGJ adenocarcinoma, the combination of trastuzumab with a modified FOLFOX regimen (mFOLFOX6) improved tolerability compared with the cisplatin plus fluorouracil regimen in previously untreated patients with HER2 overexpression-positive tumors.173 The ORR with this regimen was 41% and median PFS and OS were 9.0 months and 17.3 months, respectively. The most frequent grade 3–4 toxicities were neutropenia (8.8%) and neuropathy (17.6%). These results suggest that the combinations of trastuzumab with capecitabine and oxaliplatin or with mFOLFOX are effective regimens with acceptable safety profiles in patients with HER2 overexpression-positive gastroesophageal cancers. Trastuzumab should be added to first-line chemotherapy for patients with advanced HER2 overexpression-positive adenocarcinoma (combination with a fluoropyrimidine and a platinum agent is preferred [category 1 for cisplatin;48 category 2A for oxaliplatin]). Pembrolizumab can also be added to this regimen for treatment of advanced HER2 overexpression-positive adenocarcinoma174 (see “Pembrolizumab,” next section). Trastuzumab may be combined with other chemotherapy agents for first-line therapy, but should not be continued in second-line therapy.175
Pembrolizumab
HER2 Overexpression-Positive Tumors
Pembrolizumab is a PD-1 antibody that can be added to first-line fluoropyrimidine, platinum, and trastuzumab therapy for patients with advanced HER2 overexpression-positive gastric cancer. The phase III KEYNOTE-811 trial compared pembrolizumab to placebo in combination with trastuzumab and the investigator’s choice of chemotherapy with fluorouracil and cisplatin or capecitabine and oxaliplatin in patients with previously untreated advanced HER2-positive gastric or EGJ adenocarcinoma.176 Median PFS in patients in the pembrolizumab arm was longer than in the placebo arm (10 months vs 8.1 months; P=.0002).177 In the subgroup analyses at the second interim (median ∼28 months), patients with PD-L1 CPS ≥1 treated in the pembrolizumab arm had longer median PFS compared with placebo (10.8 months vs 7.2 months; HR, 0.70), which was not observed in patients with PD-L1 CPS <1 (9.5 months vs 9.6 months; HR, 1.17). Median OS was 20 months in the pembrolizumab arm compared with 16.9 months in the placebo arm (HR, 0.87; 95% CI, 0.72–1.06; P=.084), with the PD-L1 subgroup analysis following a similar trend to the PFS analysis.177 The third interim analysis was consistent with the second. Improved ORR (72.6% vs 59.8%) and median duration of response (11.2 vs 9 months) was observed with the addition of pembrolizumab compared with placebo. CRs were also more frequent in the pembrolizumab group compared with placebo (14% vs 11%).177 Similar incidence of AEs was observed in the pembrolizumab and placebo groups, the most common being diarrhea, nausea, and anemia.176,177 Based on KEYNOTE-811, in 2021 the FDA approved pembrolizumab in combination with trastuzumab plus fluoropyrimidine- and platinum-containing chemotherapy for locally advanced, unresectable or metastatic HER2-positive gastric or EGJ adenocarcinoma in first-line. The approval was modified in 2023 for patients in this setting whose tumor has PD-L1 CPS ≥1. Therefore, pembrolizumab combined with trastuzumab and fluoropyrimidine and platinum-based chemotherapy is a category 1 preferred first-line therapy option for treatment of patients with advanced HER2 overexpression-positive adenocarcinoma and PD-L1 CPS ≥1.
HER2 Overexpression-Negative Tumors
The randomized phase III KEYNOTE-859 trial investigated pembrolizumab plus chemotherapy versus placebo plus chemotherapy in treatment-naïve patients with advanced HER2-negative gastric or EGJ adenocarcinoma.178 At a median 31-month follow-up, OS and PFS were favorable for the pembrolizumab combination versus placebo. More specifically, in the PD-L1 CPS ≥10 subgroup, median OS was significantly longer with pembrolizumab compared with placebo (15.7 vs 11.8 months; HR, 0.65; P<.0001), and median PFS was also longer with pembrolizumab (8.1 vs 5.6 months; HR, 0.62; P<.0001). Objective responses were observed in 61% of patients with pembrolizumab versus 43% with placebo.178 In the PD-L1 CPS ≥1 subgroup, median OS was 13 months versus 11.4 months (HR, 0.74; P<.0001) and median PFS was 6.9 months versus 5.6 months (HR, 0.72; P<.0001) for pembrolizumab versus placebo, respectively. Objective responses were observed in 52% compared with 43%. Incidence of AEs were similar between the 2 treatment arms, with the most common grade 3–5 AEs being anemia and decreased neutrophils.178 Based on this study, the FDA granted approval for pembrolizumab in combination with fluoropyrimidine- and platinum-based chemotherapy for locally advanced, unresectable, or metastatic HER2-negative gastric or EGJ cancer in first-line therapy.
