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Advancements in Immunotherapy and Targeted Therapy in Gastrointestinal Cancers
Sameh Mikhail, MD, Zangmeister Cancer Center
Treatment of gastrointestinal (GI) cancers has evolved in the last two decades, which has contributed to significant improvements in the outcomes of many GI cancers. Immunotherapy and targeted therapy have revolutionized the treatment of patients with GI cancers in recent years. Not only have those treatments provided patients with better clinical outcomes but also have resulted, in many situations, in reduced treatment-related toxicity. As a result of developments in immunotherapy and targeted therapy, oncologists can provide patients, in many cases, with additional options beyond standard cytotoxic chemotherapy.
Immunotherapy
Immunotherapy is a novel treatment that allows the immune system to better recognize and fight cancer cells. Immunotherapy is currently being used in many stages of the treatment of GI cancers. In this section, we will summarize the advances in immunotherapy and describe its role in various phases of the treatment of GI cancers.
In this review, we will describe the recent advancements in immunotherapy and targeted therapy with a special focus on gastrointestinal cancer.
Role of Immunotherapy in the Curative Treatment of Early-stage Gastrointestinal Cancers
Neoadjuvant Therapy (Prior to Surgery)
Rectal Cancer: Approximately 5% to 15% of colorectal cancers have a sporadic or inherited deficiency of a mismatch repair protein (MMR). Typical treatment for patients with early-stage rectal cancer involves radiation therapy, chemotherapy followed by surgery. A recent study suggested that immunotherapy can possibly avoid the need for the typical treatment modalities. Patients were treated with the anti-PD1 inhibitor dostarlimab, which resulted in sustained complete pathological response in 12 patients with stages II and III rectal cancer. The patients received immunotherapy for at least six months and were followed up with for at least six months after completion of dostarlimab (median follow-up is 12 months after study enrollment, range six to 25 months). Follow-up consisted of serial MRI, PET scan, endoscopic or digital rectal exam and/ or biopsy evaluations. None of the patients required any additional systemic therapy, radiation therapy or surgery. These results remain preliminary but are very encouraging for the small proportion of patients that have microsatellite unstable tumors.
Gastro-Esophageal Cancer: Similarly, a small proportion of patients with gastric cancer (3% to 6%) have deficient mismatch repair proteins and microsatellite unstable tumors (MSI-H). Given the favorable activity of immunotherapy in MSI-H advanced gastric cancer, a study was recently performed to evaluate the benefit of immunotherapy with ipilumumab and nivolumab in patients with earlystage MSI-H gastric cancer. Thirty-two patients were enrolled in the study and received the immunotherapy combination for a total of 12 weeks. Twenty-nine patients underwent surgery, 59% of whom had a complete pathological response. Three patients did not undergo surgery; two of whom refused surgery due to a complete endoscopic response with tumor-negative biopsies and normal imaging studies. One patient did not undergo surgery due to the presence of metastasis at enrollment. These results are also preliminary but remain a very exciting development that could change the standard of care for treating patients with MSI-H early gastric cancer.
Colon Cancer: A similar concept was also explored in patients with locally advanced colon cancer (CRC). At least two studies evaluated the benefit of neoadjuvant immunotherapy (PD-1 monotherapy) in patients with locally advanced MSI-H colon cancer. A study by Xiao B et al. enrolled 73 patients and demonstrated an 85% radiological response rate, including a 23% complete response rate and a 62% partial response rate. Of the 50 patients who underwent surgery at the time of presentation of the data, the pathological complete response rate was 57%. Similar results were observed in the NICH-2 trial. The trial enrolled 112 patients with locally advanced colon cancer to evaluate the benefit of a short course of ipilimumab (one dose) and nivolumab (two doses). The pathological response rate was 99% with a complete response rate of 67%. It is worth noting that the median time from the first dose of immunotherapy to surgery was only five weeks. These results are very intriguing but need to be confirmed in larger trials.
Collectively, the studies outlined above suggest that immunoterapy may play a prominent role in the neoadjuvant treatment of patients with MSI-H gastrointestinal tumors. In many cases, immunotherapy can be better tolerated than cytotoxic chemotherapy, and evolving evidence raises hopes about possibly avoiding surgeries, chemotherapy and/or radiation therapy in patients who achieve a clinical and pathological complete response to immunotherapy.
