ABSTRACT
BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRASG12C). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRASG12C -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRASG12C inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRASG12C allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRASG12C inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRASG12C inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.).
Subject(s)
Acetonitriles/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Colorectal Neoplasms/drug therapy , Drug Resistance, Neoplasm/genetics , Lung Neoplasms/drug therapy , Mutation , Piperazines/therapeutic use , Proto-Oncogene Proteins p21(ras)/genetics , Pyrimidines/therapeutic use , Appendiceal Neoplasms/drug therapy , Appendiceal Neoplasms/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Colorectal Neoplasms/genetics , Humans , Lung Neoplasms/genetics , Protein Conformation , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Proto-Oncogene Proteins p21(ras)/ultrastructure , Pyridines/therapeutic useABSTRACT
BACKGROUND: Obesity is a leading contributor to disability. Treatment approaches incorporating telehealth technologies are becoming increasingly popular in treating obesity, but their benefits relative to established behavioural weight loss therapies are poorly understood. The objective of this study was to compare a new telehealth treatment (TeleMOVE) to an established behavioural treatment (MOVE!) among Veterans with obesity. METHODS: This was an observational study of Veterans in the TeleMOVE or MOVE! programs between October, 2011 and March, 2013. A total of 699 Veterans enrolled in these programs from 2011-2013. A secondary focus was on Veterans that were ≥90% adherent to their treatment. From this group, 72 (33.1%) TeleMOVE and 141 (29.3%) MOVE! participants met adherence criteria. The primary outcome criterion was changes in body weight. RESULTS: Both programs were associated with significant weight reductions, with MOVE! participants showing significantly less weight loss relative to those in TeleMOVE (MOVE! mean weight loss=4.5[7.1]lb/2.0[3.2]kg; 1.8% mean weight loss; 12.0% achieving ≥5% weight loss; TeleMOVE mean weight loss=8.6[9.9]lb/3.9[4.5]kg; 3.6% mean weight loss; 26.6% achieving ≥5% weight loss, p's<.01). Among highly adherent participants, patients in TeleMOVE versus MOVE! lost significantly more weight (TeleMOVE=11.1[9.9]lb/5.0[4.5]kg versus MOVE!=5.7[7.1]lb/2.6[3.2]kg; t=4.6, p<.001) and were significantly more likely to achieve clinically significant weight loss (% with ≥5% weight loss were 43.1% versus 13.5%, respectively, p<.001). CONCLUSIONS: In this observational study, TeleMOVE was at least as effective for weight loss as the more established multidisciplinary MOVE!
Subject(s)
Behavior Therapy/methods , Obesity/therapy , Patient Compliance , Telemedicine , Veterans , Weight Reduction Programs/methods , Aged , Female , Humans , Male , Middle Aged , Obesity/psychology , Program Evaluation , Treatment Outcome , Weight LossABSTRACT
BACKGROUND: The rates of overweight and obesity are high among United States Veterans, necessitating the development of accessible weight reduction interventions. PURPOSE: This observational study evaluated the efficacy of a novel home-based telehealth weight loss intervention (TeleMOVE) for Veterans with obesity. METHODS: We obtained weight measures of 171 patients before and after one and two 90-day cycles of TeleMOVE. RESULTS: Enrollment in the first 90-day cycle of TeleMOVE was associated with significant weight loss (M = 8.62 lbs, SD = 9.85). Those who subsequently enrolled in the second, identical, cycle lost significantly more weight overall (M = 11.68 lbs, SD = 12.53) than those who only enrolled in the first cycle (M = 5.55 lbs, SD = 8.23). However, this difference was due to two-cycle participants losing significantly more weight during the first cycle alone (M = 10.52, SD = 10.32). CONCLUSIONS: TeleMOVE is a promising intervention, warranting a further investigation of its efficacy.
