Advancements of immunotherapy in gastrointestinal cancers: a review of clinical evidence

Introduction

Over the past decades, immunotherapy has revolutionized oncology, with immune checkpoint inhibitors (ICIs) playing a pivotal role in transforming cancer treatment. Decades of research have revealed that some tumor cells evade immune detection by exploiting immune checkpoint proteins – natural brakes on T cells that prevent excessive immune activation. ICIs work by releasing these brakes, allowing the immune system to recognize and attack cancer cells more effectively.

The foundation of ICIs was laid in 1987 with the discovery of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Nearly a decade later, its immune checkpoint function was identified, leading to 16 years of preclinical and clinical research before the development of ipilimumab – the first CTLA-4 inhibitor⁽¹⁾. Approved in 2011, ipilimumab has become the first therapy to improve survival in metastatic melanoma, marking the beginning of a new era in cancer immunotherapy⁽²⁾. Inspired by this success, researchers developed ICIs targeting the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway, with pembrolizumab becoming the first such agent approved in 2014⁽³⁾. Since then, the FDA has approved 11 ICIs targeting CTLA-4, PD-1/PD-L1 or lymphocyte activation gene-3 (LAG-3) across multiple cancer types⁽⁴⁾. Moreover, beyond ICIs, therapeutic cancer vaccines are also an area of active research, given their potential to enhance anti-tumor immunity. These breakthroughs have led to remarkable and durable responses in some patients, even in advanced disease stages.

The effectiveness of ICIs is influenced by biomarkers such as PD-L1 expression, tumor mutation burden (TMB), and DNA repair deficiencies, including micro­satellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) status. Tumor-infiltrating lymphocytes (TILs) are also being explored as potential predictors of response. However, not all patients experience the same benefits, and ongoing research aims to refine patient selection criteria and optimize therapeutic strategies⁽⁵⁾. Additionally, ICIs can trigger immune-related adverse events (irAEs) due to immune system overstimulation, affecting organs such as the skin, colon, endocrine glands, liver, joints, and lungs. While most irAEs are ma­na­geable with corticosteroids and immunosuppressants, se­vere toxicities may necessitate treatment discontinua­tion. Identifying patients at higher risk for irAEs, parti­cu­larly those with preexisting autoimmune conditions, re­mains a key area of investigation⁽⁶⁾.

ICIs have rapidly expanded into gastrointestinal oncology, where they are beginning to reshape treatment paradigms. While traditional modalities such as chemotherapy, surgery, radiotherapy and targeted therapies re­main essential, immunotherapy is now recognized as a promising addition to the therapeutic arsenal for cer­tain digestive cancers. Ongoing research is refining our understanding of immune-modulating treatments, of­fe­ring hope for more effective and personalized strategies. Notably, Romania has recently implemented new reim­burse­ment policies to support access to innovative immunotherapies for digestive cancers, reflecting the growing importance of these treatments in clinical practice.

To explore the evolving role of immunotherapy, notably ICIs in digestive cancers, we conducted a systematic literature review of randomized phase II and III clinical trials published in the past eight years. This review aims to provide insights into the current landscape of immunotherapy in gastrointestinal malignancies, highlighting key advancements, challenges, and future directions.

Methodology

Search strategy

A systematic search was conducted on PubMed, on 1 February 2025, to identify randomized phase II and III clinical trials evaluating immunotherapy in gastrointestinal (GI) cancers. To ensure a comprehensive and structured approach, separate searches were performed for each cancer type, including gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, biliary tract cancer and hepatocarcinoma.

For each search, a combination of MeSH terms and keywords was used to capture relevant studies. The primary search terms included: (“immune checkpoint inhibitors” OR “immunotherapy”) AND (“[specific GI cancer]”). Additional filters included “randomized control trial” and “clinical trial”.

To refine the results, specific filters were applied. Only randomized comparative phase II and III clinical trials published in the last seven years were included. Additional restrictions were applied to limit results to English-language publications and exclude nonrandomized studies such as single-arm trials, retrospective analyses, case reports, and preclinical research.

