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Current and Future Aspects of Immunotherapy for Esophageal and Gastric Malignancies
Abstract
Esophagogastric (EG) cancer has a poor prognosis despite the use of standard therapies, such as chemotherapy and biologic agents. Recently, immune checkpoint inhibitors (ICIs) have been introduced as treatments for EG cancer; nivolumab and pembrolizumab have been approved in the United States and Europe to treat advanced EG cancer. Other ICIs, such as avelumab, durvalumab, ipilimumab, and tremelimumab, have been evaluated in several trials, although their roles are still not established in clinical practice. In addition, preclinical evidence suggests that combining an ICI with a tumor-targeting antibody can result in greater antitumor effects in metastatic EG cancer. There are not yet validated predictive biomarkers to identify which patients will respond best to ICI treatment. PD-L1 expression may predict intensity of response, although PD-L1–negative patients can still respond to ICIs. Despite differences in PD-L1 expression between Asian and non-Asian populations, no geographic differences in rates of treatment-related or immune-mediated/infusion-related adverse events have been reported. Also, several trials are currently evaluating combinations of ICIs, standard chemotherapy, and biologic agents as well as novel biomarkers to improve treatments and outcomes. Our review will address the current use of and evidence for ICIs for advanced EG cancer treatment and future trends in this area for clinical practice.
This description of potential targets for future immune therapies, including traditional cancer cell antigens such as HER2 and novel cancer cell targets such as claudin 18.2, will prepare clinicians for the introduction of future therapies targeting these or similar molecules.
This explanation of how molecular features, such as microsatellite instability status, Epstein-Barr virus status, and PD-L1 expression, affect response to pembrolizumab can inform treatment selection and timing.
The lack of differences among treatment-related adverse events and immune-mediated/infusion-related adverse events between Asia and other parts of the world may help allay concerns and increase use of immune checkpoint inhibitors.
Potential synergy between immunotherapy and other agents (e.g., trastuzumab, bevacizumab, and lapatinib) suggests that such combinations may be particularly effective and calls for further investigation.
This summary of ongoing trials, including the combination of pembrolizumab with titanium silicate/cisplatin or titanium silicate/oxaliplatin as first-line chemotherapy, and the combination of margetuximab, a chimeric immunoglobulin G monoclonal antibody against HER2, with pembrolizumab, prepares clinicians for the introduction of these combinations.
Globally, esophagogastric (EG) cancer accounts for 1.6 million new cases and 1.25 million deaths per year, making it the second most common cause of cancer-related death worldwide in the past decade.1 Recent research illustrates the biologic heterogeneity of EG cancer. Squamous cell cancers of the esophagus share many molecular features with other upper aerodigestive tract squamous cell cancers, whereas EG adenocarcinomas are now often divided into four subtypes according to The Cancer Genome Atlas (TCGA) Research Network2,3: those with chromosomal instability, those with microsatellite instability-high (MSI-H), those who are Epstein-Barr virus (EBV) positive, and those who are genomically stable.
