Expert panel composition

The guideline development group was multidisciplinary and balanced. Members were selected based on their expertise and experience in the field, including medical oncology, nursing, and patient advocacy, as well as other specialties as-needed to support recommendation development.

Conflict of interest management

Disclosures of all financial relationships that might result in actual, potential, or perceived conflicts of interest were individually reported prior to the onset of manuscript development as well as at all key decision points during manuscript development. Those with significant financial connections that may compromise the ability to fairly weigh evidence (either actual or perceived) were not eligible to participate in guideline development. Any non-disqualifying conflicts of interests among members of the SITC GI Cancer Immunotherapy Guideline Expert Panel were managed as outlined in SITC’s disclosure and conflict of interest resolution policies.

The financial support for the development of this guideline was provided solely by SITC. No commercial funding was received.

Recommendation development

Panel recommendations are based on literature evidence, where possible, and clinical experience, where appropriate. Literature searches in relevant databases were performed and publications were screened for inclusion in the evidence base for the guideline recommendations. Recommendations herein were developed based both on literature review and expert opinion presented during open communication and scientific debate. Subsequently, recommendations were refined through a modified Delphi process as described by the RAND/ University of California, Los Angelas (UCLA) Appropriateness Method, expert panel consensus discussions, and review and editing of manuscript drafts.

Evidence rating

The level of evidence (LE) for a given consensus recommendation is expressed in parentheses following the recommendation (eg, LE:1). Evidence supporting panel recommendations was graded according to the Oxford Centre for Evidence-Based Medicine (OCEBM) Levels of Evidence Working Group ‘The Oxford Levels of Evidence 2’.13 A summary of the OCEBM grading scale may be found in box 2.

External review

A draft of this CPG was made publicly available to provide an opportunity for stakeholders potentially affected by the guideline to review and comment on the content. All comments were evaluated by the expert panel and considered for inclusion into the final manuscript.

Tissue-agnostic biomarkers: high microsatellite instability/mismatch repair deficiency, tumor mutational burden, and POLE/POLD1 status

Tumor detection and eradication by the immune system relies, in large part, on expression of neoantigens, which may arise due to non-synonymous mutations in protein-coding genes. Therefore, the tumor mutational burden (TMB) is generally accepted as a surrogate measure for a tumor’s neoantigen load. Increased mutational load may arise due to genomic instability in cancer cells, including defects in one or more cell cycle checkpoints and/or DNA repair pathways. One specific phenotype of genomic instability in cancer, mismatch repair deficiency (dMMR), may lead to increased point mutation frequency as well as an amplification of short tandem repeats known as high microsatellite instability (MSI-H). MSI-H, dMMR, and high tumor mutational burden (TMB-H) are all approved as biomarkers for patient selection for treatment with ICIs, however, TMB should only be used in select circumstances. Available biomarkers that may be used to determine eligibility for ICI therapy are summarized in box 3.

The levels of tumor-infiltrating lymphocytes (TILs) and memory T cells have been observed to increase concomitantly with TMB in CRC14 and multiple other malignancies. While higher mutational load is associated with clinical benefit from immune checkpoint blockade for some cancers, it is not sufficient to fully predict response.15

Panel recommendations

• For all patients with a 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. MMR status may be obtained by IHC.

• TMB testing should be performed on tumor tissue. At the time of guideline writing, TMB assessment using ctDNA is strictly investigational and may overestimate mutational load (LE:4).

• At the time of guideline writing, PD-L1 expression is not a validated biomarker of response to ICIs for GI cancers outside of esophagogastric cancers (LE:3).

• For all patients with advanced GI cancer, tumor tissue evaluation by NGS is recommended, if feasible. NGS testing is particularly encouraged for tumors known to have actionable mutations or when results may determine clinical trial eligibility.

Diagnostic tests and biomarkers for upper GI cancers

Upper GI malignancies that are MSI-H/dMMR have demonstrated superior survival outcomes in response to ICIs in tissue-agnostic studies,7 and in subgroup analyses of registration trials enrolling all molecular subtypes.53 A post hoc analysis of patients with MSI-H gastric and GEJ cancer enrolled in KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 demonstrated a survival benefit for pembrolizumab with or without chemotherapy, regardless of line of treatment.63 Although all pretreated, unresectable or metastatic TMB-H gastric and esophageal cancers are included in the FDA tissue-agnostic indication for pembrolizumab monotherapy, neither cancer was among the 10 tumor types included in KEYNOTE-158.31 For more details on assays and indications based on MSI-H/dMMR and TMB-H, refer to the ‘Tissue-agnostic indications for immunotherapy in the treatment of GI cancer’ section.

Panel recommendations

• All patients with esophagogastric cancers should undergo tumor testing for PD-L1 expression (LE:2) and MSI-H/dMMR status (LE:3). TMB (LE:3) should also be considered. For patients with esophagogastric adenocarcinomas, tumor tissue should also be tested for HER2 expression (LE:2).

• For patients with esophagogastric cancers, PD-L1 expression testing should be performed using a validated antibody. At the time of writing, the 22C3 and 28-8 antibodies are both validated.

• For patients with esophagogastric adenocarcinoma, CPS is the most established scoring system used to quantify PD-L1 expression (LE:2). For ESCC, both CPS and TPS are valid approaches to determine eligibility for ICI therapy (LE:2).

• For patients with esophagogastric cancers, routine EBV testing is not currently recommended for ICI treatment determination.

Immunotherapy in the management of resectable upper GI cancer

Neoadjuvant chemotherapy and radiation have improved esophageal cancer survival outcomes following curative-intent esophagectomy,76 however, pathological complete response (pCR) rates following neoadjuvant therapy remain low and recurrence rates remain higher among those who do not achieve a pCR.77 The addition of adjuvant ICIs is becoming the new SOC for upper GI malignancies. In the double-blind CheckMate 577 phase III trial evaluating adjuvant nivolumab for resected (R0) stage II or III esophageal or GEJ cancer, 794 patients who had received neoadjuvant chemoradiation and had residual pathological disease at the time of esophagectomy were randomized 2 to 1 to nivolumab or placebo for up to 1 year.78 After a minimum follow-up of 14 months, median disease-free survival (DFS), the primary study end point, was significantly longer for the nivolumab group compared with the placebo group (22.4 vs 10.4 months; HR 0.67; 95% CI 0.55 to 0.81).78 This trend was observed across multiple subgroups, however, benefit seemed to be higher in tumors with a PD-L1 CPS ≥5 vs PD-L1 CPS <5 (HR 0.62 vs 0.89) in a post hoc analysis of DFS.79 Furthermore, the median distant metastases-free survival was 29.4 vs 16.6 months for the nivolumab group compared with the placebo group (HR 0.71; 95% CI 0.58 to 0.87). Median time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death (PFS2) was also improved for the nivolumab versus placebo group (not reached vs 32.1 months).80 Grade 3–4 treatment-related adverse events (TRAEs) were slightly higher in the nivolumab arm (14%) compared with the placebo arm (6%), however, there were no treatment-related deaths in either arm.

In May 2021, CheckMate 577 was the basis of the FDA approval for the use of adjuvant nivolumab for patients with completely resected esophageal/GEJ cancer who do not achieve a pCR following neoadjuvant chemoradiation. Adjuvant nivolumab plus ipilimumab versus chemotherapy is being evaluated for high risk (R1 or ypN1 to 3) resected esophageal, GEJ, and gastric cancer in the European Organisation for Research and Treatment of Cancer (EORTC) VESTIGE study, with results pending at the time of manuscript publication.81 Other studies are evaluating the efficacy and safety of perioperative ICI strategies, including the phase III KEYNOTE-585 study of neoadjuvant plus adjuvant pembrolizumab or placebo plus chemotherapy for GEJ and gastric cancer.82

Panel recommendations

• For all patients with resectable esophagogastric cancers, clinical trial enrollment should be considered at all stages of treatment, when feasible.

• For patients with resected (R0) stage II or III esophageal or GEJ cancers who received neoadjuvant CRT and have residual pathological disease, adjuvant nivolumab is a SOC option (LE:2).

Immunotherapy in the management of unresectable/metastatic upper GI cancer

ICIs, specifically anti-PD-1-based regimens, are approved as upfront treatments as well as subsequent-line options for esophagogastric cancers. Data supporting FDA approvals are summarized in this manuscript and an algorithm to support clinical decision-making for the treatment of stage IV esophagogastric cancers is provided in figure 1.

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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.226 However, the reported frequency of ESCC that is MSI-H/dMMR in studies of Asian patients is much higher.227 228 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.

Panel recommendations

• For all patients with advanced esophagogastric cancers, clinical trial enrollment should be considered at all stages of treatment, when feasible.

• For patients with untreated, advanced, MSS/pMMR esophagogastric cancers, single-agent ICIs are not recommended. Single-agent anti-PD-1 therapy may be an option for patients with untreated, advanced, MSI-H/dMMR esophagogastric cancers who are not eligible for chemotherapy (LE:3).

