Concurrent RB1 and TP53 Alterations Define a Subset of EGFR-Mutant Lung Cancers at risk for Histologic Transformation and Inferior Clinical Outcomes

EGFR exon 20 insertion driver mutations (Exon20ins) in non-small cell lung cancer (NSCLC) are insensitive to EGFR tyrosine kinase inhibitors (TKI). Amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR-MET, has shown preclinical activity in TKI-sensitive EGFR-mutated NSCLC models and in an ongoing first-in-human study in patients with advanced NSCLC. However, the activity of amivantamab in Exon20ins-driven tumors has not yet been described. Ba/F3 cells and patient-derived cells/organoids/xenograft models harboring diverse Exon20ins were used to characterize the antitumor mechanism of amivantamab. Amivantamab inhibited proliferation by effectively downmodulating EGFR-MET levels and inducing immune-directed antitumor activity with increased IFNγ secretion in various models. Importantly, in vivo efficacy of amivantamab was superior to cetuximab or poziotinib, an experimental Exon20ins-targeted TKI. Amivantamab produced robust tumor responses in two Exon20ins patients, highlighting the important translational nature of this preclinical work. These findings provide mechanistic insight into the activity of amivantamab and support its continued clinical development in Exon20ins patients, an area of high unmet medical need. SIGNIFICANCE: Currently, there are no approved targeted therapies for EGFR Exon20ins-driven NSCLC. Preclinical data shown here, together with promising clinical activity in an ongoing phase I study, strongly support further clinical investigation of amivantamab in EGFR Exon20ins-driven NSCLC.This article is highlighted in the In This Issue feature, p. 1079.

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Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR–MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion–Driven NSCLC

Purpose: SMARCA4 mutations are among the most common recurrent alterations in non–small cell lung cancer (NSCLC), but the relationship to other genomic abnormalities and clinical impact has not been established. Experimental Design: To characterize SMARCA4 alterations in NSCLC, we analyzed the genomic, protein expression, and clinical outcome data of patients with SMARCA4 alterations treated at Memorial Sloan Kettering. Results: In 4,813 tumors from patients with NSCLC, we identified 8% (n = 407) of patients with SMARCA4-mutant lung cancer. We describe two categories of SMARCA4 mutations: class 1 mutations (truncating mutations, fusions, and homozygous deletion) and class 2 mutations (missense mutations). Protein expression loss was associated with class 1 mutation (81% vs. 0%, P Conclusions: SMARCA4 alterations can be divided into two clinically relevant genomic classes associated with differential protein expression as well as distinct prognostic and treatment implications. Both classes co-occur with KEAP1, STK11, and KRAS mutations, but individually represent independent predictors of poor prognosis. Despite association with poor outcomes, SMARCA4-mutant lung cancers may be more sensitive to immunotherapy.

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The Genomic Landscape of SMARCA4 Alterations and Associations with Outcomes in Patients with Lung Cancer

Bioactive peptides are specific protein fragments that have positive impact on health. They are important sources of new biomedicine, energy and high-performance materials. The beneficial effects of bioactive peptides are due to their antioxidant, antihypertensive, anticarcinogenic, antimicrobial, and immunomodulatory activities. The structure-activity relationship of bioactive peptides plays a significant role in the development of innovative and unconventional synthetic polymeric counterparts. It provides the basis of the stereospecific synthesis, transformation, and development of bioactive peptide products. This review covers the progress of studies in the structure-activity relationship of some bioactive peptides including antioxidant peptides, angiotensin-I-converting enzyme-inhibitory peptides, and anticarcinogenic peptides in the past decade.

Research Progress in Structure-Activity Relationship of Bioactive Peptides

EGFR exon 20 insertions in advanced non-small cell lung cancer: A new history begins.