MSI-H and EBV-positive types are the most immunogenic gastric cancer subtypes.2,4 The MSI-H subtype accounts for approximately 20% of all early-stage gastric cancers and is characterized by hypermutation resulting from silenced DNA mismatch repair proteins, such as MLH1; these mutations frequently affect KRAS, PI3K, PTEN, MTOR, ALK, and ARID1A. Early-stage MSI-H gastric cancer has the lowest risk for recurrence and the best prognosis among all gastric cancer subtypes.2,4 EBV-positive gastric cancer, which accounts for approximately 10% of localized gastric cancers, exhibits a lymphoepithelioma-like carcinoma morphology and is characterized by high PD-L1 and PD-L2 expression, PIK3CA mutations, CDKN2A silencing, and JAK2 amplification. EBV-positive gastric cancer has an intermediate risk for recurrence and intermediate prognosis.2,4,5 The biologic characteristics of MSI-H and EBV-positive gastric cancers make these subtypes excellent candidates for anti–PD-1–directed immune checkpoint inhibitor (ICI) therapy.6
Although MSI-H and EBV-positive gastric cancer subtypes are restricted to the corpus and antrum of the stomach, the Esophageal Cancer Clinical and Molecular Stratification Consortium identified an immunogenic subtype of esophageal adenocarcinoma that exhibits a dominant T>G mutational pattern associated with a high mutational load and neoantigen burden. On the basis of preclinical evidence, it was suggested that this esophageal cancer subtype is more sensitive to immunotherapy, including agents targeting CTLA-4 and PD-1/PD-L1.7
The success of cancer immunotherapy has generated tremendous interest in identifying new immunotherapeutic targets. Potential targets for immune therapy include traditional cancer cell antigens, such as HER2, and novel cancer cell targets, such as claudin 18.2.8,9 Beyond cancer cell characteristics, stroma-derived factors are of utmost importance for the immune surveillance of cancer and may thus represent future immunotherapy targets. The stroma is composed of cancer-associated fibroblasts, tumor-associated macrophages (TAMs), and tumor-infiltrating T lymphocytes, as well as other immune cells, endothelial cells, extracellular matrix proteins, and signaling molecules, such as cytokines.10 Previous work has identified a stromal-response signature, enriched for genes encoding inflammatory, extracellular matrix, cytokine, and growth factors. In gastric cancer, this signature almost perfectly differentiates tumor from nonmalignant gastric tissue and hence can be regarded as highly tumor specific.11 High expression of cancer-associated fibroblast-derived secretion products, including CXC-chemokine ligand 1, interleukin-6, and interleukin-8, is a poor prognostic factor and indicates therapeutic resistance in gastric cancer. In particular, diffuse-type gastric cancer is characterized by abundant stroma. Transforming growth factor-β signaling is a major stroma-related pathway; gastric cancer transcriptome data from 940 patients showed that deregulated transforming growth factor-β signaling is associated with dysregulation of stroma-related gene expression.12
Macrophages and other myeloid immune cells are promising effectors of cancer immunotherapy. Macrophages are important in phagocytosis, antigen presentation, and production of cytokines and growth factors. In response to microenvironmental signals, TAMs may polarize into tumor-resisting M1 or tumor-promoting M2 macrophages. Recently, studies have indicated that M2-type TAMs might be used as an independent prognostic factor for gastric cancer.13,14 Molecules that target macrophage colony-stimulating factor 1 receptor and restore TAMs to an M1 phenotype are being investigated in clinical trials in several cancer types, including gastric cancer. In addition, overexpression of CD47 in gastric cancer helps cancer cells escape phagocytosis by M1 macrophages; thus, CD47 is also a potential therapeutic target.15-17
PD-1 monoclonal antibodies, currently the mainstay of immunotherapy, have been shown to be captured from the T-cell surface within minutes by TAMs in vitro. Macrophage uptake of anti–PD-1 monoclonal antibodies depends both on the drug’s Fc domain glycan and on Fcγ receptors expressed by host myeloid cells. In vivo blockade of Fcγ receptors before PD-1 monoclonal antibody administration substantially prolongs PD-1 monoclonal antibody binding to tumor-infiltrating CD8+ T cells and enhances immunotherapy-induced tumor regression in mice. These findings provide insights into PD-1 target engagement in vivo and identify specific Fc/Fcγ receptor interactions involving TAMs that can be modulated to improve ICI therapy.18
