Induction EGFR tyrosine kinase inhibitors prior to definitive chemoradiotherapy in unresectable stage III EGFR-mutated non-small cell lung cancer

INTRODUCTION: Increasing evidence suggests that consolidation durvalumab confers limited benefits for patients with stage III EGFR-mutated NSCLC. Induction or maintenance EGFR tyrosine kinase inhibitors (TKIs) added to concurrent chemoradiotherapy (CRT) may optimize definitive treatment, but there are limited data supporting an induction TKI strategy. METHODS: We evaluated the efficacy and safety of induction EGFR TKIs administered before concurrent CRT in a retrospective series of patients with unresectable locally advanced EGFR-mutated NSCLC. Circulating tumor DNA (ctDNA) analysis was performed on a patient subset using CAPP-seq and correlated with outcomes. RESULTS: Of six patients, three received erlotinib and three osimertinib as induction therapy before CRT. Induction TKIs were administered for a median of 2.5 months. The objective response rate after induction TKI was 83%. One patient had a complete response to induction erlotinib and continued erlotinib for 4 years until local progression, which was treated with CRT. Two patients completed maintenance erlotinib after CRT, and another received consolidation durvalumab. After a median follow-up of 20.5 months, only one patient developed disease recurrence, with rising ctDNA coinciding with recurrence. ctDNA remained undetectable in patients without recurrence, or low-level in a patient receiving maintenance erlotinib. Adverse events were mild and expected, and none developed pneumonitis. CONCLUSION: Induction EGFR TKI before CRT may achieve high disease control rates with promising signs of durability in patients with locally advanced EGFR-mutated NSCLC. ctDNA analysis after CRT can correlate well with clinical outcomes. Prospective studies are needed to define the role of induction EGFR TKIs in this setting

Paraneoplastic Syndromes and Thymic Malignancies: An Examination of the International Thymic Malignancy Interest Group Retrospective Database

Introduction Thymic epithelial tumors (TETs) are associated with paraneoplastic autoimmune (PN/AI) syndromes. Myasthenia gravis is the most common PN/AI syndrome associated with TETs. Methods The International Thymic Malignancy Interest Group (ITMIG) retrospective database was examined to determine (i) baseline and treatment characteristics associated with PN/AI syndromes and (ii) the prognostic role of PN/AI syndromes for patients with TETs. The competing risks model was used to estimate cumulative incidence of recurrence (CIR) and the Kaplan-Meier method was used to calculate overall survival (OS). A Cox proportional hazards model was used for multivariate analysis. Results 6670 patients with known PN/AI syndrome status were identified from 1951-2012. PN/AI syndromes were associated with younger age, female sex, type B1 thymoma, earlier stage, and an increased rate of total thymectomy and complete resection status. There was a statistically significant lower CIR in the PN/AI (+) group compared to the PN/AI (-) group (10-year 17.3% vs. 21.2%, respectively, p=0.0003). The OS was improved in the PN/AI (+) group compared to the PN/AI (-) group (HR 0.63, 95% CI 0.54-0.74, P<0.0001, median OS 21.6 years versus 17.0 years, respectively). However, in the multivariate model for recurrence-free survival and OS, PN/AI syndrome was not an independent prognostic factor. Discussion Previously, there has been mixed data regarding the prognostic role of PN/AI syndromes for patients with TETs. Here, using the largest dataset in the world for TETs, PN/AI syndromes were associated with favorable features (i.e. earlier stage, complete resection status) but were not an independent prognostic factor for TETs

Genomic clustering analysis identifies molecular subtypes of thymic epithelial tumors independent of World Health Organization histologic type

Further characterization of thymic epithelial tumors (TETs) is needed. Genomic information from 102 evaluable TETs from The Cancer Genome Atlas (TCGA) dataset and from the IU-TAB-1 cell line (type AB thymoma) underwent clustering analysis to identify molecular subtypes of TETs. Six novel molecular subtypes (TH1-TH6) of TETs from the TCGA were identified, and there was no association with WHO histologic subtype. The IU-TAB-1 cell line clustered into the TH4 molecular subtype and in vitro testing of candidate therapeutics was performed. The IU-TAB-1 cell line was noted to be resistant to everolimus (mTORC1 inhibitor) and sensitive to nelfinavir (AKT1 inhibitor) across the endpoints measured. Sensitivity to nelfinavir was due to the IU-TAB-1 cell line’s gain-of function (GOF) mutation in PIK3CA and amplification of genes observed from array comparative genomic hybridization (aCGH), including AURKA, ERBB2, KIT, PDGFRA and PDGFB, that are known upregulate AKT, while resistance to everolimus was primarily driven by upregulation of downstream signaling of KIT, PDGFRA and PDGFB in the presence of mTORC1 inhibition. We present a novel molecular classification of TETs independent of WHO histologic subtype, which may be used for preclinical validation studies of potential candidate therapeutics of interest for this rare disease