PurposeTP53 mutation (MT) in epidermal growth factor receptor (EGFR) -MT non–small cell lung cancer (NSCLC) is associated with poor response to targeted therapy; however, its impact on survival is not clearly establishedPatients and MethodsWe performed an analysis of patients with stage IV EGFR MT NSCLC with available gene sequencing data Associations between baseline characteristics; molecular profile, including TP53 MT; and survival outcomes were assessedResultsWe identified 131 consecutive patients with EGFR MT; 81 (62%) had a TP53 MT, and 55 (42%) had other coexisting oncogenic MTs Emergent EGFR T790M MT was observed in 42 patients (32%) Overall survival (OS) was longer for younger patients (P = 003), never smokers (P = 002), those with Eastern Cooperative Oncology Group performance status 0 to 1 (P = 004), and emergent T790M MT (P = 018) TP53 MT (P = 021) and other coexisting oncogenic MTs (P = 0011) were associated with inferior OS In a multivariable regression analysis adjusted for age

Influence of TP53 Mutation on Survival in Patients With Advanced EGFR-Mutant Non–Small-Cell Lung Cancer

PAH associated with connective tissue diseases is associated with significant functional impairment and morbidity, and carries with it a poor prognosis. The mortality is as high as 10% to 15% in the first year after diagnosis; making it a devastating disease. The availability of ever-increasing numbers of treatment options in the recent era have improved survival in this patient population and have made early and accurate diagnosis a more important goal. According to the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL), 1-year, 3-year, 5-year, and 7-year survival rates from time of diagnostic right-sided heart catheterization in patients with PAH were found to be 85%, 68%, 57%, and 49%, respectively, which is a considerable improvement since the National Institutes of Health registry 2 decades previously. In a study by Condliffe and colleagues, survival rates in patients with SSC-associated PAH have improved to 78%at 1 year and 47% at 3 years. Patients with SLE-related PAH have a much higher survival rate of up to 75% at 3 years. Proper screening, early diagnosis, and early treatment can have a significant impact in reducing morbidity and mortality. A small study to assess outcomes in patients with asymptomatic CTD found to have exercise induced PAH suggest that bosentan may be safe and effective in improving the hemodynamics and outcomes in these patients. This study included only 10 patients, and additional randomized trials with larger numbers of subjects are needed to affirm this hypothesis. Studies are under way to find additional therapeutic modalities in the form of PDGF receptor blockers, VEGF blockers, tyrosine kinase inhibitors, endothelial dysfunction inhibitors, multikinase inhibitor of Raf-1, serotonin receptor antagonists,and rho kinase inhibitors. Despite these, clinical suspicion, early diagnosis, early

https://www.rheumatic.theclinics.com/article/S0889-857X(13)00088-4/pdf

Pulmonary arterial hypertension related to connective tissue disease: a review

Pulmonary hamartomas are rare benign tumors consisting of multiple mesenchymal cell lines like cartilage, bone and fat. We discuss an interesting case of a 53-year-old male patient, who was referred to our clinic for persistent cough. Chest X-ray revealed a left suprahilar density associated with plate like atelectasis, which on chest CT was found to be a densely calcified nodule, causing narrowing of the left upper lobe (LUL) bronchus with calcified bilateral hilar lymph nodes. A bronchoscopy revealed a smooth endobronchial mass with calcification, which was removed. Histopathology revealed pulmonary hamartoma.

Endobronchial hamartoma; a rare structural cause of chronic cough

Pulmonary lymphoid disorders span from benign lesions to various forms of malignant lymphoma. Interestingly, they may have similar clinical and radiographic presentations, making histopathological exam vital in differentiation. We present one such diagnostic conundrum. (see Table 1, Table 2)

Table 1

Classification of pulmonary lymphoproliferative disorders.

Saman Ahmed

Papers

Influence of TP53 Mutation on Survival in Patients With Advanced EGFR-Mutant Non–Small-Cell Lung Cancer

Pulmonary arterial hypertension related to connective tissue disease: a review

Endobronchial hamartoma; a rare structural cause of chronic cough

Benign pulmonary nodular lymphoid hyperplasia (NLH) in an HIV infected patient; A diagnostic dilemma.