The panel includes pembrolizumab in combination with fluoropyrimidine- and platinum-based chemotherapy as a preferred option for first-line treatment of advanced HER2 overexpression-negative gastric cancer with PD-L1 CPS ≥1 if no prior ICI therapy or no tumor progression while on an ICI. This is a category 1 preferred option when PD-L1 CPS is ≥5.
MSI-H/dMMR Tumors
Pembrolizumab was FDA approved in 2017 for the treatment of patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. This first-ever tissue- and site-agnostic approval was based on data from 149 patients with MSI-H/dMMR cancers (90 patients had colorectal cancer) enrolled across five multicenter single-arm clinical trials.61,162,163 The ORR was 39.6% and responses lasted ≥6 months for 78% of those whose disease responded to pembrolizumab. There were 11 CRs and 48 partial responses, and the ORR was similar irrespective of cancer type. In an updated analysis of cohort K in KEYNOTE-158, 351 patients were enrolled with 28 tumor types represented.179 By independent central radiologic review, the ORR was 30.8%, with 27 patients having a CR, and median duration of response (DOR) was 47.5 months. Among the 42 patients with gastric cancer, the ORR was 31%.179
A few studies investigating pembrolizumab monotherapy and/or plus chemotherapy in advanced gastric or EGJ adenocarcinoma included patients whose tumors were MSI-H. In the phase II KEYNOTE-059 trial of a cohort of previously treated recurrent or metastatic gastric and EGJ cancers, four out of seven patients with an MSI-H tumor obtained an objective response with pembrolizumab monotherapy, with an ORR of 57.1%. Median OS and PFS were not reached among these same patients.58,180 Previously treated patients in the phase III KEYNOTE-061 trial received either pembrolizumab or paclitaxel.181 Among the 5.3% of patients with MSI-H tumors, median OS was not reached with pembrolizumab compared with 8.1 months with paclitaxel only. Median PFS was 17.8 months and ORR was 46.7% in patients with MSI-H tumor who received pembrolizumab versus 3.5 months and 16.7%, respectively, with paclitaxel alone.58,181 In the phase III KEYNOTE-062 trial, treatment-naïve patients received pembrolizumab ± chemotherapy.182 Similar to the other trials, median OS was not reached in the 7% of patients with MSI-H untreated locally advanced/unresectable or metastatic disease who received pembrolizumab ± chemotherapy versus 8.5 months with chemotherapy. Median PFS was 11.2 months among these patients with pembrolizumab and not reached with pembrolizumab plus chemotherapy versus 6.6 months with chemotherapy alone.58,182 ORR was 57.1% and 64.7% with pembrolizumab and pembrolizumab plus chemotherapy, respectively, compared with 36.8% with chemotherapy alone.58 Similar incidences of treatment-related all-grade or grade 3–5 AEs were observed with pembrolizumab and were lower than chemotherapy in the two phase III trials.181–183
Both pembrolizumab monotherapy and pembrolizumab in combination with fluoropyrimidine and oxaliplatin are recommended as category 2A preferred first-line therapy options for patients with advanced MSI-H/dMMR gastric cancer, independent of PD-L1 expression. Pembrolizumab monotherapy is also a category 2A option useful in certain circumstances for MSI-H/dMMR tumors in second- and subsequent-line.
