Globally, gastroesophageal cancers are the second most common cause of cancer-related deaths.1 A majority are diagnosed at an advanced stage and palliative treatment offers a median survival of <2 years.2–6 After the approval of trastuzumab for HER2-positive disease in 2010,7 new biomarkers have been identified, including PD-L1, mismatch repair deficiency/microsatellite instability-high (dMMR/MSI-H), CLDN18.2, and emerging biomarkers such as fibroblast growth factor receptor 2 (FGFR2), creating important strides in the treatment landscape for newly diagnosed advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (GA/GEJA). This review summarizes the progress in biomarker-driven treatment of metastatic GA/GEJA.
Biomarker Assessment in Gastric or Gastroesophageal Adenocarcinoma
Currently, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer recommend: (1) MSI testing using PCR or next-generation sequencing (NGS), or MMR expression using immunohistochemistry (IHC); (2) HER2, PD-L1, and CLDN18.2 testing by IHC testing; and (3) consideration of NGS at the time of diagnosis of advanced/metastatic disease.8,9 Other tumor agnostic biomarkers that are recommended for testing include tumor mutational burden (TMB), NTRK gene fusion, RET gene fusion, and BRAF V600E mutation.8,9
HER2
Frequency and Evaluation of HER2 Status
HER2 positivity is reported in 12% to 23% of patients with GA/GEJA.8 Approximately 85% of these cases exhibit a PD-L1 combined positive score (CPS) of ≥1.2 An IHC score of 3+ (strong membranous reactivity in ≥10% of tumor cells) is determined as positive for HER2.10 In case of an IHC score of 2+ (weak to moderate membranous reactivity in ≥10% of tumor cells), a reflex fluorescence in situ hybridization/in situ hybridization (FISH/ISH) testing characterized by an ERBB2::CEP17 ratio ≥2 or an average ERBB2 copy number ≥6 signals per cell is considered positive.8,10
First-Line Anti-HER2 Therapy
The pivotal phase III ToGA randomized clinical trial (RCT) evaluated trastuzumab + chemotherapy (fluoropyrimidine/platinum, n=294) versus chemotherapy alone (n=290) in systemic therapy–naive patients with HER2-positive advanced GA (82%) or GEJA (18%), with overall survival (OS) as the primary endpoint.7 Trastuzumab + chemotherapy demonstrated a significant improvement in median OS compared with chemotherapy alone (13.8 vs 11.1 months; hazard ratio [HR], 0.74; 95% CI, 0.60–0.91; P=.0046).7 More recently, the phase III KEYNOTE-811 RCT evaluated frontline pembrolizumab + trastuzumab and chemotherapy (n=350) versus placebo, trastuzumab, and chemotherapy in HER2-positive GA (67%) or GEJA (33%), with OS and progression-free survival (PFS) as dual primary endpoints.2 In 2021, based on the first interim analysis demonstrating a higher objective response rate (ORR) in the pembrolizumab arm compared with the placebo arm (74% vs 52%; P=.00006),11,12 the FDA granted accelerated approval to pembrolizumab as frontline treatment in combination with trastuzumab and chemotherapy, regardless of PD-L1 status, for patients with HER2-positive advanced GA/GEJA. However, in the final analysis, although there was improved OS in the pembrolizumab arm compared with the placebo arm in the intention-to-treat (ITT) population (median, 20.0 vs 16.8 months; HR, 0.8; 95% CI, 0.67–0.94; P=.004) and in the PD-L1 CPS ≥1 subgroup (median, 20.1 vs 15.7 months; HR, 0.79; 95% CI, 0.66–0.95; P=.006), there was lack of PFS and OS improvement in the PD-L1 CPS <1 subgroup.13,14 The FDA modified the approval in 2023, limiting the use of pembrolizumab with trastuzumab and chemotherapy to only patients with HER2-positive and PD-L1–positive (CPS ≥1) GA and GEJA.
Other anti-HER2 agents, such as lapatinib15 and the combination of trastuzumab and pertuzumab,16 have been tested in GA/GEJA but have not demonstrated an OS benefit in the frontline setting.
