Immunotherapy in GI Cancers has transitioned from therapeutic expansion to biological precision. Immune checkpoint inhibitors are embedded in treatment algorithms for gastric cancer, hepatocellular carcinoma, and colorectal cancer. Regulatory approvals span disease stages and lines of therapy.
In 2026, the central question is which patients derive durable benefit based on tumor biology, immune phenotype, and disease context. The evolution of Immunotherapy in GI Cancers is defined by selection rather than saturation.
How Has Immunotherapy in GI Cancers Evolved in Gastric and GEJ Cancer?
Advanced gastric and gastroesophageal junction (GEJ) adenocarcinomas represent heterogeneous diseases shaped by molecular subtype and immune microenvironment.
CheckMate-649
The phase III CheckMate-649 established nivolumab plus chemotherapy as a first-line treatment option for patients with previously untreated, non-HER2–positive advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma. Earlier analyses demonstrated significant improvements in overall survival and progression-free survival, particularly in patients with PD-L1 combined positive score (CPS) ≥5.
The 5-year follow-up, published in Annals of Oncology in February 2026, confirmed the durability of benefit with long-term outcomes. Nivolumab plus chemotherapy maintained a sustained overall survival advantage (HR 0.71), with a 5-year overall survival rate of 16% compared with 6% with chemotherapy alone. Progression-free survival benefit was also sustained (HR 0.71), with 10% of patients remaining progression-free at five years. Responses were more frequent (ORR 58% vs 46%) and more durable, with no new safety signals observed.
These findings established chemo-immunotherapy as a backbone in advanced gastric cancer, particularly in PD-L1–selected populations.
KEYNOTE-811
KEYNOTE-811 evaluated pembrolizumab added to trastuzumab and chemotherapy in patients with previously untreated, unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma.
In this phase III trial, pembrolizumab significantly improved progression-free survival compared with placebo (10.0 vs 8.1 months; HR 0.72), with greater benefit observed in PD-L1 CPS ≥1 tumors. Objective response rates were higher with pembrolizumab (72.6% vs 59.8%), with more complete responses observed. Overall survival was numerically improved (20.0 vs 16.8 months; HR 0.84) but did not meet prespecified criteria for statistical significance at interim analysis. No new safety signals were observed (Janjigian YY et al., 2023).
Updated results, presented at the ESMO Congress 2024 and published in Annals of Oncology in 2024, confirmed a statistically significant improvement in overall survival with pembrolizumab plus trastuzumab and chemotherapy (HR 0.80).
KEYNOTE-859
The phase III KEYNOTE-859 trial evaluated pembrolizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment in patients with locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma.
Published in The Lancet Oncology in November 2023, the study demonstrated a significant and clinically meaningful improvement in overall survival with pembrolizumab plus chemotherapy compared with chemotherapy alone (HR 0.78). Median overall survival was 12.9 months versus 11.5 months in the intention-to-treat population, with greater benefit observed in PD-L1–positive subgroups (CPS ≥1: HR 0.74; CPS ≥10: HR 0.65). Progression-free survival and objective response rates were also improved, with a manageable safety profile.
Together with KEYNOTE-811, these results demonstrate that treatment selection in gastric cancer is defined by HER2 status and PD-L1 expression.
KEYNOTE-585
Perioperative immunotherapy is regimen-specific. KEYNOTE-585 evaluated perioperative pembrolizumab combined with chemotherapy in locally advanced, resectable gastric and gastroesophageal junction adenocarcinoma.
In the phase III trial, pembrolizumab plus FLOT increased pathologic complete response rates compared with chemotherapy alone (17.0% vs 6.8%). Event-free survival showed a numerical trend favoring pembrolizumab (HR 0.79), while no overall survival benefit was observed (HR 1.04). The regimen was feasible with no new safety concerns. (Al-Batran SE et al., 2024)
MATTERHORN
In contrast to KEYNOTE-585, MATTERHORN evaluated perioperative chemo-immunotherapy with durvalumab in locally advanced, resectable gastric and gastroesophageal junction adenocarcinoma.
In the phase III trial, the addition of durvalumab to FLOT significantly improved pathologic complete response rates compared with chemotherapy alone (19% vs 7%). Updated analyses demonstrated a significant improvement in event-free survival (HR 0.71), and final results confirmed an overall survival benefit (HR 0.78), with consistent benefit across biomarker subgroups. (Janjigian YY et al., 2024; updated 2025)
These data highlight that perioperative immunotherapy is not a class effect, but depends on regimen-specific efficacy.
Why Is Hepatocellular Carcinoma a Model of Combination Precision?
Hepatocellular carcinoma (HCC) reflects an immune environment shaped by chronic liver inflammation, cirrhosis, and angiogenic signaling.
IMbrave150
IMbrave150 established anti–PD-L1 plus anti-VEGF combination therapy in unresectable hepatocellular carcinoma.
In the phase III trial, atezolizumab plus bevacizumab significantly improved overall survival compared with sorafenib (HR 0.58), with higher 12-month overall survival rates (67.2% vs 54.6%). Progression-free survival was also prolonged (6.8 vs 4.3 months; HR 0.59), with improved response rates and no new or unexpected safety signals. (Finn RS et al., 2020)
A post hoc updated analysis confirmed sustained benefit with longer follow-up, including a median overall survival of 19.2 months versus 13.4 months with sorafenib. (Ann-Lii Cheng et al., 2022)
These results established combination strategies targeting both immune and angiogenic pathways as a standard approach in HCC.