Adjuvant Therapy (Following Surgery)
CheckMate 577 demonstrated significant clinical benefit in patients with resected esophageal and gastroesophageal junction cancer who were treated with nivolumab for a year following the desophageal surgery. Of note, all patients had received neoadjuvant chemoradiation prior to surgery. Median disease-free survival was significantly better with nivolumab compared to placebo (22.4 versus 11 months). As a result of this study, nivolumab was approved by the U.S. Food and Drug Administration (FDA) as adjuvant therapy for patients with esophageal and gastroesophageal junction cancer who had residual disease following chemoradiation and surgery.
Role of Immunotherapy in the Treatment of Advanced Gastrointestinal Cancers
Typical treatment for advanced gastrointestinal cancers includes cytotoxic chemotherapy that can be associated with excessive toxicity. Several studies demonstrated improvement in outcomes of patients with advanced gastrointestinal cancers when treated with immunotherapy.
The combinations of atezolizumab plus bevacizumab as well the combination of tremelimumab plus durvalumab are associated with favorable outcomes in patients with hepatocellular carcinoma. Similarly, immune checkpoint inhibitors plus chemotherapy (gemcitabine and cisplatin) are associated with improved outcomes in patients with biliary cancers compared to chemotherapy alone.
In advanced upper gastrointestinal cancers, immune checkpoint inhibitor combinations are associated with improved outcomes when combined with chemotherapy in the first-line setting. Subgroup analysis has suggested that the benefit of immunotherapy in this patient population increases as the expression of PD-L1 increases. PD-L1 is a protein on the tumor and surrounding cells that can be measured to predict the response of certain tumors to immunotherapy. In HER-2 neu positive metastatic gastric and gastroesophageal cancer, the combination of pembrolizumab plus trastuzumab and cytotoxic chemotherapy was associated with impressive response rates (74%) and duration of response. This combination is currently approved by the FDA in this patient population. Of note, pembrolizumab was also approved by the FDA for the firstline treatment of patients with advanced colorectal cancer and microsatellite instability. The immunotherapy combination of ipilimumab and nivolumab was also approved by the FDA for this patient population.
In summary, immunotherapy treatments are part of the treatment regimen for many GI cancers. They have helped improve outcomes for many patients with GI cancers, and in many cases, the improved outcome was not associated with increased toxicity. It is very likely that the use of immunotherapy will continue to increase over the next few years and will yield greater benefits to patients with GI cancers.
Targeted Therapy
Targeted therapy is a novel treatment that has improved outcomes of many cancers including gastrointestinal cancers. Targeted therapy is a highly sophisticated treatment that recognizes certain genetic changes that lead to the growth and spread of cancer cells. Once the targeted therapy attaches to its target genetic alteration, it helps control the growth and spread of cancer cells. Targeted therapy options are being explored in various GI cancers. Some remain investigational while others have been adequately researched and are now approved by the FDA for routine use in patients with GI cancers that harbor special genetic changes.
Targeted therapy options continue to increase and have resulted in significant improvement in patient outcomes. Genetic mutations are typically tested using genetic next-generation sequencing (NGS), which has advanced significantly in the last few decades. NGS tests can test tumor biopsy or blood samples for genetic changes that can act as targets for targeted therapy. In the next section, we will summarize genetic changes related to various GI cancers and discuss potential targeted therapy treatments that have shown promising activity against those genetic changes.
Colon Cancer
HER-2 Neu: Approximately, 3% to 5% patients with CRC are HER-2 neu positive. Several combinations have been developed to target HER-2 neu positive CRC such as trastuzumab plus lapatinib or trastuzumab plus tucatinib. Additionally, single-agent fam-trastuzumab deruxtecan has demonstrated favorable activity in patients with HER-2 neu positive CRC with an impressive response rate of 45%.
BRAF: BRAF mutations are detected in approximately 5% to 12% of patients with metastatic CRC. Based on results from the BEACON trial, the combination of the BRAF inhibitor encorafenib and the EGFR inhibitor cetuximab has emerged as a recommended regimen in patients with advanced BRAF mutated CRC following first-line therapy. This combination is currently approved by the FDA.
