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Trailblazers in foregut surgery: Alia Qureshi, MD (Harvard university) interviews Ralph Aye, MD (providence swedish seattle).
No full textGarsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation.
No full textMutations in the KRAS gene have long been implicated in the pathogenesis of colorectal cancer (CRC). KRAS G12C inhibitors overcome the undruggable challenge, enabling precision therapy. Garsorasib (D-1553), a highly potent and selective KRAS G12C inhibitor, has demonstrated promising anti-tumor activity and favorable safety profile in early clinical trials. We conducted an open-label, nonrandomized phase II trial (ClinicalTrials.gov, NCT04585035) to assess the safety and efficacy of garsorasib with or without cetuximab in KRAS G12C-mutated CRC. In the monotherapy cohort (n = 26), objective response rate (ORR) was 19.2% (95% CI, 6.6-39.4), disease control rate (DCR) was 92.3% (95% CI, 74.9-99.1), median progression-free survival (PFS) was 5.5 months (95% CI, 2.9-11.6) and median overall survival (OS) was 13.1 months (95% CI, 9.5-NE). In the combination cohort (n = 42), ORR was 45.2% (95% CI, 29.8-61.3), DCR was 92.9% (95% CI, 80.5-98.5), median PFS was 7.5 months (95% CI, 5.5-8.1), and median OS was not reached. Grade ≥3 treatment-related adverse events occurred in 5 (19.2%) and 6 (14.3%) patients in monotherapy and combination cohort, respectively. Garsorasib with or without cetuximab showed a promising efficacy and manageable safety profiles in heavily pretreated patients with KRAS G12C-mutated CRC, providing a potential new treatment approach for such population
Monitoring the rate and variability of somatic genomic alterations using long-read sequencing.
No full textCancer initiation occurs when a cell acquires and accumulates mutations in genes involved in the regulation of cell processes: each cell division throughout a person\u27s life introduces novel mutations in the cells\u27 DNA and under normal circumstances, the body is primed to prevent those from leading to cancer. Occasionally, a subset of those mutations escapes those safeguards and might eventually result in the emergence of the disease. To understand the dynamics of accumulation of somatic mutations, we have performed longitudinal whole genome sequencing of DNA obtained from whole blood from healthy individuals and cancer patients using Oxford Nanopore Technologies\u27 Long Read Sequencing. Here we show that the number of somatic single nucleotide variants detected increases with their age and that for specific mutational processes, changes can be detected within months. We computed aggregated metrics for unique participants at each timepoint across types of variants (based on single based substitution molecular signatures) and identified patterns of change both over an individual\u27s lifespan (age) and over the sampling period (months). This study showcases the suitability of long read sequencing of blood DNA for detecting coarse-grained differences over time and enable future development of state of the system personalized prevention programs
Results of a phase 1/2 study of sacituzumab tirumotecan in patients with unresectable locally advanced or metastatic solid tumors refractory to standard therapies.
No full textBACKGROUND: Sacituzumab tirumotecan (sac-TMT) is an antibody-drug conjugate composed of an anti-TROP2 monoclonal antibody coupled to a cytotoxic belotecan-derived topoisomerase I inhibitor (KL610023) via a novel linker. We report results from the phase 1 dose-escalation cohorts in advanced solid tumors and phase 2 expansion cohorts for metastatic triple-negative breast cancer (TNBC) from the first-in-human MK-2870-001 (KL264-01) study (NCT04152499).
METHODS: Patients had unresectable locally advanced/metastatic solid tumors refractory to standard therapies. In the phase 1 dose-escalation cohorts, patients had unresectable locally advanced/metastatic solid tumors refractory to standard therapies. Sac-TMT was administered by intravenous administration every 2 weeks at 2 to 12 mg/kg. In phase 2, patients with TNBC and HR+/HER2- breast cancer received sac-TMT per recommended doses for expansion (RDEs) identified in phase 1. Primary objectives were determining maximum tolerated dose (MTD) of sac-TMT and establishing RDEs (phase 1) and determining ORR per RECIST v1.1 by investigator assessment (phase 2). Adverse events were assessed per NCI-CTCAE version 5.0.
RESULTS: Thirty patients were enrolled in phase 1 and received sac-TMT 2 mg/kg (n = 4), 4 mg/kg (n = 7), 5 mg/kg (n = 7), 5.5 mg/kg (n = 5), and 6 mg/kg (n = 7). Five patients had dose-limiting toxicities: grade 3 stomatitis at 4, 5.5, and 6 mg/kg; grade 3 rash at 5 mg/kg; and grade 3 urticaria at 6 mg/kg. MTD was 5.5 mg/kg and RDEs were 4 and 5 mg/kg. In the phase 2 dose expansion, ORR (95% CI) was 34.8% (16.4%, 57.3%) in the 4-mg/kg group (n = 23) and 38.9% (23.1%, 56.5%) in the 5-mg/kg group (n = 36) for TNBC. ORR (95% CI) was 31.7% (18.1%, 48.1%) for HR+/HER2- breast cancer (n = 41).
CONCLUSIONS: Sac-TMT demonstrated manageable safety profile in patients with unresectable locally advanced/metastatic solid tumors and promising antitumor activity in metastatic TNBC and HR+/HER2 - breast cancer. Sac-TMT is being investigated in phase 3 studies.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT04152499
Lisocabtagene maraleucel for R/R LBCL in patients not intended for HSCT: final results of the phase 2 PILOT study.
