ACRT Journal

Introduction

Recently, immune checkpoint inhibitors have represented an amazing revolution of standard of care for several solid tumours. Currently, immune checkpoint inhibitors in gastric cancer are limited to metastatic setting and for a restricted number of patients with programmed death ligand-1 (PD-L1) positive tumours or microsatellite instability tumours (MSI-H), that are the 22% of gastric cancers [1].

After diagnosis of metastatic gastric cancer, PD-L1 CPS score, MSI status and HER2 status are mandatory information to define drug therapy (Figure 1).

Currently, the accepted scoring system for the assessment of PDL1 expression is the combined positive score (CPS). In particular, the PD-L1 CPS score consists of the number of positive tumour cells, lymphocytes and macrophages, divided by the total number of viable tumour cells multiplied by 100. The convincing rationale of efficacy in the use of immunotherapy in these patients could be related to the presence of lymphocytes.

In a retrospective cohort study it was found that EBV positivity and high tumour mutational burden (TMB) were associated with higher PDL-1 expression, and consequently with “inflamed microenvironment”. In addition, tumours located in the fundus and cardia had more frequently higher PD-L1 expression.

The PDL-1 expression, as mentioned, is considered as a predictive biomarker for response to ICI therapy. It could be also considered as a positive prognostic biomarker that correlates with overall survival [2,3].

In consideration of the poor prognosis of patients affected by gastric cancer, introduction of new strategies is essential. In this regard, several trials have explored the efficacy and safety of the use of immunotherapy in metastatic gastric cancer.

The Checkmate 649 trial enrolled 1581 patients and studied the role of immunotherapy in combination with chemotherapy in first line setting. In this study overall survival was 13.1 months in the combination group and 11.1 months in the chemotherapy group (HR of 0.71). In particular, nivolumab led to an improvement in PFS (progression free survival) in patients with PD-L1 CPS ≥5, with a median PFS of 7.7 months versus 6.05 months in the chemotherapy group. In summary, the study demonstrated superior OS, along with PFS benefit, with an acceptable safety profile [4].

From this evidence, currently, in first line setting nivolumab is approved in combination with Platinum-fluoropyrimidine doublet chemotherapy in case of a PD-L1 CPS ≽5. While the role of immunotherapy in metastatic setting is clear, several trials investigated the efficacy of PD-1 inhibitors in other settings. The ATTRACTION-5 compared chemotherapy plus nivolumab with chemotherapy plus placebo in stage III gastric or gastroesophageal cancer after surgery. The relapse free survival (RFS) rates were 68.4% in the combination group and 65.3% in the chemotherapy group, so the addition of nivolumab failed to improve RFS [5].

A Japanese multicentre single arm phase I study evaluated Nivolumab monotherapy in patients with diagnosis of respectable gastric cancer (from stage I to stage III). 31 patients received two cycles of Nivolumab before surgery (23% of patients had MSI-H tumours and 64% had PDL-1 positive tumours). 30 patients received surgery, with 5 major partial responses and 1 complete response. 27 patient of 31 had R0 resection, and only one patient had treatment-related adverse event of grade 3-4 [6]. The recent phase II study NEONIPIGA investigated neoadjuvant approach with nivolumab plus ipilimumab (three months of therapy) in MSI-H resectable gastric cancer. 19% of patients had adverse events of grade 3-4. 29 patients of 32 underwent R0 gastrectomy, with 58.6% of complete responses. After surgery, patients received 9 cycles of adjuvant Nivolumab [7].

In a Chinese phase 2 trial standard chemotherapy was compared to a combination of camrelizumab (PD-1 inhibitor) and apatinib (VEGFR-2 tyrosine kinase inhibitor) combined plus chemotherapy (nab-paclitaxel and S-1). 106 patients were randomised to receive nab-paclitaxel and S-1 with or without camrelizumab and apatinib for three cycles. The combination group reached a significantly higher major pathological response (33% versus 17%) and RO resection rate (94.1% versus 81.1). The combination therapy was well tolerated with 33.3% of adverse events of grade 3-4 versus 26.4% in the chemotherapy alone group.

