The Efficacy and Safety of Treating Acquired MET Resistance Through Combinations of Parent and MET Tyrosine Kinase Inhibitors in Patients With Metastatic Oncogene-Driven NSCLC.

Introduction: Acquired MET gene amplification, MET exon 14 skip mutations, or MET fusions can emerge as resistance mechanisms to tyrosine kinase inhibitors (TKIs) in patients with lung cancer. The efficacy and safety of combining MET TKIs (such as crizotinib, capmatinib, or tepotinib) with parent TKIs to target acquired MET resistance are not well characterized. Methods: Multi-institutional retrospective chart review identified 83 patients with metastatic oncogene-driven NSCLC that were separated into the following two pairwise matched cohorts: (1) MET cohort (n = 41)-patients with acquired MET resistance continuing their parent TKI with a MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable resistance continuing their parent TKI with a platinum-pemetrexed added. Clinicopathologic features, radiographic response (by means of Response Evaluation Criteria in Solid Tumors version 1.1), survival outcomes, adverse events (AEs) (by means of Common Terminology Criteria for Adverse Events version 5.0), and genomic data were collected. Survival outcomes were assessed using Kaplan-Meier methods. Multivariate modeling adjusted for lines of therapy, brain metastases, TP53 mutations, and oligometastatic disease. Results: Within the MET cohort, median age was 56 years (range: 36-83 y). Most patients were never smokers (28 of 41, 68.3%). Baseline brain metastases were common (21 of 41, 51%). The most common oncogenes in the MET cohort were EGFR (30 of 41, 73.2%), ALK (seven of 41, 17.1%), and ROS1 (two of 41, 4.9%). Co-occurring TP53 mutations (32 of 41, 78%) were frequent. Acquired MET alterations included MET gene amplification (37 of 41, 90%), MET exon 14 mutations (two of 41, 5%), and MET gene fusions (two of 41, 5%). After multivariate adjustment, the objective response rate (ORR) was higher in the MET cohort versus the chemotherapy cohort (ORR: 69.2% versus 20%, p < 0.001). Within the MET cohort, MET gene copy number (≥10 versus 6-10) did not affect radiographic response (54.5% versus 68.4%, p = 0.698). There was no difference in ORR on the basis of MET TKI used (F [2, 36] = 0.021, p = 0.978). There was no difference in progression-free survival (5 versus 6 mo; hazard ratio = 0.64; 95% confidence interval: 0.34-1.23, p = 0.18) or overall survival (13 versus 11 mo; hazard ratio = 0.75; 95% confidence interval: 0.42-1.35, p = 0.34) between the MET and chemotherapy cohorts. In the MET cohort, dose reductions for MET TKI-related toxicities were common (17 of 41, 41.4%) but less frequent for parent TKIs (two of 41, 5%). Grade 3 AEs were not significant between crizotinib, capmatinib, and tepotinib (p = 0.3). The discontinuation rate of MET TKIs was 17% with no significant differences between MET TKIs (p = 0.315). Among pre- and post-treatment biopsies (n = 17) in the MET cohort, the most common next-generation sequencing findings were loss of MET gene amplification (15 of 17, 88.2%), MET on-target mutations (seven of 17, 41.2%), new Ras-Raf-MAPK alterations (three of 17, 17.6%), and EGFR gene amplification (two of 17, 11.7%). Conclusions: The efficacy and safety of combining MET TKIs (crizotinib, capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are efficacious. Radiographic response and AEs did not differ significantly on the basis of the underlying MET TKI used. Loss of MET gene amplification, development of MET on-target mutations, Ras-Raf-MAPK alterations, and EGFR gene amplification were molecular patterns found on progression with dual parent and MET TKI combinations.

Institutional financial toxicity of failure to adhere to treatment guidelines for head and neck squamous cell carcinoma.

BACKGROUND: Delays in treatment of head and neck squamous cell carcinoma (HNSCC) are known to increase disease recurrence, generating the need for additional salvage treatment, often with immunotherapy. METHODS: Three treatment metrics were identified: time from diagnosis to treatment initiation (TTI), time from surgery to postoperative radiotherapy (surg → PORT), and total treatment package time (TPT). Financial toxicity was calculated using hazard ratios, pembrolizumab cost, and dosing data for a Veterans Health Administration (VHA) institutional cohort (n = 338) and a standardized cohort (n = 100). RESULTS: Estimated financial toxicity for the VHA cohort was $2 047 407, $316 545, and $1 114 101 for TTI, surg → PORT, and TPT, respectively. Estimated financial toxicity for the standardized patient cohort was $454 028, $544 576, and $1 879 628 for TTI, surg → PORT, and TPT, respectively. CONCLUSIONS: Failure to meet established HNSCC treatment metrics generates significant, yet avoidable, institutional financial toxicity which is particularly relevant to integrated single-payer systems such as the VHA in the modern immunotherapy era.

Approach to radiation therapy in the Jehovah's Witness patient: An overview.

Jehovah's Witnesses are well-known in the medical community for their inability to accept blood products. Novel methods of treatment are often needed to avoid anemia and hematologic toxicity as inability to receive blood products may increase the risk of treatment related complications. We provide an overview of radiation treatment for Jehovah's Witness patients with an emphasis on bone marrow sparing strategies with intensity modulated radiation therapy (IMRT) to minimize hematologic toxicity.

Remnant lipoprotein size distribution profiling via dynamic light scattering analysis.

BACKGROUND: Remnant lipoproteins (RLP) are a metabolically derived subpopulation of triglyceride-rich lipoproteins (TRL) in human blood that are involved in the metabolism of dietary fats or triglycerides. RLP, the smaller and denser variants of TRL particles, are strongly correlated with cardiovascular disease (CVD) and were listed as an emerging atherogenic risk factor by the AHA in 2001. METHODS: Varying analytical techniques used in clinical studies in the size determination of RLP contribute to conflicting hypotheses in regard to whether larger or smaller RLP particles contribute to CVD progression, though multiple pathways may exist. RESULTS: We demonstrated a unique combinatorial bioanalytical approach involving the preparative immunoseparation of RLP, and dynamic light scattering for size distribution analysis. CONCLUSIONS: This is a new facile and robust methodology for the size distribution analysis of RLP that in conjunction with clinical studies may reveal the mechanisms by which RLP cause CVD progression.