• For patients with untreated, advanced, TPS ≥1 ESCC, nivolumab in combination with fluoropyrimidine-based and platinum-based chemotherapy is a preferred SOC option (LE:2).

• For patients with untreated, advanced, CPS ≥10 ESCC, chemotherapy plus pembrolizumab is a preferred SOC option (LE:2).

• For patients with untreated, advanced, TPS ≥1 ESCC, nivolumab in combination with ipilimumab is also an approved option (LE:2).

• For patients with untreated, advanced, CPS ≥10, HER2-negative esophageal or Siewert type I GEJ adenocarcinoma, chemotherapy plus pembrolizumab is a SOC option (LE:2).

• For patients with untreated, advanced, HER2-negative esophageal/GEJ/gastric adenocarcinomas with CPS ≥5 or that are MSI-H/dMMR, chemotherapy plus nivolumab is a SOC option (LE:2).

• For patients with untreated, HER2-positive, advanced esophagogastric adenocarcinoma, chemotherapy plus trastuzumab plus pembrolizumab is recommended (LE:2).

Emerging data on immunotherapies for the treatment of esophageal, GEJ, and gastric cancer

The following studies are discussed because of their potential to be impactful, however, at the time of manuscript publication, FDA evaluation was ongoing for all of these ICIs, and these data should not be used to guide treatment decisions outside of a clinical trial or forthcoming FDA approval.

Although the role of neoadjuvant or potentially even definitive immunotherapy for the treatment of resectable, MSI-H/dMMR gastric cancer was still an area of ongoing investigation at the time of this guideline’s publication, emerging data will determine the optimal treatment strategy for these patients. A retrospective meta-analysis of several trials of resectable gastric cancer demonstrated no benefit for the addition of perioperative chemotherapy to surgery for patients with MSI-H, resectable gastric cancer.93 In the randomized, phase IIb DANTE study of patients with resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N+), the addition of perioperative atezolizumab to 5-FU-leucovorin-oxaliplatin-docetaxel (FLOT) chemotherapy increased pathological regression rates for the 25 enrolled patients with MSI-H tumors.94 Results of the phase III MATTERHORN study (NCT04592913) of the addition of perioperative durvalumab to FLOT chemotherapy for patients with stage II or higher, resectable gastric or GEJ adenocarcinoma were pending at the time of publication.95 In cohort 1 of the phase II INFINITY trial, 9 of 15 (60%) patients with MSI-H/dMMR resectable cT2-4 and N gastric or GEJ adenocarcinoma who received neoadjuvant durvalumab plus tremelimumab followed by resection achieved a pCR.96 The phase II GERCOR/NEONIPIGA study is evaluating the efficacy of neoadjuvant nivolumab plus ipilimumab, followed by adjuvant nivolumab (for Becker tumor regression grade [TRG] <3), in patients with resectable, MSI-H/dMMR, T2–T4 NxM0 gastric and esophagogastric adenocarcinoma.97 With a median follow-up of 14.9 months, 29 of the 32 participants had undergone surgery with a pCR (pathological T0N0) rate of 58.6%, postoperative morbidity of 55% (Clavien-Dindo classification), and one postoperative death occurred due to a cardiovascular adverse event. Of the three patients who did not undergo resection, two refused surgery and had CR on endoscopic biopsy, and one had metastatic progression of disease prior to surgery. At the time of data lock, no patients had relapsed and one patient had died without relapse.98

Several ongoing studies are evaluating first-line ICI strategies for unresectable esophagogastric cancers as well. Many of these studies include anti-PD-1 ICIs developed in regions outside the US, most predominantly in Asia. The expected benefit of adding an anti-PD-1 agent to chemotherapy in the first line has been maintained with these newer agents, with one agent demonstrating activity as a monotherapy in the second line. If and how these emerging anti-PD-1 agents will be integrated into the SOC in the US and other regions remains to be determined.

ESCORT-1st is a phase III trial randomizing 596 patients with advanced, untreated ESCC recruited from 60 hospitals in China to receive chemotherapy (paclitaxel plus cisplatin) with or without the PD-1 inhibitor camrelizumab.8 The addition of camrelizumab in the first line improved median OS (HR 0.70; 95% CI 0.56 to 0.88; one-sided p=0.001) as well as median PFS (HR 0.56; 95% CI 0.46 to 0.68; one-sided p<0.001). In another study from China, the phase III JUPITER-06 trial, 514 patients with advanced ESCC were randomized to receive chemotherapy (paclitaxel plus cisplatin) with or without the anti-PD-1 toripalimab.99 Again, the addition of toripalimab to chemotherapy in the front line resulted in a significant improvement in OS (17.0 vs 11.0 months; HR 0.58; 95% CI 0.43 to 0.78; p=0.00037) and PFS (HR 0.58; 95% CI 0.46 to 0.74; p<0.00001), with these survival benefits maintained across PD-L1 expression subgroups.

The PD-1 inhibitor sintilimab is being evaluated in combination with chemotherapy (cisplatin plus either paclitaxel or 5-FU) as first-line therapy for advanced ESCC in the ORIENT 15 study, a global, phase III trial (NCT03748134) with 659 patients enrolled at the time of interim analysis.100 Primary study end points will be OS in the randomized population and for patients with PD-L1-positive (CPS ≥10) tumors. Another trial evaluating sintilimab, the phase III ORIENT 16 study, has randomized 650 Chinese patients with advanced gastric and GEJ adenocarcinoma to receive first-line chemotherapy (oxaliplatin plus capecitabine) with or without sintilimab.101 At interim analysis, it was announced that ORIENT 16 had met its primary end point of improved OS in both the intention-to-treat (ITT) and PD-L1-positive subgroups.102

Tislelizumab, an anti-PD-1 antibody that binds with higher affinity than pembrolizumab and is engineered for reduced Fc gamma receptor affinity, was studied in the first-line setting in the global RATIONALE 305 study, which enrolled patients with previously untreated, unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma.103 After a median follow-up of 11.8 and 11.7 months for the tislelizumab plus chemotherapy and placebo plus chemotherapy arms, respectively, the addition of tislelizumab provided a significant median OS improvement (17.2 vs 12.6 months; HR 0.74; 95% CI 0.59 to 0.94; one-sided p=0.0056) for 546 PD-L1-positive patients (primary end point). The tislelizumab arm also achieved a longer median PFS, higher ORR, longer median DOR, and improved health-related quality of life (HRQOL) with no new safety signals.

Tislelizumab has also demonstrated improved OS compared with investigator’s choice chemotherapy when administered as a second-line monotherapy in the global phase III RATIONALE 302 study, which enrolled 512 patients with ESCC.104 With a median follow-up of 8.5 months for the tislelizumab arm and 5.8 months for investigator’s choice chemotherapy arm, the median OS was significantly greater for the tislelizumab arm in the ITT population at 8.6 vs 6.3 months (HR 0.70; 95% CI 0.57 to 0.85; p=0.0001). Even greater benefit was observed in the CPS ≥10 subgroup, with median OS of 10.3 vs 6.8 months (HR 0.54; 95% CI 0.36 to 0.79; p=0.0006). In the ITT population, tislelizumab was also associated with an improved ORR (20.3% vs 9.8%), more durable responses (median DOR 7.1 vs 4.0 months; HR 0.42; 95% CI 0.23 to 0.75), and fewer grade ≥3 TRAEs (19% vs 56%) compared with investigator’s choice chemotherapy.

Emerging data on immunotherapy for the treatment of BTC

Based on TOPAZ-1, there is now an FDA-approved frontline immunotherapeutic treatment option for BTC.5 Other prospective studies of immunotherapy in the frontline treatment of BTC were ongoing at the time of guideline publication, including the phase III KEYNOTE-966 study (NCT04003636) evaluating patients with advanced, treatment-naïve BTC,125 which demonstrated a statistically significant improvement in OS with the addition of pembrolizumab to gemcitabine plus cisplatin. Nivolumab in combination with gemcitabine plus cisplatin was compared with nivolumab plus ipilimumab in the phase II BilT-01 trial, which enrolled 71 patients with advanced, untreated BTC.126 The 6-month PFS rates were 70% for the nivolumab plus chemotherapy arm and 18.6% in the dual immunotherapy arm. Median PFS was 8.8 and 4.1 months in the immunotherapy plus chemotherapy and dual immunotherapy arms, respectively. OS data were maturing at the time of manuscript preparation. An open-label, single-center phase II trial including 121 patients with chemotherapy-naïve, advanced BTC demonstrated efficacy and tolerable safety of gemcitabine plus cisplatin plus durvalumab with or without the anti-CTLA-4 ICI tremelimumab and described markers of response in a dedicated biomarker cohort.124 The ORRs for gemcitabine plus cisplatin plus durvalumab (n=47 evaluable patients) and gemcitabine plus cisplatin plus durvalumab plus tremelimumab (n=47 evaluable patients), were 72% and 70%, respectively.127 Finally, the randomized, placebo-controlled phase II IMbrave 151 study of treatment-naïve patients with advanced BTC demonstrated a numerically higher but not statistically significant improvement in median PFS (primary end point) with the addition of bevacizumab to atezolizumab plus gemcitabine plus cisplatin (8.3 vs 7.9 months; HR 0.76; 95% CI 0.51 to 1.14).128 And although the ORRs were similar between the two arms (24.1% vs 25.3%), the addition of bevacizumab prolonged the DOR with 88.5% vs 47.4% of responders having a response lasting at least 6 months in the bevacizumab versus placebo arms, respectively.

