Immunotherapy for Gastrointestinal Malignancies: Is It Ready for Prime Time?

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In less than a decade, immunotherapy has reshaped the treatment landscape of cancer, but some histologies tend to be more responsive to this modality than others. During the Society of Surgical Oncology 2022 International Conference on Surgical Care, Yuman Fong, MD, of the City of Hope Medical Center, and Ronald P. DeMatteo, MD, of the University of Pennsylvania, debated the impact of immunotherapy for gastrointestinal (GI) malignancy, which has benefited less from immune checkpoint inhibitors than other solid tumor types, such as melanoma, renal cell, and lung.1

Immunotherapy: The Future Is Now

According to Dr. Fong, several studies have highlighted the potential for immunotherapy in gastrointestinal malignancy. Dr. Fong is Sangiacomo Family Chair in Surgical Oncology; Chair and Professor, Department of Surgery; Director of the Center for International Medicine; and Director of the Center for Surgical Innovation at the City of Hope Medical Center, Duarte, California.

Yuman Fong, MD

Yuman Fong, MD

Results of the phase III KEYNOTE-177 trial, involving 192 cancer centers in 23 countries, showed significantly longer progression-free survival among treatment-naive patients with microsatellite instability (MSI)-high or mismatch repair–deficient (dMMR) metastatic colorectal cancer who received pembrolizumab monotherapy vs chemotherapy, with fewer treatment-related adverse events.2 Dr. Fong also noted clinically meaningful improvements in several quality-of-life endpoints, including physical functioning, social functioning, and fatigue scores.

“Not only do tumors stay under control longer, but people feel better, too,” said Dr. Fong. He underscored the “very real separation” of the progression-free survival curves. “Immunotherapy is clearly ready for prime time in GI malignancy.”

In addition to the U.S. Food and Drug Administration (FDA) approval of pembrolizumab and nivolumab as single-agent immunotherapies, ipilimumab is approved in combination with nivolumab for dMMR and MSI-high colorectal cancer.3

Chemoimmunotherapy combinations have also demonstrated efficacy in gastric cancer, said Dr. Fong. The combination of nivolumab and chemotherapy yielded superior overall survival vs chemotherapy alone in previously untreated patients with advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma whose tumors had high expression of PD-L1.4 Pembrolizumab showed efficacy in combination with chemotherapy in patients with Siewert type 1 gastroesophageal junction adenocarcinoma and is beneficial as monotherapy in a subgroup of patients with gastric cancer who have high PD-L1 expression and MSI-high tumors.5,6

“These responses are directly related to the [immunohistochemistry] staining, so the biology stands behind the clinical data,” said Dr. Fong.

Nivolumab (CheckMate 040 and CheckMate 459) and pembrolizumab (KEYNOTE-224) are also approved as second-line therapies in hepatocellular carcinoma.

“The tumors shrink,” said Dr. Fong. “Immune checkpoint inhibitors perform much better than some of the small molecules that we are using in this disease.”

In addition to checkpoint inhibitors, investigators are exploring oncolytic viruses, allogeneic whole-cell vaccines, dendritic cell vaccines, and peptide vaccines as active immunotherapies. There is also significant work being done with passive immunotherapies, such as monoclonal antibodies, cytokines, and adoptive cell transfers. The field of B-cell vaccines is growing especially fast, according to Dr. Fong.

“We’ve been using monoclonal antibodies to target cancer for a long time, but active immunization with antigenic B-cell peptides can stimulate the patient’s own immune system to develop specific high-affinity polyclonal antibodies, which may protect patients even more,” he explained.

Results of a phase I trial of the B-cell peptide vaccine IMU-131 showed 1 complete response, 5 partial responses, and 4 cases of stable disease among 14 patients with gastric cancer who were treated with the vaccine.7

Immunotherapy: Worth Televising but Not in Prime Time

Dr. DeMatteo, Chair of the Department of Surgery and John Reah Barton Professor of Surgery at The Hospital of the University of Pennsylvania, noted that the development of immunotherapy in cancer has been a “fantastic story”—just not for gastrointestinal malignancy. As he explained, tumors defend themselves in a variety of ways, including immunosuppressive cells and cytokine secretion, but first-generation immunotherapy has focused mainly on T-cell checkpoints. Unfortunately, said Dr. DeMatteo, the latter approach has not had much success in gastrointestinal malignancy.