The subgroup analysis revealed a higher benefit of the combination treatment in patients with PDL-1 positive and MSI-H tumors [8].

In February 2023 a single-arm multi-cohort phase 2 trial (INFINITY) investigated the combination of tremelimumab and durvalumab in neoadjuvant setting in patients with MSI-H resectable gastric cancer. Among 15 patients recruited, 14 underwent surgery and 9 patients had a complete response (60%). 80% of patients had a major-complete pathological response and only 1 patient had disease progression. The treatment was welltolerated with grade 3 or more immune-related adverse events occurring only in 3 patients [9]. From this evidence it is clear the importance of investigating the effectiveness of immunotherapy in neoadjuvant/perioperative setting in selected patients.

Figure 1: Molecular profiling for drug therapy.

Case Presentation

Herein, we discuss two clinical cases of patients affected by inoperable gastric cancer who received a combination of chemotherapy and PD-1 Inhibitor and who achieved complete pathologic response.

First clinical case

A 66-year-old female came to our observation in March 2023 with a diagnosis of unrespectable gastric cancer. In her clinical history, the following data were recorded: a papillary thyroid carcinoma operated and treated with radiotherapy in 2013, former smoker, no alcohol use/abuse, no cancer familiarity. In April 2023 she had an esophagogastroduodenoscopy. A gastric ulcer on the pyloric region and on the posterior wall of the stomach antrum was diagnosed and 12 fine-needle biopsies were taken (see Figure 2), the histological examination indicated tubular gastric adenocarcinoma, without finding of H. Pylori infection.

Figure 2: the gastric ulcer on the pyloric region and on the posterior wall of the stomach antrum during gastroscopy.

Immunohistochemistry (IHC) demonstrated: HER2 (-). The tumour was microsatellite unstable (MSI-H) and PD-L1-positive with a CPS score of 10 (measured with immunohistochemistry). At diagnosis, tumour markers (CEA, CA19.9, CA 125) were negative. Then she had a contrast-enhanced computed Tomography (CT) that showed gastric thickening and abdominal pathological lymphadenopathy (see Figure 3).

Figure 3: slice from staging CT scan.

We discussed the case during our weekly gastrointestinal Multidisciplinary Team (MDT), and we agreed with the proposal of first line therapy for advanced gastric cancer, which was defined “never radically operable” for abdominal lymph nodes. Therefore she started in June 2023 the first line of chemotherapy with Nivolumab 240 mg - mFOLFOX (Oxaliplatin 85 mg/mq, Calcio Levofolinato 200 mg/mq, 5-Fluorouracile 2800 mg/mq DT) , according to PDL1 CPS.

At the end of 7 cycles a CT scan described partial response of the gastric mass and lymph nodes. We therefore updated the case during our MDT and agreed with an exploratory laparoscopy with possible gastrectomy. In October 2023 she underwent a total gastrectomy with D2 lymphadenectomy and jejunojejunostomy, and the histological exam showed a pathological complete response and negative peritoneal washing. A postoperative CT scan performed after two months demonstrated that there was no tumour recurrence. The patient recovered well after surgery and resumed treatment with Nivolumab - mFolfox. We have planned 12 cycles of chemo-immunotherapy (7 before surgery and 5 after surgery). If no relapse will be noted, Nivolumab maintenance will be administered up to one year.

Second Clinical case

A 64-year-old female came to our observation in November 2023 with a diagnosis of unresectable gastric cancer.

In her clinical history the following data were recorded: never smoker, no alcohol use/abuse, no cancer familiarity.

Physical examination showed epigastric tenderness. Patient’s weight was 56 kg and her height was 156 cm. Also, no comorbidities were collected. A CT showed a mass of 4.5 cm of diameter indissociable from gastric antrum characterised by increased thickness and locoregional lymph node involvement (see Figure 4).

Figure 4: CT slices of the staging exam.