Later-Line Anti-HER2 Therapy
In the phase II DESTINY-Gastric01 study, patients in Northeast Asia with advanced HER2-positive GA (87%) or GEJA (13%) were randomized (2:1) to receive fam-trastuzumab deruxtecan-nxki (T-DXd) (n=125) versus chemotherapy (paclitaxel or irinotecan; n=62) as a third- or later-line therapy following fluoropyrimidine/platinum and trastuzumab, with ORR as the primary endpoint.17 The T-DXd arm demonstrated superior ORR (51% vs 14%; P<.001), PFS (median, 5.6 vs 3.5 months; HR, 0.47; 95% CI, 0.31–0.71), and OS (median, 12.5 vs 8.4 months; HR, 0.59; 95% CI, 0.39–0.88; P=.01).17,18 Subsequently, the phase II DESTINY-Gastric02 single-arm study evaluated T-DXd (n=79) as a second-line therapy in Western countries, with ORR as the primary endpoint.19 The efficacy outcomes were similar to those in DESTINY-Gastric01, with a confirmed ORR of 42%, a median PFS of 5.6 months, and a median OS of 12.1 months.19 According to a recent press release, the phase III DESTINY-Gastric04 RCT (ClinicalTrials.gov identifier: NCT04704934) demonstrated an OS benefit with T-DXd compared with ramucirumab and paclitaxel as a second-line therapy following progression on trastuzumab-based frontline treatment in patients with HER2-positive GA/GEJA.20
Similar to the first-line setting, other anti-HER2 agents such as lapatinib21 and trastuzumab emtansine22 failed to demonstrate OS benefit in the second-line or beyond setting.
Notably, studies have reported that up to 69% of cases may lose HER2 positivity after frontline trastuzumab therapy, which is considered a primary cause of acquired resistance.23,24 Additionally, the exploratory biomarker analysis of DESTINY-Gastric01 demonstrated that patients who maintained HER2 positivity after or during frontline trastuzumab-containing therapy had improved ORR and OS with trastuzumab deruxtecan compared with chemotherapy.25 These findings support the NCCN Guidelines’ recommendation to consider repeat HER2 testing upon disease progression in GA/GEJA.8
PD-L1
Frequency and Evaluation of PD-L1 Status
PD-L1 status is evaluated by IHC and measured using the following formula: CPS = [PD-L1–stained cells]/[total viable tumor cells] × 100.8 Approximately 80% of HER2-negative gastric cancers have a PD-L1 CPS ≥1, and 35% to 60% have a PD-L1 CPS ≥5.4,26
Chemoimmunotherapy Based on PD-L1 Score
The phase III CheckMate 649 RCT evaluated frontline nivolumab + chemotherapy (n=789) versus chemotherapy alone (n=792) in HER2-negative GA (70%), GEJA (17%), or esophageal adenocarcinoma (13%), with PFS and OS as the primary endpoints for PD-L1 CPS ≥5.3,26 The nivolumab/chemotherapy arm showed superior PFS (median, 7.7 vs 6.0 months; HR, 0.68; 95% CI, 0.56–0.81; P<.0001) and OS (median, 14.4 vs 11.1 months; HR, 0.71; 95% CI, 0.59–0.86; P<.0001) compared with the chemotherapy alone arm.26 Similarly, the phase III KEYNOTE-859 RCT evaluated frontline pembrolizumab + chemotherapy (n=790) versus placebo + chemotherapy (n=789) in HER2-negative GA (79%) or GEJA (21%), with OS as the primary endpoint in the ITT, PD-L1 CPS ≥1, and PD-L1 CPS ≥10 populations.4 The pembrolizumab arm showed improved OS (median, 12.9 vs 11.5 months; HR, 0.78; 95% CI, 0.70–0.87; P<.0001) compared with the placebo arm in the overall population and in the PD-L1 CPS ≥10 subgroup (median OS, 15.7 vs 11.8 months; HR, 0.65; 95% CI, 0.53–0.79; P<.0001).4