Several studies are also exploring ICIs to address the unmet need for second-line treatment of MSS/pMMR BTC following progression on first-line chemotherapy. However, given the FDA approval for frontline durvalumab plus chemotherapy based on TOPAZ-1, the future generalizability of these studies may be limited as fewer patients will receive chemotherapy alone as first-line treatment. A phase II study that enrolled 54 patients (46 of whom were evaluated for an objective response with imaging) with advanced, pretreated BTC for treatment with nivolumab monotherapy129 demonstrated an investigator-assessed ORR of 22% with a DCR of 59%. All of the responders had pMMR disease. The median PFS in the ITT population was 3.68 months and higher tumor PD-L1 expression was associated with improved PFS (HR 0.23; 95% CI 0.10 to 0.51; p<0.001 with PD-L1 cut-off ≥1%; HR 0.37; 95% CI 0.17 to 0.84); p=0.02 with PD-L1 cut-off >10%). A subgroup analysis of 39 patients with previously treated, advanced MSS BTC from the non-randomized phase II CA209-538 study demonstrated an ORR of 23% and a DCR of 44% with nivolumab plus ipilimumab treatment.130 The median PFS was 2.9 months and the median DOR was not reached.

In the open-label, multicohort, non-randomized phase II LEAP-005 study evaluating the anti-angiogenic multikinase inhibitor lenvatinib combined with pembrolizumab for patients with pretreated solid tumors, 31 patients were enrolled in the BTC cohort.131 With a median follow-up of 9.5 months, the ORR was 10% while the DCR was 68%. Median DOR was 5.3 months, median PFS was 6.1 months, and median OS was 8.6 months. A total of 48% of patients experienced a grade ≥3 TRAE. There were no treatment-related deaths. The most frequent TRAE was hypertension (42%). Enrollment into the BTC cohort of LEAP-005 has been expanded to 100 patients based on these results. Another single-arm study evaluating lenvatinib plus pembrolizumab in 32 patients with previously treated, advanced BTC in China demonstrated an ORR of 25% and a DCR of 78.1%, with a median PFS and OS of 4.9 and 11.0 months, respectively.132

The combination of the anti-PD-L1 atezolizumab with the MEK inhibitor cobimetinib met its primary end point of PFS (median PFS 3.65 months for combination vs 1.87 months for atezolizumab monotherapy; HR 0.58; 90% CI 0.35 to 0.93; one-tail p=0.027) in patients with pretreated, metastatic BTC.133 The combination of atezolizumab and the anti-CD27 antibody varlilumab with or without cobimetinib is now being evaluated for previously treated, unresectable BTC (NCT04941287).

Panel recommendations

• For all patients with SBA, PDAC, and BTC, clinical trial enrollment should be considered at all stages of treatment, when feasible.

• For patients with previously treated, advanced MSI-H/dMMR SBA, PDAC, or BTC, pembrolizumab monotherapy is a recommended treatment option (LE:3) and dostarlimab monotherapy is a recommended treatment option for dMMR tumors only (LE:3).

• For patients with previously treated TMB-H (≥10 mut/Mb) SBA, PDAC, or BTC, anti-PD-1 ICI monotherapy may be considered if no other treatment options are available (LE:3); however, at the time of guideline publication, there were insufficient data on efficacy in these tumor types.

• For patients with MSS/pMMR, TMB-L (<10 mut/Mb) SBA or PDAC, ICIs should not be used outside of a clinical trial (LE:3).

• For patients with untreated, advanced BTC, treatment with combination gemcitabine/cisplatin/durvalumab (LE:2) is recommended (LE:2) unless a contraindication to immunotherapy exists.

• For patients with treatment-refractory, immunotherapy-naïve, advanced MSS/pMMR BTC, treatment with combination lenvatinib plus pembrolizumab (LE:3) or nivolumab with (LE:3) or without (LE:3) ipilimumab may be considered if a suitable clinical trial is not available.

Diagnostic tests and biomarkers for immunotherapy for colorectal and anal cancer

Many disease features and biomarkers are used to guide treatment of advanced CRC and SCCA and recommendations on non-immunotherapy-specific diagnostics may be found in other published guidelines.138 139 MSI-H/dMMR (CRC and SCCA) or a pathogenic POLE/POLD1 mutation with an associated ultramutated TMB (CRC) are the only biomarkers that can determine eligibility for ICI use in lower GI tract tumors. Importantly, PD-L1 expression status does not predict response to immunotherapy for CRC.7 140 While there may be some correlation between PD-L1 expression and response to ICIs for advanced SCCA (discussed in the ‘Immunotherapy for the treatment of colorectal and anal cancer’ section), these data are based on small studies. As such, PD-L1 expression should not be used to inform treatment decisions for either CRC or SCCA. Distinct from the tissue-agnostic indications for these biomarkers, patients with MSI-H/dMMR CRC are eligible for first-line treatment with ICIs. Although dMMR is characteristic of Lynch syndrome (formerly known as hereditary non-polyposis CRC), it can also be found in about 15% of sporadic cases of CRC,141 and all patients with newly diagnosed CRC should be considered for MSI or MMR testing.

Although MSI is a common driver of high mutational burden in CRC, at least 4% of TMB-H tumors are MSS/MSI-L45 and around 1%–2% of MSS tumors have an ultramutated TMB.45 Pathogenic POLE/POLD1 mutations resulting in an ‘ultramutated’ tumor phenotype are another driver of high mutational burden and, although reports vary, may occur with a relatively high frequency in CRC (7.4%).46 As pathogenic POLE/POLD1 mutations are associated with an excellent response to ICI therapy, even in the absence of MSI, patients with advanced MSS/pMMR CRC should be considered for POLE/POLD1 mutation testing in the absence of other indications for immunotherapy.47 See the ‘Tissue-agnostic biomarkers: high microsatellite instability/mismatch repair deficiency, tumor mutational burden, and POLE/POLD1 status’ section for further discussion of this biomarker.

Patients with CRC were well-represented in the studies leading to tissue-agnostic approvals of ICIs based on dMMR and/or MSI-H.142 However, no patients with CRC were included in the KEYNOTE-158 study that led to the TMB-H indication for pembrolizumab and only 21 patients with CRC were included in the MyPathway study. Emerging evidence suggests that the etiology of a tumor’s hypermutated state may influence response to checkpoint blockade. A single-institution retrospective analysis that included 137 patients with advanced CRC who were treated with ICIs found that although OS was longer for patients whose tumors were TMB-H compared with TMB low (HR 0.40; 95% CI 0.24 to 0.65), this survival benefit disappeared if patients were stratified by mismatch repair or POLE/POLD1 pathogenic mutation status (HR 1.17; 95% CI 0.59 to 2.32).143 Furthermore, the ORRs for the patients with anal cancer in KEYNOTE-158 were similar regardless of TMB status (11% for TMB low [n=75] vs 7% for TMB-H [n=14]). The data from KEYNOTE-158 and the MyPathway study are not adequate to support the use of ICI monotherapy for pretreated MSS/pMMR CRC or SCCA based on TMB elevation in the absence of a known driver such as MSI or a pathogenic POLE/POLD1 mutation. Further discussion of the KENOTE-158 and MyPathway data, along with assay considerations for evaluation of TMB, MSI and MMR status, may be found in the ‘Tissue-agnostic indications for immunotherapy in the treatment of gastrointestinal cancer’ section.

Panel recommendations

• All patients with metastatic CRC should have tumor tissue evaluated by NGS.

• For all patients with CRC and SCCA, PD-L1 expression does not currently inform treatment decisions for ICIs.

• For patients with CRC, MSI/MMR status (LE:2) and a POLE/POLD1 mutation with an associated ultramutated TMB (LE:3) are the primary biomarkers that should be used to inform ICI treatment decisions.

Immunotherapy for the treatment of colorectal cancer

CRC that is MSS/pMMR does not generally respond to anti-PD-(L)1 antibodies, regardless of PD-L1 expression.7 Although numerous strategies using immunotherapy to treat MSS/pMMR CRC are being explored, none of these studies have led to FDA approvals, and immunotherapy should not be used in this setting outside of a clinical trial (except for POLE/POLD1 mutated CRC with an associated ultramutated TMB). While some patients with MSI-H/dMMR CRC benefit from ICI therapy in the first and subsequent lines, a proportion of these patients will have primary or secondary resistance to immunotherapy and further studies are needed to identify additional biomarkers of response.

