Randomized, open-label, phase 2 study of andecaliximab plus nivolumab versus nivolumab alone in advanced gastric cancer identifies biomarkers associated with survival

Abstract

BackgroundMatrix metalloproteinase-9 (MMP9) selectively cleaves extracellular matrix proteins contributing to tumor growth and an immunosuppressive microenvironment. This study evaluated andecaliximab (ADX), an inhibitor of MMP9, in combination with nivolumab (NIVO), for the treatment of advanced gastric cancer.MethodsPhase 2, open-label, randomized multicenter study evaluating the efficacy, safety, and pharmacodynamics of ADX+NIVO versus NIVO in patients with pretreated metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events (AEs). We explored the correlation of efficacy outcomes with biomarkers.Results144 patients were randomized; 141 were treated: 81% white, 69% male, median age was 61 years in the ADX+NIVO group and 62 years in the NIVO-alone group. The ORR was 10% (95% CI 4 to 19) in the ADX+NIVO group and 7% (95% CI 2 to 16) in the NIVO-alone group (OR: 1.5 (95% CI 0.4 to 6.1; p=0.8)). There was no response or survival benefit associated with adding ADX. AE rates were comparable in both treatment groups; the most common AEs were fatigue, decreased appetite, nausea, and vomiting. Programmed cell death ligand 1, interferon-γ (IFN), and intratumoral CD8+ cell density were not associated with treatment response or survival. The gene signature most correlated with shorter survival was the epithelial-to-mesenchymal gene signature; high transforming growth factor (TGF)-β fibrosis score was negatively associated with OS (p=0.036). Gene expression analysis of baseline tumors comparing long-(1+ years) and short-term (<1 year) survivors showed that GRB7 was associated with survival beyond 1 year. Human epidermal growth factor receptor 2 (HER2)-positive disease was associated with significantly longer survival (p=0.0077). Median tumor mutation burden (TMB) was 2.01; patients with TMB ≥median had longer survival (p=0.0025) and improved PFS (p=0.016). Based on a model accounting for TMB, TGF-β fibrosis, and HER2, TMB was the main driver of survival in this patient population.ConclusionCombination of ADX+NIVO had a favorable safety profile but did not improve efficacy compared with NIVO alone in patients with pretreated metastatic gastric or GEJ adenocarcinoma. HER2 positivity, higher TMB or GRB7, and lower TGF-β were associated with improved outcomes.Trial registration numberNCT02864381 or GS-US-296–-2013.

Case Report: Complete Remission of a Patient With Metastatic Gastric Cancer Treated With Nivolumab Combined With Chemotherapy After Palliative Surgery

“…Although the differentiated histological type is an advantage of AGC ( 52 ), this case was a poorly differentiated adenocarcinoma with a good response to nivolumab. Distinct from our case, previous studies have suggested that HER-2 -positive status is related to the improvement of prognosis ( 18 , 53 ). Furthermore, some studies have proposed that the co-expression of HER-2 and PD-L1 may contribute to the immune escape of GC, meaning that HER-2 -negative status creates favorable conditions for effective immunotherapy ( 12 ).…”

Peripheral cytokine levels as novel predictors of survival in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis

“…For TGF-β, only four studies roughly met our inclusion criteria after screening title and abstracts. Two studies ( 60 , 61 ) investigated gene signatures of TGF-β rather than peripheral TGF-β concentration. One study ( 62 ) measured the peripheral level of TGF-β 1 week after anti-PD-1 immunotherapy, which did not meet our requirement.…”

How to place the duality of specific MMP-9 inhibition for treatment of inflammatory bowel diseases into clinical opportunities?

“…This effect may also be present and play a role in chronic diseases, including chronic stages of IBD and cancer. Along this line, it may be relevant to mention that recent oncology studies with Andecaliximab in cancer did not yield beneficial effects ( 75 , 76 ).…”