Currently available immunotherapies stimulate the adaptive immune system to attack cancer by inhibiting co-inhibitory signaling through CTLA-4 and PD-1/PD-L1.19 Expression of these immune checkpoints varies widely and may correlate with prognosis (Fig. 1). Immunohistochemistry and somatic mutation profiling revealed that CTLA-4 and PD-L1 were expressed in 87% and 45%, respectively, of gastric cancer tumors. Expression was associated with poor prognosis in some studies.20 Furthermore, PD-L1 expression in tumor cells (12% of cases) and immune stromal cells (44% of cases) has been shown to correlate with CD8+ T-cell infiltration.21 However, the pattern and prognostic implication of PD-1/PD-L1 expression require further study. Recently, PD-L1 expression was found to be significantly more prevalent in men; in gastric cancers of the proximal stomach; and in unclassified, papillary, HER2-positive, EBV-positive, MSI, and PIK3CA-mutated cancers. High PD-L1 expression was associated with a significantly better patient outcome and was an independent predictor of survival in this study.22
FIGURE 1. Adaptive T-Cell Response
T-cell-mediated adaptive tumor immune responses are controlled by co-stimulatory and co-inhibitory signaling. Esophagogastric cancer exhibits enhanced expression of inhibitory checkpoint proteins, including PD-L1, PD-L2, PD-1, and CTLA-4. In addition, several co-inhibitory ligands, such as B7-H3 (also known as CD276) and B7X (also known as B7-H4), are upregulated in gastric cancer. Other potential immune checkpoint proteins, such as HHLA2, galectin 9, and galectin 3, are overexpressed in some tumors and mediate immune suppression through transmembrane and immunoglobulin domain-containing 2 (TMIGD2), T-cell immunoglobulin and mucin domain-containing 3 (TIM-3), and lymphocyte activation gene 3 (LAG-3). These immune signaling pathways are potential therapeutic targets for gastric cancer.
Abbreviations: MHC, major histocompatibility complex class I; TCR, T-cell receptor.
Adapted from Ajani et al.23
Several immune checkpoint pathways have been reported to be frequently upregulated in EG cancer and may represent targets for future therapies. Suppressive immune checkpoint proteins include lymphocyte activation gene 3 protein (LAG-3), a lymphocyte surface protein, and T-cell immunoglobulin-and mucin-domain-containing molecule-3, both of which have been found to be overexpressed in patients with EG cancer. Indoleamine 2,3-dioxygenase is often overexpressed in EG cancer; it catabolizes tryptophan to create an immunosuppressive tumor microenvironment.24,25 Inhibitors of these proteins may work in synergy with anti–PD-1/PD-L1 antibodies to produce a more robust antitumor immune response. Trials examining this strategy in EG cancer and various other cancers include nivolumab plus BMS-986016 (anti–LAG-3; NCT01968109) and pembrolizumab plus epacadostat (indoleamine 2,3-dioxygenase inhibitor; NCT02178722 and NCT03196232). In addition, the FRACTION-GC study (NCT02935634) is assessing nivolumab plus BMS-986016 (LAG-3 inhibitor) or ipilimumab specifically in patients with advanced gastric cancer.24
EG cancer is highly genetically heterogeneous, both among subtypes as well as within individual tumors, which may limit the efficacy of precision medicine in EG cancer.26,27 Heterogeneity affecting the targets and potential biomarkers for immunotherapy, including PD-1/PD-L1 expression, EBV-associated PIK3CA mutations, and MSI,22,28,29 is anticipated to similarly affect its applicability. Given the frequency of baseline heterogeneity in targetable genomic alterations in EG cancer, current tissue sampling practices for biomarker testing have been found to be ineffective in guiding precision medicine, calling for evaluation of routine profiling of metastatic lesions and/or cell-free DNA.27
In addition, recent studies suggest that intratumoral molecular heterogeneity is the basis for biologic evolution that eventually leads to resistance against immunotherapy and targeted therapy in EG cancer.6,30 Thus, progression-free survival may be prolonged by integrating evolutionary principles into clinical cancer treatment protocols, a strategy termed natural adaptive therapy.31 This approach aims to prevent or slow the proliferation of resistant malignant cell populations by applying understanding of ecological and evolutionary processes.