KRAS G12C: Although KRAS mutations are present in approximately 50% of patients with CRC, KRAS G12C, which is the only potentially targetable KRAS mutation, is present in only 3% of patients. The role of the KRAS G12 inhibitors, sotorasib and adagrasib, in patients with KRAS G12C mutant CRC is currently being evaluated. The combination of KRAS G12C inhibitors with EGFR inhibitors is a promising combination that is being explored in clinical trials.
Other Molecular Alterations: Molecular alterations such as RET fusion and TRK fusions are less common in patients with CRC (1% each) but can be effectively treated with targeted therapy. Selpercatinib (for RET fusions) and larotrectinib or entrectinib (for TRK fusions) are associated with a very favorable response rate in patients with the respective molecular alterations.
Gastroesophageal Cancer
HER-2 Neu: The combination of trastuzumab, pembrolizumab and chemotherapy is now considered the mainstay of treatment of patients with advanced HER-2 neu positive gastroesophageal (GE) cancer in the first-line setting. Several trials, however, evaluated the role of HER-2 neu targeted therapy in the second line setting but, unfortunately, failed to demonstrate improved outcomes. Trastuzumab, iapatinib and adotrastuzumab emtansine have not demonstrated favorable efficacy in this patient population. Recently, however, the DESTINY-Gastric-01 trial has demonstrated improved outcomes of fam-trastuzumab deruxtecan in patients with HER-2 neu positive tumors in the second-line setting. This agent was associated with both favorable response rates and overall survival in the study population and was therefore approved by the FDA as the only second-line therapy in patients who have progressed on trastuzumab-based therapy.
Pancreatic Cancer
BRCA Mutations: The PARP inhibitor olaparib is currently approved by the FDA in patients who have advanced pancreatic cancer that is stable following treatment with platinum-based chemotherapy. The role of PARP inhibitors in other treatment settings in pancreatic cancer is currently being explored.
Other Mutations: Other alterations such as RET and TRK fusions are rare in pancreatic cancer but can be treated with selpercatinib (for RET fusions) and larotrectinib or entrectinib (for NTRK fusions). Similarly, KRAS G12C mutation is rare in pancreatic cancer. Studies are currently exploring the role of KRAS G12 C inhibitors (sotorasib or adagrasib) in this patient population.
Biliary Cancers
FGFR 2 Alterations: FGFR 2 alterations are present in 16% of patients with cholangiocarcinoma including 20% of patients with intrahepatic cholangiocarcinoma. Recently, the oral FGFR inhibitors pemigatinib, infigratinib and futibatinib were approved by the FDA for patients with biliary cancers and FGFR alterations who have failed first-line therapy.
IDH Mutations: IDH1 mutations are present in approximately 25% of patients with biliary cancers. Ivosidenib was approved by the FDA in patients with biliary cancer and IDH1 mutations who have progressed on first-line therapy.
HER-2 Neu: Approximately 20% of patients with biliary cancers harbor a HER-2 neu molecular abnormality. Studies have suggested a potentially favorable effect of HER-2 neu targeted therapy such as trastuzumab plus pertuzumab or lapatinib, or trastuzumab deruxtecan in these patients.
BRAF Mutations: BRAF V600E mutation is present in up to 5% of patients with biliary cancers. Studies have suggested a favorable benefit of dabrafenib and trametinib in patients with BRAF V600E mutant cancers including biliary tract cancers. This combination was approved by the FDA in patients whose tumors harbor this mutation, have progressed on previous treatment and who have no satisfactory alternative treatment options.
Other Mutations: Similar to other gastrointestinal cancers, RET and TRK fusions are rare in biliary cancers but can be treated with selpercatinib (for RET fusions) and larotrectinib or entrectinib (for NTRK fusions) if present. Treatment of RET and TRK with their respective inhibitors is typically associated with a high response rate and favorable clinical benefit.
In summary, multiple new treatment modalities have evolved to help cancer patients and oncologists in the battle against cancer. Advances in the testing of tumors for genetic changes and in the discovery of targeted therapy and immunotherapy have provided cancer patients and their families with renewed hope of experiencing improved treatment outcomes without sacrificing their quality of life. Research will continue to help advance cancer treatment and possibly allow patients to triumph in the war against cancer.