In 2021, the FDA approved nivolumab or pembrolizumab in combination with chemotherapy, regardless of PD-L1 status, for frontline therapy in HER2-negative disease. In September 2024, the FDA’s Oncologic Drugs Advisory Committee (ODAC) determined that PD-1 inhibitors in the first-line setting should be offered only to patients with PD-L1 CPS ≥1 GA/GEJA.27 The phase III RATIONALE-305 RCT demonstrated OS benefits with the addition of tislelizumab to frontline chemotherapy, leading to its FDA approval for PD-L1 ≥1% (tumor area positivity [TAP] score with the VENTANA SP263 assay) GA/GEJA.28
dMMR/MSI-H and TMB-High
Frequency and Evaluation of MMR/MSI Status
Approximately 3% to 5% of advanced gastric cancers are reported as dMMR and/or MSI-H.4,26,29
Immune Checkpoint Inhibitors for dMMR/MSI-H
Given the rarity of dMMR/MSI-H in GA, prospective data driven by the dMMR/MSI-H biomarker specifically in metastatic GA/GEJA is lacking. However, subgroup analyses from phase II/III trials have shown promising clinical benefits with immune checkpoint inhibitors (ICIs) in metastatic GA.30 In a post hoc analysis of 3 phase II/III trials involving 84 patients with MSI-H advanced GA (81%) or GEJA (19%), pembrolizumab monotherapy demonstrated improved OS (1-year OS, 71%–79% vs 25%–47%), PFS (median, not reached–11.2 months vs 3.5–6.6 months), and ORR (46%–57% vs 17%–37%) compared with chemotherapy.30 In a CheckMate649 subgroup analysis of MSI-H tumors (n=21), nivolumab + ipilimumab demonstrated improved OS (median, not reached vs 10 months; unstratified HR, 0.28) and a higher ORR (70% vs 57%) compared with chemotherapy.31 In this analysis, nivolumab + chemotherapy also demonstrated improved OS (median, 39 vs 12 months; HR, 0.34; 95% CI, 0.16–0.74) compared with chemotherapy.3 Similarly, in the KEYNOTE-859 MSI-H subgroup analysis (n=74), the addition of pembrolizumab to chemotherapy demonstrated improved OS (HR, 0.34; 95% CI, 0.18–0.66), PFS (HR, 0.27; 95% CI, 0.14–0.53), and ORR (79% vs 37%).4
Based on available data, chemoimmunotherapy or immunotherapy alone are both valid treatment options for patients with dMMR/MSI-H GA/GEJA. Factors such as disease burden and symptoms related to disease must be considered when making treatment decisions for these patients.
TMB-High
TMB can be measured as the number of somatic mutations per megabase (mut/Mb) of interrogated genomic sequence, with high TMB (TMB-H) associated with increased neoantigen formation and enhanced immune recognition.32 TMB is commonly measured using commercially available NGS panels. Tissue TMB (tTMB) ≥10 mut/Mb is considered TMB-H.33 Equivalent TMB-H on blood-based (liquid biopsy) TMB (bTMB) measurements are proposed at higher cutoffs (16–20 mut/Mb).34–36 In June 2020, the FDA approved pembrolizumab for metastatic solid tumors with TMB-H (≥10 mut/Mb) in patients who have no satisfactory alternative treatment options, primarily based on exploratory biomarker analysis from the phase II KEYNOTE-158 trial that did not represent GA or GEJA tumors.33 The recent phase II TAPUR study showed limited clinical benefit of pembrolizumab in other microsatellite-stable (MSS) TMB-H gastrointestinal tumors, such as colorectal cancer.37 Currently, prospective data on ICIs in MSS TMB-H upper gastrointestinal tumors are limited.