Anti–PD-1 antibodies pembrolizumab and nivolumab are routinely used for the treatment of patients with metastatic EG adenocarcinoma. Pembrolizumab was approved in 2017 in the United States for the treatment of PD-L1–positive or MSI-H EG cancer.32-34 In 2017, nivolumab was approved in Japan for the treatment of gastric cancer irrespective of PD-L1 status,35 motivated by the results of randomized trials (described in the MSI-H and EBV-Positive Gastric Cancer and PD-L1 as a Biomarker sections).
The anti–PD-L1 antibodies avelumab and durvalumab have shown promising early activity in gastric cancer, but avelumab ultimately failed to improve survival over standard chemotherapy.36-38 Furthermore, ICIs targeting CTLA-4, ipilimumab, and tremelimumab were evaluated in gastric cancer with minimal efficacy.39,40 Thus, CTLA-4 inhibitors are currently only used in clinical trials in combination with other agents, such as PD-1 inhibitors.
Tumor immunogenicity is proportional to the number of the neoantigens that a T cell can target, and EG cancer is among the most immunogenic tumors, after melanoma, bladder, and lung cancer.41
MSI-H and EBV-positive gastric cancers have the highest immunogenicity and responses to anti–PD-1 therapy because of their high neoantigen burden and PD-L1 expression, respectively.6,33,34 MSI-H and EBV-positive tumors each comprise approximately 5% of metastatic and 10%–20% of localized gastric cancers.4 In an initial small, phase II study in patients with metastatic treatment-refractory solid tumors, overall response rates (ORRs) to pembrolizumab were 71% (five of seven patients) in MSI-H gastric and endometrial tumors.34 In a follow-up study enrolling 86 metastatic treatment–refractory patients with 12 cancer types, including gastric tumors, the ORR was 53%, which included 21% complete responses, supporting the notion that MSI-H status is predictive of response regardless of histology.33 A similar ORR (57%) was reported for MSI-H gastric cancers in the KEYNOTE-059 study.32 On the basis of these data indicating durable response and survival, pembrolizumab was approved by the U.S. Food and Drug Administration for use in patients with chemotherapy-refractory metastatic MSI-H tumors, irrespective of site of origin.
High levels of PD-L1 expression and a dramatic response to pembrolizumab have been reported in EBV-positive gastric cancer. As EBV-positive and MSI-H tumors are mutually exclusive, these associations highlight the importance of routine biomarker testing in EG cancer.6,30 Multiple biomarkers, including ERBB2 gene amplification, MSI status and EBV status, and—likely—tumor mutational burden, should be assessed in all patients with metastatic EG cancer, using assays that interrogate all simultaneously, and using small quantities of tumor tissues. With this goal in mind, probes for EBV and other viral sequences are being incorporated into tumor sequencing panels, allowing detection of these DNA sequences at no additional cost and without the need for additional tumor material.
The majority of pembrolizumab trials have required that patients have tumors with a PD-L1 combined positivity score (CPS), defined as immunohistochemistry-detected protein, in at least 1% of cells in the tumor or surrounding stroma. In the phase II KEYNOTE-059 study of pembrolizumab in metastatic gastric cancer, a 22.7% durable ORR was observed in patients with PD-L1–positive tumors receiving pembrolizumab as third-line treatment, with a median response duration of 8.1 months, compared with an ORR of 16.4% among the third-line population overall, leading to U.S. Food and Drug Administration approval specifically for PD-L1–positive gastric cancer, preferably in the third-line setting.32