Initial trials of immunotherapy for advanced MSI-H/dMMR CRC were performed in the setting of pretreated disease. In the phase II KEYNOTE-164 study of 124 patients with metastatic, MSI-H/dMMR CRC, pembrolizumab monotherapy was associated with an ORR of 33% (as measured by RECIST v1.1) for patients who had received at least one prior line of treatment or two or more previous lines including fluoropyrimidine, oxaliplatin, and irinotecan.144 The median PFS was 2.3 months for patients with two or more prior lines of treatment and 4.1 months for patients with one or more prior lines of treatment. Median OS was 31.4 months (median follow-up 31.3 months) for patients with two or more prior lines of treatment and not reached (median follow-up 24.2 months) for patients with one or more prior lines of treatment. In May 2017, KEYNOTE-164 was one of five studies leading to the first tissue-agnostic FDA approval of pembrolizumab for the treatment of unresectable or metastatic, MSI-H/dMMR cancers that have progressed on prior therapy with no satisfactory alternative treatment options. The indication was extended specifically to MSI-H/dMMR CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.16

Nivolumab monotherapy was evaluated in the treatment of patients with metastatic, pretreated, MSI-H/dMMR CRC in one arm of the phase II CheckMate 142 study. Among the 74 enrolled patients, most (54.1%) had received three or more prior lines of therapy.145 With a median follow-up time of 12.0 months, the investigator-assessed ORR was 31.1%, with 68.9% of patients achieving disease control for ≥12 weeks and 34.8% maintaining a response for ≥12 months. The OS rates at 9 and 12 months were 78% and 73%, respectively. This cohort of CheckMate 142 led to the accelerated approval of nivolumab in July 2017 for the treatment of metastatic, MSI-H/dMMR CRC that has progressed following fluoropyrimidine, oxaliplatin, and irinotecan treatment.

In a separate cohort of CheckMate 142, 119 patients with pretreated, metastatic, MSI-H/dMMR CRC received nivolumab with four doses of ipilimumab.4 With a median follow-up time of 13.4 months, the investigator-assessed ORR was 55%, with 80% of patients achieving disease control for ≥12 weeks. PFS rates at 9 and 12 months were 76% and 71%, respectively, with OS rates at 9 and 12 months of 87% and 85%, respectively. Notably, 82 of the 119 patients in this study arm had received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan, and the ORR for this subgroup was 46%, with 89% of patients still responding to treatment at 6 months.146 For the 58 patients pretreated with fluoropyrimidine, oxaliplatin, and irinotecan in the nivolumab monotherapy arm of Checkmate 142, the ORR was 28% with 67% of these patients maintaining a response at ≥6 months.146 147 Formal statistical comparisons between cohorts were not performed. Accelerated approval of nivolumab plus ipilimumab for the treatment of metastatic, MSI-H/dMMR CRC that has progressed following fluoropyrimidine, oxaliplatin, and irinotecan treatment was granted in July 2018 based on the 82 heavily pretreated patients in this cohort, and this combination is recommended in the second line.

Most recently, in August 2021, the FDA granted accelerated approval for use of dostarlimab-gxly for pretreated, recurrent/advanced, dMMR tumors. This approval was based on data from the ongoing phase I GARNET study, which evaluated 106 patients with pretreated (or prior treatment intolerant) dMMR non-endometrial solid tumors.111 The ORR as assessed by RECIST v1.1 was 38.7% for the overall cohort, which included 69 patients with CRC, with median DOR not yet reached after a median follow-up time of 12.4 months.

ICIs have demonstrated safety and efficacy in patients with MSI-H/dMMR CRC following progression of disease on chemotherapy. However, data supporting the use of dual immune checkpoint blockade with nivolumab plus ipilimumab following disease progression on single agent anti-PD-(L)1 therapy for this disease are limited. Case studies148 149 and a small case series150 have described patients with advanced, MSI-H/dMMR CRC who achieved a response to dual checkpoint blockade following anti-PD-(L)1 monotherapy. However, at the time of manuscript writing, prospective data to support the use of nivolumab plus ipilimumab to treat advanced, MSI-H/dMMR CRC that has progressed on a prior line of ICI therapy were lacking.

Pembrolizumab monotherapy for the first-line treatment of unresectable or metastatic MSI-H/dMMR CRC (regardless of PD-L1 expression) was approved by the FDA in June 2020. Approval was based on the phase III open-label KEYNOTE-177 trial, in which 307 patients with advanced, untreated MSI-H/dMMR CRC were randomized 1:1 to receive either pembrolizumab monotherapy or SOC chemotherapy (with or without bevacizumab or cetuximab).3 At second interim analysis, with a median follow-up of 32.4 months, the pembrolizumab arm met the co-primary PFS end point with significant improvement compared with chemotherapy (median PFS 16.5 vs 8.2 months; HR 0.60; 95% CI 0.45 to 0.80; p=0.0002). Additionally, the radiographic ORR was 43.8% (including a 17% CR rate) and 33.1% (including a 6% CR rate) for the pembrolizumab and chemotherapy arms, respectively. At time of final analysis 12 months later, OS (the second co-primary end point) demonstrated a trend toward reduced risk of death for the pembrolizumab arm (HR 0.74; 95% CI 0.53 to 1.03; p=0.0359), however, the difference was not statistically significant according to the prespecified alpha of 0.0246 (one-sided). Potentially confounding the analysis was a high crossover rate with 60% of participants in the ITT population receiving subsequent anti-PD-(L)1 therapies.151 Although nivolumab monotherapy does not have a corresponding FDA indication for the treatment of metastatic, untreated, MSI-H/dMMR CRC, data from an arm of the phase II CheckMate 142 study evaluating nivolumab plus ipilimumab in the first-line setting for metastatic, MSI-H/dMMR have demonstrated promising results.152 For the 45 patients treated with nivolumab plus ipilimumab who were followed for a median of 29.0 months in CheckMate 142, the ORR was 69% (including a 13% CR rate) and the DCR was 84%. With a minimum follow-up of 24.2 months, neither median PFS nor median OS were reached. The confirmatory, randomized phase III CheckMate 8HW study (NCT04008030), designed to compare the efficacy and safety of nivolumab plus ipilimumab versus chemotherapy or nivolumab monotherapy in patients with MSI-H/dMMR metastatic CRC is ongoing. Pending results from CheckMate 8HW, however, the phase III data supporting pembrolizumab monotherapy in the frontline setting for MSI-H/dMMR CRC are more robust than the phase II data for nivolumab plus ipilimumab.

While the efficacy of ICI therapy has been well-established in both the first and subsequent lines of treatment for advanced, MSI-H/dMMR CRC, there have been no head-to-head trials comparing anti-PD-1 monotherapy with combination ICI therapy (eg, nivolumab plus ipilimumab). For example, anecdotal comparisons of ORR and DCR from separate cohorts of CheckMate 142 suggest that nivolumab plus ipilimumab is more effective than nivolumab monotherapy for pretreated, advanced MSI-H/dMMR CRC, including for patients pretreated with a fluoropyrimidine, oxaliplatin, and irinotecan.4 145 146 An indirect, interstudy web-based statistical comparison suggested a small (1 month) restricted mean survival time benefit of nivolumab plus ipilimumab versus pembrolizumab monotherapy for pretreated, advanced MSI-H/dMMR CRC.153 Long-term follow-up has demonstrated that responses to nivolumab plus ipilimumab were durable, with 4-year OS rates of 93% (95% CI 82% to 97%) in patients with CR/PR, 66% (95% CI 49% to 78%) in patients with SD, and 71% (95% CI 61% to 78%) overall.154

Emerging data on immunotherapy for the treatment of colorectal cancer

The phase III, multicenter COMMIT study (NCT02997228) is evaluating the efficacy of chemotherapy plus bevacizumab with or without atezolizumab and atezolizumab monotherapy for patients with metastatic, MSI-H/dMMR CRC. Other studies are evaluating ICI therapy in the resectable and metastatic settings for tumors both deficient and proficient in MMR. Clinical trial enrollment should be considered for all patients with CRC regardless of disease stage and biomarker status.