CLDN18.2
Frequency and Evaluation of CLDN18.2
CLDN18.2 is a tight junction protein normally expressed exclusively in gastric mucosal cells.5,6 During malignant transformation, the loss of cell polarity in the gastric mucosa can cause CLDN18.2 to become more exposed, making it more accessible to targeted therapeutic agents.5,6 Approximately 38% of HER2-negative advanced gastric cancers are CLDN18.2-positive using the VENTANA CLDN18 (43-14A) RxDx Assay (Roche Diagnostics), with ≥75% of tumor cells exhibiting moderate to strong membranous staining (2+ or 3+) considered positive.5,6 Notably, an overlap of 13% to 22% between CLDN18.2 positivity and PD-L1 CPS ≥5 has been observed in advanced GA.5,6
Zolbetuximab + Chemotherapy as Frontline Therapy
Zolbetuximab is a first-in-class immunoglobulin G1 monoclonal antibody targeting CLDN18.2. Two global phase III RCTs have demonstrated significant clinical benefit from the addition of zolbetuximab to chemotherapy in HER2-negative, CLDN18.2-positive advanced gastric cancer as a front-line therapy.5,6,38
The phase III SPOTLIGHT RCT evaluated frontline zolbetuximab + mFOLFOX6 (n=283) versus placebo + mFOLFOX6 (n=282) in treatment-naïve HER2-negative, CLDN18.2-positive GA (76%) or GEJA (24%), with PFS as the primary endpoint.5 The zolbetuximab arm demonstrated improved PFS (median, 10.6 vs 8.7 months; HR, 0.75; 95% CI, 0.60–0.94; P=.0066) and OS (median, 18.2 vs 15.5 months; HR, 0.75; 95% CI, 0.60–0.94; P=.0053) compared with the placebo arm.5 Similarly, the phase III GLOW RCT compared zolbetuximab + CAPOX (n=254) versus placebo + CAPOX (n=253) as frontline therapy in GA (84%) or GEJA (16%), with PFS as the primary endpoint.6 The zolbetuximab arm showed improved PFS (median, 8.2 vs 6.8 months; HR, 0.69; 95% CI, 0.54–0.87; P=.0007) and OS (median, 14.4 vs 12.2 months; HR, 0.77; 95% CI, 0.62–0.97; P=.0118) compared with the placebo arm.6 Combined analysis of the SPOTLIGHT and GLOW trials showed superior PFS (median, 9.2 vs 8.2 months; HR, 0.71; 95% CI, 0.61–0.83) and OS (median, 16.4 vs 13.7 months; HR, 0.77; 95% CI, 0.67–0.89) in the zolbetuximab group compared with the placebo group.38 Notable side effects associated with zolbetuximab include nausea (grade ≥3; 13%) and vomiting (grade ≥3; 14%).5,6,38 This drug received FDA approval in October 2024 in combination with frontline chemotherapy for HER2-negative, CLDN18.2-positive GA/GEJA.39 Given the observed overlap between CLDN18.2 and PD-L1 expression, the next key question in the field is the potential role of combining chemoimmunotherapy with zolbetuximab. Currently, the phase II ILUSTRO trial (ClinicalTrials.gov identifier: NCT03505320), Cohort 4, is evaluating zolbetuximab in combination with chemoimmunotherapy in metastatic HER2-negative, CLDN18.2-positive GA/GEJA.40
Other Rare Targetable Genomic Alterations
Metastatic GA can occasionally present with rare actionable genomic alterations, including NTRK gene fusion (<0.1%), BRAF V600E mutation (<0.5%), and RET fusion (<1%) which are usually detected by commercially available NGS panels.41–43 Targeted therapies, such as entrectinib, larotrectinib, or repotrectinib for NTRK fusion, dabrafenib plus trametinib for BRAF V600E mutation, and selpercatinib for RET fusion, can be considered as second-line or later therapeutic options.8,44–48 These treatments are primarily based on tumor-agnostic approvals derived from early-phase clinical data. Table 1 summarizes practice-changing biomarker-driven studies in GA/GEJA. Figure 1 presents an algorithm for the biomarker-driven treatment approach in metastatic GA/GEJA.