TMB-H Tumors
In June 2020, the FDA approved pembrolizumab for the treatment of patients with metastatic TMB-H solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This approval was based on a prospective analysis of 102 patients enrolled in the KEYNOTE-158 trial who had tumors identified as TMB-H.166 The ORR for these patients was 29%, with a 4% complete response (CR) rate. The median duration of response was not reached, with 50% of patients having response duration for ≥24 months.166 Based on these data, pembrolizumab may be used for the second-line or subsequent treatment of TMB-H gastroesophageal tumors. However, it should be noted that no patients with gastroesophageal cancer were included in this TMB analysis from the KEYNOTE-158 trial.
Nivolumab
HER2 Overexpression-Negative Tumors
Nivolumab is a monoclonal PD-1 antibody. It was approved by the FDA in April 2021, in combination with fluoropyrimidine- and platinum-based chemotherapy, for the first-line treatment of patients with advanced or metastatic gastric cancer. This approval was based on results from the phase III Checkmate-649 trial, which randomized 1,581 patients with previously untreated, HER2-negative, unresectable gastric, EGJ, or esophageal adenocarcinoma to receive chemotherapy alone or nivolumab plus chemotherapy (capecitabine and oxaliplatin or mFOLFOX).184 The 3-year follow-up was consistent with initial efficacy results. At 3 years, median OS was 14.4 months for those with PD-L1 CPS ≥5 treated with nivolumab plus chemotherapy compared with 11.1 months with chemotherapy alone (HR, 0.70).185 Median PFS was 8.3 months with nivolumab plus chemotherapy versus 6.1 months with chemotherapy (HR, 0.70) in the same patient population. OS and PFS benefit was maintained with nivolumab plus chemotherapy compared with chemotherapy alone in the 5-year follow-up.186 These patients also had an ORR of 60%, and 13% achieved CR with nivolumab plus chemotherapy compared with an ORR of 45% and CR rate of 7% with chemotherapy.185 In the PD-L1 CPS ≥1 cohort, median OS for nivolumab plus chemotherapy was 13.8 versus 11.3 months with chemotherapy (HR, 0.75) and median PFS was 7.5 versus 6.9 months (HR, 0.77), respectively.185,186 Among all patients, 59% of those in the nivolumab plus chemotherapy group and 44% of those in the chemotherapy alone group experienced grade 3–4 treatment-related AEs, remaining consistent in the 3-year follow-up.184,185 The most common any-grade treatment-related AEs were nausea, diarrhea, and peripheral neuropathy across both groups. Sixteen treatment-related deaths occurred in the nivolumab plus chemotherapy group compared with 4 in the chemotherapy alone group.184 Therefore, nivolumab plus fluoropyrimidine- and oxaliplatin-based chemotherapy is a preferred first-line treatment option for patients with HER2-negative gastric tumors with PD-L1 expression levels by CPS ≥1 if no prior ICI therapy or no tumor progression while on an ICI. This combination is a category 1 preferred option when CPS is ≥5.
MSI-H/dMMR Tumors
About 3% of patients enrolled in Checkmate-649 had MSI-H tumors.184,185 In the 3-year follow-up, the OS benefit observed with nivolumab plus chemotherapy was better for those with MSI-H tumors than chemotherapy alone. This was true in patients who had MSI-H tumors with PD-L1 CPS ≥5 (n=34; 44.8 vs 8.8 months; HR, 0.29) and in all randomized patients with MSI-H tumors (n=44; 38.7 vs 12.3 months; HR, 0.34).185
The Checkmate-649 trial also randomized some patients to nivolumab plus ipilimumab or chemotherapy. At a minimum 24-month follow-up, patients with tumors having PD-L1 CPS ≥5 and all randomized patients did not have improved OS, PFS, or ORR with nivolumab plus ipilimumab versus chemotherapy alone.164 However, patients with MSI-H tumors treated with nivolumab plus ipilimumab had improved median OS versus chemotherapy (not reached vs 10 months; HR, 0.28). ORR was also improved with the combination versus chemotherapy (70% vs 57%) in those with an MSI-H tumor. There was no survival benefit in the microsatellite stable cohort.164
For MSI-H/dMMR tumors, independent of PD-L1 status, the panel recommends nivolumab plus fluoropyrimidine and oxaliplatin as a category 2A preferred option in first-line. The panel also recommends nivolumab plus ipilimumab as a category 2A preferred option in first-line and a category 2A option useful in certain circumstances in second- and subsequent-line for patients with MSI-H/dMMR tumors.