Several trials are evaluating the role of perioperative ICI therapy for both dMMR and pMMR colon cancer. Pathological response is a common end point for neoadjuvant ICI studies; however, it is not yet known whether this biomarker corresponds to improvements in EFS or OS for colon cancer. Because of the lack of randomized evidence, perioperative immunotherapy for this disease should not be administered outside of a clinical trial until more safety and efficacy data are available. However, if an R1 resection is anticipated and appropriate clinical trial enrollment is not feasible, then administration of neoadjuvant ICIs with multidisciplinary oversight could be considered for resectable MSI-H/dMMR colon cancer given data for disease response, although in the metastatic setting. Encouraging early results are emerging, however. The exploratory, randomized phase II NICHE study (NCT03026140) evaluated patients with early stage, dMMR and pMMR colon cancer who received 1 month of neoadjuvant nivolumab plus ipilimumab (with or without celecoxib for pMMR disease).155 Pathological response was observed in all 20 evaluable dMMR tumors (including 12 pCRs). Four of the 15 evaluable pMMR tumors demonstrated a pathological response, with CD8⁺PD-1⁺ T-cell infiltration predictive of response in these tumors. The NICHE-2 study, which enrolled exclusively for patients with dMMR non-metastatic colon cancer, demonstrated unprecedented 95% major pathologic response (MPR) and 67% pCR rates (secondary end points) for 107 patients following one dose of neoadjuvant ipilimumab and two doses of neoadjuvant nivolumab.156 Although the primary end point of 3-year DFS has yet to be reported, no patients had experienced a recurrence of their disease at a median follow-up time of 13 months. Furthermore, the primary end point of safety was met, with just three patients experiencing a grade 3 or 4 irAE and three patients experiencing a delay in surgery. Patients with resectable, early stage (T3–T4), MMR unselected colon cancer received neoadjuvant nivolumab in the NICOLE study, which resulted in a MPR (<10% viable tumor) in 3 of 19 patients with pMMR disease and 0 out of 3 patients with dMMR disease.157 Neoadjuvant nivolumab also resulted in a higher TIL immunoscore compared with a control cohort (p=0.028). Results of the phase III ATOMIC trial (NCT02912559), in which patients with stage III dMMR colon cancer were randomized to receive adjuvant leucovorin, fluorouracil, and oxaliplatin (FOLFOX) with or without atezolizumab, were pending at the time of manuscript publication.

Perioperative ICI therapy is also being explored in trials enrolling exclusively for MSI-H/dMMR rectal cancer. In a report on 12 of the first patients with untreated, stage II–III, MSI-H/dMMR rectal cancer enrolled in one pilot single-institution phase II study (NCT04165772), single-agent dostarlimab administered every 3 weeks for 6 months prior to planned surgery resulted in a 100% complete clinical response rate (95% CI 74% to 100%) at a median follow-up time of 12 months (range 6–24 months).158 In addition, patients were able to defer radiation therapy and surgery. While these data are provocative, this Expert Panel cannot endorse routine use of PD-1 inhibitors as definitive therapy for MSI-H/dMMR rectal cancer without longer follow-up data. The therapeutic landscape is evolving quickly, however. On February 9, 2023, the FDA ODAC voted eight to five in favor of data from two proposed single-arm trials enrolling a total of 130 patients being sufficient to characterize the benefits and risks of dostarlimab in the curative intent setting for patients with dMMR/MSI-H locally advanced rectal cancer.159 Rationale in support of this approach included a discussion of the highly morbid multimodality SOC treatment for patients with this disease, as well as proposed trial end points including clinical CR at 12 and 36 months. The ongoing multicenter EA2201 trial (NCT04751370) is evaluating the role of dual immune checkpoint blockade combined with short-course radiation in locally advanced MSI-H/dMMR rectal cancer.

Other trials investigating perioperative ICI therapy for CRC include a phase II study (NCT04082572), which demonstrated a pCR of 79% among 14 patients with localized unresectable or high-risk resectable (defined as ≥20% recurrence risk) MSI-H/dMMR CRC who underwent surgery following treatment with neoadjuvant pembrolizumab.160 A randomized phase II trial of pre-operative PD-1 inhibitor toripalimab with or without celecoxib enrolled 34 patients with clinical stage II or III MSI-H/ dMMR CRC.161 The pCR rate was 65% with toripalimab and 88% with toripalimab plus celecoxib.

Several ongoing clinical trials are also evaluating novel ICI combinations to address the significant unmet need for immunotherapy treatments for metastatic MSS/pMMR CRC. In the open-label, phase II comparative AtezoTRIBE trial, 218 patients with MMR-unselected, metastatic CRC were randomized 1:2 to first-line treatment with FOLFOXIRI plus bevacizumab without (arm A) or with (arm B) atezolizumab, followed by maintenance 5-FU plus bevacizumab with (arm B) or without (arm A) atezolizumab.162 163 With a median follow-up time of 19.9 months, the ORR was similar for the two arms (64% for patients receiving atezolizumab vs 59% for the chemotherapy plus bevacizumab alone group; p=0.412). However, the study did meet its primary end point, as median PFS was significantly longer for the atezolizumab group (13.1 vs 11.5 months; HR 0.69; 80% CI 0.56 to 0.85; p=0.012). Furthermore, although the effect size was smaller, the addition of atezolizumab to chemotherapy plus bevacizumab demonstrated activity in the subgroup of 199 patients with pMMR tumors, with a median PFS of 12.9 vs 11.4 months (HR 0.78; 80% CI 0.62 to 0.97); p=0.071). In the phase II, open-label MAYA study of metastatic MSS and O-6-methylguanine-DNA methyltransferase (MGMT) silenced CRC, patients received two cycles of temozolomide priming followed by nivolumab plus ipilimumab in the absence of disease progression.164 Acquired MMR deficiency is a well-characterized resistance mechanism to temozolomide, providing rationale for the combination approach. Although 135 patients started temozolomide priming, only 33 patients moved on to receive the dual ICI treatment. With temozolomide priming, the 8-month PFS rate (primary end point) was 32%, with a median PFS of 7.1 months and a median OS of 18.5 months. The rate of severe irAEs was relatively low at 6% for grade ≥3 events. The phase II CheckMate 9X8 study randomized 195 patients with treatment-naïve, MSI-unselected metastatic CRC 2:1 to receive FOLFOX plus bevacizumab with or without nivolumab.165 The median PFS and OS did not differ significantly between the two treatment arms with considerably greater toxicity observed for the nivolumab group.

The addition of a tyrosine kinase inhibitor (TKI) to ICIs is one strategy being explored in clinical trials to overcome primary immunotherapy resistance in MSS/pMMR CRC, although these data are conflicting, with some studies showing a lack of efficacy for liver metastases and other studies suggesting a benefit in RAS-wild-type (WT) tumors. The combination of lenvatinib (a multikinase TKI) and pembrolizumab was evaluated for safety and efficacy in multiple cohorts of MSS/pMMR solid tumors in the open-label, phase II LEAP-005 study.166 The CRC cohort included 32 patients with unresectable/metastatic, MSS/pMMR CRC that had progressed on separate prior lines of oxaliplatin and irinotecan.167 The ORR (the study’s primary end point) for the CRC cohort was 22%, with a DCR of 47%. Grade ≥3 TRAEs occurred in 50% of patients, including one treatment-related death due to intestinal perforation. Enrollment in the CRC cohort has been expanded to 100 patients. Other prospective clinical trials of anti-PD-(L)1 ICIs in combination with TKIs inclusive of patients with MSS/pMMR CRC are ongoing and include the REGONIVO (phase Ib),168 COSMIC-021 (phase Ib),169 and CAMILLA (phase II)170 171 trials, with positive efficacy signals for patients with RAS-WT disease reported for small numbers of patients in the COSMIC-021 and CAMILLA studies. The liver is generally considered immunologically cold and patients with hepatic metastases have experienced poor outcomes with ICI treatment.172 A retrospective cohort study including 95 patients with pretreated, MSS/pMMR metastatic CRC receiving PD(L)-1-targeting agents with or without a variety of investigational agents including TKIs demonstrated improved efficacy for patients without liver metastases (ORR 19.5%; median PFS 4.0 months) compared with those with disease metastatic to the liver (ORR 0%; median PFS 1.5 months).173 Liver metastases were the most predictive variable for progression of disease after controlling for age, Eastern Cooperative Oncology Group (ECOG) performance status, RAS and BRAF status, TMB, metastatic sites, and primary tumor location. Improved efficacy for patients with metastatic CRC without liver involvement was also observed in the REGONIVO study,174 and data from the expanded CRC cohort of LEAP-005 were pending at the time of publication. While promising responses have been noted in some studies of ICI plus TKI combinations, patient heterogeneity, sample size, and lack of mature data from phase III trials continue to make this approach strictly investigational and not to be used outside of a clinical trial.

Ongoing studies are also investigating the optimal duration of ICI therapy for patients with advanced MSI-H/dMMR CRC. While the standard label indication for anti-PD-1 therapy duration is up to 2 years or until disease progression or dose-limiting toxicity, new data suggest that 1 year of ICI therapy may be sufficient for some patients. Furthermore, a CR may be difficult to determine in the setting of persistent but stable radiographic findings. With a median of 34.5 months follow-up, the GERCOR NIPICOL study demonstrated 1-year, 2-year, and 3-year PFS rates of 75.4%, 70.0%, and 70.0%, respectively, for 57 patients with chemotherapy-pretreated metastatic, MSI-H/dMMR CRC receiving 4 doses of nivolumab plus ipilimumab followed by nivolumab monotherapy for a total treatment duration of 1 year.175 Furthermore, two of three patients with stable disease at 12 months who later developed progressive disease achieved a PR with a second course of nivolumab.

Panel recommendations

• For all patients with CRC, clinical trial enrollment should be considered at all stages of treatment, when feasible.