Practice-Changing Pivotal Studies by Biomarker-Driven Approaches
| Trial (ClinicalTrials.gov Identifier) | Phase, Design | Eligibility | Line of Therapy | Primary Endpoint | Intervention | Outcomes | Reference |
|---|---|---|---|---|---|---|---|
| Anti-HER2 | |||||||
| ToGA (NCT01041404) | III, RCT | Advanced/Metastatic HER2+ GA or GEJA | First | OS | Trastuzumab + CTx (n=294) vs CTx (n=290) | mOS: 13.8 vs 11.1 mo mPFS: 6.7 vs 5.5 mo ORR: 47% vs 35% |
7 |
| KEYNOTE-811 (NCT03615326) | III, RPCT | Advanced/Metastatic HER2+ GA or GEJA | First | PFS & OS | Pembrolizumab + trastuzumab + CTx (n=350) vs placebo + trastuzumab + CTx (n=348) | ITT mOS: 20.0 vs 16.8 mo mPFS: 10.0 vs 8.1 mo ORR: 73% vs 60% PD-L1 CPS ≥1 mOS: 20.1 vs 15.7 mo mPFS: 10.9 vs 7.3 mo |
13,14 |
| DESTINY-Gastric01 (NCT03329690) | II, RCT | Advanced/Metastatic HER2+ GA or GEJA | Third or later | ORR | T-DXd (n=125) vs CTx (n=62, irinotecan or paclitaxel) | mOS: 12.5 vs 8.4 mo mPFS: 5.6 vs 3.5 mo ORR: 51% vs 14% |
17 |
| DESTINY-Gastric02 (NCT04014075) | II, SA | Advanced/Metastatic HER2+ GA or GEJA | Second | ORR | T-DXd (n=79) | mOS: 12.1 mo mPFS: 5.6 mo ORR: 42% |
19 |
| Anti–PD-1 | |||||||
| CheckMate 649 (NCT02872116) | III, RCT | Advanced/Metastatic HER2− GA, GEJA, or EA | First | PFS or OS | Nivolumab + CTx (n=789) vs CTx (n=792) | ITT mOS: 13.7 vs 11.6 mo mPFS: 7.7 vs 6.9 mo ORR: 58% vs 46% PD-L1 CPS ≥5 mOS: 14.4 vs 11.1 mo mPFS: 8.3 vs 6.1 mo ORR: 60% vs 45% |
3 |
| KEYNOTE-859 (NCT03675737) | III, RPCT | Advanced/Metastatic HER2− GA or GEJA | First | OS | Pembrolizumab + CTx (n=790) vs placebo + CTx (n=789) | ITT mOS: 12.9 vs 11.5 mo mPFS: 6.9 vs 5.6 mo ORR: 51% vs 42% PD-L1 CPS ≥1 mOS: 13.0 vs 11.4 mo mPFS: 6.9 vs 5.6 mo ORR: 52% vs 43% PD-L1 CPS ≥10 mOS: 15.7 vs 11.8 mo mPFS: 8.1 vs 5.6 mo ORR: 61% vs 43% |
4 |
| RATIONALE-305 (NCT03777657) | III, RPCT | Advanced/Metastatic HER2− GA or GEJA | First | OS | Tislelizumab + CTx (n=501) vs placebo + CTx (n=496) | ITT mOS: 15.0 vs 12.9 mo mPFS: 6.9 vs 6.2 mo ORR: 47% vs 41% PD-L1 TAP ≥5% mOS: 17.2 vs 12.6 mo mPFS: 7.2 vs 5.9 mo ORR: 50% vs 43% |
28 |
| Anti-CLDN18.2 | |||||||
| SPOTLIGHT (NCT03504397) | III, RPCT | Advanced/Metastatic HER2−, CLDN18.2+ GA or GEJA | First | PFS | Zolbetuximab + mFOLFOX6 (n=283) vs placebo + mFOLFOX6 (n=282) | mOS: 18.2 vs 15.5 mo mPFS: 10.6 vs 8.7 mo ORR: 48% vs 48% |
5 |
| GLOW (NCT03653507) | III, RPCT | Advanced/Metastatic HER2−, CLDN18.2+ GA or GEJA | First | PFS | Zolbetuximab + CAPOX (n=254) vs placebo + CAPOX (n=253) | mOS: 14.4 vs 12.2 mo mPFS: 8.2 vs 6.8 mo ORR: 43% vs 40% |
6 |
Abbreviations: CPS, combined positive score; CTx, chemotherapy; EA, esophageal adenocarcinoma; GA, gastric adenocarcinoma; GEJA, gastroesophageal junction adenocarcinoma; ITT, intention-to-treat; mOS, median overall survival; mPFS, median progression-free survival; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RCT, randomized clinical trial; RPCT, randomized placebo-controlled trial; SA, single-arm; TAP, tumor area positivity.
