Gastric cancer is the fifth most common cancer by incidence and third highest in mortality worldwide (1). For early-stage disease, the only curative option continues to be surgical or endoscopic resection, with a 5-year survival rate of 69.5% for localized disease in the United States (2). For clinical ≥ T2 or node-positive, locally advanced disease, perioperative 5-fluorouracil-based regimens (e.g., FLOT or FOLFOX) represent current treatment standards (3,4). Pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor is currently approved in treatment-refractory unresectable locally advanced, recurrent, or metastatic gastric cancer programmed death-ligand 1 (PD-L1) positivity by combined positive score (CPS) or microsatellite instability (MSI)/mismatch repair deficiency (dMMR) (5,6).
This report demonstrates a successful case of treating a resectable gastric cancer with only a traditionally neoadjuvant regimen. PD-1 inhibitors are currently limited to use in the metastatic setting, and their benefit in non-metastatic gastric cancer (i.e., neoadjuvant and/or adjuvant) has not been definitively established. Furthermore, there is an active search to identify other immunogenic biomarkers to support the use of checkpoint inhibitors in gastric cancer.
We present the following case in accordance with the CARE reporting checklist (available at http://dx.doi.org/10.21037/acr-21-11).
A 78-year-old man presented to the emergency department with hematemesis and melena. Previous medical history was unremarkable for liver pathology or GI malignancy. Additionally, he was a non-smoker and did not report notable alcohol consumption. On Day 0, upper endoscopy revealed a 3 cm friable mass in the gastric cardia; hematoxylin-and-eosin (H&E) stained histologic sections of the biopsy results confirmed poorly differentiated gastric adenocarcinoma with tumor cells associated with a prominent lymphoid infiltrate (Figure 1A). Helicobacter pylori was identified. Additional studies were notable for Epstein-Barr encoding region (EBER) in-situ hybridization positivity (Figure 1B). Immunohistochemistry showed intact nuclear expression for mismatch repair proteins (MLH1, PMS2, MSH2 and MSH6) indicative of microsatellite stability (MSS). The formalin-fixed, paraffin-embedded tumor tissue was evaluated utilizing the DAKO FDA-approved PD-L1, 22C3 pharmDX™ protocol using the Dako Automated Link 48 platform. PD-L1 protein expression is determined by using CPS, which is the number of PD-L1 staining cells divided by the total number of viable tumor cells and then multiplied by 100. PD-L1 staining cells is defined as: tumor cells showing partial or complete membrane staining at any intensity plus PD-L1 staining in tumor infiltrating or tumor adjacent mononuclear inflammatory cells (lymphocytes and macrophages) with membrane and/or cytoplasmic staining at any intensity. A specimen with CPS ≥1 is considered to have PD-L1 expression. The patient’s tumor had a high CPS of 40 (Figure 1C). Staging work-up was negative for metastatic disease, and the plan was made to start neoadjuvant systemic therapy followed by resection and adjuvant therapy for cT2N2M0 disease (Day 54).
In the extenuating circumstances of the SARS-CoV-2 pandemic, the patient preferred to limit his exposure to the hospital environment. Given this preference and the tumor’s unique features, a multidisciplinary decision was made to trial a neoadjuvant therapy regimen that would minimize SARS-CoV-2 exposure and frequency of infusion visits, while maintaining safety and efficacy of the regimen. As such, the patient was started on pembrolizumab (200 mg intravenous) and capecitabine (850 mg/m2 oral twice daily for 14 days) every 3 weeks for the first 2 cycles, followed by spacing out the pembrolizumab (400 mg) to every 6 weeks onward per tolerability (Day 54, 76, 97). Capecitabine was held on cycle #4 due to neutropenia but pembrolizumab was continued (Day 118). After receiving 4 cycles of neoadjuvant therapy, the patient underwent repeat imaging, endoscopy and biopsies showing complete radiographic and pathologic resolution of the cancer (Figures 2,3). A complete pathologic response was documented by upper GI endoscopy with no evidence of cancer on multiple biopsies (Day 154). Given the dramatic response both radiographically and pathologically—with mapping GI endoscopy—as well as the patient’s wish to avoid total gastrectomy as well as high surgical risk candidate in a 78-year-old man, we opted for surveillance rather than surgery. The patient continued on maintenance pembrolizumab (400 mg every 6 weeks for 1 year) and surveillance. At the time of this report, which has been nearly a year from the time of starting neoadjuvant therapy, the patient remains in complete remission and has not experienced any adverse events or unanticipated interruptions to his care (Figure 4).
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committees and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient.
We present a unique case of complete response to neoadjuvant chemoimmunotherapy in a patient with MSS, PD-L1-positive, and EBV-positive locally advanced gastric cancer deemed otherwise medically inoperable. There are similar case reports of partial response of locally advanced gastric cancer to neoadjuvant nivolumab (7). However, the current clinical guidelines recommend chemotherapy rather than immunotherapy in the perioperative setting for locally advanced gastric adenocarcinoma (8). FOLFOX or FLOT are the most commonly used regimens in this scenario. PD-1 blockade is currently only approved in advanced gastric cancer patients with MSI who are refractory to standard therapies and those following progression on ≥2 systemic therapies with tumors that are PD-L1 positive (CPS ≥1) (5,6). More recently, nivolumab was U.S. Food and Drug Administration (FDA) approved for the second-line treatment of advanced esophageal squamous cell carcinoma (ESCC) after fluoropyrimidine- and platinum-based chemotherapy based on results of ATTRACTION-3 (9). Immunotherapy is not approved in the non-metastatic gastric cancer setting.