Nivolumab single-agent activity in gastric cancer is similar to that of pembrolizumab, but results regarding the effect of PD-L1 expression on efficacy are inconsistent. In the phase III, placebo-controlled ATTRACTION-2 study in Asia, nivolumab monotherapy led to an ORR of 11% and increased 12-month OS to 27% versus 11% with placebo (hazard ratio [HR] 0.63; p < .0001); this survival benefit was independent of PD-L1 positivity.35 In the CheckMate-032 study in Western patients, ORR was higher in PD-L1–positive tumors (27% vs. 12% in PD-L1–negative tumors).42
Pembrolizumab monotherapy demonstrated promising activity and manageable safety in the third-line setting, although clinical benefit from anti–PD-1 therapy in the fourth-line setting is lower because of patient frailty and deterioration. When compared with second-line paclitaxel chemotherapy in KEYNOTE-061, pembrolizumab did not significantly improve overall survival (OS) in patients with metastatic PD-L1–positive (CPS ≥ 1) EG adenocarcinoma (HR 0.82; 95% CI, 0.66–1.03; one-sided p = .0421).43 Although ORR was comparable in the two groups (16% vs. 14% for pembrolizumab and paclitaxel, respectively) and responses were more durable in the pembrolizumab group, response onset was more rapid in the chemotherapy group.43 Post hoc analysis revealed that the pembrolizumab treatment effect was greater for patients with a PD-L1 CPS of 10 or greater (HR 0.64; 95% CI, 0.41–1.02), with a median OS of 10.4 months and an ORR of 24.5% with pembrolizumab versus a median OS of 8.0 months and 9.1% with paclitaxel. Once again, patients with MSI-H tumors, irrespective of CPS, did well on pembrolizumab in this study (HR 0.42; median OS, not reached).
Taken together, the data suggest that, for patients with MSI-H tumors (representing 5% of EG cancer cases), those with EBV-positive tumors (5%), or those with a PD-L1 CPS greater than 10 (19%), pembrolizumab should be considered in earlier lines of therapy, particularly because pembrolizumab is less toxic than second-line chemotherapy (grade 3–5 treatment-related adverse events, 14% for pembrolizumab vs. 35% for chemotherapy).43 Results are expected soon from the phase III KEYNOTE 62 (NCT02494583) and CheckMate 649 (NCT03215706) studies examining the role of anti–PD-1 therapy in combination with first-line therapy.
Although single-agent anti–PD-1 is clearly a therapeutic breakthrough, the majority of patients do not benefit, and, in addition to PD-L1 expression, there are no validated predictive biomarkers of drug sensitivity. Furthermore, the mechanisms by which EG tumors and the tumor microenvironment adapt to immune checkpoint blockade and the implications of these adaptive changes for therapeutic benefit have not been studied systematically in patients.
Combined anti–PD-1 and anti-CTLA 4 blockade is synergistic in preclinical studies,44,45 and the combination led to enhanced response rates in patients with metastatic EG cancer in the CheckMate 032 study.42 The ORR for nivolumab plus ipilimumab was 24% in EG cancer regardless of PD-L1 status, and it was 44% in a PD-L1–positive cohort (defined by tumor PD-L1 expression, not CPS score). Although these data are promising and led to inclusion of a nivolumab/ipilimumab group in the phase III CheckMate 649 study, the observed 47% grade 3/4 adverse event rate makes it difficult to combine this regimen with chemotherapy.
Preclinical evidence suggests that combining an ICI with a tumor-targeting antibody can result in greater antitumor effects in metastatic EG cancer. In patients with HER2-positive metastatic EG cancer, first-line treatment with the combination of pembrolizumab and trastuzumab plus chemotherapy demonstrated promising clinical activity (ORR, 87%; disease control rate, 100%; median PFS, 11.4 months; median OS, not reached).46 The randomized, phase III KEYNOTE 811 trial (NCT036153260) of pembrolizumab in combination with trastuzumab and chemotherapy is currently underway.