“Immunotherapy works great in MSI-high, esophageal and squamous cell carcinomas, but it has underperformed in almost every other GI malignancy.”
— Ronald P. DeMatteo, MD

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The results of the CheckMate 459 study of nivolumab in advanced hepatocellular carcinoma showed first-line nivolumab treatment did not significantly improve overall survival compared with sorafenib (16.4 months vs 14.7 months).8 In the second-line setting of advanced hepatocellular carcinoma, pembrolizumab also failed to demonstrate a significant improvement in overall and progression-free survival vs placebo, according to the findings of the KEYNOTE-240 study.9 Median overall survival was 13.9 months with pembrolizumab vs 10.6 months with placebo (P = .0238).

“These patients have already failed to respond to a line of therapy, and we’re giving them placebo,” Dr. DeMatteo questioned. “I’m not even sure that’s ethically justified.”

The results of the CheckMate 649 trial showed a “small ray of hope” in advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma with the addition of nivolumab to chemotherapy in the first line, but an 8-week improvement in survival is “not a big difference,” according to Dr. DeMatteo. In addition, CheckMate 649 was the first study to demonstrate an improvement with immunotherapy in this disease after several large, negative trials taking the same approach (ie, ATTRACTION 4, KEYNOTE-062, and JAVELIN Gastric 100).

In KEYNOTE-590, the addition of pembrolizumab to chemotherapy for first-line treatment of advanced esophageal squamous cell carcinoma also demonstrated a difference in median overall survival vs chemotherapy alone (12.6 months vs 9.8 months). “Immunotherapy in metastatic, unresectable disease definitely seems to work,” Dr. DeMatteo acknowledged.

In CheckMate 577, the use of adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer showed a significant improvement in median disease-free survival vs placebo (22.4 months vs 11.0 months).10 According to Dr. DeMatteo, however, the change of primary endpoint during the trial is “suspicious,” and a difference in overall survival looks unlikely.

With respect to MSI-high metastatic colorectal cancer, there is “no question” about the efficacy of checkpoint inhibition, stated Dr. DeMatteo. However, microsatellite instability is found in just 4% of colorectal cancer.

“Immunotherapy works great in MSI-high, esophageal and squamous cell carcinomas, but it has underperformed in almost every other GI malignancy,” he said.

Finally, Dr. DeMatteo underscored the toxicity and cost associated with immunotherapy. “These drugs cost approximately $150,000 per year, per patient, so it’s not surprising that the pharmaceutical industry is banking on them,” he continued. “In the hepatocellular carcinoma trials, we also saw grade 3 toxicities in nearly 10% of patients who received immunotherapy…. That’s a lot of toxicity for a 1- or 2-month improvement in survival.”

Dr. DeMatteo concluded: “Immunotherapy for GI malignancy is worth televising but certainly not in prime time.” 

DISCLOSURE: Dr. Fong reported financial relationships with Eureka, Imugene, Iovance Biotherapeutics, Medtronic, Merck, Sangamo Therapeutics, and Vergent. Dr. DeMatteo reported no conflicts of interest.


1. Immuno-oncology Great Debate: Immunotherapy for GI malignancy. Is it primetime? Society of Surgical Oncology 2022 International Conference on Surgical Care. Presented March 12, 2022.

2. André T, Shiu KK, Kim TW, et al: Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 383:2207-2218, 2020.

3. Lenz HJ, Van Cutsem E, Luisa Limon M, et al: First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: The phase II CheckMate 142 study. J Clin Oncol 40:161-170, 2022.

4. Janjigian YY, Shitara K, Moehler M, et al: First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial. Lancet 398:27-40, 2021.

5. Sun JM, Shen L, Shah MA, et al: Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study Lancet 398:759-771, 2021.

6. Shitara K, Van Cutsem E, Bang YJ, et al: Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: The KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol 6:1571-1580, 2020.

7. Wiedermann U, Garner-Spitzer E, Chao Y, et al: Clinical and immunologic responses to a B-cell epitope vaccine in patients with HER2/neu-overexpressing advanced gastric cancer—Results from phase Ib trial IMU.ACS.001. Clin Cancer Res 27:3649-3660, 2021.

8. Yau T, Park JW, Finn RS, et al: Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): A randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 23:77-90, 2022.

9. Finn RS, Ryoo BY, Merle P, et al: Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: A randomized, double-blind, phase III trial. J Clin Oncol 38:193-202, 2020.

10. Kelly RJ, Ajani JA, Kuzdzal J, et al: Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med 384:1191-1203, 2021.