Gastric cancer (GC), responsible for ~700,000 deaths worldwide annually, is a dismal disease, with median survival for metastatic disease less than 1 year. We examined the efficacy and safety of cabazitaxel, a novel 3rd generation taxane, in the 2nd line treatment setting in advanced GC. Comprehensive correlative studies were performed to identify genetic aberrations or tumor microenvironment signatures associated with cabazitaxel activity.
Patients with previously treated GC were eligible for this multicenter phase II study of single agent cabazitaxel (NCT01757171). The progression-free survival (PFS) rate at 3-mo using RECIST 1.1 was 28% (95%CI 17-42%) in taxane-naïve and 35% (95%CI 16-57%) in taxane treated cohorts. A fresh tissue biopsy of the tumor and matching adjacent non-tumor tissue was obtained from each of the 66 patients (87% of the study population) and was examined using whole exome sequencing (WES) and bulk RNAseq. We performed CIBERSORT deconvolution of the RNA expression data into its constituent immune cell types. Tumor samples were segregated into those with high or low macrophage M2 levels using the cohort specific median M2 abundance as the threshold. 26 tumor samples were examined for validation of the M2 signature by immunohistochemistry (IHC) using CD68 (pan-macrophage), CD163 (M2), and iNOS (M1) markers.
GC WES showed numerous somatic alterations including missense mutations, chromosomal rearrangements, SNVs, small indels and CNAs with prevalent mutations in TP53 (26/47 cases), RHOA, and RTK/RAS signaling. Clinically actionable alterations included BRAF V600E, EGFR amplifications (10/47) and HER2 amplifications (8/47). One patient had a KRAS Q61H mutation predictive of resistance to a broad spectrum of RTK inhibitors. Other alterations included mutations in RTK signaling components, deletions of MTOR and STK11 suppressor gene and mutations in PI3K/mTOR pathway.
We found that HER2 amplification was significantly more prevalent in responders, 50% HER2 positive among patients with PR/SD vs 10% in patients with PD (p=0.003). Patients with HER2 positive tumors had better PFS (p=0.04) and OS (45% 2-year survival vs 15%, p=0.002). Deconvolution analysis revealed an enrichment of an M2 macrophage signature in a cohort of patients having an improved PFS (45% vs 20% at 12 months, p=0.031). IHC analysis also showed M2 enrichment in 65% tissue samples examined (n=26). The M2-like macrophage signature was associated with improved outcome independent of HER2 amplification/ over-expression. In 8 out of 10 matched on-treatment biopsies, the M2-like signature significantly decreased post treatment.
We have identified two novel biomarkers, HER2 overexpression and M2-high tumor macrophage signature, associated with improved outcomes in patients with GC treated with cabazitaxel. Additional correlative analyses and integration are underway.
Citation Format: Sandipto Sarkar, Prashant K. Thakkar, Heinz Lenz, Peter Enzinger, Andrew H. Ko, Allyson J. Ocean, Yao Lu, Chao Zhang, Bhavneet Bhinder, Olga Plotnikova, Nikita Kotlov, Feliz Frenkel, Aleksander Bagaev, Olivier Elemento, Doron Betel, Paraskevi Giannakakou, Meredith E. Pittman, Manish A. Shah. HER2 expression and M2-like tumor infiltrating macrophages associated with Cabazitaxel activity in gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2011.