RRx-001 followed by platinum plus etoposide in patients with previously treated small-cell lung cancer

BACKGROUND: This exploratory single-arm phase II study evaluated the efficacy and safety of RRx-001 followed by reintroduction of platinum plus etoposide in patients with previously treated small-cell lung cancer (SCLC). METHODS: Patients were treated with RRx-001 4 mg IV on day 1 of each week of a 21-day cycle followed at progression by re-challenge with etoposide 80-100 IV mg/m RESULTS: Twenty-six patients were enroled and received at least one dose of RRx-001. The median number of prior lines of therapy was 2 (range 1-9) and 19 (73.1%) patients had platinum-resistant disease. In the intention-to-treat population, one patient (3.8%) had complete response and six (23.1%) had partial response on platinum plus etoposide. The estimated median and 12-month OS from enrolment were 8.6 months and 44.1%, respectively. The most common treatment-emergent adverse event from RRx-001 was mild discomfort at the infusion site (23%). CONCLUSIONS: RRx-001 followed by re-challenge with platinum plus etoposide chemotherapy is feasible and associated with promising results. CLINICAL TRIAL REGISTRATION: NCT02489903

Resolution of Crizotinib-Associated Fulminant Hepatitis following Cessation of Treatment

Targeted cancer treatments offer the prospect of precise inhibition of tumor growth without the untoward off-target toxicity of traditional chemotherapies. Still, unintended, often idiosyncratic side effects, such as drug-induced liver injury, can occur. We discuss the case of a 26-year-old female with a history of ROS1-rearranged lung adenocarcinoma, undergoing treatment with the tyrosine kinase inhibitor crizotinib, who presented to our hospital with abdominal pain and scleral icterus. Liver chemistries were notable for hyperbilirubinemia (5 mg/dL total) and marked transaminasemia (AST 1736 U/L, ALT >3500 U/L); liver biopsy demonstrated acute hepatitis with extensive necrosis. There was no evidence of an infectious or autoimmune etiology. It was discovered that the patient was taking a 500 mg once daily dose of crizotinib, in lieu of the intended dose of 250 mg twice daily. After immediate cessation of crizotinib therapy upon hospital admission, there was complete biochemical resolution of the hepatitis. This case highlights the potential reversibility of fulminant crizotinib-associated hepatoxicity, possibly related to supratherapeutic dosing, when managed with abrupt stoppage of the drug and initiation of supportive care

Role of KEAP1/NFE2L2 Mutations in the Chemotherapeutic Response of Patients with Non-Small Cell Lung Cancer.

Purpose: Activation of NFE2L2 has been linked to chemoresistance in cell line models. Recently, somatic mutations that activate NFE2L2, including mutations in NFE2L2, KEAP1, or CUL3, have been found to be associated with poor outcomes in patients with non–small cell lung cancer (NSCLC). However, the impact of these mutations on chemoresistance remains incompletely explored. Experimental Design: We investigated the effect of Keap1 deletion on chemoresistance in cell lines from Trp53-based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD). Separately, we identified 51 patients with stage IV NSCLC with KEAP1, NFE2L2, or CUL3 mutations and a matched cohort of 52 wild-type patients. Time to treatment failure after first-line platinum doublet chemotherapy and overall survival was compared between the two groups. Results: Deletion of Keap1 in Trp53-null murine LUAD and LSCC resulted in increased clonogenic survival upon treatment with diverse cytotoxic chemotherapies. In patients with NSCLC, median time to treatment failure (TTF) after first-line chemotherapy for the KEAP1/NFE2L2/CUL3-mutant cohort was 2.8 months compared with 8.3 months in the control group (P &lt; 0.0001). Median overall survival (OS) was 11.2 months in the KEAP1/NFE2L2/CUL3-mutant group and 36.8 months in the control group (P ¼ 0.006). Conclusions: Keap1 deletion confers chemoresistance in murine lung cancer cells. Patients with metastatic NSCLC with mutations in KEAP1, NFE2L2, or CUL3 have shorter TTF and OS after first-line platinum doublet chemotherapy compared with matched controls. Novel approaches for improving outcomes in this subset of patients with NSCLC are therefore needed. ©2019 American Association for Cancer Research.1