Tislelizumab-Jsgr
Another PD-1 inhibitor, tislelizumab, was recently approved by the FDA in combination with fluoropyrimidine- and platinum-based chemotherapy for the treatment of unresectable or metastatic HER2-negative gastric or EGJ adenocarcinoma with PD-L1 CPS ≥1. The randomized, global multicenter phase III trial RATIONALE-305 investigated the use of tislelizumab plus chemotherapy (investigator’s choice, capecitabine plus oxaliplatin or fluorouracil plus cisplatin) in the first-line setting for unresectable locally advanced or metastatic gastric of EGJ adenocarcinoma.187 Patients received either tislelizumab plus chemotherapy (n=501) or placebo plus chemotherapy (n=496). In all randomized patients, median OS for tislelizumab was 15 versus 12.9 months with placebo (HR, 0.80; P=.001). Median PFS was 6.9 versus 6.2 months with tislelizumab versus placebo, respectively (HR, 0.78). In the interim analysis, in patients whose tumors had a PD-L1 tumor area positivity of ≥5%, median OS for tislelizumab was 17.2 versus 12.6 months with placebo (HR, 0.74; P=.006) and PFS was 7.2 versus 5.9 months, respectively (HR, 0.67; P<.001).187 The authors found concordance between the tumor area positivity score and CPS and reported similar OS in each treatment arm in a post hoc analysis of PD-L1 CPS of ≥5. AEs of grade 3 or higher were observed in 54% of patients treated with tislelizumab compared with 50% with placebo. Common grade 3 or 4 AEs included decreased neutrophil and platelet counts, anemia, and neutropenia. In the tislelizumab arm, 23% experienced serious treatment-related AEs and 31% experienced immune-related AEs, compared with 15% and 12% with placebo, respectively.187 Based on these data, the panel recommends tislelizumab in combination with fluoropyrimidine (fluorouracil or capecitabine) and platinum (oxaliplatin or cisplatin) as a first-line treatment option for patients whose tumors are PD-L1 CPS ≥1, if no prior ICI therapy or no tumor progression while on an ICI. For tumors with PD-L1 CPS ≥5, this is a category 1, preferred option.
Zolbetuximab-Clzb
The FDA recently approved zolbetuximab combined with fluoropyrimidine- and platinum-based therapy for patients with HER2-negative, CLDN18.2-positive, unresectable locally advanced or metastatic gastric or EGJ adenocarcinoma in the first-line setting. Zolbetuximab is a novel monoclonal antibody targeting the tight junction protein, CLDN18.2, that demonstrated significant survival benefit in 2 global, randomized, multicenter phase III trials in this setting.72,82
In the SPOTLIGHT trial, 565 treatment-naïve patients with HER2-negative, CLDN18.2-positive, unresectable locally advanced or metastatic gastric or EGJ tumors received either zolbetuximab plus mFOLFOX6 (n=283) or placebo plus mFOLFOX6 (n=282).72 Median PFS was 10.61 months with zolbetuximab compared with 8.67 months with placebo, with the HR for disease progression or death being 0.75 (P=.0066). Median OS was also longer with zolbetuximab at 18.23 months versus placebo at 15.54 months (HR for risk of death, 0.75; P=.0053). ORR and median DOR were similar between treatment groups.72 In the GLOW trial, 507 untreated patients with unresectable locally advanced or metastatic HER2-negative, CLDN18.2-positive gastric or EGJ adenocarcinoma received either zolbetuximab plus CAPOX (n=254) or placebo plus CAPOX (n=253).82 Median PFS was longer in the zolbetuximab arm versus the placebo arm (8.21 vs 6.8 months; HR, 0.687; P=.0007). Median OS was also improved with zolbetuximab compared with placebo (14.39 vs 12.16 months; HR, 0.771; P=.0118). In the zolbetuximab group, ORR and DOR were 42.5% and 6.14 months versus placebo, which was 40.3% and 6.08 months, respectively.82
In both studies, treatment-emergent all grade AEs with a greater than 10% difference between zolbetuximab and placebo arms were nausea and vomiting. These events were also accounted for in the most frequent AEs of grade 3 or higher. Other AEs of grade 3 or higher in the GLOW trial were anemia and neutropenia, while decreased appetite was also observed in the SPOTLIGHT trial.72,82 Based on these data, fluoropyrimidine-based chemotherapy plus oxaliplatin and zolbetuximab is a category 1, preferred first-line therapy option for patients with unresectable locally advanced, recurrent or metastatic gastric cancer whose tumors are HER2-negative and CLDN18.2-positive.