In addition to PubMed, references from relevant systematic reviews were screened to identify any additional studies that met the inclusion criteria. The focus of this review was on trials that contributed to the new regulatory approvals of ICIs in Romania.

Results and discussion

1. Gastric and gastroesophageal junction (GEJ) cancers

Table 1 summarizes our findings on phase II and III clinical trials evaluating ICIs in gastric and GEJ cancers. We identified 16 randomized clinical trials, including 10 phase III trials (six in the first-line metastatic setting, three in later-line treatment, and one in the adjuvant setting) and six phase II trials (two in the perioperative/neoadjuvant setting, two in the adjuvant setting, and two in metastatic disease). The ICIs studied included nivolumab alone or in combination (five trials), nivolu­mab plus ipilimumab (two trials), pembrolizumab (five trials), tislelizumab (one trial), sintilimab (one trial), toripalimab (two trials), and atezolizumab (one trial).

First-line immunotherapy strategies

The CheckMate 649 study provided pivotal insights into nivolumab plus chemotherapy as a first-line treatment for advanced or metastatic gastroesophageal adenocarcinoma. With a three-year follow-up, this regimen demonstrated substantial improvements in overall survival (OS), progression-free survival (PFS) and objective response rate (ORR), particularly in patients with a combined positive score (CPS) ≥5. These findings underscore the importance of PD-L1 expression as a key predictor of response. The addition of nivolumab not only conferred a meaningful survival advantage, but also maintained an acceptable safety profile⁽⁷⁾. Notably, this combination has recently become reimbursed in Romania, expanding access to an important treatment option.

The KEYNOTE-062 trial initially explored pembrolizumab plus chemotherapy in the first-line setting, but it yielded mixed results. While the overall study was considered negative, subgroup analyses suggested greater benefit in patients with PD-L1 CPS ≥10. These findings were later confirmed by the KEYNOTE-859 trial, which demonstrated a significant overall survival improvement, ultimately leading to pembrolizumab’s approval in combination with chemotherapy for metastatic gastric and GEJ cancers^(8,9).

For HER2-positive unresectable or metastatic gastric/GEJ cancer, a phase III trial demonstrated that pem­bro­li­zumab plus trastuzumab and chemotherapy sig­ni­fi­cantly improved OS compared to trastuzumab and chemotherapy alone (median OS: 20 versus 16.8 months; HR 0.80; 95% CI; 0.67-0.94; p=0.0040). The be­ne­fit was even more pronounced in patients with PD-L1 CPS ≥1 (OS: 20.1 versus 15.7 months; HR 0.79; 95% CI; 0.66-0.95). These findings support the approval of this combination as the new standard of care (SOC) for HER2-positive metastatic gastric/GEJ cancer⁽¹⁰⁾.

Adjuvant immunotherapy strategies

In the adjuvant setting, a notable phase III trial evaluated nivolumab in patients with resected esophageal or gastroesophageal junction cancer who had previously undergone neoadjuvant chemoradiotherapy. The study found a significantly longer disease-free survival (DFS) with nivolumab compared to placebo (median DFS: 22.4 versus 11 months; HR 0.69; 95% CI; 0.56-0.86; p<0.001). These results highlight nivolumab’s role in reducing recurrence risk and prolonging survival in high-risk patients post-surgery⁽¹¹⁾.

Perioperative/neoadjuvant strategies

In the perioperative and neoadjuvant setting, emerging evidence supports the role of ICIs in combination with chemotherapy to enhance tumor regression. A phase II trial evaluating toripalimab plus chemotherapy demonstrated a significantly higher tumor regression grade (TRG) 0/1 in the combination group compared to chemotherapy alone (44.4% versus 20.4%; risk difference: 22.7%; p=0.009), meeting its prespecified endpoint. Additionally, the pathological complete response rate (ypT0N0) was also improved in the toripalimab arm⁽¹²⁾. Similarly, in the DANTE trial, the addition of atezolizumab (ATZ) to perioperative FLOT chemotherapy was safe and improved postoperative staging and histopathologic regression. Histopathologic complete regression rates (pCR or TRG1a) were higher with FLOT + ATZ (24% versus 15%; p=0.032), with an even more pronounced benefit in patients with PD-L1 CPS ≥10 (33% versus 12%) and MSI tumors (63% versus 27%)⁽¹³⁾. These findings highlight the potential of ICI-based perioperative approaches in improving tumor response, particularly in biomarker-selected populations.

