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Small molecule mesenchymal-epithelial transition (MET) inhibitors, such as crizotinib, capmatinib, and tepotinib, are treatment options for metastatic non-small cell lung cancer (NSCLC) in adult patients whose tumors have a mutation that leads to MET exon 14 skipping. In clinical trials, these MET inhibitors were associated with a high incidence of peripheral edema, although this was generally mild-to-moderate in severity. There is limited information about the mechanism involved in MET inhibitor-induced peripheral edema. Perturbation of hepatocyte growth factor (HGF)/MET signaling may disrupt the permeability balance in the vascular endothelium and thus promote edema development. Another potential mechanism is through effects on renal function, although this is unlikely to be the primary mechanism. Because edema is common in cancer patients and may not necessarily be caused by the cancer treatment, or other conditions that have similar symptoms to peripheral edema, a thorough assessment is required to ascertain the underlying cause. Before starting MET-inhibitor therapy, patients should be educated about the possibility of developing peripheral edema. Patient limb volume should be measured before initiating treatment, to aid assessment if symptoms develop. Since the exact mechanism of MET inhibitor-induced edema is unknown, management is empiric, with common approaches including compression stockings, specific exercises, massage, limb elevation, and/or diuretic treatment. Although not usually required, discontinuation of MET inhibitor treatment generally resolves peripheral edema. Early diagnosis and management, as well as patient information and education, are vital to decrease the clinical burden associated with edema, and to reinforce capmatinib treatment adherence.

Criteria for discontinuation of nivolumab

Purpose: Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI), whereas exon 20 insertions (Ins20) are resistant to them. However, little is known about mutations in exon 18.Experimental Design: Mutational status of lung cancers between 2001 and 2015 was reviewed. Three representative mutations in exon 18, G719A, E709K, and exon 18 deletion (Del18: delE709_T710insD) were retrovirally introduced into Ba/F3 and NIH/3T3 cells. The 90% inhibitory concentrations (IC90s) of first-generation (1G; gefitinib and erlotinib), second-generation (2G; afatinib, dacomitinib, and neratinib), and third-generation TKIs (3G; AZD9291 and CO1686) were determined.Results: Among 1,402 EGFR mutations, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Exon 18 mutations, including G719X, E709X, and Del18, were present in 3.2%. Transfected Ba/F3 cells grew in the absence of IL3, and NIH/3T3 cells formed foci with marked pile-up, indicating their oncogenic abilities. IC90s of 1G and 3G TKIs in G719A, E709K, and Del18 were much higher than those in Del19 (by >11–50-fold), whereas IC90s of afatinib were only 3- to 7-fold greater than those for Del19. Notably, cells transfected with G719A and E709K exhibited higher sensitivity to neratinib (by 5–25-fold) than those expressing Del19. Patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (∼80%) than to 1G TKIs (35%–56%) by compilation of data in the literature.Conclusions: Lung cancers harboring exon 18 mutations should not be overlooked in clinical practice. These cases can be best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits cannot detect all exon 18 mutations. Clin Cancer Res; 21(23); 5305–13. ©2015 AACR.

Kaplan-Meier curves for overall survival (A) and progressionfree survival (B) for all patients according tumor type (epithelioid and non-epithelioid subtypes)

Supplementary Figure 1. Western blot analyses for phospho-HER2.

Supplementary Table 1. Individual data on the clinical response of lung cancers harboring E709K/A or G719A/S to gefitinib or erlotinib.

Legend for supplementary figure 1.

Supplementary Table 2 from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

Supplementary Figure 2 from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

Supplementary Figure 3 from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

Supplementary Figure 1 from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

Supplementary Materials and Methods from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

Supplementary Table 1 from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

Supplementary Figure Legends 1-3 from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

Malignant pleural mesothelioma (MPM) is a fatal thoracic malignancy, the epigenetics of which are poorly defined. We performed high-throughput methylation analysis covering 6,157 CpG islands in 20 MPMs and 20 lung adenocarcinomas. Newly identified genes were further analyzed in 50 MPMs and 56 adenocarcinomas via quantitative methylation-specific PCR. Targets of histone H3 lysine 27 trimethylation (H3K27me3) and genetic alterations were also assessed in MPM cells by chromatin immunoprecipitation arrays and comparative genomic hybridization arrays. An average of 387 genes (6.3%) and 544 genes (8.8%) were hypermethylated in MPM and adenocarcinoma, respectively. Hierarchical cluster analysis showed that the two malignancies have characteristic DNA methylation patterns, likely a result of different pathologic processes. In MPM, a separate subset of genes was silenced by H3K27me3 and could be reactivated by treatment with a histone deacetylase inhibitor alone. Integrated analysis of these epigenetic and genetic alterations revealed that only 11% of heterozygously deleted genes were affected by DNA methylation and/or H3K27me3 in MPMs. Among the DNA hypermethylated genes, three (TMEM30B, KAZALD1, and MAPK13) were specifically methylated only in MPM and could serve as potential diagnostic markers. Interestingly, a subset of MPM cases (4 cases, 20%) had very low levels of DNA methylation and substantially longer survival, suggesting that the epigenetic alterations are one mechanism affecting progression of this disease. Our findings show a characteristic epigenetic profile of MPM and uncover multiple distinct epigenetic abnormalities that lead to the silencing of tumor suppressor genes in MPM and could serve as diagnostic or prognostic targets. [Cancer Res 2009;69(23):9073–82]