Ramucirumab
Ramucirumab, a vascular endothelial growth factor receptor-2 antibody, has shown favorable results in patients with previously treated advanced or metastatic gastroesophageal cancers in 2 phase III clinical trials.157,188 An international randomized multicenter phase III trial (REGARD) demonstrated a survival benefit for ramucirumab in patients with advanced gastric or EGJ adenocarcinoma progressing after first-line chemotherapy.157 In this study, 355 patients were randomized to receive ramucirumab (n=238) or placebo (n=117). Median OS was 5.2 months in patients treated with ramucirumab compared with 3.8 months for those in the placebo group (P=.047). Ramucirumab was associated with higher rates of hypertension than placebo (16% vs 8%), whereas rates of other AEs were similar.157
An international phase III randomized trial (RAINBOW) evaluated paclitaxel with or without ramucirumab in patients (n=665) with metastatic gastric or EGJ adenocarcinoma progressing on first-line chemotherapy.188 Patients randomized to receive ramucirumab plus paclitaxel (n=330) had significantly longer median OS (9.63 months) compared with patients receiving paclitaxel alone (n=335; 7.36 months; P<.0001). The median PFS was 4.4 months and 2.86 months, respectively, and the ORR was 28% for ramucirumab plus paclitaxel compared with 6% for paclitaxel alone (P=.0001). Neutropenia and hypertension were more common with ramucirumab plus paclitaxel. An exposure-response analysis revealed that ramucirumab was a significant predictor of OS and PFS in both studies.189 Based on these results, ramucirumab (as a single agent or in combination with paclitaxel) was approved by the FDA for the treatment of patients with advanced gastric or EGJ adenocarcinoma refractory to or progressive following first-line therapy with platinum- or fluoropyrimidine-based chemotherapy. The guidelines recommend ramucirumab as a single agent (category 1, other recommended) or in combination with paclitaxel (category 1, preferred) as treatment options for second-line or subsequent therapy in patients with advanced or metastatic gastric adenocarcinoma.
Ramucirumab combined with FOLFIRI is a category 2A other recommended option for second-line or subsequent therapy. In a multi-institutional retrospective analysis of 29 patients with advanced gastric or EGJ adenocarcinoma who received FOLFIRI plus ramucirumab in the second-line setting, the ORR was 23% with a disease control rate of 79%.160 Median PFS was 6 months and median OS was 13.4 months. Six- and 12-month OS were 90% and 41%, respectively. No new safety signals were observed with the combination treatment, making FOLFIRI plus ramucirumab a safe, non-neurotoxic alternative to ramucirumab plus paclitaxel. Ramucirumab combined with irinotecan is also a category 2A other recommended option for second-line or subsequent therapy for patients with advanced gastric cancer.159
Due to the results of the international phase III RAINFALL trial, in which treatment with ramucirumab did not reduce the risk of disease progression or death in treatment-naïve patients with metastatic gastroesophageal adenocarcinoma, the addition of ramucirumab to first-line chemotherapy is not recommended at this time.190
Fam-Trastuzumab Deruxtecan-Nxki
Fam-trastuzumab deruxtecan-nxki is an antibody-drug conjugate consisting of trastuzumab and a cytotoxic topoisomerase I inhibitor connected by a cleavable tetrapeptide-based linker. The efficacy and safety of fam-trastuzumab deruxtecan-nxki in advanced or metastatic gastric or EGJ adenocarcinoma was evaluated in the phase II DESTINY-Gastric01 trial, which included 188 patients with progressive disease following at least 2 prior lines of therapy, including trastuzumab.191 Patients were randomized 2:1 to receive either fam-trastuzumab deruxtecan-nxki or physician’s choice of chemotherapy (paclitaxel or irinotecan). The confirmed ORR for patients on fam-trastuzumab deruxtecan-nxki was 40.5% compared with 11% for those on chemotherapy. OS (12.5 vs 8.4 months; P=.0097), median PFS (5.6 vs 3.5 