• For patients with untreated, metastatic, MSI-H/dMMR CRC, pembrolizumab monotherapy is recommended (LE:2). Treatment with combination nivolumab plus ipilimumab may be considered for this indication as well (LE:3), although there are no randomized data to suggest that this regimen is superior to pembrolizumab monotherapy.

• For patients with untreated, metastatic, MSS/pMMR CRC, treatment with ICIs is not recommended outside of a clinical trial. This applies to patients with tumors that are TMB-H while being MSS/pMMR (LE:3), except for patients with POLE/POLD1 mutations with an associated ultramutated TMB (LE:3).

• For patients with previously treated, metastatic, MSI-H/dMMR CRC who have not received prior ICI therapy, pembrolizumab monotherapy (LE:3) or nivolumab with (LE:3) or without (LE:3) ipilimumab are all recommended options. Dostarlimab monotherapy is a recommended treatment option for dMMR disease only (LE:3).

• For patients with resected pathological stage I–III MSI-H/dMMR colon cancer, ICIs should not be used in the adjuvant setting outside of a clinical trial. A non-randomized multicenter study of neoadjuvant ICI therapy for patients with resectable dMMR colon cancer demonstrated a pCR (ypT0N0) in 67% of patients (LE:3), but longer follow-up is needed to address survival outcomes. Clinical trial participation is preferred.

• For patients with MSI-H/dMMR resectable rectal cancer, phase II data from a single group study of neoadjuvant ICI therapy suggest remarkable activity (LE:3), but longer follow-up is needed to address the DOR. Clinical trial participation is preferred.

Immunotherapy for the treatment of anal cancer

For patients with SCCA who present with metastatic disease or progression beyond chemoradiation without an option for salvage surgery, there are no FDA-approved treatment options following near certain progression on first-line platinum-based chemotherapy.176 About 70% of SCCA cases are caused by the human papillomavirus genotype 16 (HPV16) virus genotype, and many patients with SCCA have HIV.177 Other HPV-related cancers, including cervical carcinoma and head and neck squamous cell carcinoma, have demonstrated a response to PD-(L)1 inhibition, which invokes reactivation of HPV-specific T cells.178 179

While there are no SCCA-specific FDA approvals for immunotherapy, patients with advanced SCCA were included in the KEYNOTE studies leading to some of the tissue-agnostic FDA approvals. Small, early phase immunotherapy studies have suggested some benefit with checkpoint blockade for advanced, pretreated SCCA, particularly for PD-L1-expressing tumors. The phase Ib KEYNOTE-028 study demonstrated a DCR of 58% (17% PR, 42% SD) with pembrolizumab monotherapy in 24 patients with PD-L1-positive (CPS ≥1%) advanced SCCA, with a median PFS of 3.0 months and median OS of 9.3 months.180 The open-label, phase II KEYNOTE-158 study included multiple cohorts of patients with previously treated, biomarker-unselected, advanced solid tumors, including 112 patients with SCCA.181 Pooled results from the anal cancer cohorts of the KEYNOTE-028 and KEYNOTE-158 studies (n=137) demonstrated an ORR of 14.0% for PD-L1-positive patients and 3.3% for PD-L1-negative patients.182 With a median follow-up time of 11.7 months, the 12-month PFS and OS rates were 14.5% and 47.4%, respectively. With further follow-up for a median time of 34.7 months, the ORR was 11% (15% for PD-L1-positive tumors and 3% for PD-L1-negative tumors).183 In the phase II multicenter NCI9673 (part A) study of 37 patients with treatment-refractory, metastatic SCCA, nivolumab monotherapy was associated with an ORR of 24%, including two CRs.184 Although only a limited number of patients had pretreatment PD-L1 expression available (four responders and five non-responders), tumor cell PD-L1 expression was higher for patients with responding disease (p=0.0056). Median PFS was 4.1 months and median OS was 11.5 months at a median follow-up time of 10.1 months. While these studies suggest that low or negative PD-L1 expression in SCCA may negatively impact response to ICIs, patients should not be selected for ICI treatment based on PD-L1 expression.

Emerging data on immunotherapy for the treatment of anal cancer

The phase III EA2176 study (NCT04444921) is randomizing patients with advanced SCCA 2:1 to first-line carboplatin/paclitaxel with or without nivolumab for 6 months followed by maintenance nivolumab, with a primary end point of PFS.185 This will be the first phase III randomized trial dedicated to studying advanced, treatment-naïve SCCA, with a target enrollment of 205 patients to be stratified by HIV status and history of prior chemoradiation. The double-blind, phase III POD1UM-303/InterAACT 2 study (NCT04472429) is similarly recruiting patients with unresectable/metastatic SCCA to evaluate the efficacy and safety of adding the anti-PD-1 ICI retifanlimab to frontline carboplatin and paclitaxel.

There are several ongoing studies for SCCA in the second-line/treatment-refractory setting as well. Results of part B of the phase II NCI9673 study (NCT02314169) comparing nivolumab with or without ipilimumab for metastatic, treatment-refractory SCCA are pending. The phase II POD1UM-202 study of retifanlimab enrolled 94 patients with advanced SCCA pretreated with platinum-based chemotherapy, including 9 patients with well-controlled HIV infection. Treatment resulted in an ORR of 14% for retifanlimab, with responses observed regardless of PD-L1 status, presence of liver metastases, age, or HIV status.186 Furthermore, with a median follow-up time of 7 months, observed responses were durable (median DOR 9.5 months). The use of retifanlimab for pretreated, advanced SCCA was granted orphan drug and fast track designation by the FDA and received priority review status. However, in June 2021, the ODAC deferred approval of retifanlimab for this indication due to concerns that an ORR as low as 14% may not reasonably predict clinical benefit, particularly as many of the responders did not have bulky or non-lymph node (LN) target lesions.187

Studies evaluating immunotherapy for early stage SCCA are ongoing as well. The phase III EA2165 study (NCT03233711), for example, is recruiting patients to receive adjuvant nivolumab versus placebo following combined modality treatment for high-risk stage II–IIIB SCCA (T >4 cm; LN-positive), with a primary end point of DFS.

Special patient populations

Patients with Lynch syndrome are uniquely poised to benefit from ICIs as their disease arises from germline dMMR. However, ICI therapy does not appear to confer an increased benefit for patients with Lynch syndrome compared with patients with sporadic MSI-H/dMMR CRC. For example, an analysis of 86 patients with MSI-H/dMMR tumors (including CRC) treated with ICIs showed no significant difference in ORR (46% vs 59%; p=0.27), PFS (HR 1.2; 95% CI 0.582 to 2.512; p=0.61), or OS (HR 1.71; 95% CI 0.697 to 4.196; p=0.24) between Lynch and non-Lynch syndrome-associated disease, respectively.188 A systematic review of large cohort studies of ICI therapy demonstrated ORRs between 46% and 71% for Lynch-associated CRC compared with 48% to 100% for sporadic MSI-H/dMMR CRC—essentially no difference in response, but as the authors concluded, sample sizes were limited and CIs were wide.189

Patients living with HIV (PLWH) have commonly been excluded from clinical trials evaluating immunotherapy due to presumed immune compromise. Substantial unmet need exists for effective anticancer treatments for PLWH, however, especially for SCCA. As many as 1% of women and 28% of men with SCCA are living with HIV.177 Although not specific to GI malignancies, two studies have demonstrated acceptable safety and no notably reduced efficacy with PD-(L)1 blockade for a small number of patients with advanced solid tumors and HIV.190 191 Examination of SCCA specimens from 23 PLWH and 17 HIV-negative patients revealed that PD-L1 expression, immune cell density, and interferon-gamma gene expression did not differ significantly based on HIV status.192 Increasing numbers of clinical trials evaluating immunotherapy for SCCA are now including PLWH. For example, the phase II POD1UM-202 study of retifanlimab for previously treated, advanced SCCA enrolled 9 (9.6%) PLWH and found that HIV status affected neither the efficacy nor the safety of this PD-1 inhibitor.186 At the time of manuscript publication, the National Cancer Institute (NCI) was specifically recruiting PLWH with SCCA to receive chemoradiation with or without nivolumab according to disease risk (NCT04929028). The FDA recommends that PLWH with a CD4 count <350 cells/µL should ‘generally’ be eligible for clinical trials only in the setting of a potentially curable malignancy or for interventions ‘in a later stage of development that have demonstrated prior activity’.193 However, there are no data to suggest that immunotherapy for PLWH should be adjusted based on CD4 count, and many HIV-negative patients may also have low CD4 counts due to prior cancer therapies. In fact, a retrospective cohort study of 84 patients with relapsed/refractory cancers who received ICIs in two NCI clinical trials found no significant difference in the proportion of patients with a CD4 count <350 cells/µL between PLWH and HIV-negative patients (p=0.5).194 Furthermore, 3-year survival rates for patients with HPV-related malignancies did not differ significantly for patients with a CD4 count <350 cells/µL (32.2%) vs ≥350 cells/µL (21.2%; p=0.7). All-in-all, PLWH and cancer should have the opportunity to receive treatment with ICIs under FDA-approved indications and through clinical trial enrollment, regardless of CD4 count.

