Immunotherapy in the neoadjuvant treatment of gastrointestinal tumors - is the time ripe

Sep 21, 2026

Uploaded by Eliana

Immune checkpoint inhibitors (ICIs) have transformed care for mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) gastrointestinal cancers. Despite encouraging metastatic data, neoadjuvant approaches for localized dMMR/MSI-H disease show strong clinical and pathological responses, potentially reducing the need for chemotherapy, radiotherapy, and even surgical resection. Evidence remains limited, largely driven by small phase II proof-of-concept trials, and key questions persist.

LanguageEnglish

CategoryResearch & Report

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Pages14

Reading Time35 min

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Abstract

Introduction

Principle of immunotherapy

Open access Review Immunotherapy in the neoadjuvant treatment of gastrointestinal tumors: is the time ripe? Lorenzo Gervaso,1,2 Davide Ciardiello,1 Rivadavio Antunes Oliveira,3 Michele Borghesani,1 Lorenzo Guidi,4 Lavinia Benini,1 Laura Algeri,1 Francesca Spada,1 Maria Giulia Zampino,1 Chiara Alessandra Cella,1 Nicola Fazio1 To cite: Gervaso L, Ciardiello D, Oliveira RA, et al. Immunotherapy in the neoadjuvant treatment of gastrointestinal tumors: is the time ripe? Journal for ImmunoTherapy of Cancer 2024;12:e008027 . doi:10 . 1136/ jitc-2023-008027 Accepted 11 April 2024 © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. 1Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO IRCCS, European Institute of Oncology, Milano, Italy 2Molecular Medicine Program, University of Pavia, Pavia, Lombardia, Italy 3Clinical Oncology, Londrina Cancer Hospital, Londrina, Paranà, Brazil 4Division of New Drugs and Early Drug Development for Innovative Therapies, IEO IRCCS, European Institute of Oncology, Milano, Italy Correspondence to Dr Nicola Fazio; [nicola.fazio@ieo.it](nicola.fazio@ieo.it) ABSTRACT Immune checkpoint inhibitors (ICIs) revolutionized the management of mismatch repair-deficient (dMMR)/ microsatellite instability-high (MSI-H) gastrointestinal (GI) cancers. Based on notable results observed in the metastatic setting, several clinical trials investigated ICIsas neoadjuvant treatment (NAT) for localized dMMR/MSI-H GI cancers, achieving striking results in terms of clinical and pathological responses and creating the opportunity to spare patients from neoadjuvant chemotherapy and/ or radiotherapy and even surgical resection. Nevertheless, these impressive findings are mainly derived from small proof of concept phase II studies and there are still several open questions to address. Moreover, dMMR/MSI-H represents a limited subgroup accounting for less than 10% of GI cancers. Consequently, many efforts have been produced to investigate neoadjuvant ICIs also in mismatch repair-proficient/microsatellite stable (MSS) cancers, considering the potential synergistic effect in combining immune-targeted agents with standard therapies such as chemo and/or radiotherapy. However, results for combining ICIs to the standard of care in the unselected population are still unsatisfactory, without improvements in event-free survival in esophago-gastric adenocarcinoma for the addition of pembrolizumab to chemotherapy, and sometimes limited benefit in patients with locally advanced rectal cancer. Therefore, a major challenge will be to identify among the heterogenous spectrum of this disease, those patients that could take advantage of neoadjuvant immunotherapy and deliver the most effective treatment. In this review we discuss the rationale of NAT in GI malignancies, summarize the available evidence regarding the completed trials that evaluated this treatment strategy in both MSI-H and MSS tumors. Finally, we discuss ongoing studies and future perspectives to render neoadjuvant immunotherapy another arrow in the quiver for the treatment of locally advanced GI tumors. INTRODUCTION Over the last decades, immunotherapy, and specifically immune checkpoint inhibitors (ICIs), has become one of the pillars of cancer treatment, with increasing applications indifferent malignancies, both in palliative and in the curative setting. As for gastrointestinal (GI) cancers, including esophageal, gastric and colorectal, ICIs have been approved by Food and Drug Agency only in the metastatic setting, including pembrolizumab for firstline deficient mismatch repair (dMMR)/ microsatellite high (MSI-H) colorectal cancer (CRC), nivolumab +/− ipilimumab for secondline for dMMR/MSI-H CRC, nivolumab plus chemotherapy for first-line esophagogastric cancer (EGC), pembrolizumab for pretreated patients with programmed deathligand 1 (

FAQs

Why are immune checkpoint inhibitors considered important in GI cancer treatment?

ICIs have become a pillar of cancer therapy by modulating the immune system to recognize and eliminate tumor cells, with expanding applications across malignancies. In GI cancers, approval has largely focused on metastatic settings.

What has neoadjuvant immunotherapy shown for localized dMMR/MSI-H gastrointestinal tumors?

Clinical trials in the neoadjuvant setting have produced striking clinical and pathological responses. These results also suggest the possibility of sparing patients from neoadjuvant chemotherapy and/or radiotherapy, and even reducing the need for surgical resection.

What challenges remain for neoadjuvant ICIs in gastrointestinal cancers?

Many findings are derived from small phase II proof-of-concept studies, leaving multiple unanswered questions. For mismatch repair-proficient/microsatellite stable (MSS) cancers, outcomes in unselected populations have been less satisfactory, with limited improvements in event-free survival in specific settings.

Sep 21, 2026

Uploaded by Eliana