Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer

Abstract

Clinical studies support the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic gastric cancer (mGC). With the goal of identifying determinants of response, we performed molecular characterization of tissues and circulating tumor DNA (ctDNA) from 61 patients with mGC who were treated with pembrolizumab as salvage treatment in a prospective phase 2 clinical trial. In patients with microsatellite instability-high and Epstein-Barr virus-positive tumors, which are mutually exclusive, dramatic responses to pembrolizumab were observed (overall response rate (ORR) 85.7% in microsatellite instability-high mGC and ORR 100% in Epstein-Barr virus-positive mGC). For the 55 patients for whom programmed death-ligand 1 (PD-L1) combined positive score positivity was available (combined positive score cut-off value ≥1%), ORR was significantly higher in PD-L1(+) gastric cancer when compared to PD-L1(-) tumors (50.0% versus 0.0%, P value <0.001). Changes in ctDNA levels at six weeks post-treatment predicted response and progression-free survival, and decreased ctDNA was associated with improved outcomes. Our findings provide insight into the molecular features associated with response to pembrolizumab in patients with mGC and provide biomarkers potentially relevant for the selection of patients who may derive greater benefit from PD-1 inhibition.

Immunotherapy: New Options in Gastrointestinal Cancers?

“…On the other hand, among EBV-negative gastric cancers, only those with MSI seem to express PD-L1 within tumor cell. As recently shown by Kim et al [4] in Nature Medicine , PD-1-targeted therapy was most effective in subgroups of patients with MSI-high, EBV-positive, or PD-L1(+) metastatic gastric cancer. Therefore, we now regularly test for both MSI and EBV and consider immunotherapy as a reasonable therapy option in these patients after failure of standard first-line therapy.…”

“…The recent publication in Nature Medicine in September 2018 [4] presented excellent data for the correlation to pembrolizumab. For hepatitis-associated HCC, this is not yet so clear.…”

“…Hacker: Due to the extraordinarily high overall response rates (up to 100%) reported so far for EBV-positive gastric cancer with pembrolizumab treatment, immune checkpoint therapy will definitely have a strong role in this indication [4]. Recovery of adaptive immunity has been demonstrated in models of viral hepatitis and HCC models during treatment with immune checkpoint inhibitors.…”

“…Moreover, a combined positive score (CPS) of > 10 was successfully applied in the Keynote 181 (press release Merck Nov. 14, 2018) and 180 [3] trials, in patients with both adenocarcinomas and squamous cell carcinomas (SCCs) of the esophagus for second- or third-line pembrolizumab treatment, respectively. Epstein-Barr virus (EBV) positivity represents another very powerful biomarker in gastric cancer, as dramatic overall response rates up to 100% to pembrolizumab have recently been reported [4]. Finally, immunoscore analysis based on mRNA expression analysis of immune/interferon-related gene products holds promise to improve prediction of immune checkpoint therapy efficacy over MSI-H/dMMR in colorectal cancer (CRC) [5] and possibly other GI cancers.…”

Immunotherapy in Esophagogastric Adenocarcinoma

“…Beside dMMR/MSI-H and PD-L1 positivity by CPS, EBV plays a highly predictive role in determining response to PD-1 inhibitors in EGA [25]. However, particularly EBV status and, to a lesser extent, dMMR/MSI-H status are largely overlapping with PD-L1 positivity according to CPS score.…”