Anti-PD-1 plus anti-angiogenesis combined with chemotherapy in patients with HER2-negative advanced or metastatic gastric cancer: a multi-institutional retrospective study.

Background: Immunotherapy plus chemotherapy have been confirmed to be effective in treating advanced or metastatic gastric cancer (GC). Anti- programmed death-1 (PD-1) plus antiangiogenic agents have shown promising activity and tolerant toxicity in subsequent therapy of late-stage gastric cancer. The aim of this study was to assess the efficacy and safety of anti-PD-1 plus anti-angiogenic agents and chemotherapy in advanced or metastatic GC and to explore the potential biomarkers associated with response. Methods: We retrospectively reviewed thirty human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic GC patients who received PD-1 plus anti-angiogenic drugs and chemotherapy. Conversion therapy was defined when the patients could undergo resection post combination therapy. Clinical data were retrieved from medical records. We conducted exploratory biomarker analysis of baseline gene mutations and tumor mutation burden (TMB) using the next-generation sequencing (NGS), PD-L1 by immunohistochemistry (IHC), and the tumor immune microenvironment (TIME) by multiplex immunofluorescence. Results: A total of 30 patients received anti-PD-1plus anti-angiogenic drugs and chemotherapy during the study period. The objective response rate (ORR) was 76.7% [95% confidence interval (CI): 57.7-90.1%] and disease control rate (DCR) was 86.7% (95% CI: 69.3-96.2%). A total of 11 patients (36.7%) achieved conversion therapy and underwent surgery. The R0 resection rate was 90.9%. Of the 11 patients, 9 (81.8%) responded to the treatment, 1 with a pathological complete response (pCR) and 8 with a major pathological response (MPR). No adverse events of grade 3 or higher occurred. Neither PD-L1 expression nor TMB was significantly correlated with treatment response. Analysis of TIME revealed that the fraction of CD8+ T cell in the invasive margin was higher in responders than non-responders before treatment. TAM2 in the tumor center and CD8+ T cell in the invasive margin was significantly increased after combination therapy, which suggested that combination therapy promoted infiltration of CD8+ T cells, thereby exerting an antitumor effect. Conclusions: Immunotherapy plus anti-angiogenic drugs and chemotherapy is a promising treatment strategy for advanced or metastatic GC patients. Tumor infiltration CD8+ T cells may serve as potential predictive biomarker.

Molecular Landscape of ERBB2 Alterations in 14,956 Solid Tumors.

ERBB2 abnormalities frequently occur and serve as rationale therapeutic targets in cancer. In this study, clinical and next-generation sequencing data from 14,956 patients across more than 20 tumor types were collected. A total of 406 (2.7%) patients were identified with ERBB2 amplifications, and 303 (2.0%) patients with pathogenic somatic ERBB2 mutations. ERBB2 amplifications fell most frequently in breast (15.9%) and stomach (8.3%) cancers. Somatic ERBB2 SNVs/indels occurred most common in bladder/urinary tract (7.3%) and intestine (6.1%) cancers. The top mutated ERBB2 SNVs/indels were p.Y772_A775dup (25.5%) and p.S310F/Y (19.9%). Significantly higher rates of ERBB2 SNV/indels were found in women compared to men (2.8% vs. 1.5%, p < 0.0001). CDK12 was the most common co-amplification gene with ERBB2 in cancers with a high frequency of ERBB2 amplifications. Patients with ERBB2 amplifications or mutations had higher TMB compared with patients with non-ERBB2 alterations. The study provided the landscape of ERBB2 alterations across a variety of solid tumors that may benefit from anti-HER2 agents.

Clinical Impact of Switching to Ceritinib After Severe AEs Related to Crizotinib/Alectinib in a Novel PTH2R-ALK Fusion Lung Adenocarcinoma: A Case Report.

Lung cancer is still the leading cause of morbidity and mortality by cancer among men, according to the latest epidemiological data in China. Anaplastic lymphoma kinase (ALK) rearrangements act as key oncogenic drivers of non-small cell lung cancer (NSCLC) and have been identified in 5-6% of NSCLC. Although ALK inhibitors (ALK-TKIs) were proven to be more effective than chemotherapy in ALK-positive NSCLC patients and the safety profile of these drugs was favorable, novel ALK fusions NSCLC might discontinue or switch treatment because of adverse events (AEs) have rarely previously been reported. Here, we describe a male patient with stage IV lung adenocarcinoma who carried a novel PTH2R-ALK fusion identified by next-generation sequencing (NGS). The patient first took crizotinib but switched to alectinib due to gastrointestinal AEs. Although alectinib remained effective on tumors, ceritinib (450 mg) was replaced after the AEs of hyperbilirubinemia occurred. After reducing the dose to 300mg, the diarrhea AEs caused by ceritinib were effectively relieved, and the patient obtained sustained clinical benefit with progression-free survival nearly 12 months. Our findings offer valuable information for the safety management of NSCLC patients with a novel PTH2R-ALK fusion treated by ALK-TKIs.