Highlights d We build the genomic and transcriptomic landscape of 465 primary TNBCs d Chinese TNBC cases demonstrate more PIK3CA mutations and LAR subtype d Transcriptomic data classify TNBCs into four subtypes d Multi-omics profiling identifies potential targets within specific TNBC subtypes

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, and molecular subtyping may result in improved diagnostic precision and targeted therapies. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we conducted the FUTURE trial (ClinicalTrials.gov identifier: NCT03805399), a phase Ib/II subtyping-based and genomic biomarkerguided umbrella trial, to evaluate the efficacy of these targets. Patients with refractory metastatic TNBC were enrolled and stratified by TNBC subtypes and genomic biomarkers, and assigned to one of these seven arms: (A) pyrotinib with capecitabine, (B) androgen receptor inhibitor with CDK4/6 inhibitor, (C) anti PD-1 with nab-paclitaxel, (D) PARP inhibitor included, (E) and (F) anti-VEGFR included, or (G) mTOR inhibitor with nab-paclitaxel. The primary end point was the objective response rate (ORR). We enrolled 69 refractory metastatic TNBC patients with a median of three previous lines of therapy (range, 1-8). Objective response was achieved in 20 (29.0%, 95% confidence interval (CI): 18.7%-41.2%) of the 69 intention-to-treat (ITT) patients. Our results showed that immunotherapy (arm C), in particular, achieved the highest ORR (52.6%, 95% CI: 28.9%-75.6%) in the ITT population. Arm E demonstrated favorable ORR (26.1%, 95% CI: 10.2%-48.4% in the ITT population) but with more high grade (≥ 3) adverse events. Somatic mutations of TOP2A and CD8 immunohistochemical score may have the potential to predict immunotherapy response in the immunomodulatory subtype of TNBC. In conclusion, the phase Ib/II FUTURE trial suggested a new concept for TNBC treatment, demonstrating the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC.

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IMPORTANCE Patients with malignant mesothelioma whose disease has progressed after platinum and pemetrexed treatment have limited options. Anti-programmed cell death 1 (PD-1) antibodies have antitumor activity in this disease, but little is known about the activity of anti-programmed cell death ligand 1 (PD-L1) antibodies in patients with mesothelioma. OBJECTIVE To assess the efficacy and safety of avelumab in a cohort of patients with previously treated mesothelioma. DESIGN, SETTING, AND PARTICIPANTS Phase 1b open-label study (JAVELIN Solid Tumor) in patients with unresectable mesothelioma that progressed after platinum and pemetrexed treatment, enrolled at 25 sites in 3 countries between September 9, 2014, and July 22, 2015. INTERVENTIONS Participants received avelumab, 10 mg/kg, every 2 weeks until disease progression, unacceptable toxic effects, or withdrawal from the study. MAIN OUTCOMES AND MEASURES Prespecified end points included confirmed best overall response based on Response Evaluation Criteria In Solid Tumors, version 1.1; duration of response; progression-free survival (PFS); overall survival (OS); PD-L1 expression-based analyses; and safety. RESULTS Of 53 patients treated with avelumab, the median age was 67 (range, 32-84) years; 32 (60%) were male. As of December 31, 2016, median follow-up was 24.8 (range, 16.8-27.8) months. Twenty patients (38%) had 3 or more previous lines of therapy (median, 2; range, 1-8). The confirmed objective response rate (ORR) was 9% (5 patients; 95% CI, 3.1%-20.7%), with complete response in 1 patient and partial response in 4 patients. Responses were durable (median, 15.2 months; 95% CI, 11.1 to not estimable months) and occurred in patients with PD-L1-positive tumors (3 of 16; ORR, 19%; 95% CI, 4.0%-45.6%) and PD-L1-negative tumors (2 of 27; ORR, 7%; 95% CI, 0.9%-24.3%) based on a 5% or greater PD-L1 cutoff. Disease control rate was 58% (31 patients). Median PFS was 4.1 (95% CI, 1.4-6.2) months, and the 12-month PFS rate was 17.4% (95% CI, 7.7%-30.4%). Median OS was 10.7 (95% CI, 6.4-20.2) months, and the median 12-month OS rate was 43.8% (95% CI, 29.8%-57.0%). Five patients (9%) had a grade 3 or 4 treatment-related adverse event, and 3 (6%) had a grade 3 or 4 immune-related, treatment-related adverse event. There were no treatment-related deaths. CONCLUSIONS AND RELEVANCE Avelumab showed durable antitumor activity and disease control with an acceptable safety profile in a heavily pretreated cohort of patients with mesothelioma. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01772004

BackgroundThe neutrophil to lymphocyte ratio (NLR) is known to be prognostic for patients with advanced cancers treated with immune checkpoint inhibitors (ICI), but has generally been evaluated as a single threshold value at baseline. We evaluated NLR at baseline and within first month during treatment in patients who received ICI for advanced cancer to evaluate the prognostic value of baseline and of changes from baseline to on-treatment NLR.MethodsA retrospective review of patients with advanced cancer treated with ICI from 2011 to 2017 at the Ohio State University was performed. NLR was calculated at the initiation of ICI and repeated at median of 21 days. Overall survival (OS) was calculated from the initiation of ICI to date of death or censored at last follow-up. Significance of Cox proportional hazards models were evaluated by log-rank test. Calculations were performed using the survival and survminer packages in R, and SPSS.Results509 patients were identified and included in the analysis. Patients with baseline and on-treatment NLR < 5 had significantly longer OS (P < 0.001). The change in NLR overtime was a predictor of OS and was observed to be non-linear in nature. This property remained statistically significant with P < 0.05 after adjusting for age, body mass index, sex, cancer type, performance status, and days to repeat NLR measurement. Patients with a moderate decrease in NLR from baseline had the longest OS of 27.8 months (95% CI 21.8–33.8). Patients with significant NLR decrease had OS of 11.4 months (95% CI 6.1–16.7). Patients with a significant increase in NLR had the shortest OS of 5.0 months (95% CI 0.9–9.1).ConclusionsWe confirmed the prognostic value of NLR in patients with advanced cancer treated with ICIs. We found that change in NLR over time is a non-linear predictor of patient outcomes. Patients who had moderate decrease in NLR during treatment with ICI were found to have the longest survival, whereas a significant decrease or increase in NLR was associated with shorter survival. To our knowledge, this is the first study to demonstrate a non-linear change in NLR over time that correlates with survival.