Patients with inflammatory bowel disease (IBD) have also been excluded from clinical trials of immunotherapy for GI cancer, and data-driven guidelines are lacking for this patient population. A phase Ib basket study of nivolumab for patients with advanced malignancies and an autoimmune disease (NCT03816345) is enrolling patients with IBD, although many clinical trials continue to exclude this population due to risk of toxicity. For additional discussion of patients with IBD, please refer to the ‘Patient education and QOL support for patients with gastrointestinal cancer receiving immunotherapy’ section.

Panel recommendations

• For all patients with SCCA, clinical trial enrollment should be considered at all stages of treatment, when feasible.

• For patients with treatment-naïve, metastatic SCCA with any MSI/MMR status and/or TMB, there are insufficient data to recommend first-line ICI therapy.

• For patients with previously treated, metastatic SCCA, nivolumab (LE:3) or pembrolizumab (LE:3) are recommended treatment options regardless of MSI/MMR, TMB, and PD-L1 status.

Patient education for immunotherapy for GI cancers

Providing timely education to patients about their cancer care can improve anxiety and self-care decisions and enhance QOL. As immunotherapy gains more indications and its use becomes more widespread, emerging data are demonstrating that patient education also plays a key role in early recognition and reporting of irAEs.195 A mismatch still persists, however, between the education that providers offer and the content that patients desire. In a Cancer Support Community needs assessment conducted at nine oncology centers across the US, 46% of healthcare providers reported that patient education should go ‘quite a bit’ in depth into the science of immunotherapy, while only about one-third of patients and caregivers (31% and 38%, respectively) reported a need for this knowledge.196 Patients and caregivers were far more interested in education about managing immunotherapy-related side effects (55% and 85%, respectively).

There are few published data to inform healthcare providers about the best practices for educating patients about immunotherapy. For example, 50% of patients and 73% of healthcare providers reported difficulty in obtaining information about how to cope with side effects of ICIs.195 Barriers to educating patients about irAEs include the following: a constant need to update educational materials as more data become available, the high level of organization required to coordinate multidisciplinary team involvement (eg, medical subspecialists), and the unique presentation of irAEs compared with traditional chemotherapy side effects. Immunotherapy & Me (NCT03347058) is one patient education program in development that aims to identify and implement the most meaningful resources to improve outcomes and decrease cost for patients receiving immunotherapy treatment for their cancer.

Extrapolation of data from studies of patients receiving chemotherapy suggests that cancer treatment education is most effective when provided prior to treatment initiation in a quiet environment by the primary oncology team, and education should be tailored to the patient’s individual learning preference.195 Furthermore, education regarding irAEs should be reinforced periodically throughout treatment, with emphasis on the importance of notifying the treatment team promptly at the first sign of a potential irAE. It is helpful to provide patients with a handout or card with the name(s) of their oncologic drug(s) clearly written out in order to avoid confusion, for example, if they were to seek emergency care outside of their designated institution. Additionally, there are several credible online educational resources available to patients and clinicians through the National Cancer Institute (NCI), the American Cancer Society, and SITC. Downloadable resources that may be provided directly to patients and caregivers include, ‘SITC CPG on ICI-related adverse events’,12 ‘The European Society for Medical Oncology Patient Guide on Immunotherapy-Related Side Effects and their Management’,197 ‘The Oncology Nursing Society Immunotherapy Patient Wallet Card’,198 and ‘The Hematology Oncology Pharmacy Association Time to Talk Immuno-Oncology Immune Checkpoint Inhibitors Toolkit’.199

Immunotherapy-related toxicities are influenced by the patient’s immune system and the ICI(s) used, and by the underlying cancer being treated.200 For example, IBD is a risk factor for immune-mediated diarrhea and colitis, and patients who develop CRC in the setting of IBD should be educated about their increased risk for developing this irAE. While some risk factors have been identified for the development of irAEs in the short-term, the incidence and pattern of long-term immunotherapy complications are largely unknown as clinical studies rarely report safety data beyond 2 years. It is therefore incumbent upon providers to educate patients receiving immunotherapy on the need for long-term vigilance and reporting for suspected irAEs. Particular attention should be paid to organ systems prone to inflammation secondary to a pre-existing autoimmune disease, radiation exposure, or the location of the primary tumor and any metastatic sites of spread. Box 4 provides call parameters for patients with GI cancers receiving immunotherapy. Prior to initiation of immunotherapy and throughout the duration of treatment, clinicians should discuss how irAEs may look or feel with their patients. Patients should be invited to ‘call soon and call often’ for any symptoms that are abnormal, even for symptoms that are normally present but may have worsened in severity (eg, increased frequency or volume of diarrhea). The potential for late onset irAEs should also be discussed, especially if immunotherapy is administered in the perioperative setting. Patients should be advised that irAEs may manifest at any time, including years after the last dose of ICI, which is why it is important to communicate a history of immunotherapy treatment to future healthcare providers. In addition to irAE guidance, providers should also educate their patients about the importance of reporting any medication changes (including receipt of vaccinations) while receiving immunotherapy as several medications, most notably steroids, may alter the efficacy of ICIs. Some patients may forget the name of a new medication by the time they arrive for their visit, and for these patients, reporting medication changes may be most feasible through an online patient portal.

In addition to understanding irAEs, it is imperative that patients understand the goals of their specific immunotherapy treatment. Over the past decade, immunotherapy has transformed some cancers (such as stage IV melanoma) from almost universally fatal diseases to potentially curable conditions. At the time of guideline writing, however, this was not necessarily the case for advanced stage GI cancers (with the potential exception of some patients with MSI-H/dMMR tumors). Patients receiving immunotherapy for a GI cancer may experience prolonged disease control, a more limited-term extension of survival and relief from disease symptoms, or no response at all. Without definitive biomarkers to predict whether tumors will respond to immunotherapy and how long these responses will last, it can be challenging for clinicians to communicate expectations for outcomes of treatment. Regardless of these challenges, the goals of treatment with immunotherapy should be presented to patients in a realistic yet hopeful manner, with transparency about disease-specific prognosis and our current limitations on predicting long-term outcomes with immunotherapy.

The nuances of clinical trial outcome measures (eg, DFS vs OS), a lack of predictive tools, and the variable goals of immunotherapy treatment indications can understandably contribute to patient and caregiver confusion. In one study of patients with advanced melanoma and NSCLC, 34% of participants responded in a Prognosis and Treatment Perceptions Questionnaire (PTPQ) that the primary goal of their treatment is to cure their cancer.201 This underscores the importance of patient education provided by the primary oncology team, as patients who understand their cancer treatment goals are more likely to enroll in and derive the benefits of hospice at the end of life.202 Clinicians should endeavor to use plain language whenever possible when discussing the goals of treatment with their patients and be receptive to questions or a need for multiple explanations.

QOL support for patients with gastrointestinal cancer being treated with immunotherapy

QOL should be proactively assessed and all patients receiving immunotherapy should receive aggressive and early symptom management regardless of the stage of their GI cancer. Cancer-related symptoms are likely to change throughout the course of treatment, and an ongoing provider-to-patient conversation should be established to assess the patient’s dynamic needs.

Some data suggest that QOL is predictive of survival for patients receiving cancer treatment. For example, a prospective study of 110 patients with ESCC treated with RT with or without chemotherapy demonstrated that EORTC-quality of life questionnaire (QLQ)-core (C)30 pretreatment physical function and 2-month post-treatment dysphagia scores were independently predictive of survival. Although postmarket ‘real-world’ data on HRQOL measures for patients receiving immunotherapy for GI cancers are not yet widely available, existing QOL data from other disease settings support the use of immunotherapy. A meta-analysis of 13 randomized controlled trials compared patient-reported outcomes (PROs) from studies comparing single-agent anti-PD-(L)1 antibodies versus SOC treatment (mammalian target of rapamycin [mTOR] inhibitor, CTLA-4 inhibitor, or chemotherapy) for patients with a variety of advanced cancers.203 With a median follow-up of 15 weeks, the pooled difference in mean change of EORTC-QLQ-C30 item score between treatment groups was 5.1 (p<0.001) in favor of the anti-PD-(L)1 treatment group and the time to deterioration (TTD) was significantly longer for the anti-PD-(L)1 group (HR 0.72; p=0.011).

Patients living with cancer have disproportionately high rates of affective disorders such as anxiety and depression.204 Patients with esophageal cancer are at particularly high risk for these disorders, with an estimated prevalence of depression of 75.81% in one study (compared with 66.72% among all patients with cancer). Through mechanisms not fully understood, depression increases mortality and non-compliance and worsens postoperative outcomes in patients with cancer. While there are no established criteria for the treatment of affective disorders in patients with cancer, a variety of interventions have been studied in this population with some success. Oncology providers should maintain a high index of suspicion for anxiety and depression to promptly identify patients in need of psychological support.

