Prior antibiotic administration disrupts anti-PD-1 responses in advanced gastric cancer by altering the gut microbiome and systemic immune response.

Evidence on whether prior antibiotic (pATB) administration modulates outcomes of programmed cell death protein-1 (PD-1) inhibitors in advanced gastric cancer (AGC) is scarce. In this study, we find that pATB administration is consistently associated with poor progression-free survival (PFS) and overall survival (OS) in multiple cohorts consisting of patients with AGC treated with PD-1 inhibitors. In contrast, pATB does not affect outcomes among patients treated with irinotecan. Multivariable analysis of the overall patients treated with PD-1 inhibitors confirms that pATB administration independently predicts worse PFS and OS. Administration of pATBs is associated with diminished gut microbiome diversity, reduced abundance of Lactobacillus gasseri, and disproportional enrichment of circulating exhaustive CD8+ T cells, all of which are associated with worse outcomes. Considering the inferior treatment response and poor survival outcomes by pATB administration followed by PD-1 blockade, ATBs should be prescribed with caution in patients with AGC who are planning to receive PD-1 inhibitors.

Real World Characteristics and Clinical Outcomes of HER2-Mutant Non-Small Cell Lung Cancer Patients Detected by Next-Generation Sequencing.

PURPOSE: This study was conducted to investigate the clinical characteristics of patients with advanced non-small cell lung cancer (NSCLC) harboring human epidermal growth factor receptor 2 (HER2) mutations and to evaluate response to standard treatment and HER2-targeted agents. Materials and Methods: Using tissue and/or blood next-generation sequencing, we identified 44 patients with NSCLC harboring HER2 mutations who were treated at Severance Hospital between December 2016 and February 2021. Clinical data, including patient characteristics, mutation status, incidence of metastasis for distant lesions, and response to chemotherapy, were retrospectively analyzed. RESULTS: The median age was 58 years, and 61% of the patients were female. Most patients (64%) were never-smokers. Adenocarcinoma was the most predominant subtype (98%). A total of 66% of the patients had extrathoracic metastatic lesions, and 32% had intracranial lesions at initial presentation. The median time to the development of brain metastasis was 15.6 months (range, 2.4 to 43.7). The most common type of HER2 mutation was 12 base pair in-frame insertion in exon 20, A775_G776insYVMA. Of the 44 patients, two had concomitant driver mutations, one with epidermal growth factor receptor (EGFR) mutation (V769M), and one with BRAF mutation (V600E). Patients treated with pemetrexed-based chemotherapy (75%) had an overall response rate (ORR) and progression-free survival (PFS) of 30% and 8.3 months (95% confidence interval [CI], 3.9 to 12.7), respectively. The ORR and PFS of HER2-targeted agent treated patients (14%) were 0.0% and 1.9 months (95% CI, 0.1 to 2.8), respectively. CONCLUSION: Given its distinct characteristics and treatment responses, novel treatment strategies for HER2-mutant NSCLC should be developed promptly to improve survival outcomes of patients.

Hyperprogressive disease during PD-1 blockade in patients with advanced gastric cancer.

BACKGROUND: Investigations for programmed cell death-1 (PD-1) blockade-induced hyperprogressive disease (HPD) have not been stringently conducted in patients with advanced gastric cancer (AGC). We explored the occurrence of HPD and its clinical implications in patients with AGC and treated with PD-1 inhibitors. METHODS: We enrolled 169 patients with AGC and treated with either the PD-1 blockade (nivolumab or pembrolizumab; N = 112) or irinotecan monotherapy (N = 57) as a single agent. Tumour growth dynamics based on tumour growth kinetics and tumour growth rate (TGR) and time to treatment failure were analysed to define HPD. The incidence, clinical consequences and predictive markers of HPD were investigated. RESULTS: The optimal criteria for HPD were 4-fold increases in both tumour growth kinetics and TGR ratios and a 40% increase in TGR based on the analysis for patients treated with irinotecan. In total, 10.7% (12/112) of patients experienced HPD after PD-1 inhibitor treatment. Patients with HPD had both shorter progression-free survival (hazard ratio: 2.318; 95% confidence interval: 1.205-4.460) and overall survival (hazard ratio: 2.542; 95% confidence interval: 1.314-4.918) than patients with progressive disease without HPD, losing opportunities for subsequent systemic treatments. Although other variables including PD-L1 expression were not associated with the occurrence of HPD, hypoalbuminemia (<3.25 mg/dL) at baseline was significantly associated with the occurrence of HPD (P < 0.001) and inferior survival outcomes. CONCLUSIONS: HPD occurs in a proportion of patients with AGC and treated with PD-1 inhibitors. PD-1 inhibitor-induced HPD is associated with worse outcome, loss of eligibility for subsequent treatment and hypoalbuminemia, warranting further investigation.

Predicting treatment outcomes using 18F-FDG PET biomarkers in patients with non-small-cell lung cancer receiving chemoimmunotherapy.

BACKGROUND: Predictive markers for treatment response and survival outcome have not been identified in patients with advanced non-small-cell lung cancer (NSCLC) receiving chemoimmunotherapy. We aimed to evaluate whether imaging biomarkers of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and routinely assessed clinico-laboratory values were associated with clinical outcomes in patients with advanced NSCLC receiving pembrolizumab plus platinum-doublet chemotherapy as a first-line treatment. METHODS: We retrospectively enrolled 52 patients with advanced NSCLC who underwent baseline 18F-FDG PET/CT before treatment initiation. PET/CT parameters and clinico-laboratory variables, constituting the prognostic immunotherapy scoring system, were collected. Optimal cut-off values for PET/CT parameters were determined using the maximized log-rank test for progression-free survival (PFS). A multivariate prediction model was developed based on Cox models for PFS, and a scoring system was established based on hazard ratios of the predictive factors. RESULTS: During the median follow-up period of 16.7 months (95% confidence interval: 15.7-17.7 months), 43 (82.7%) and 31 (59.6%) patients experienced disease progression and death, respectively. Objective response was observed in 23 (44.2%) patients. In the multivariate analysis, maximum standardized uptake value, metabolic tumour volume2.5, total lesion glycolysis2.5, and bone marrow-to-liver uptake ratio from the PET/CT variables and neutrophil-to-lymphocyte ratio (NLR) from the clinico-laboratory variables were independently associated with PFS. The scoring system based on these independent predictive variables significantly predicted the treatment response, PFS, and overall survival. CONCLUSION: PET/CT variables and NLR were useful biomarkers for predicting outcomes of patients with NSCLC receiving pembrolizumab and chemotherapy as a first-line treatment, suggesting their potential as effective markers for combined PD-1 blockade and chemotherapy.