2. Esophageal cancers

Our review identified eight clinical trials evaluating ICIs in esophageal cancers, including seven phase III trials and one phase II trial. Among these, one trial investigated adjuvant therapy, four trials focused on first-line treatment, and three evaluated later-line therapies. The ICIs studied included nivolumab (three trials, one in combination), pembrolizumab (two trials), camrelizumab (one trial), sintilimab (one trial), and toripalimab (one trial). Three trials included adenocarcinoma (ADK), while the remaining focused exclusively on squamous cell carcinoma (SCC).

Advanced/metastatic setting

For esophageal squamous cell carcinoma (ESCC), ICIs have emerged as highly effective treatment options. The CheckMate 648 trial established nivolumab plus chemotherapy (NIVO + chemo) and nivolumab plus ipilimumab (NIVO + IPI) as first-line treatment options for advanced ESCC, leading to their approval in the US, EU, Japan and other countries. Recently, Romania has also included these therapies in its reimbursement list. With a minimum follow-up of 45 months, both regimens demonstrated sustained OS benefits and improved long-term survival rates in patients with PD-L1 tumor cell expression ≥1%, without new safety concerns⁽²³⁾.

Nivolumab as a second-line therapy also demonstrated clinically meaningful long-term improvement in overall survival compared with chemotherapy in previously treated patients with advanced ESCC. In this setting, median OS was longer with nivolumab than with chemotherapy (10.9 versus 8.5 months; HR 0.79; p=0.0264), with three-year OS rates of 15.3% versus 8.7%, respectively. The OS benefit was consistent across different best overall response (BOR) categories: complete/partial response (19.9 versus 15.4 months), stable disease (17.4 versus 8.8 months), and progressive disease (7.6 versus 4.2 months)⁽²⁴⁾.

Another promising ICI for esophageal and gastroesophageal junction (GEJ) cancers is pembrolizumab. The KEYNOTE-590 trial demonstrated that pembrolizumab plus chemotherapy was superior to chemotherapy alone in first-line treatment, particularly in patients with PD-L1 CPS ≥10⁽²⁵⁾.

Adjuvant setting

In the adjuvant setting, nivolumab has also shown benefit. Among patients with resected esophageal or GEJ cancer who had previously received neoadjuvant chemoradiotherapy, adjuvant nivolumab significantly prolonged disease-free survival (DFS) compared to placebo. How­ever, grade 3 or 4 treatment-related adverse events occurred in 13% of nivolumab-treated patients versus 6% in the placebo group, leading to treatment discontinuation in 9% versus 3% of cases, respectively. These findings underscore the need to carefully balance efficacy and toxicity when considering adjuvant ICI therapy⁽²⁶⁾.

3. Hepatocellular carcinoma (HCC)

Our review identified nine clinical trials investigating ICIs in HCC, including eight phase III trials and one phase II trial. Among these, six trials focused on first-line therapy, two on second-line treatment, and one on the adjuvant setting. The ICIs evaluated were atezolizumab (two trials), camrelizumab (one trial), durvalumab (one trial), durvalumab + tremelimumab (one trial), pembrolizumab (three trials), nivolumab (one trial), and sintilimab (one trial).

First-line treatment

The IMbrave150 trial, a phase III study, enrolled 501 systemic treatment-naive patients with unresectable HCC, Child-Pugh class A liver function, and ECOG PS 0/1. The patients were randomized (2:1) to receive atezolizumab (1200 mg i.v. Q3W) + bevacizumab (15 mg/kg i.v. Q3W) versus sorafenib (400 mg b.i.d.) until unacceptable toxicity or loss of clinical benefit. Median OS was significantly improved with atezolizumab + bevacizumab (19.2 versus 13.4 months; HR 0.66; 95% CI; 0.52-0.85; p=0.0009)⁽³¹⁾. As a result, atezolizumab + bevacizumab is now established as a standard of care for previously untreated, unresectable HCC.

