Today we’re going to spotlight the new Society for Immunotherapy of Cancer (SITC) clinical practice guidelines on immunotherapy for the treatment of gastrointestinal cancer. These guidelines were originally published on June 07, 2023, but underwent a focused update on May 28, 2025. 

Links:

There were many important changes since the last version of the guidelines were published in June 2023, including the following FDA approvals for new or expanded indications:

  • Nivolumab in combination with ipilimumab for adult and pediatric patients 12 years of age and older with unresectable or metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer (April 2025)
  • Tislelizumab in combination with platinum and fluoropyrimidine-based chemotherapy for the first-line treatment of adult patients with unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (≥1) (December 2024)
  • Zolbetuximab-clab in combination with platinum and fluoropyrimidine-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma whose tumors are claudin 18.2 positive (October 2024)
  • Tislelizumab for the treatment of adult patients with unresectable or metastatic esophageal squamous cell carcinoma after prior systemic chemotherapy that did not include a PD-L1 inhibitor (March 2024)
  • Pembrolizumab with trastuzumab, fluoropyrimidine, and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma was restricted to patients with CPS greater than or equal to 1 (November 2023)
  • Pembrolizumab with fluoropyrimidine- and platinum-containing chemotherapy as first-line treatment for adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma (November 2023)
  • Pembrolizumab with gemcitabine and cisplatin for the treatment of locally advanced unresectable or metastatic biliary tract cancer (October 2023)

So without further ado, let’s jump into the highlights of the new gastrointestinal cancer immunotherapy guidelines from SITC, including key additions and changes for May 2025!

We’ll start off with the tissue-agnostic indications for immunotherapy in the treatment of GI cancer, specifically in the DNA polymerase epsilon and delta (POLE/POLD1) section:
  • The first recommendation was updated to include the statement “MSI can also be determined by PCR”; The full recommendation now reads, “For all patients with GI cancer, MSI/MMR status and TMB testing (for MSS/pMMR tumors) should be performed on tumor tissue in a CLIA-certified lab (LE:3). MSI status and TMB may be obtained by NGS. MSI can also be determined by PCR. MMR status may be obtained by IHC.”

Next, we’ll take a look at new and updated recommendations that were added in the esophageal/gastroesophageal junction/gastric cancer section:

  • Intrapatient biomarker heterogeneity sub-section:
    • “For patients with gastric or GEJ adenocarcinoma, CLDN 18.2 testing should be performed using a validated antibody (LE:2).”
  • Immunotherapy in the management of resectable upper GI cancer:
    • For patients with resectable gastric/GEJ adenocarcinoma that is dMMR/MSI-H, pre-operative ICIs should be considered in consultation with a multidisciplinary team (LE:2).
  • Immunotherapy for previously treated disease:
    • For patients with unresectable or metastatic ESCC following prior systemic chemotherapy that did not include a PD-1/PD-L1 inhibitor, tislelizumab is recommended (LE:2).
    • For patients with untreated, locally advanced unresectable or metastatic, HER2-negative, PD-L1 ≥1 gastric or GEJ adenocarcinoma, nivolumab, pembrolizumab, or tislelizumab with fluoropyrimidine- and platinum-containing chemotherapy is recommended (LE:2). For patients with locally advanced unresectable or metastatic HER2-negative, CLDN18.2-positive gastric or GEJ adenocarcinoma, zolbetuximab in combination with fluoropyrimidine- and platinum-containing chemotherapy is recommended (LE:2). There are no comparative data regarding the efficacy of zolbetuximab plus chemotherapy versus an ICI plus chemotherapy where both zolbetuximab and ICI therapy are indicated.
  • There was also an updated recommendation in this section:
    • The first recommendation was updated to specify “PD-L1 CPS ≥1”; The full recommendation now reads, “For patients with untreated, PD-L1 CPS ≥1, HER2-positive, advanced esophagogastric adenocarcinoma, chemotherapy plus trastuzumab plus pembrolizumab is recommended (LE:2).”

Now we’ll move on to the biliary tract cancers section, where we find two updated recommendations:

  • The option for pembrolizumab was added for patients with untreated, advanced BTC. The recommendation now reads, “For patients with untreated, advanced BTC, treatment with combination gemcitabine and cisplatin with durvalumab (LE:2) or pembrolizumab (LE:2) is recommended unless a contraindication to immunotherapy exists.”
  • For patients with treatment-refractory, immunotherapy-naïve, advanced MSS/pMMR BTC, rather than clinician trials alone, there are multiple therapies included as suggested approaches. The full recommendation reads “For patients with treatment-refractory, immunotherapy-naïve, advanced MSS/pMMR BTC, treatment with a clinical trial is preferred but the following are considered suitable if a trial is not available: a) lenvatinib plus pembrolizumab (LE:3) or nivolumab (LE:3), b) nivolumab plus ipilimumab (LE:3), or c) nivolumab (LE:3) or pembrolizumab (LE:3).”

Finally, we’ll cover two additional updated recommendations for colorectal and anal cancers

  • For patients with untreated, metastatic, MSI-H/dMMR CRC, any mention of superiority of one regiment versus another was removed. The recommendation now reads, “For patients with untreated, metastatic, MSI-H/dMMR CRC, pembrolizumab monotherapy (LE:2) or nivolumab plus ipilimumab (LE:2) are treatment options.”
  • The final recommendation in the guideline was slightly revised, and now reads, “For patients with MSI-H/dMMR resectable rectal cancer, phase II data from a single-center study of neoadjuvant ICI therapy suggest remarkable activity (LE:3). ICI as neoadjuvant or definitive therapy with non-operative management in consultation with a multidisciplinary team can be considered, but clinical trial participation is preferred.”

This concludes our hybrid guideline spotlight/guideline timeline on the new, May 2025, Society for Immunotherapy of Cancer guidelines for immunotherapy for the treatment of gastrointestinal cancer. We’ll see you next time! 


Check out other clinical guidelines and sign up for alerts to stay informed on the latest published guidelines and insights.

Copyright © 2025 Guideline Central, all rights reserved.