HIMALAYA
HIMALAYA evaluated dual immune checkpoint blockade with tremelimumab plus durvalumab (STRIDE regimen) in unresectable hepatocellular carcinoma.
In the phase III trial, STRIDE significantly improved overall survival compared with sorafenib (HR 0.78), with a median overall survival of 16.4 months versus 13.8 months. Three-year overall survival rates were higher with STRIDE (30.7% vs 20.2%). Progression-free survival did not differ significantly between treatment groups. Durvalumab monotherapy was non-inferior to sorafenib for overall survival. (Abou-Alfa GK et al., 2022)
Together, these approaches demonstrate that different immunotherapy combinations can achieve survival benefits through distinct biological mechanisms.
Therapeutic selection in HCC is defined by clinical and hepatic phenotype.
● Child–Pugh liver function classification
● Portal hypertension status
● Bleeding risk and variceal assessment
● Transplant eligibility
● Performance status
How Does Colorectal Cancer Demonstrate Biological Divergence?
Colorectal cancer (CRC) shows marked divergence within Immunotherapy in GI Cancers.
MSI-H tumors exhibit deficient mismatch repair (dMMR), resulting in high tumor mutational burden and neoantigen formation.
KEYNOTE-177
KEYNOTE-177 established PD-1 blockade as first-line therapy in microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) metastatic colorectal cancer.
In the phase III trial, pembrolizumab significantly improved progression-free survival compared with chemotherapy (16.5 vs 8.2 months; HR 0.60). Objective response rates were higher with pembrolizumab (43.8% vs 33.1%), with more durable responses, as 83% of responders remained in response at 24 months. Treatment-related adverse events of grade 3 or higher were less frequent with pembrolizumab (22% vs 66%), while overall survival data were not mature at the time of analysis. (André T et al., 2020)
Updated 5-year results, presented at the ESMO Congress 2023 and published in Annals of Oncology in 2023, demonstrated sustained benefit with pembrolizumab, including a median overall survival of 77.5 months versus 36.7 months with chemotherapy (HR 0.73), and higher 5-year overall survival rates (54.8% vs 44.2%). Responses remained markedly durable, with a median duration of response of 75.4 months.
These findings confirm that MSI-H colorectal cancer represents a uniquely immunotherapy-sensitive population.
NICHE-2
NICHE-2 evaluated neoadjuvant dual immune checkpoint blockade with nivolumab plus ipilimumab in patients with non-metastatic mismatch repair–deficient (dMMR) colon cancer.
In this phase II study, treatment resulted in a pathologic response in 98% of patients, including a major pathologic response rate of 95% and a pathologic complete response rate of 68%. Treatment was well tolerated, with grade 3–4 immune-related adverse events in 4% of patients, and no disease recurrences were observed at a median follow-up of 26 months. (Chalabi M et al., 2024)
PD-1 blockade in dMMR rectal cancer evaluated single-agent dostarlimab in patients with locally advanced mismatch repair–deficient rectal adenocarcinoma.
In this phase II study, all 12 patients who completed treatment achieved a clinical complete response (100%), with no evidence of tumor on imaging, endoscopy, or biopsy. At a follow-up ranging from 6 to 25 months, no patients required chemoradiotherapy or surgery, and no cases of disease progression or recurrence were observed. No grade 3 or higher adverse events were reported. (Cercek A et al., 2022)
PD-1 blockade in dMMR rectal cancer supports nonoperative, organ-preserving approaches.
Across disease stages, these results demonstrate the potential for immunotherapy not only to improve outcomes, but also to enable treatment de-escalation.
Microsatellite stable (MSS) CRC remains largely resistant to single-agent checkpoint inhibition. Combination strategies are under investigation.
What Defines Precision in 2026?
Precision in Immunotherapy in GI Cancers is increasingly defined by biological alignment.
● Mandatory biomarker testing (PD-L1 CPS, MSI/MMR status, HER2)
● Durability prioritized over response rate
● Selective perioperative immunotherapy
● Phenotype-driven HCC treatment
● Organ preservation in molecularly defined rectal cancer
● MSS CRC as ongoing unmet need
Together, these principles highlight that immunotherapy is no longer universally applied, but guided by biological context and patient selection.
Takeaway
Immunotherapy in GI cancers is increasingly defined by tumor biology and patient selection. Across gastric, hepatocellular, and colorectal cancers, outcomes vary according to molecular subtype, immune context, and treatment strategy.
While durable responses and long-term survival are observed in selected populations, benefit is not uniform across all patients or disease settings. Current evidence supports a structured, biomarker-driven approach, with ongoing efforts focused on improving selection, optimizing combinations, and addressing resistance.
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Written by Maria Maddalena Laterza, MD, PhD
FAQ
What defines MSI-H in colorectal cancer?
MSI-H tumors exhibit deficient mismatch repair leading to high mutation burden and increased immunogenicity.
What is PD-L1 CPS?
Combined Positive Score measures PD-L1 expression in tumor and immune cells relative to total viable tumor cells.
Why does VEGF inhibition enhance immunotherapy?
VEGF promotes immune suppression and abnormal vasculature; inhibition improves T-cell infiltration.
Is perioperative immunotherapy a class effect?
Current data indicate regimen-specific benefit rather than universal effect.
Why is MSS colorectal cancer resistant?
MSS tumors demonstrate low neoantigen load and immune exclusion within the tumor microenvironment.