Algorithm for biomarker-driven treatment of metastatic gastric or gastroesophageal adenocarcinoma.
Abbreviations: CPS, combined positive score; dMMR, deficient mismatch repair; ICI, immune checkpoint inhibitor; IHC, immunohistochemistry; ISH, in situ hybridization; MMR, mismatch repair; MSI, microsatellite instability; MSI-H, microsatellite instability-high; NGS, next-generation sequencing; TAP, tumor area positivity; T-DXd, fam-trastuzumab deruxtecan-nxki; TMB-H, tumor mutational burden-high.
*An overlap of 13%–22% between CLDN18.2 positivity and PD-L1 CPS ≥5 has been observed.5,6 Management of dual CLDN18.2+ and PD-L1+ cases will be the next area of investigation in the field.
aMMR status evaluated by IHC.
bMSI testing using PCR or NGS.
cChemotherapy: fluoropyrimidine (fluorouracil or capecitabine) + oxaliplatin. Cisplatin can be considered as an alternative to oxaliplatin in some regimens.
dHER2 status evaluated by IHC, followed by ISH in cases showing 2+ expression by IHC.
ePD-L1 testing by IHC.
fCLDN18.2 testing by IHC.
gFluoropyrimidine + oxaliplatin + nivolumab is recommended for patients with PD-L1 CPS ≥5 (NCCN Category 1).8 Chemotherapy + pembrolizumab is recommended for patients with PD-L1 CPS ≥10 (NCCN Category 1).8 Chemotherapy + pembrolizumab may be an appropriate option for patients with PD-L1 CPS 1–9, based on NCCN consensus (NCCN Category 2B).8
hPD-L1 ≥1% by TAP score with the VENTANA SP263 assay.
iPreferred other subsequent options include ramucirumab and paclitaxel, FOLFIRI, docetaxel, paclitaxel, and irinotecan.8
Citation: Journal of the National Comprehensive Cancer Network 23, 5; 10.6004/jnccn.2025.7036
Future Directions
Investigational Therapies/Ongoing Clinical Trials Targeting HER2
The phase Ib/II DESTINY-Gastric03 (ClinicalTrials.gov identifier: NCT04379596) trial is evaluating frontline T-DXd combined with chemotherapy and/or immunotherapy in HER2-expressing GA, GEJA, and esophageal adenocarcinoma.49,50 The dose-expansion Part 1 revealed manageable toxicity and determined the recommended phase II trial dose.50 Currently, dose-expansion Part 2 (multiple arms with T-DXd with or without chemotherapy and/or immunotherapy) and Part 3 (T-DXd + fluoropyrimidine + volrustomig, a PD-1/CTLA-4 bispecific antibody) are underway (NCT04379596).49 Interim analyses of Part 2 were reported at ESMO 2024, revealing that arm D, which received T-DXd at 6.4 mg/kg with full-dose fluoropyrimidine + pembrolizumab, exhibited infeasible toxicity. This finding highlights the need for T-DXd dose reduction at 5.4 mg/kg, as used in Arm F, for further investigation.51 Notably, inferior efficacy was observed in the pembrolizumab arms for patients with PD-L1 CPS <1.51
Zanidatamab is a biparatopic antibody that targets 2 HER2 domains, ECD4 and ECD2.52 In a phase II trial (NCT03929666), zanidatamab combined with chemotherapy was evaluated as frontline therapy in GA/GEJA.53 The combination demonstrated a confirmed ORR of 79%, a median PFS of 12.5 months, and an 18-month OS rate of 84%.53 The safety profile was manageable with the use of antidiarrheal prophylaxis.53 A phase III RCT (HERIZON-GEA-01, NCT05152147) is currently underway to evaluate frontline zanidatamab + chemotherapy ± tislelizumab, compared with trastuzumab + chemotherapy, for HER2-positive metastatic GA or GEJA.54
Investigational Therapies Against Other Emerging Targets