There were multiple indications that suggested our patient would have a favorable response to immune checkpoint inhibition. Tumor microsatellite instability and PD-L1 positivity are the conventional predictors of response to immunotherapy in gastric cancer. Our case demonstrated high PD-L1 expression (CPS 40), whereby prior phase III evidence has shown that the benefit of pembrolizumab over chemotherapy is significantly pronounced in the first- or second-line treatment of advanced gastroesophageal cancer when PD-L1 CPS is ≥10 (10).
However, our case also demonstrated EBV-positivity in the setting of MSS status. Recently, molecular profiling of metastatic gastric tumors treated by PD-1 inhibition in a single-arm phase II study demonstrated that high microsatellite instability and EBV positivity were each strongly correlated with exceptional response rates of 85.7–100% (11). Importantly, cases of EBV-positive metastatic gastric cancer were exclusive to those with MSI tumors in this study. Pathologic review in our case also identified a prominent tumor lymphoid infiltrate. Tumor-infiltrating lymphocytes (TILs) have also emerged as a predictive biomarker for immune checkpoint inhibition across multiple solid tumors and have been associated with a gene inflammation signature and high tumor mutational burden (TMB) (12). Interestingly, in EBV-associated gastric cancer, TIL-positivity has been associated with a positive prognosis (13). In summary, although our patient’s dramatic response to neoadjuvant pembrolizumab occurred in the setting of PD-L1 positivity, there were other features including EBV-positivity and TILs that likely contributed to a robust antitumor immune response in an otherwise MSS tumor. Consequently, a limitation of this case is the baseline immunogenicity of this patient’s tumor may predispose him to better outcomes to immunotherapy.
Pressure from a global pandemic to decrease the frequency of infusions and clinic visits catalyzed our decision to trial chemo-immunotherapy as neoadjuvant therapy. We are not yet aware of any data demonstrating the objective response rates to neoadjuvant immunotherapy in gastric cancer. In terms of major clinical trials investigating pembrolizumab in metastatic gastric cancer, KEYNOTE-059, KEYNOTE-61, and KEYNOTE-62 have previously reported complete response rates of 2.3%, 4%, and 3.5% respectively (5,10,14). However, there are now ongoing randomized, double-blinded, multicenter Phase III trials such as KEYNOTE-585 investigating the efficacy of pembrolizumab with or without chemotherapy in the perioperative treatment of localized gastric adenocarcinoma (15). If the evidence proves robust, the role of immunotherapy in the neoadjuvant treatment of gastric adenocarcinoma may continue to expand in the future. Our case lends support to this novel treatment paradigm where perioperative immunotherapy-based approaches could be offered in select patients with resectable gastric cancer.
In summary, the key take-away lessons from this case include the possible use of neoadjuvant immunotherapy in place of surgery for limited cases of gastric cancer, the curative potential of PD-1 blockade in patients with limited tumor burden, and adaptation of treatment plans for individual and societal circumstances. With further investigation of the efficacy of neoadjuvant immunotherapy, then we may have another treatment option to offer patients who would not tolerate or qualify for surgical interventions.
Reporting Checklist: The authors have completed the CARE reporting checklist. Available at http://dx.doi.org/10.21037/acr-21-11
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/acr-21-11). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committees and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
- Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424. [Crossref] [PubMed]
- Howlader N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review. National Cancer Institute. 2015.
- Cunningham D, Allum WH, Stenning SP, et al. Perioperative Chemotherapy versus Surgery Alone for Resectable Gastroesophageal Cancer. N Engl J Med 2006;355:11-20. [Crossref] [PubMed]
- Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 2019;393:1948-57. [Crossref] [PubMed]
- Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: Phase 2 clinical KEYNOTE-059 trial. JAMA Oncol 2018;4:e180013 [Crossref] [PubMed]
- Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015;372:2509-20. [Crossref] [PubMed]
- Chubenko V, Inusilaev G, Imyanitov E, et al. Clinical case of the neoadjuvant treatment with nivolumab in a patient with microsatellite unstable (MSI-H) locally advanced gastric cancer. BMJ Case Rep 2020;13:e236144 [Crossref] [PubMed]
- Ajani J, D’Amico T, Bentrem D, et al. NCCN Clinical Practice Guidelines in Oncology Gastric cancer - Version 4.2020 — December 23, 2020 [Internet]. NCCN Clinical Practice Guidelines in Oncology. 2020. Available online: https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
- Kato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2019;20:1506-17. [Crossref] [PubMed]
- Shitara K, Özgüroğlu M, Bang YJ, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet 2018;392:123-33. [Crossref] [PubMed]
- Kim ST, Cristescu R, Bass AJ, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med 2018;24:1449-58. [Crossref] [PubMed]
- Linette GP, Carreno BM. Tumor-Infiltrating Lymphocytes in the Checkpoint Inhibitor Era. Curr Hematol Malig Rep 2019;14:286-91. [Crossref] [PubMed]
- Kang BW, Seo AN, Yoon S, et al. Prognostic value of tumor-infiltrating lymphocytes in Epstein-Barr virus-associated gastric cancer. Ann Oncol 2016;27:494-501. [Crossref] [PubMed]
- 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 2020;6:1571-80. [Crossref] [PubMed]
- Bang YJ, Van Cutsem E, Fuchs CS, et al. KEYNOTE-585: Phase III study of perioperative chemotherapy with or without pembrolizumab for gastric cancer. Future Oncol 2019;15:943-52. [Crossref] [PubMed]
Cite this article as: Lin CY, Mehta P, Waters KM, Chang E, Hendifar A, Osipov A, Burch M, Lin DC, Gangi A, Cho M, Gong J. Complete response to neoadjuvant pembrolizumab and capecitabine in microsatellite stable, Epstein-Barr virus-positive, locally advanced gastric adenocarcinoma: case report. AME Case Rep 2021;5:30.