Several registrational trials for the treatment of GI cancers have reported HRQOL as secondary or exploratory end points, and these data have demonstrated equivalent or superior PROs for immunotherapy compared with chemotherapy and/or placebo, as summarized in table 4. Exploratory HRQOL analyses from the CheckMate 577 trial of adjuvant nivolumab vs placebo demonstrated a trend toward improvement in Functional Assessment of Cancer Therapy – Esophageal (FACT-E) and EuroQol (EQ)-5 dimension (D)-3 level (L) PROs measured at baseline and 12 months for both treatment groups.205 The KEYNOTE-590 study of chemotherapy plus pembrolizumab versus chemotherapy plus placebo for advanced esophageal/GEJ cancer included change in QOL questionnaire scores as prespecified secondary end points.206 Median TTD in EORTC-QLQ-C30 global health status (GHS)/QOL was not significantly different between the two treatment arms (HR 0.86; 95% CI 0.66 to 1.13; p=0.2864). The least squares mean (LSM) changes for the questionnaires were either not significantly different between the two treatments or favored the pembrolizumab arm. For example, the LSM change from baseline to 18 weeks for the EORTC-QLQ-OES18 pain subscale favored pembrolizumab plus chemotherapy (−2.94; 95% CI −5.86 to −0.02; p=0.0487) whereas there was no significant difference between the treatment groups for change in reflux (−1.19; 95% CI −4.49 to 2.10; p=0.4781) or dysphagia (−2.35; 95% CI −7.78 to 3.07; p=0.3945). In the KEYNOTE-062 study of pembrolizumab monotherapy versus chemotherapy for advanced, PD-L1-positive gastric/GEJ cancer, change in HRQOL questionnaire data from baseline to 18 weeks was also measured as a secondary end point.207 At week 18, the mean EORTC-QLQ-C30 GHS/QOL scores for pembrolizumab versus chemotherapy were similar (66.4 and 63.6, respectively) with no difference in LSM between arms (−0.16; 95% CI −5.0 to 4.7; nominal p=0.948). While the TTD for the EORTC-QLQ-C30 appetite loss and EORTC-QLQ-STO22 pain subscales was similar between treatment arms, the EORTC-QLQ-C30 nausea/vomiting subscale TTD was significantly longer for pembrolizumab compared with chemotherapy (HR 0.61; 95% CI 0.44 to 0.85; nominal p=0.003). Prespecified HRQOL exploratory end points were reported from the KEYNOTE-177 study of pembrolizumab monotherapy versus chemotherapy for the first-line treatment of patients with metastatic, MSI-H/dMMR CRC.208 The change in EORTC-QLQ-C30 GHS/QOL LSM from baseline to 18 weeks was significantly better for the pembrolizumab group (LSM difference 8.96; 95% CI 4.24 to 13.69; p=0.0002), with median TTD favoring pembrolizumab as well (HR 0.61; 95% CI 0.38 to 0.98; one-sided nominal p=0.019). Pembrolizumab median TTD subscale scores were also significantly better than chemotherapy in the physical functioning (HR 0.50; 95% CI 0.32 to 0.81; one-sided log-rank p=0.0016), social functioning (HR 0.53; 95% CI 0.32 to 0.87; one-sided log-rank p=0.0050), and fatigue domains (HR 0.48; 95% CI 0.33 to 0.69; one-sided log-rank p<0.0001). The CheckMate 649 study of patients with advanced, untreated gastric, GEJ, and esophageal adenocarcinoma demonstrated a quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) improvement of 2.8 and 1.8 months with the addition of nivolumab to chemotherapy for patients with PD-L1 CPS ≥5 and all randomized patients, respectively.209

Financial hardship, which is associated with worse QOL and survival outcomes, is common among patients with cancer as they navigate costly medications, procedures, and hospitalizations.210 211 Immunotherapy agents are also among the most expensive anticancer drugs. In a survey of patients receiving immunotherapy for stage IV NSCLC, 52% of participants reported financial hardship across multiple Medical Expenditure Panel Survey-Experiences with Cancer Survivorship Supplement (MEPS-ECSS) psychological, behavioral, or material domains.212 Only 7% of patients reported no out-of-pocket expenses and 37% reported worry about losing health insurance due to their cancer diagnosis. A cancer diagnosis can also impact caregivers—42% of patients reported that their caregiver reduced their employment level (ie, took time off or changed working hours). This reduction in caregiver employment was significantly associated with patient financial hardship (p=0.03) and financial distress as measured by Comprehensive Score for Financial Toxicity–Functional Assessment of Chronic Illness Therapy (FACIT-COST; p=0.01). Although longitudinal data to establish a causal relationship between immunotherapy and patient financial hardship are lacking, caregiver employment reduction may be an important sign of financial hardship for the patient.

Providers must be attuned to the likely possibility for financial distress for their patients and proactive in establishing open lines of communication throughout treatment. For example, a provider might initiate a conversation by asking if patients are feeling concerned about money for any reason and emphasizing that resources to help pay for the costs associated with treatment are available. This should not be a one-time conversation but rather an ongoing discussion to identify any difficulties with finances before they become crises. Patients should be encouraged to voice their financial concerns to any of their treating providers, and these concerns should be addressed with immediate referral to a social worker or financial counselor. Early referrals for financial support can help to address multiple potential barriers to care (eg, cost of medications and transportation) and improve overall care and communication.

Resources to support quality of life during and after immunotherapy treatment

Different strategies can be offered to proactively improve QOL for patients with GI cancers including participation in a cancer support group, which has been shown to lower anxiety and depression.213 National support groups specific for GI cancers include the Anal Cancer Foundation (ACF), Farrah Fawcett Foundation, Colorectal Cancer Alliance, Love Your Buns, Esophageal Cancer Action Network (ECAN), Esophageal Cancer Awareness Association (ECAA), Esophageal Cancer Education Foundation, The Cholangiocarcinoma Foundation, the Hirshberg Foundation for Pancreatic Cancer Research, Pancreatic Cancer Action Network (PanCAN), Debbie’s Dream Foundation: Curing Stomach Cancer, Hope for Stomach Cancer, and No Stomach for Cancer, among others.

Early referral for professional dietary support services is another way to improve QOL for some patients with GI cancers, particularly for patients with esophageal cancer.214 Up to 85% of patients diagnosed with esophageal cancer are malnourished, and their nutritional status often worsens during cancer treatment. Patients’ nutritional status should be regularly assessed throughout treatment with a validated oncology nutrition tool with prompt referral of moderate-risk to high-risk patients to a nutrition specialist.

Some patients with GI cancers face the additional challenge of an enteral ostomy, which is associated with adverse impacts on HRQOL.215 216 Although immunotherapy-specific data are lacking, ostomy complications (eg, pyoderma gangrenosum) have been reported in the context of autoimmune disease.217 218 It is therefore imperative for oncology providers to proactively assess stoma health for patients receiving ICIs. Providing ostomy education to patients results in improved HRQOL, and an increase in psychosocial adjustment.219 In addition to referral to a specialized ostomy nurse, patients may be referred to the following online resources: American Cancer Society Colostomy Guide, Memorial Sloan Kettering Cancer Center Caring for your Ileostomy or Colostomy, and the United Ostomy Associations of America New Ostomy Patient Guide.

Palliative care is associated with improved QOL as well as improved survival, decreased need for acute hospital care, and decreased cost of end-of-life care.220 While hospice care should be offered, when appropriate, providers should clearly communicate that palliative care is distinct from end of life care and is meant to provide symptomatic management throughout a patient’s cancer journey regardless of disease stage or treatment intent. Patients should be frequently encouraged to reach out to their primary oncology provider to request palliative care if or when they require symptom management.

Immunotherapy can present unique challenges to delivering palliative care warranting careful consideration of the risks versus benefits of certain palliating treatments. For example, glucocorticoids used to alleviate pain and swelling, improve energy, and stimulate appetite have a known immunosuppressive effect and patients receiving steroids are commonly excluded from clinical trials of immunotherapy.221 Although steroids used to manage irAEs do not seem to diminish checkpoint blockade efficacy in real-world studies,222 receipt of ≥10 mg prednisone for palliative indications has been associated with shorter PFS and OS.223 Lastly, antibiotics may profoundly perturb the immune system due to dysbiosis, which could alter the efficacy of immunotherapy.224 Patients receiving immunotherapy with concomitant palliative care should be monitored closely, with prompt taper or discontinuation of these potentially counteracting palliative medications when clinically appropriate.

Panel recommendations

• Patient and caregiver education should include a focused discussion of the fundamental differences between immunotherapy, targeted therapy, and chemotherapy tailored to the patient’s learning style. Patient education should include an extensive discussion of irAEs.

• Providers should initiate a conversation about the cost associated with ICIs and cancer care early and address financial hardship throughout the course of care.

• Realistic expectations and goals of treatment should be discussed at the time of diagnosis and at times of changes in clinical status for all patients with GI cancer.

• Providers should advise their patients to promptly report all medication changes to their oncology team as several medications, particularly steroids (LE:4), may impact the efficacy of immunotherapy.