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4013 Background: Trastuzumab (tras) plus chemotherapy (chemo) is standard-of-care (SOC) 1L therapy for HER2+ metastatic G/GEJ cancer. In two phase 2 studies, tras, chemo, and pembrolizumab (pembro) in combination showed promising efficacy and manageable safety. The ongoing global, randomized, double-blind, placebo-controlled phase 3 KEYNOTE-811 study is assessing whether adding pembro to SOC improves efficacy vs SOC alone for HER2+ metastatic G/GEJ cancer (NCT03615326). Methods: Eligible patients (pts) with previously untreated, unresectable or metastatic HER2+ G/GEJ cancer and ECOG PS 0 or 1 are randomized 1:1 to pembro 200 mg IV Q3W or placebo IV Q3W. All pts receive tras and investigator’s choice of 5-fluorouracil and cisplatin (FP) or capecitabine and oxaliplatin (CAPOX). Treatment is given up to 2 y or until intolerable toxicity or PD. Dual primary end points are PFS per RECIST v1.1 by blinded, independent central review (BICR) and OS. Secondary end points are ORR and DOR per RECIST v1.1 by BICR and safety. Planned enrollment in the global cohort is 692 pts; accrual is almost complete. The protocol-specified first interim analysis (IA1) was to occur when the first 260 pts enrolled had ≥8.5 mo of follow-up and tested whether pembro + SOC significantly improved ORR; the superiority boundary was P = 0.002. The ORR difference was calculated using the Miettinen and Nurminen method stratified by the randomization stratification factors of geographic region, PD-L1 status, and chemo choice. Efficacy is presented for the first 264 pts enrolled. Safety is presented for all treated pts enrolled as of Jun 17, 2020. Results: Among the first 264 pts enrolled, 133 were randomized to pembro + SOC, 131 to placebo + SOC; 0.8% had MSI-H tumors, CAPOX was chosen for 87.1%, and median study follow-up was 12.0 mo (range, 8.5-19.4). Confirmed ORR (95% CI) was 74.4% (66.2-81.6) for pembro + SOC vs 51.9% (43.0-60.7) for placebo + SOC (difference, 22.7 percentage points [95% CI, 11.2-33.7], P = 0.00006); CR rate was 11.3% vs 3.1% and DCR (95% CI) was 96.2% (91.4-98.8) vs 89.3 (82.7-94.0). Median (range) DOR was 10.6 mo (1.1+ to 16.5+) for pembro + SOC vs 9.5 mo (1.4+ to 15.4+) for placebo + SOC; KM estimates of DOR ≥6 mo and ≥9 mo were 70.3% vs 61.4% and 58.4% vs 51.1%. As of data cutoff, 433/434 enrolled pts were treated (217/217 pembro + SOC, 216/217 placebo + SOC). AEs were grade 3-5 in 57.1% of pts with pembro + SOC vs 57.4% with placebo + SOC, led to death in 3.2% vs 4.6%, and led to discontinuation of any drug in 24.4% vs 25.9%. Conclusions: Adding pembro to tras and chemo resulted in a substantial, statistically significant increase in ORR versus trastuzumab and chemo alone as 1L therapy for HER2+ metastatic G/GEJ cancer; responses were durable and safety was manageable. These initial data support pembro plus tras and chemo as a potential new treatment option for this population. Clinical trial information: NCT03615326.

Latin Americans are highly heterogeneous regarding the type of Native American ancestry. Consideration of specific associations with common diseases may lead to substantial advances in unraveling of disease etiology and disease prevention.Here we investigate possible associations between the type of Native American ancestry and leading causes of death. After an aggregate-data study based on genome-wide genotype data from 1805 admixed Chileans and 639,789 deaths, we validate an identified association with gallbladder cancer relying on individual data from 64 gallbladder cancer patients, with and without a family history, and 170 healthy controls. Native American proportions were markedly underestimated when the two main types of Native American ancestry in Chile, originated from the Mapuche and Aymara indigenous peoples, were combined together. Consideration of the type of Native American ancestry was crucial to identify disease associations. Native American ancestry showed no association with gallbladder cancer mortality (P = 0.26). By contrast, each 1% increase in the Mapuche proportion represented a 3.7% increased mortality risk by gallbladder cancer (95%CI 3.1–4.3%, P = 6×10−27). Individual-data results and extensive sensitivity analyses confirmed the association between Mapuche ancestry and gallbladder cancer. Increasing Mapuche proportions were also associated with an increased mortality due to asthma and, interestingly, with a decreased mortality by diabetes. The mortality due to skin, bladder, larynx, bronchus and lung cancers increased with increasing Aymara proportions. Described methods should be considered in future studies on human population genetics and human health. Complementary individual-based studies are needed to apportion the genetic and non-genetic components of associations identified relying on aggregate-data.

Background & aims: Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here we investigate the causal effects of risk factors considered in current GBC prevention programmes as well as C-reactive protein (CRP) level as a marker of chronic inflammation. Approach & results: We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (p = 9 × 10-5) and Europeans (p = 9 × 10-5). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (p = 0.03), while higher CRP concentrations increased GBC risk in Europeans (p = 4.1 × 10-6). European results suggest causal effects of BMI on gallstone disease (p = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. Conclusions: Two risk factors considered in the current Chilean programme for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk.