Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of gastrointestinal cancer

Abstract

Gastrointestinal (GI) cancers, including esophageal, gastroesophageal junction, gastric, duodenal and distal small bowel, biliary tract, pancreatic, colon, rectal, and anal cancer, comprise a heterogeneous group of malignancies that impose a significant global burden. Immunotherapy has transformed the treatment landscape for several GI cancers, offering some patients durable responses and prolonged survival. Specifically, immune checkpoint inhibitors (ICIs) directed against programmed cell death protein 1 (PD-1), either as monotherapies or in combination regimens, have gained tissue site-specific regulatory approvals for the treatment of metastatic disease and in the resectable setting. Indications for ICIs in GI cancer, however, have differing biomarker and histology requirements depending on the anatomic site of origin. Furthermore, ICIs are associated with unique toxicity profiles compared with other systemic treatments that have long been the mainstay for GI cancer, such as chemotherapy. With the goal of improving patient care by providing guidance to the oncology community, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of GI cancer. Drawing from published data and clinical experience, the expert panel developed evidence- and consensus-based recommendations for healthcare professionals using ICIs to treat GI cancers, with topics including biomarker testing, therapy selection, and patient education and quality of life considerations, among others.

Keywords: gastrointestinal neoplasms; guidelines as topic.

Figure 1

Advanced esophagogastric diagnostic testing and treatment algorithm. (A) Advanced esophageal squamous cell carcinoma. *ESCC is rarely reported as MSI-H/dMMR in global studies. However, the reported frequency of ESCC that is MSI-H/dMMR in studies of Asian patients is much higher. All patients who are chemotherapy eligible with advanced, MSI-H/dMMR ESCC should receive chemotherapy plus an anti-PD-1 inhibitor in the first line and should be considered for pembrolizumab monotherapy or dostarlimab monotherapy (for dMMR disease only) following progression of disease on a non-immunotherapy regimen. †Patients with advanced ESCC that is TMB-H (≥10 mut/Mb) may be considered for pembrolizumab monotherapy following progression of disease on a non-immunotherapy regimen. §For patients whose disease progresses on a regimen containing immunotherapy, consideration for clinical trial is preferred. If clinical trial enrollment is not feasible, then guidelines-directed subsequent therapy is recommended. ¶Although the FDA-approved frontline nivolumab+chemotherapy and pembrolizumab+chemotherapy for ESCC regardless of tumor PD-L1 expression, outcomes from CheckMate 648 and KEYNOTE-590 suggest that superiority compared with chemotherapy is most pronounced in patients with tumors with a TPS ≥1 or a CPS ≥10, respectively. (B) Advanced esophageal adenocarcinoma, GEJ, or gastric carcinomas. *Patients with tumors that are MSI-H/dMMR may be considered for pembrolizumab monotherapy or dostarlimab monotherapy (for dMMR disease only) following progression of disease on a non-immunotherapy regimen. Patients with tumors that are TMB-H (≥10 mut/Mb) may be considered for pembrolizumab monotherapy following progression of disease on a non-immunotherapy regimen. †For patients whose disease progresses on a regimen containing immunotherapy, consideration for clinical trial is preferred. If clinical trial enrollment is not feasible, then guidelines-directed subsequent therapy is recommended. §Although the FDA has approved nivolumab+chemotherapy for esophageal, GEJ, or gastric adenocarcinoma regardless of tumor PD-L1 expression, data from CheckMate 649 suggest that this benefit is driven by tumors with a CPS ≥5. Use of an ICI in combination with chemotherapy for patients with esophagogastric adenocarcinomas with CPS <5 may be considered on a case-by-case basis. CPS, combined positive score; dMMR, mismatch repair deficiency; ESCC, esophageal squamous cell carcinoma; FDA, Food and Drug Administration; GEJ, gastroesophageal junction; ICI, immune checkpoint inhibitor; MSI-H, high microsatellite instability; mut/Mb, mutations per megabase; NGS, next-generation sequencing; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; SCC, squamous cell carcinoma; TMB-H, high tumor mutational burden.

Figure 2

Advanced CRC testing and treatment algorithm. *Patients with tumors that are MSI-H/dMMR may be considered for pembrolizumab monotherapy or nivolumab with or without ipilimumab following progression of disease on a non-immunotherapy regimen. Dostarlimab monotherapy may be considered in this instance for dMMR disease only. †For patients whose disease progresses on a regimen containing immunotherapy, consideration for clinical trial is preferred. If clinical trial enrollment is not feasible, then guideline-directed subsequent therapy is recommended. ‡Patients with tumors with POLE/POLD1 mutations and associated ultramutated TMB may be considered for treatment with ICIs. While there are no widely accepted TMB cut-offs to define the ‘ultramutated’ phenotype, these tumors typically have TMB values well above 10 mut/Mb, with reports citing TMBs of 31 mut/Mb for POLE-mutated cancers with known genomic alterations and 122–303 mut/Mb for POLE-associated cancers. CRC, colorectal cancer; dMMR, mismatch repair deficiency; ICI, immune checkpoint inhibitor; MSI-H, high microsatellite instability; mut/Mb, mutations per megabase; NGS, next-generation sequencing; TMB-H, high tumor mutational burden.