Advanced metastatic esophageal cancer, the seventh most common cancer worldwide, is highly lethal, causing almost 572,000 cases and 509,000 deaths in 2018.47 Esophageal cancers comprise two main histologic types: squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). ESCC accounts for approximately 90% of cases of metastatic EC in Asia, Africa, and France, whereas EAC is more common in North America and Western Europe, representing 62% of cases in the United States.47,48 Patients with advanced EC after first-line chemotherapy, usually a combination of a platinum agent with a fluoropyrimidine, have poor prognosis and limited treatment options.49,50 Taxanes and irinotecan are used after first-line therapy, but no OS benefit has been demonstrated in phase III studies.51
Gastric cancer is the fifth most common cancer and the third most common cause of cancer mortality worldwide.47 Incidence and mortality rates are highest for both men and women in Eastern and Western Asia, Latin America, and some Eastern European countries,52 whereas the incidence of gastric cancer in North America and Western Europe is rare. Gastric cancer represents a major health care challenge across Asia, and particularly Eastern Asia. Asian and non-Asian populations may differ in their gastric cancer risk factors. For example, Asian Helicobacter pylori strains are enriched in cagPAI pathogenicity gene variants compared with non-Asian strains, which may modulate carcinogenicity.53 H. pylori is one of the most common gastric pathogens worldwide and is a major cause of peptic ulcer disease, chronic gastritis, and gastric cancer.54 Both in Asia and elsewhere, first-line therapy is a platinum/fluoropyrimidine combination based on the demonstrated improvement in survival. The triple combination of docetaxel, cisplatin, and fluorouracil has been shown to improve OS compared with the cisplatin and fluorouracil in Western countries55; thus, it also is considered standard of care in North America and Western Europe. Use of the FLOT regimen (docetaxel, oxaliplatin, fluorouracil/leucovorin) is limited because of toxicity.56
H. pylori colonization results in a local infiltration of neutrophils and macrophages as well as T and B cells, some of which are specific for the H. pylori antigen.57 However, the infection normally persists, suggesting that H. pylori may alter the normal host immune response.58 Several studies addressing H. pylori effects on immune infiltrates, and specifically on T cells, have demonstrated that exposure to H. pylori impairs T cells’ ability to proliferate,59 that H. pylori can cause apoptosis in Fas-bearing T cells by inducing the expression of Fas ligand,60 that VacA H. pylori toxin impairs antigen presentation on the class II major histocompatibility complex,61 and that VacA blocks T-cell proliferation by inducing G1–S cell cycle arrest.62 Hence, H. pylori infection persistence has been associated with less-responsive T cells and increased PD-L1 expression, favoring peripheral tolerance to H. pylori, which appears to reduce immunity to gastric cancer.
Investigation of more than 1,600 gastric cancers revealed that tumor immunity signatures differ significantly between Asian and non-Asian patients.63 Enrichment of tumor-infiltrating T cells and T-cell gene expression signatures, including CTLA-4 signaling, was more frequent among non-Asian gastric cancers. Furthermore, in non-Asian gastric cancers, expression of the immunosuppressive T-regulatory cell marker FOXP3 was lower compared with Asian tumors (p < .05).
Molecular subtyping may also shed light on geographic/ethnic differences in gastric cancer immunity. The TCGA consortium, which analyzed gastric tumors from mostly Western (with some Korean and Vietnamese) patients,2 and the Asian Cancer Research Group4 each subdivided gastric cancers into four molecular subtypes, but these were distinct. TCGA subtypes included EBV-positive, MSI-high, genome-stable, and chromosomal instability types, whereas the Asian Cancer Research Group categorized subtypes as mesenchymal-like, MSI, microsatellite stable–TP53+, or microsatellite stable–TP53−. Of these subtypes, EBV-positive and MSI are most responsive to available immunotherapies (see the Tumor Biology and Immunotherapy Targets and MSI-H and EBV-Positive Gastric Cancer sections). The prevalence of both subtypes is similar between Asian and non-Asian populations; MSI accounted for 21% of the TCGA sample and 24% of the Asian Cancer Research Group, and EBV-positive accounted for 9% of the TCGA tumors; EBV prevalence was reported elsewhere as 8.3% in Asia.64
As mentioned earlier, ESCC is more prevalent in Asia, and multiple trials have found higher ORRs for ICIs in ESCC compared with EAC. In the KEYNOTE-180 global phase II trial, the ORR for pembrolizumab was 14.3% (95% CI, 6.7%–25.4%) among patients with ESCC and 5.2% (95% CI, 1.1%–14.4%) among patients with EAC.65 In the Japanese phase II trial of nivolumab in advanced, chemotherapy-refractory ESCC, a similar ORR, 17% (95% CI, 10%–28%), was observed.66 Given this higher response rate in ESCC, ICIs might be especially effective in treating Asian patients with esophageal cancer. Results of the KEYNOTE 181 phase III study reported at the ASCO Gastrointestinal Cancers Symposium in 2019 showed that pembrolizumab improved OS in patients with metastatic esophageal cancer with a PD-L1 CPS of at least 10% who had experienced progression after one prior therapy compared with chemotherapy (HR 0.69; 95% CI, 0.52–0.93; p = .0074).67 The key subgroup analysis for OS found especially favorable outcomes with pembrolizumab in patients with ESCC in Asia who were younger than age 65. Thus, there may be differences in ICI efficacy between Asian and non-Asian patients even within ESCC.