Other frontline options include camrelizumab plus rivoceranib, which significantly extended OS to 22.1 months versus 15.2 months with sorafenib (HR 0.62; p<0.0001)⁽³²⁾, and durvalumab plus tremelimumab, which showed a median OS of 16.43 months compared to 13.77 months with sorafenib⁽³³⁾. However, pembrolizumab and lenvatinib combination and nivolumab monotherapy did not demonstrate a survival benefit in this setting^(34,35).

4. Colorectal cancer (CRC)

A total of 13 clinical trials (five phase III trials and seven phase II trials) evaluated immunotherapy in CRC. These included two first-line studies for MSI-H/dMMR CRC, three studies in MSS CRC (two first-line, one later-line), and two neoadjuvant trials in rectal cancer. The ICIs assessed were pembrolizumab (three trials), atezolizumab (two), durvalumab-tremelimumab (one), nivolumab-ipilimumab (one), nivolumab (three), avelumab (one), toripalimab (one), and one phase III trial evaluating autologous PD-1 T-cell immunotherapy.

First-line MSI-H/dMMR

In the first-line treatment of MSI-H/dMMR metastatic colorectal cancer (mCRC), immunotherapy has shown significant efficacy over chemotherapy. Data from CheckMate 8HW confirmed that this combination improves progression-free survival (PFS) in the first-line setting for MSI-H/dMMR mCRC, offering a meaningful and statistically significant advantage over chemotherapy. With a median follow-up of 31.5 months (range: 6.1 to 48.4), progression-free survival was significantly improved in the nivolumab plus ipilimumab group compared to chemotherapy (p<0.001; two-sided stratified log-rank test). At 24 months, the PFS rate was 72% (95% CI; 64-79) with nivolumab plus ipilimumab, whereas it was only 14% (95% CI; 6-25) with chemotherapy⁽⁴⁰⁾. Similarly, the KEYNOTE-177 trial established pembrolizumab as a superior first-line option, showing a significantly longer PFS compared to chemotherapy (median 16.5 versus 8.2 months; HR 0.60; 95% CI; 0.45-0.80; p=0.0002), with the added benefit of fewer treatment-related adverse events⁽⁴¹⁾.

First-line MSS/pMMR

In the first-line treatment of MSS mCRC, the results with immune checkpoint inhibitors have been less promising. Two phase II trials evaluating avelumab with chemotherapy and nivolumab failed to demonstrate a significant PFS improvement in MSS CRC^(42,43). However, the AtezoTRIBE trial provided promising results, showing that the addition of atezolizumab to FOLFOXIRI plus bevacizumab led to a significant improvement in both PFS and overall survival (OS) in metastatic CRC, including patients with proficient mismatch repair (pMMR). In the pMMR cohort of 202 patients, the median overall survival was 30.8 months in the FOLFOXIRI plus bevacizumab and atezolizumab group, compared to 29.2 months in the FOLFOXIRI plus bevacizumab group (HR 0.80; 80% CI; 0.63-1.02; p=0.117). Additionally, a notable interaction between treatment group, tumor mutational burden (TMB), and Immunoscore IC was observed (pint = 0.043 and 0.092, respectively), suggesting that patients with TMB-high and Immunoscore IC-high tumors derived greater benefit from the addition of atezolizumab⁽⁴⁴⁾.

Neoadjuvant setting

In the neoadjuvant setting for rectal cancer, the TORCH trial evaluated immunotherapy in combination with chemoradiotherapy. Patients with clinical T3-4 and/or N+ rectal adenocarcinoma were randomized to re­ceive either short-course radiotherapy (SCRT) followed by six cycles of consolidation immunochemotherapy with toripalimab or an alternative sequencing with two cycles of induction immunochemotherapy followed by SCRT. The SCRT-first group had higher complete response rates (cCR: 43.5% versus 35.6%) and lower grade 3-4 thrombocytopenia (24.2% versus 33.9%), making it the preferred strategy for future trials⁽⁴⁵⁾. Additionally, pembrolizumab added to chemoradiotherapy as part of total neoadjuvant therapy was found to be safe, but the NAR score difference did not support further investigation of this approach⁽⁴⁶⁾.