FGFR2b overexpression is an emerging therapeutic target in GA. Bemarituzumab is a recombinant, afucosylated IgG1 kappa monoclonal antibody that specifically targets FGFR2b.55,56 The phase II FIGHT RCT compared bemarituzumab + mFOLFOX6 (n=77) with placebo + mFOLFOX6 (n=78) as first-line therapy in FGFR2b-selected GA/GEJA, with PFS as the primary endpoint.55,56 Notably, FGFR2b positivity in the study was defined as either 2+ or 3+ staining by IHC in >0% of tumor cells or FGFR2 amplification detected by circulating tumor DNA.55,56 Subgroup analysis of patients with 2+ or 3+ IHC staining in ≥10% of tumor cells showed significant benefits in PFS (median, 14.0 vs 7.3 months; HR, 0.43; 95% CI, 0.26–0.73) and OS (median, 24.7 vs 11.1 months; HR, 0.52; 95% CI, 0.31–0.85) in the bemarituzumab arm.55 A notable adverse event associated with bemarituzumab was corneal toxicity, with grade 3 events occurring in 24% of patients and treatment discontinuation due to this toxicity in 26%.55,56 Ongoing phase III RCTs (ClinicalTrials.gov identifiers: NCT05052801, NCT05111626) aim to confirm the benefit of adding bemarituzumab to chemotherapy with or without nivolumab as frontline therapy in HER2-negative GA/GEJA, with a focus on enhanced FGFR2b selection using the ≥10% IHC 2+ or 3+ criterion.55,57,58
Domvanalimab is an IgG1 monoclonal antibody that targets the T-cell immunoglobulin and ITIM domain (TIGIT).59 The phase II EDGE-Gastric trial (Arm A1) evaluated the combination of domvanalimab, zimberelimab (an anti–PD-1 antibody), and mFOLFOX6 in HER2-negative advanced gastroesophageal cancer, with safety and ORR as the primary endpoints.59,60 The regimen demonstrated a promising ORR of 59% and a median PFS of 12.9 months, with a similar adverse event profile to anti–PD-1 + FOLFOX, without new safety concerns.59,60 Currently, the phase III RCT STAR-221 (NCT05568095) is underway, comparing domvanalimab + zimberelimab + chemotherapy versus nivolumab + chemotherapy as frontline therapy in HER2-negative GA, GEJA, and esophageal adenocarcinoma.61
DKN-01 is an anti-DKK1 monoclonal antibody that has demonstrated antitumor activity in combination with anti–PD-1 therapy in patients with advanced gastroesophageal adenocarcinoma and low tumor PD-L1 expression, with no new safety signals observed in a phase I trial.62 The phase II DisTinGuish trial (Part A) evaluated DKN-01 + tislelizumab and chemotherapy as first-line therapy in HER2-negative advanced GA/GEJA.63 This regimen resulted in an ORR of 73%, a median PFS of 11.3 months, and a median OS of 19.5 months, with the most common grade ≥3 adverse events being diarrhea, hypokalemia, and anemia.63 Part C of this randomized phase II trial (ClinicalTrials.gov identifier: NCT04363801), comparing chemotherapy + tislelizumab with or without DKN-01 as frontline therapy in HER2-negative advanced GA/GEJA, has completed accrual, and further data are awaited.63 AZD0901, a CLDN18.2-targeted antibody–drug conjugate with a monomethyl auristatin E payload linked via a protease-cleavable linker, has demonstrated manageable toxicity and potential clinical activity in a phase I study in advanced GA/GEJA.64 Currently, the phase III CLARITY-Gastric 01 RCT is underway to evaluate AZD0901 compared with later-line chemotherapy in GA/GEJA.65 Multiple other agents targeting CLDN18.2 are in development, but they are beyond the scope of this paper.64,66–68 Table 2 summarizes key ongoing biomarker-driven clinical trials in GA/GEJA.