The efficacy and toxicity of ICIs appear similar between Asian and non-Asian patients with gastric cancer. In the KEYNOTE-012 study, the first trial of an ICI for advanced gastric cancer, the ORR for pembrolizumab monotherapy was 22.2% (95% CI, 10.2%–39.2%), and ethnic subgroup analysis found no differences in rates of treatment- or immune-related toxicity or ORR between the 19 Asian and 20 non-Asian participants.68 In the KEYNOTE-059 study, a global phase II trial of pembrolizumab monotherapy for patients with pretreated gastric cancer, the ORR was slightly lower in Asian patients (41 patients), at 7.3% (95% CI, 1.5%–19.9%), versus 12.8% (95% CI, 8.7%–18.0%) in the non-Asian population (218 patients).69 This may relate to the higher rate of PD-L1 expression among non-Asians (60.1% vs. 41.5% in Asia).69 No geographic differences in rates of treatment-related or immune-mediated/infusion-related adverse events and incidences were observed. In contrast, in the phase III ATTRACTION-2 study in Asian (Japanese, Korean, and Taiwanese), heavily pretreated patients with gastric cancer, the ORR for nivolumab was 11.2% (95% CI, 7.7%–15.6%), the median OS was 5.3 months (95% CI, 4.6–6.4 months), and the 1-year OS rate was 26.6%.35 These efficacy data are quite similar to those of pembrolizumab in the KEYNOTE-059 study (which included predominantly non-Asian patients), which found an ORR of 11.6% (95% CI, 8.0%–16.1%), a median OS of 5.5 months (95% CI, 4.2–6.5 months), and a 1-year OS rate of 23.4%,32 and to those of nivolumab monotherapy in the CheckMate-032 study (all non-Asian patients), which found an ORR of 12% (95% CI, 12.5%–23%).42 In general, the efficacy and toxicities of ICIs are not believed to differ among geographic regions or ethnicities on the basis of cross-trial comparisons or the prevalence of various molecular subtypes (see the Geographic/Ethnic Variations in the Biology and Immunology of EG Cancer section).
At this time, EG cancer faces a new era in terms of treatment innovation and novel options for patients in later-line systemic therapies. Locally advanced, resectable EG cancer has a 5-year OS expectancy of approximately 30%. Despite use of systemic chemotherapy, median OS for stage IV EG cancer remains poor and rarely exceeds 1 year. With such poor prognosis, novel treatment options for the management of metastatic gastric cancer are urgently needed.
Until the past decade, therapeutic options for EG cancer were limited, in part because of incomplete knowledge of its molecular drivers and how they vary among tumors. Fluoropyrimidine and platinum-based chemotherapy has long been the main backbone of EG cancer systemic treatment.70 The discovery of HER2 as a driver of a subset of gastric cancers led to the introduction of the HER2-targeted antibody trastuzumab, which improved outcomes for patients with HER2-positive tumors after positive trial results in 2010.71 In addition to HER2, other biomarkers of gastric cancer prognosis and treatment response have been discovered. Deficiencies in the mismatch repair mechanism (linked to MSI-H) have been associated with strong benefit from immunotherapy, especially pembrolizumab, as indicated by the impressive ORR (53%).35 As previously mentioned, a subset of EG cancers, such as MSI and EBV-positive tumors, have a rich immune infiltrate that makes them more responsive to ICIs.72 These agents are currently approved for the treatment of the more than 40% of gastric cancers with meaningful PD-L1 expression, although the correlation with response and prognosis is still unclear (see the PD-L1 as a Biomarker section).73 EG cancer predictive and prognostic biomarkers should be further explored to improve treatment outcomes.
Furthermore, combinations of immunotherapy with other agents (e.g., trastuzumab, bevacizumab, and lapatinib) may have synergistic effects with the immune response according to findings from metastatic renal cell carcinoma.74 Several trials are evaluating combinations of targeted therapies or standard chemotherapy with immunotherapy (Table 1). Of note, a phase II trial (NCT03382600; still recruiting) is assessing the safety and efficacy of pembrolizumab (MK-3475) in combination with titanium silicate/cisplatin or titanium silicate/oxaliplatin as first-line chemotherapy in gastric cancer (MK-3475-659/KEYNOTE-659). Another phase II trial (NCT03342937; expected results in 2022) is assessing the combination of pembrolizumab, oxaliplatin, and capecitabine in gastric cancer. Finally, another phase II trial (NCT02689284; results expected in 2020) is evaluating the combination of pembrolizumab with margetuximab, a chimeric immunoglobulin G monoclonal antibody against HER2, in HER2-positive gastric cancer. The toxicities and tolerability of these new combinations are important issues to be addressed in these trials, as these can limit completion of treatment.
|
Considering the recent advances of immunotherapy, treatment options for EG cancer are rapidly increasing. At this time, there are still only a few strong established agents apart from chemotherapy. The manageable and favorable toxicity profiles of immunotherapies open possibilities for new combinations with both traditional and novel agents to optimize outcomes. Although the understanding of mechanisms of resistance, biologic effects of therapies, and pharmacokinetic and pharmacodynamic characteristics has advanced, the failure to identify appropriate predictive biomarkers has limited the success of many targeted therapies in esophageal and gastric cancer. A deeper knowledge of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies in the near future.
Disclosures provided by the authors and data availability (if applicable) are available with this article at DOI https://doi.org/10.1200/EDBK_236699.
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc.
Honoraria: AstraZeneca BioNTech AG Bristol-Myers Squibb Elsevier Infomedica Lilly Merck KGaA Merck Sharp & Dohme Roche SERVIER
Consulting or Advisory Role: Astellas Pharma Bristol-Myers Squibb Lilly Merck Sharp & Dohme SERVIER
Research Funding: Bristol-Myers Squibb (Inst)
Travel, Accommodations, Expenses: Bristol-Myers Squibb Lilly
Honoraria: AstraZeneca Novartis
Consulting or Advisory Role: MSD Oncology Pfizer Zodiac
Speakers' Bureau: AstraZeneca
Travel, Accommodations, Expenses: Amgen AstraZeneca BMS Brazil Merck Pierre Fabre Roche
Honoraria: Bayer Chugai Pharma Lilly Merck Serono Ono Pharmaceutical Taiho Pharmaceutical Takeda Yakult Honsha
Research Funding: Daiichi Sankyo (Inst) Gilead Sciences (Inst) Kyowa Hakko Kirin (Inst) Merck Serono (Inst) MSD (Inst) Ono Pharmaceutical (Inst) Pfizer (Inst) Sanofi (Inst) Shionogi (Inst)
Consulting or Advisory Role: Bristol-Myers Squibb Lilly Merck Merck Serono Pfizer
Research Funding: Amgen Bayer Boehringer Ingelheim Genentech Lilly Roche
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