Supplementary Figures 1-3, Tables 1-5 from Epigenetic Profiles Distinguish Malignant Pleural Mesothelioma from Lung Adenocarcinoma

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy is an emerging type of treatment for lung cancer (LC). However, hyperprogressive disease (HPD) has been observed in patients treated with ICIs that lacks a prognostic prediction model. There is an urgent need for a simple and easily implementable predictive model to predict the occurrence of HPD. This study aimed to establish a novel scoring system based on a nomogram for the occurrence of HPD. METHODS: We retrospectively identified 1473 patients with stage III–IV LC or inoperable stage I–II LC (1147 in training set, and 326 in testing set), who had undergone ICI therapy at the Shanghai Chest Hospital between January 2017 and March 2022. Available computed tomography (CT) data from the previous treatment, before ICI administration, and at least 2 months after the first the course of ICI administration is collected to confirm HPD. Data from these patients’ common blood laboratory test results before ICI administration were analyzed by the univariable and multivariable logistic regression analysis, then used to develop nomogram predictive model, and made validation in testing set. RESULTS: A total of 1,055 patients were included in this study (844 in the training set, and 211 in the testing set). In the training set, 93 were HPD and 751were non-HPD. Multivariate logistic regression analyses demonstrated that lactate dehydrogenase [LDH, P

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD‐L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum‐based chemotherapy (four to six cycles). The primary end‐point was progression‐free survival; secondary end‐points included overall survival and safety. Of 305 patients randomized in KEYNOTE‐024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression‐free survival was 41.4 (95% confidence interval [CI], 4.2‐42.5) months with pembrolizumab and 4.1 (95% CI, 2.8‐8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11‐0.65]; one‐sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9‒NR) and 21.5 (95% CI, 5.2‐35.0) months, respectively (HR, 0.39 [95% CI, 0.17‐0.91]; one‐sided, nominal P = .012). Treatment‐related adverse events occurred in 21/21 (100%) pembrolizumab‐treated and 18/19 (95%) chemotherapy‐treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3‐5 events. Immune‐mediated adverse events and infusion reactions occurred in 11 pembrolizumab‐treated patients (52%) and four chemotherapy‐treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3‐5 events. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738., This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among 40 Japanese patients in the study.

Introduction: Nazartinib, a novel third-generation EGFR-tyrosine kinase inhibitor, previously demonstrated antitumor activity and manageable safety in patients with EGFR-mutant advanced non−small cell lung cancer (NSCLC) who received ≤ 3 prior lines of systemic therapy. Herein, we report phase 2 efficacy and safety of first-line nazartinib. Methods: This single-arm, open-label, global study enrolled treatment-naive adult patients with stage IIIB/IV NSCLC harboring EGFR-activating mutations (eg, L858R and/or ex19del). Patients with neurologically stable and controlled brain metastases were also eligible. Patients received oral nazartinib 150 mg once daily. The primary endpoint was Blinded Independent Review Committee (BIRC)-assessed overall response rate (ORR) per RECIST v1.1. Results: Forty-five patients received ≥ 1 dose of nazartinib. The median follow-up time from enrollment to data cutoff (November 1, 2019) was 30 months (range: 25–34). The BIRC-assessed ORR was 69% (95% CI, 53–82). The median progression-free survival (PFS) was 18 months (95% CI, 15-not estimable [NE]). The median overall survival was NE. In patients with baseline brain metastases (n = 18), the ORR and median PFS (95% CIs) were 67% (41–87) and 17 months (11–21). Seventeen of 18 patients had brain metastases as non-target lesions; the CNS lesions were absent/normalized in 9 of 17 (53%). Only 2 of 27 patients without baseline brain metastases developed new brain metastases postbaseline. Most frequent adverse events (≥ 25%, any grade, all-causality) were diarrhea (47%), maculopapular rash (38%), pyrexia (29%), cough, and stomatitis (27% each). Conclusions: First-line nazartinib demonstrated promising efficacy, including clinically meaningful antitumor activity in the brain, and manageable safety in patients with EGFR-mutant NSCLC. Trial registration: ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02108964.