months), and DOR (11.3 vs 3.9 months) were also higher in the fam-trastuzumab deruxtecan-nxki group compared with the chemotherapy group. Fam-trastuzumab deruxtecan-nxki resulted in more toxicities than systemic chemotherapy in this trial. The most common AEs (grade 3 or higher) were a decreased neutrophil count (51% of the fam-trastuzumab deruxtecan-nxki group and 24% of the chemotherapy group), anemia (38% and 23%, respectively), and decreased white blood cell count (21% and 11%). Fam-trastuzumab deruxtecan-nxki–related interstitial lung disease or pneumonitis occurred in 12 patients resulting in 1 drug-related death (due to pneumonia). No drug-related deaths occurred in the physician’s choice group.191
The single-arm, multicenter, phase II trial, DESTINY-Gastric02 investigated fam-trastuzumab deruxtecan-nxki in patients in Western countries with unresectable or metastatic HER2-positive gastric or EGJ cancer who experienced progression on or after first-line therapy.192 Based on HER2 status, the ORR was 47.1% in patients whose tumor was IHC 3+ compared with 10 months for IHC 2+/ISH+. Patients had a median DOR of 8.1 months, as well as median PFS and OS of 5.6 months and 12.1 months, respectively. The most common grade 3 or higher AEs were similar to DESTINY-Gastric01 and also included nausea. Interstitial lung disease/pneumonitis occurred in 8 patients, and for 2 patients it was a grade 5 event.192
The FDA has approved fam-trastuzumab deruxtecan-nxki to treat patients with unresectable or metastatic HER2 overexpression-positive solid tumors in second-line or subsequent therapy. Therefore, fam-trastuzumab deruxtecan-nxki is a category 2A preferred second-line or subsequent treatment option for patients with HER2 overexpression-positive adenocarcinoma after disease progression on prior treatment with a trastuzumab-based regimen. However, careful selection of patients and close monitoring of patients for excessive toxicity is recommended.
Entrectinib, Larotrectinib, and Repotrectinib
Gene fusions involving NTRK1, NTRK2, or NTRK3 encode TRK fusion proteins (TRKA, TRKB, TRKC), which have increased kinase function and are implicated in the oncogenesis of many solid tumors including head and neck, thyroid, soft tissue, lung, and colon.168,193 Although believed to be extremely rare in gastroesophageal cancers, one case report provides evidence that NTRK gene fusions do occur in gastric adenocarcinoma and may be associated with an aggressive phenotype.194–196
In 2018, the FDA granted accelerated approval of the TRK inhibitor larotrectinib for the treatment of adult and pediatric patients (aged ≥12 years) with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed after treatment. This second-ever tissue-agnostic FDA approval for the treatment of patients with cancer was based on data from 3 multicenter, single-arm clinical trials. Patients with prospectively identified NTRK gene fusion-positive cancers were enrolled into 1 of 3 protocols: a phase I trial involving adults (LOXO-TRK-14001), a phase I–II trial involving children (SCOUT), and a phase II trial involving adolescents and adults (NAVIGATE).168 A total of 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion who experienced disease progression after systemic therapy were enrolled across the 3 trials and treated with larotrectinib. The most common cancer types represented were salivary gland tumors, soft tissue sarcoma, infantile fibrosarcoma, and thyroid cancer. In an updated pooled analysis of the 3 trials (n=153), the ORR was 79%, with a CR rate of 16%.197 At a median follow-up of 12.9 months, 23% of patients who had responses experienced a progression event. Median DOR, PFS, and OS were 35.2 months, 28.3 months, and 44.4 months, respectively. AEs were predominantly grade 1–2, the most common being fatigue, increased aspartate aminotransferase and alanine aminotransferase levels, vomiting, constipation, and dizziness.197 The SCOUT (ClinicalTrials.gov identifier: NCT02637687) and NAVIGATE (ClinicalTrials.gov identifier: NCT02576431) trials are ongoing.
