Subcutaneous versus Intravenous Amivantamab, both in Combination with Lazertinib, in Refractory EGFR-mutated NSCLC: Primary Results from the Phase 3 PALOMA-3 Study.

PURPOSE: Phase 3 studies of intravenous amivantamab demonstrated efficacy across EGFR-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy. PATIENTS AND METHODS: Patients with EGFR-mutated advanced NSCLC who progressed following osimertinib and platinum-based chemotherapy were randomized 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Co-primary pharmacokinetic noninferiority endpoints were trough concentrations (Ctrough; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUCD1-D15). Key secondary endpoints were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory endpoint. RESULTS: Overall, 418 patients underwent randomization (subcutaneous group, n=206; intravenous group, n=212). Geometric mean ratios of Ctrough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04-1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27-1.61) at cycle-4-day-1; the cycle-2 AUCD1-D15 was 1.03 (90% CI, 0.98-1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42-0.92; nominal P=0.02). Fewer patients in the subcutaneous group experienced infusion-related reactions (13% versus 66%) and venous thromboembolism (9% versus 14%) versus the intravenous group. Median administration time for first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab from 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; end-of-treatment rates were 85% and 35%, respectively. CONCLUSION: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced infusion-related reactions, increased convenience, and prolonged survival.

Exploring the Genomic Landscape of Hepatobiliary Cancers to Establish a Novel Molecular Classification System.

Taxonomy of hepatobiliary cancer (HBC) categorizes tumors by location or histopathology (tissue of origin, TO). Tumors originating from different TOs can also be grouped by overlapping genomic alterations (GA) into molecular subtypes (MS). The aim of this study was to create novel HBC MSs. Next-generation sequencing (NGS) data from the AACR-GENIE database were used to examine the genomic landscape of HBCs. Machine learning and gene enrichment analysis identified MSs and their oncogenomic pathways. Descriptive statistics were used to compare subtypes and their associations with clinical and molecular variables. Integrative analyses generated three MSs with different oncogenomic pathways independent of TO (n = 324; p < 0.05). HC-1 "hyper-mutated-proliferative state" MS had rapidly dividing cells susceptible to chemotherapy; HC-2 "adaptive stem cell-cellular senescence" MS had epigenomic alterations to evade immune system and treatment-resistant mechanisms; HC-3 "metabolic-stress pathway" MS had metabolic alterations. The discovery of HBC MSs is the initial step in cancer taxonomy evolution and the incorporation of genomic profiling into the TNM system. The goal is the development of a precision oncology machine learning algorithm to guide treatment planning and improve HBC outcomes. Future studies should validate findings of this study, incorporate clinical outcomes, and compare the MS classification to the AJCC 8th staging system.

Microplastics/nanoplastics released from facemasks as contaminants of emerging concern.

Facemasks have become a global medical necessity and are a key preventive measure against COVID-19. Typically, facemasks (FMs) are fabricated from non-renewable polymers, particularly polypropylene (PP) and polyethylene (PE), which release secondary microplastic (MPs) due to the chemical, physical, and biological processes. In light of the widespread usage and improper disposal of single-use facemasks, there is concern about their environmental impact since they contribute to plastic pollution during and after pandemics. The repercussions of this have led to millions of tons of plastic waste being dumped into the environment. Due to lack of awareness and improper disposal, the occurrence of micro/nanoplastics released from facemasks in wastewater treatment plants and landfills poses a concern. Infiltration of wastewater treatment processes by micro/nanoplastics at various levels can be problematic because of their chemical nature and broad but small size. Thus, operational and process stability issues can arise during wastewater treatment processes. In addition, landfilling and illegal waste disposal are being used to dispose of potentially infectious COVID-19 waste, leading to an environmental threat to animal and human health and exacerbating plastic pollution. This paper reviews the fate of facemasks in the environment and the repercussions of improper waste management of facemasks in wastewater treatment plants, landfills, and ultimately the environment.

Hybrid continuous reassessment method with overdose control for safer dose escalation.

Phase 1 oncology studies focus on safety of novel treatments and identifying a dose associated with acceptable toxicity level. Various model-based designs have been proposed for guiding dose escalation and estimating maximum tolerated dose in dose-finding studies. However, these methods are either excessively conservative or imprudent by allowing overly toxic doses. Transparent and easy to implement model-assisted designs have also received increasing attention but require pre-set rules including perceived dose levels. Therefore, we propose a hybrid model-based design that has a high probability to select MTD with a good balance of overdose control by disentangling in two separate models, which is flexible and easy to implement. Extensive simulations show the model to have real promise.

Inaccurate pretreatment staging can impact survival in early stage esophageal adenocarcinoma.

BACKGROUND: Given the survival advantage of neoadjuvant treatment for locally advanced esophageal cancer, accurate clinical staging is necessary. The aim of this study was to assess the clinical (c) and pathologic (p) staging concordance rates for presumably early stage esophageal adenocarcinoma patients that had upfront esophagectomy (UFE) and evaluate if survival (OS) was negatively affected by inaccurate preoperative staging and subsequent treatment selection. METHODS: An NCDB retrospective review of nonmetastatic esophageal adenocarcinoma patients that had UFE. The rates of concordance between c and p staging system and OS were calculated. RESULTS: Of 2775 patients, most patients presented with cN0 (82.8%) and cT1 tumors (53.6%). The overall concordance between c and p staging was 78.8% for T-classification (moderate agreement; weighted κ = 0.729; P < .001) and 78.8% for N-classification (weak agreement; weighted κ = 0.448; P < .001). Patients that were upstaged due to a lack of concordance between T-classification had decreased 5- and 10-year OS (30% and 16%, P < .001) and those upstaged due to discordant N-classification had decreased 5- and 10-year OS (28% and 23%, P < .001)." CONCLUSIONS: Preoperative staging of esophageal adenocarcinoma has moderate reliability and accuracy for predicting pT and pN classification. Up to 25% of patients have discordant clinical and pathological staging, which impacts OS.