No full textWe report final analysis results from the PILOT study of lisocabtagene maraleucel (liso-cel) for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Sixty-one adults with R/R LBCL who had received 1 previous line of therapy and met ≥1 hematopoietic stem cell transplantation (HSCT) not intended criterion. Overall response rate (primary end point) was 80%; 54% achieved complete response. After median on-study follow-up of 18.2 months, median duration of response was 23.3 months (95% confidence interval [CI], 6.2 to not reached [NR]). Median progression-free survival (PFS) was 9.0 months (95% CI, 4.2 to NR), median overall survival (OS) was NR (95% CI, 16.3 to NR), and 18-month PFS and OS rates were 43% (95% CI, 30-55) and 59% (95% CI, 45-70), respectively. In the treatment-emergent (TE) period (≤90 days after liso-cel administration), 79% had grade ≥3 adverse events (AEs), 38% had cytokine release syndrome (2% grade 3; no grade 4/5), 31% had neurological events (5% grade 3; no grade 4/5), and 7% had grade ≥3 infections. Of 57 patients in the post-TE period (≥91 days after liso-cel administration), 18% experienced grade ≥3 AEs; 1 patient had grade ≥3 infections. Thirty patients in the leukapheresis set (n = 74) died, mostly of disease progression (n = 24). In this population with high incidence of high-grade B-cell lymphoma, primary-refractory disease, advanced age, and comorbidities, liso-cel demonstrated durable efficacy and a favorable safety profile, consistent with previous reports. These results support liso-cel as second-line therapy for this underserved population of patients with R/R LBCL not intended for HSCT. This trial was registered at www.clinicaltrials.gov as #NCT03483103
From Genome to Phenome: Opportunities and Challenges of Molecular Imaging.
No full textThe study of the human phenome is essential for understanding the complexities of wellness and disease and their transitions, with molecular imaging being a vital tool in this exploration. Molecular imaging embodies the 4 principles of human phenomics: precise measurement, accurate calculation or analysis, well-controlled manipulation or intervention, and innovative invention or creation. Its application has significantly enhanced the precision, individualization, and effectiveness of medical interventions. This article provides an overview of molecular imaging\u27s technologic advancements and presents the potential use of molecular imaging in human phenomics and precision medicine. The integration of molecular imaging with multiomics data and artificial intelligence has the potential to transform health care, promoting proactive and preventive strategies. This evolving approach promises to deepen our understanding of the human phenome, lead to preclinical diagnostics and treatments, and establish quantitative frameworks for precision health management
Molecular Correlates of Long-Term Response to Bevacizumab in Glioblastoma.
No full textPurpose: The use of bevacizumab in glioblastoma has been associated with increased progression-free survival and improvement in symptoms and quality of life. There are no clinical indicators on how to choose patients who would benefit the most from this agent. We aim to describe molecular markers in patients with glioblastoma who may benefit from treatment.
Methods: We analyzed glioblastoma tumor samples that underwent comprehensive molecular profiling analysis at Caris Life Sciences.
Results: The data set consisted of 3,106 glioblastoma tumor samples, of which 571 were from patients treated with bevacizumab. The majority were males (65%) and older than 60 years. Median survival was 17.5 months in patients receiving bevacizumab. In patients who were treated with bevacizumab for ≥1 year, median survival was 33.8 months, compared with 15 months in those treated for ≤6 months. Patients who received bevacizumab for ≥1 year had higher prevalence of LRIG3 (9% v 1%), CDK4 (22% v 8%), and DDIT3 amplification (14% v 4%), SETD2 mutations (10% v 3%), and MGMT methylation (66% v 32%). EGFR amplification was more frequent in patients who received bevacizumab for ≤6 months (46% v 20%). Multivariate analysis showed that CDK4 amplification was associated with longer time on bevacizumab, and EGFR amplification with shorter time after correcting for age, sex, and other molecular alterations.
Conclusion: CDK4 amplification is a potential genetic biomarker to identify patients who may derive prolonged benefit from bevacizumab
A novel structural modeling magnitude and orientation radiomic descriptor for evaluating response to neoadjuvant therapy in rectal cancers via MRI.
No full textWith advances in neoadjuvant therapies for rectal cancer, accurately evaluating tumor regression and response is increasingly critical for enabling personalized follow-up, including non-operative management. Given the lack of reliable assessment methods, there is an opportunity to develop computerized image-based markers for identifying early responders. We present a novel radiomic signature, the STructural mOdeling magnituDE and Orientation (StODeO) descriptor for quantifying image-based surrogates of tumor shrinkage within and around the rectum via routine MRI scans. StODeO descriptors measure both the magnitude (how much) and direction (inward/outward) of structural displacements in the diseased rectal wall, with respect to a newly constructed, first-of-its-kind image-based reference atlas of the non-diseased rectum. Combined with traditional radiomic texture features, StODeO showed superior performance in distinguishing pathologic response groups of rectal cancer patients post-chemoradiation (hold-out validation AUC 0.77) as well as segregating composite response groups in a clinical trial of immune checkpoint inhibitors (external validation accuracy 0.71; NCT02688712). The integrated StODeO-texture signature demonstrated robustness across annotation sources and imaging variations, intuitive modeling of therapy-associated structural changes, and statistical associations with tumor-immune biology, including macrophages and CD8+ T-cells from multiplexed biopsy analysis. StODeO offers a novel image-based surrogate of tissue displacements from treatment effects and residual disease after neoadjuvant therapy in rectal cancers