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Immunotherapy-Based Management of Gastric/GEJ Cancers

CME

Expert Think Tank: New Developments in Immunotherapy-Based Management of Gastric/GEJ Cancers Across the Disease Continuum

Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™

Released: June 26, 2026

Expiration: December 25, 2026

Jaffer A. Ajani
Jaffer A. Ajani, MD
CME/CE Information

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Rationale for Moving Immunotherapy Into Early Disease

In gastric/GEJ cancers, there are very large numbers of cases every year with continuing unmet needs in treatment. Fortunately, some patients with gastric/GEJ cancers are highly susceptible to immune modulation, and those patients are shown to survive for 3-4 years. Based on clinical trial data and results from studies, we should be considering immunotherapy for every patient, given the correct clinical circumstances.1,2

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NCCN Guidelines on Immunotherapy in Gastric/GEJ

The NCCN guidelines for localized disease use fluorouracil/leucovorin/oxaliplatin/ docetaxel (FLOT) as the baseline chemotherapy, but it is toxic and the treating healthcare professional must be careful. Durvalumab can be added for some patients, including those with tumors that are PD-L1 positive (≥1), those with nondiffuse subtype, and those who have clinical node positivity. Patients who cannot tolerate FLOT can receive fluorouracil and oxaliplatin. Many options exist for neoadjuvant immunotherapy in MSI-high tumors (3.9%-12.4%).3 The preferred option is nivolumab plus ipilimumab (pathologic complete response [pCR]: 59%),4 but other options include pembrolizumab (pCR: 25%),5 tremelimumab plus durvalumab (pCR: 60%),6 or dostarlimab (clinical CR: 50%).7,8

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MATTERHORN: (Neo)adjuvant Durvalumab + FLOT

MATTERHORN was a 1:1 randomized, double-blind, placebo-controlled, multicenter study that enrolled 948 treatment-naive patients with gastric cancer or stage II-IVa GEJ adenocarcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1. Patients received durvalumab with FLOT (n = 475) or placebo with FLOT (n = 469). The median duration of durvalumab (1500 mg IV every 4 weeks) exposure in the neoadjuvant phase was 8 weeks and 48 weeks in the adjuvant phase. The primary endpoint was event-free survival (EFS), and the key secondary endpoints were OS and pCR by central review. The MATTERHORN study was conducted for patients with localized gastroesophageal cancer without regard to PD-L1 level.9,10

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MATTERHORN: EFS (Primary) and OS (Secondary) Endpoints

Results from the MATTERHORN trial demonstrated superior EFS with the treatment regimen of durvalumab plus FLOT vs perioperative FLOT alone (not reached vs 32.8 months; HR: 0.71; P <.001). At 24 months, patients who received durvalumab had a better median EFS compared with those who received placebo control (67.4% vs 58.5%, respectively). Similarly, after 36 and 48 months, the EFS continued to demonstrate improvement for the cohort receiving durvalumab and FLOT compared with those receiving placebo and FLOT.

The OS at 24 months was similar between the durvalumab and placebo groups (75.7% and 70.4%, respectively) and showed a late separation between the curves; however, the P value was 0.03 exceeding the threshold for significance. In the final analysis, a statistically significant and clinically meaningful improvement in OS was seen with the combination of durvalumab plus FLOT compared with the placebo plus FLOT with an approximately 7% absolute improvement in 3-year OS rates with the addition of durvalumab (68.6% vs 61.9%; HR: 0.78; P = .021). The OS improved regardless of PD-L1 status in the tumor.2,9

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KEYNOTE-585: (Neo)adjuvant Pembrolizumab + Chemotherapy for Gastric/GEJ Adenocarcinoma

KEYNOTE-585 was an international, double-blind, randomized phase III study that compared treatment-naive adults with localized gastric cancer or GEJ adenocarcinoma, ≥T3 primary lesion or with positive lymph nodes without evidence of metastatic disease, and ECOG PS 0/1, treated with either neoadjuvant pembrolizumab plus chemotherapy (n = 502) or placebo plus chemotherapy (n = 505). The chemotherapy regimens included either cisplatin plus capecitabine or cisplatin plus 5-fluorouracil. Patients were selected based on clinical stage, regardless of PD-L1 status. With a median follow-up of 59.9 months, the mOS was 71.8 months vs 55.7 months (HR: 0.86) with pembrolizumab plus chemotherapy vs placebo plus chemotherapy. The median EFS was 47.0 months in the pembrolizumab plus chemotherapy cohort and 26.9 months in the placebo plus chemotherapy cohort (HR: 0.81). At this final study analysis, the data showed perioperative pembrolizumab plus chemotherapy continued to provide improvement in pCR vs placebo plus chemotherapy.

Future studies are needed to determine the effectiveness of immune checkpoint inhibitors (ICIs) for gastric/GEJ cancers and assess whether pCR is an effective endpoint prediction for survival outcomes (NCT03221426).11,12

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Tumor-Agnostic Prevalence of HER2 Alterations (Mutations and Amplifications) in GI Cancers

HER2 alterations are found in many different types of cancers. In gastric and GEJ carcinomas, HER2 alterations are seen in approximately 15% of cases, with HER2 amplification being the most common alteration. Testing HER2 status in patients with gastric and GEJ carcinomas is necessary to guide optimized treatment decisions. Here in blue are amplifications, in orange are mutations, and in black are multiple alterations. As the management of gastric and GEJ adenocarcinomas evolves, HER2 testing will remain important in most patients.13

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