Ongoing Biomarker-Driven Clinical Trials
| Trial (ClinicalTrials.gov Identifier) | Phase, Design | Eligibility | Line of Therapy | Intervention | Target Enrollment n | Primary Endpoint | |
|---|---|---|---|---|---|---|---|
| Anti-HER2 | |||||||
| DESTINY-Gastric03 (NCT04379596) | Ib/II, dose-escalation (Part 1) & dose-expansion (Part 2) | Advanced/Metastatic HER2+ GA, GEJA, or EA | First (Part 2, 3) | Part 2 T-DXd T-DXd + CTx T-DXd + anti–PD-1 T-DXd + CTx + anti–PD-1 Part 3 T-DXd + CTx + volrustomig (anti–PD-1/CTLA-4) |
413a | ORR | |
| DESTINY-Gastric04 (NCT04704934) | III, RCT | Advanced/Metastatic HER2+ GA or GEJA | Second | T-DXD vs ramucirumab + paclitaxel | 490 | OS | |
| HERIZON-GEA-01 (NCT05152147) | III, RCT | Advanced/Metastatic HER2+ GA, GEJA, or EA | First | Zanidatamab + CTx vs zanidatamab + CTx + tislelizumab (anti–PD-1) vs trastuzumab + CTx | 918 | PFS, OS | |
| Anti-CLDN18.2b | |||||||
| ILUSTRO (NCT03505320) Cohort 4 | II, non-randomized, parallel cohorts | Advanced/Metastatic HER2− GA or GEJA | First | Zolbetuximab + mFOLFOX6 + nivolumab | 143c | Safety and efficacy | |
| CLARITY-Gastric 01 (NCT06346392) | III, RCT | Advanced/Metastatic HER2− GA, GEJA, or distal EA | Second or later | AZD0901 (dose level 1) vs AZD0901 (dose level 2) vs investigator’s choice arm | 589 | PFS, OS | |
| Anti-FGFR2b | |||||||
| FORTITUDE-101 (NCT05052801) | III, RPCT | Advanced/Metastatic HER2−, FGFR2b+ GA or GEJA | First | Bemarituzumab + mFOLFOX6 vs placebo + mFOLFOX6 | 516 | OS | |
| FORTITUDE-102 (NCT05111626) | III, RPCT | Advanced/Metastatic HER2−, FGFR2b+ GA or GEJA | First | Bemarituzumab + nivolumab + CTx (mFOLFOX6 or CAPOX) vs placebo + nivolumab + CTx (mFOLFOX6 or CAPOX) | 528 | OS | |
| Other Agents | |||||||
| STAR-221 (NCT05568095) | III, RCT | Advanced/Metastatic HER2− GA, GEJA, or EA | First | Domvanalimab (anti-TIGIT) + zimberelimab (anti–PD-1) + CTx (FOLFOX or CAPOX) vs nivolumab + CTx (FOLFOX or CAPOX) | 1,040 | OS | |
| DisTinGuish (NCT04363801) Part C | III, RCT | Advanced/Metastatic HER2− GA or GEJA | First | DKN-01 (anti-DKK1) + tislelizumab (anti–PD-1) + CTx (CAPOX or mFOLFOX6) vs tislelizumab + CTx (CAPOX or mFOLFOX6) | 232d | PFS | |
Abbreviations: ADC, antibody–drug conjugate; BiTE, bispecific T-cell engager; CAR-T, chimeric antigen receptor T cell; CTx, chemotherapy; EA, esophageal adenocarcinoma; GA, gastric adenocarcinoma; GEJA, gastroesophageal junction adenocarcinoma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RCT, randomized clinical trial; RPCT, randomized placebo-controlled trial.
The number includes all DESTINY-Gastric03 patients, including Parts 2 and 3.
Given the extensive range of investigational agents targeting CLDN18.2, including CAR-T, ADC, and BiTE therapies,64–67 a comprehensive review of these agents is beyond the scope of the current article.
The number includes all ILUSTRO patients, including Cohort 4.
The number includes all DisTinGuish patients, including Part C.
Conclusions
The management of metastatic GA/GEJA has dramatically evolved over the years, driven by robust biomarker-driven clinical trials. Currently, frontline decisions are guided by key biomarkers, including dMMR/MSI-H, HER2, PD-L1, and CLDN18.2. Numerous ongoing biomarker-driven clinical trials are investigating new targeted agents, including those directed at FGFR2b, that have the potential to continue to transform the landscape of GA and GEJA management. However, the overlap of multiple biomarkers presents a significant challenge in optimizing patient selection, underscoring the need for more precise strategies in designing future clinical trials.
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