In 2019, the FDA approved the second TRK inhibitor, entrectinib, for the same indications as larotrectinib, as well as for adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1 positive. The approval of entrectinib for the treatment of NTRK gene fusion-positive tumors was based on data from three multicenter, single-arm phase I and phase II clinical trials. A total of 54 patients aged ≥18 years with metastatic or locally advanced NTRK gene fusion-positive solid tumors were enrolled into 1 of the 3 protocols (ALKA-372-001, STARTRK-1, and STARTRK-2).167 The most common cancer types represented were sarcoma, NSCLC, mammary analog secretory carcinoma, breast, thyroid, and colorectal. The ORR across the 3 trials was 57%, with a CR rate of 7%. Response duration was ≥6 months for 68% of patients and ≥12 months for 45% of patients. The median duration of response was 10 months. The most common grade 3–4 treatment-related AEs were increased weight and anemia while the most common serious treatment-related AEs were nervous system disorders. STARTRK-2 (ClinicalTrials.gov identifier: NCT02568267) is ongoing.
Repotrectinib was FDA approved in 2023 for patients with locally advanced or metastatic ROS1-positive NSCLC. It was given accelerated approval by the FDA in 2024 for similar indications to larotrectinib and entrectinib in patients with NTRK gene fusion-positive solid tumors. This was based on data from the phase I/II TRIDENT-1 trial investigating repotrectinib in previously tyrosine kinase inhibitor (TKI)-treated and TKI-treatment–naïve patients with NSCLC and NTRK+ solid tumors (ongoing, ClinicalTrials.gov identifier: NCT03093116).169 The most common tumor types were NSCLC, salivary gland, thyroid, and soft tissue sarcoma. Confirmed ORR was 58% in the TKI-naïve group and 50% in the previously treated group. The 12-month DOR and PFS were 86% and 56% for the TKI-naïve patients, respectively, and 39% and 22%, respectively, for the previously treated patients. Dizziness was the most common treatment-emergent AE of any grade, and AEs grade 3 or higher were observed in 51% of patients.169
These data demonstrate that these NTRK inhibitors induce durable and clinically meaningful responses in patients with NTRK gene fusion-positive tumors with manageable safety profiles. Entrectinib, larotrectinib, or repotrectinib are recommended as first-line (category 2B) and second-line or subsequent treatment options (category 2A) for patients with NTRK gene fusion-positive gastric tumors.
Dostarlimab-Gxly
Dostarlimab-gxly, an anti-PD-1 antibody, was approved by the FDA in August 2021 for the treatment of patients with dMMR recurrent or advanced solid tumors that have progressed on or following prior treatment, who have no satisfactory alternative treatment options, and who had not previously received a PD-1 or PD-L1 inhibitor. This approval was based on data from the nonrandomized phase 1 multicohort GARNET trial that evaluated the safety and antitumor activity of dostarlimab-gxly in patients with dMMR solid tumors who had not received prior PD-1, PDL-1, or CTLA4 inhibitors.198,199 The majority of patients had endometrial or gastrointestinal cancers. At median follow-up of 27.7 months, the ORR was 44% and DOR was not reached.199 Median PFS and OS were 6.9 months and not reached, respectively. The most common treatment-related AEs of any grade were fatigue, diarrhea, asthenia, pruritus, and hypothyroidism. Immune-related AEs that occurred in 34% of patients included hypothyroidism, elevated ALT, and arthralgia.199 Based on these data, dostarlimab-gxly is a category 2A, preferred option for first-line therapy for MSI-H/dMMR tumors. It is also useful in certain circumstances for second-line therapy in patients with MSI-H/dMMR gastric tumors whose disease is progressing on or after prior treatment that does not include immuno-oncology therapy and who have no satisfactory alternatives.
Dabrafenib and Trametinib
In June 2022, the FDA granted tumor-agnostic approval for the combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, for treatment of patients with unresectable or metastatic solid tumors with BRAF V600E mutations who have progressed after prior treatment and have no satisfactory alternative treatment options. This approval was based in part on data from the phase II BRF117019 and NCI-MATCH trials, which enrolled a combined 131 adult patients with various BRAF V600E-mutated tumor types.170 In subprotocol H (EAY131-H) of the NCI-MATCH platform trial, patients with BRAF V600E-mutated solid tumors (except for melanoma, thyroid cancer, or colorectal cancer) received combined dabrafenib and trametinib continuously until disease progression or intolerable toxicity. The ORR was 38% (P<.0001) and PFS was 11.4 months.170 The median OS in this cohort was 29 months. For the 131 patients across both trials, the ORR was 41%. The most common treatment-related AEs included pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, and vomiting.170 Based on these data, dabrafenib and trametinib may be used for second-line or subsequent therapy (category 2A) for patients with BRAF V600E-mutated gastroesophageal tumors.