5. Biliary tract cancer (BTC) and pancreatic cancer

A total of nine clinical trials have evaluated immune checkpoint inhibitors (ICIs) in BTC and pancreatic cancer, comprising three phase III and six phase II trials. Of these, five trials focused on BTC and four on pancreatic cancer. The ICIs assessed included pembrolizumab (n=2), durvalumab (n=1), atezolizumab (n=2), nivolumab (n=2), and ipilimumab (n=1). Additionally, three trials incorporated cancer vaccines (GVAX and Hep A).

Treatment in BTC

Two notable phase III trials, KEYNOTE-966 and TOPAZ-1, have evaluated the role of ICIs in BTC. In TOPAZ-1, durvalumab plus chemotherapy significantly improved overall survival (OS) and progression-free survival (PFS) compared to placebo plus chemotherapy. The hazard ratio (HR) for OS was 0.80 (95% CI; 0.66-0.97; p=0.021), with an estimated 24-month OS rate of 24.9% (95% CI; 17.9-32.5) for durvalumab versus 10.4% (95% CI; 4.7-18.8) for placebo. The HR for PFS was 0.75 (95% CI; 0.63-0.89; p=0.001)⁽⁵³⁾. In KEYNOTE-966, pembrolizumab plus chemotherapy demonstrated a median OS of 12.7 months (95% CI; 11.5-13.6) compared to 10.9 months (95% CI; 9.9-11.6) in the placebo group (HR 0.83; 95% CI; 0.72-0.95]; one-sided p=0.0034, significance threshold p=0.0200)⁽⁵⁴⁾.

Additionally, the IMbrave-151 trial evaluated the combination of atezolizumab and bevacizumab with cisplatin/gemcitabine in the first-line setting, showing modest improvements in PFS and a higher six-month PFS rate compared to atezolizumab/placebo/cisplatin/gemcitabine⁽⁵⁵⁾. In the second-line setting, a combination of atezolizumab with cobimetinib demonstrated some PFS benefit, though the results were not practice-changing⁽⁵⁶⁾.

Pancreatic cancer

In pancreatic ductal adenocarcinoma (PDAC), the impact of immune checkpoint inhibitors remains limited, with most patients deriving minimal or no clinical benefit. Trials evaluating cancer vaccines such as GVAX and HAPa failed to meet overall survival (OS) endpoints.

Overall, while immunotherapy has shown promising results in BTC, particularly in the first-line setting, its role in pancreatic cancer remains modest, necessitating further research to identify effective combinations and predictive biomarkers.

Conclusions

The integration of immune checkpoint inhibitors (ICIs) into the treatment landscape of gastrointestinal cancers has led to significant advancements, particularly in gastric, esophageal, colorectal, hepatocellular and biliary tract cancers. The efficacy of ICIs is largely biomarker-dependent, with PD-L1 expression, micro­satellite instability (MSI), and tumor mutation burden (TMB) serving as key predictors of response. Notably, MSI-high/dMMR colorectal cancer and PD-L1-positive gastroesophageal cancers have shown the most benefit, while microsatellite-stable (MSS) colorectal and pancreatic cancers remain resistant, necessitating alternative therapeutic strategies. Landmark trials such as CheckMate 649 and KEYNOTE-859 in gastric cancer, IMbrave150 in hepatocellular carcinoma and TOPAZ-1 in biliary tract cancer have established ICIs as essential components of treatment. Despite these successes, challenges remain, including immune-related toxicities, resistance mechanisms, and the need for combination approaches to improve efficacy in MSS tumors. With recent regulatory approvals expanding access in Romania, ongoing research is focused on refining patient selection, optimizing treatment combinations, and exploring novel immunotherapies to further improve outcomes in gastrointestinal malignancies.   

Corresponding author: Alexandra Pușcașu E-mail: puscasu.alexandra4@gmail.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.