An upper gastrointestinal endoscopy was performed that resulted in a major macroscopic alteration in gastric antrum, 12 fine-needle biopsies were taken (see Figure 5). Histological examination described undifferentiated gastric adenocarcinoma, without finding of H. Pylori infection. Immunohistochemistry (IHC) demonstrated: HER2 (-). The tumour microenvironment (TME) of the patient was microsatellite instability (MSI-H) and PD-L1positive by IHC with a CPS score of 60.

Figure 5: endoscopic view of diagnostic gastroscopy.

At diagnosis, tumour markers (CEA, CA19.9, CA 125) were negative. After diagnosis, we discussed the patient’s case during our multidisciplinary team meeting and decided to perform a diagnostic laparoscopy to exclude peritoneal involvement. The laparoscopy and peritoneal washing were negative and clinical TNM stage was defined as cT4bN3 with paracaval lymph nodes involved.

We therefore updated the case during our MDT with the laparoscopic information and agreed, all together, with the proposal of systemic therapy for advanced stomach cancer, defined by our surgery team as “never radically operable” for the paracaval lymph nodes involvement.

In December 2023, a first-line chemo-immunotherapy was started according to the CheckMate 649 regimen (Nivolumab plus oxaliplatin, fluorouracil and leucovorin), considering PDL1 CPS score, The cycles were well tolerated and no G3-4 adverse reactions were observed. Surprisingly, after the first two cycles of therapy the patient began to report less dysphagia and to gain weight. Eight cycles of treatment were performed, interspersed with a radiological check after the first 4 cycles, which showed reduction in the diameters of the gastric mass and lymph nodes (Figures 6&7).

At the end of 8 cycles, a CT scan demonstrated a major reduction of the primary tumour and lymph nodes, which pushed us to rediscuss the non-operability during our weekly multidisciplinary team: an exploratory laparoscopy with possible gastrectomy was thus scheduled. In March 2024 a laparoscopic subtotal gastrectomy with D2 lymphadenectomy and jejunojejunostomy was performed, without complications. Concurrently, the pathology review of his specimen revealed non-viable tumour cells identified in the primary tumour lesion as well as in all resected lymph nodes, that is pathological complete response (pCR).

Figure 6: Mild chronic superficial inflammation with focal dysepithelialization and mucosal erosions, hyperemia, marked submucosal edema, ectasia and congestion vascular, stromal fibrosis; there is associated incomplete intestinal metaplasia and regenerative hyperplasia sometimes adenomatous glandular epithelium with low-grade dysplasia.

Figure 7: A postoperative CT scan performed after two months demonstrated that there was no tumour recurrence.

The patient recovered well after surgery and resumed treatment with Nivolumab 240 mg - mFOLFOX (Oxaliplatin 85 mg/mq, Calcio Levofolinato 200 mg/mq, 5-Fluorouracile 2800 mg/mq DT). We have planned 12 cycles of chemo-immunotherapy in total (8 before surgery and 4 after surgery), then, if no relapse will be registered, immunotherapy will be administered for up to one year.

Discussion

With the introduction of immunotherapy, the landscape of gastric cancer treatments has been changed. Immunotherapy has demonstrated efficacy in advanced gastric cancer, in particular in first line setting in combination with standard chemotherapy, but it has become necessary to explore the combination of chemotherapy and PD-1/PDL-1 inhibitors in other settings.

From several studies in the metastatic setting, we know that patients with positive PD-L1 expression and/or with MSI- high benefit from the addition of immunotherapy to standard chemotherapy. (CHK649)

Neoadjuvant chemotherapy has been widely used to improve R0 resection rates and event-free survival, but its efficacy is still limited to low pathological regressions. By combining immunotherapy or eventually target therapy in this setting, the outcomes could improve with an acceptable toxicity profile.

Based on preliminary data, the neoadjuvant immunotherapy obtains good responses, especially in “inflamed tumours”, characterised by MSI-H or PD-L1 positive status.