Selpercatinib
In September 2022, the FDA granted tumor-agnostic approval for selpercatinib, a TKI, for treatment of patients with locally advanced or metastatic solid tumors with RET gene fusions who have progressed following prior treatment and have no satisfactory alternative treatment options. This approval was based on an interim analysis of data from the ongoing phase I/II LIBRETTO-001 trial, which evaluated 41 patients with RET fusion-positive tumors (other than NSCLC and thyroid cancer) who received selpercatinib until disease progression or unacceptable toxicity.171 The ORR was 44% with a duration of response of 25 months. The most common treatment-related AEs included edema, diarrhea, fatigue, dry mouth, hypertension, and abdominal pain. The most common grade 3 or higher treatment-related AEs were hypertension, increased alanine aminotransferase, and increased aspartate aminotransferase.171 Based on these data, selpercatinib may be used for second-line or subsequent therapy (category 2A) for patients with RET gene fusion–positive gastroesophageal tumors.
Summary
Gastric cancer is rampant in many parts of the world and is often diagnosed at an advanced stage. Risk factors for gastric cancer include H pylori infection, smoking, and high salt intake. Some gastric cancers are associated with inherited gastric cancer predisposition syndromes. See the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric (available at NCCN.org) for more information. The NCCN panel strongly recommends multidisciplinary team management as essential for treating localized gastric cancer. Best supportive care is an integral part of treatment, especially in patients with unresectable locally advanced, recurrent, or metastatic disease.
ER (EMR or endoscopic submucosal dissection) is the primary treatment option for patients with early-stage (Tis or T1a) tumors. Patients who are medically fit with resectable T1b or higher, any N tumors can receive surgery with D2 lymph node dissection. Perioperative chemotherapy is a category 1 recommendation for patients with resectable T2 or higher, any N tumors or neoadjuvant/perioperative ICI can be considered for certain patients with MSI-H/dMMR tumors (category 2A). Patients who are medically fit with surgically unresectable tumors have the option of chemoradiation or systemic therapy. Nonsurgical candidates (patients who cannot tolerate surgery or decline surgery) and patients with metastatic disease should receive palliative management, which is highlighted in this article.
Following an R0 resection, observation is an option for patients with Tis or T1,N0 tumors who did not receive previous systemic therapy. Postoperative chemoradiation is recommended for patients with T3–T4, any N tumors or any T, N+ tumors in patients who had received less than a D2 lymph node dissection and had not received previous systemic therapy (category 1). Selected patients with T2, N0 tumors and high-risk features can also be considered for postoperative chemoradiation. Postoperative chemotherapy should be reserved for patients with T3–T4, any N and or any T, N+ tumors who received D2 lymph node dissection (category 1). Postoperative chemoradiation is recommended for all patients with residual disease at surgical margins, if it was not received previously. Palliative management is also an option for certain patients following R2 resection. Options for patients who have received previous systemic therapy include systemic therapy (category 1) following R0 resection. Patients with R1 or R2 resection have the option of chemoradiation. Patients with R1 resection can also be considered for reresection, while patients with R2 resection can receive palliative management. Palliative management is an option for patients with M1 disease, regardless of whether they received preoperative therapy.
Histologic subtype and molecular characteristics have important implications in diagnosing and treating gastric cancer. The list of biomarkers that will characterize more subsets will continue to evolve. This selection from the NCCN Guidelines for Gastric Cancer highlighted several targeted therapeutic agents, including HER2-directed therapies, ICIs, and various kinase inhibitors that have been approved by the FDA for advanced gastric cancer. Targeted therapies have produced encouraging results in the treatment of patients with advanced gastric cancer. The NCCN Guidelines for Gastric Cancer are based on evidence- and consensus-based treatment approaches for the comprehensive care of patients with gastric cancer. The panel encourages patients with gastric cancer to participate in well-designed clinical trials investigating novel therapeutic strategies to enable further advances in the management of this disease.
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