Targeted Therapies for Lung Cancer Patients With Oncogenic Driver Molecular Alterations

Lung cancer has traditionally been classified by histology. However, a greater understanding of disease biology and the identification of oncogenic driver alterations has dramatically altered the therapeutic landscape. Consequently, the new classification paradigm of non–small-cell lung cancer is further characterized by molecularly defined subsets actionable with targeted therapies and the treatment landscape is becoming increasingly complex. This review encompasses the current standards of care for targeted therapies in lung cancer with driver molecular alterations. Targeted therapies for EGFR exon 19 deletion and L858R mutations, and ALK and ROS1 rearrangements are well established. However, there is an expanding list of approved targeted therapies including for BRAF V600E, EGFR exon 20 insertion, and KRAS G12C mutations, MET exon 14 alterations, and NTRK and RET rearrangements. In addition, there are numerous other oncogenic drivers, such as HER2 exon 20 insertion mutations, for which there are emerging efficacy data for targeted therapies. The importance of diagnostic molecular testing, intracranial efficacy of novel therapies, the optimal sequencing of therapies, role for targeted therapies in early-stage disease, and future directions for precision oncology approaches to understand tumor evolution and therapeutic resistance are also discussed.

Stabilized COre gene and Pathway Election uncovers pan-cancer shared pathways and a cancer specific driver

Approaches systematically characterizing interactions via transcriptomic data usually follow two systems: (1) co-expression network analyses focusing on correlations between genes; (2) linear regressions (usually regularized) to select multiple genes jointly. Both suffer from the problem of stability: a slight change of parameterization or dataset could lead to dramatic alternations of outcomes. Here, we propose Stabilized Core gene and Pathway Election, or SCOPE, a tool integrating bootstrapped LASSO and co-expression analysis, leading to robust outcomes insensitive to variations in data. By applying SCOPE to six cancer expression datasets (BRCA, COAD, KIRC, LUAD, PRAD and THCA) in The Cancer Genome Atlas, we identified core genes capturing interaction effects in crucial pan-cancer pathways related to genome instability and DNA damage response. Moreover, we highlighted the pivotal role of CD63 as an oncogenic driver and a potential therapeutic target in kidney cancer. SCOPE enables stabilized investigations towards complex interactions using transcriptome data.

Encorafenib plus binimetinib in patients with BRAFV600-mutant non-small cell lung cancer: Phase II PHAROS study design

BRAFV600 oncogenic driver mutations occur in 1–2% of non-small cell lung cancers (NSCLCs) and have been shown to be a clinically relevant target. Preclinical/clinical evidence support the efficacy and safety of BRAF and MEK inhibitor combinations in patients with NSCLC with these mutations. We describe the design of PHAROS, an ongoing, open-label, single-arm, Phase II trial evaluating the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib in patients with metastatic BRAFV600-mutant NSCLC, as first- or second-line treatment. The primary endpoint is objective response rate, based on independent radiologic review (per RECIST v1.1); secondary objectives evaluated additional efficacy endpoints and safety. Results from PHAROS will describe the antitumor activity/safety of encorafenib plus binimetinib in patients with metastatic BRAFV600-mutant NSCLC.

Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients Treated at Phramongkutklao Hospital between 2011 and 2018: Comparison between Those With and Without Brain Metastases

Background: Brain metastases (BM) remain a significant problem in NSCLC patients. The reports of factors associated with BM are varied in previous studies including age, histology subtypes, and oncogenic driver alterations. Objective: To determine the prevalence and factors associated with BM in advanced NSCLC patients and to analyze the median overall survival (OS) of the patients that had BM at the time of diagnosis of NSCLC and during the course of the disease. Materials and Methods: The medical records of 552 advanced NSCLC patients between 2011 and 2018 were reviewed. The prevalence of BM was calculated by descriptive statistics. Factors associated with BM were analyzed by using univariate and multivariate analyses. Kaplan-Meier methods were used to analyze the median OS of NSCLC patients with BM. Results: Between January 2011 and December 2018, of the 552 patients newly diagnosed with advanced NSCLC, there were 164 patients who had BM. The prevalence of BM was 29.7%. In multivariate analysis, younger age (adjusted odd ratio [OR] 1.547, 95% confidence interval [CI] 1.049 to 2.280), and adenocarcinoma subtype (adjusted OR 2.529, 95% CI 1.262 to 5.067) were significantly associated with BM. The median OS of patients who had BM at time of advanced NSCLC diagnosis was 7.5 months (95% CI 6.4 to 8.5) and the median OS of patients who had BM during the course of disease was 14.4 months (95% CI 12.2 to 16.5). Conclusion: One-third of the advanced NSCLC patients developed BM. Younger age and adenocarcinoma subtype were associated with BM. Patients who had BM during the course of diseases had better survival outcomes compared to those who had BM at the time of advanced NSCLC diagnosis. Keywords: Advanced NSCLC; Brain metastases

Afatinib combined with anlotinib in the treatment of lung adenocarcinoma patient with novel HER2 mutation: a case report and review of the literature

Background HER2 is a member of the ERBB family of receptor tyrosine kinases, and HER2 mutations occur in 1–4% of non-small cell lung cancer (NSCLC) as an oncogenic driver mutation. We found a rare mutation of HER2 p.Asp769Tyr in NSCLC. Case presentation We presented a case of a 68-year-old nonsmoking male patient with brain metastasis from lung adenocarcinoma harboring a rare mutation of HER2 p.Asp769Tyr. After multiple lines of treatment, he obtained a durable response (10 months) to afatinib and anlotinib. Conclusion We reported for the first time that afatinib and anlotinib have successfully treated lung adenocarcinoma with HER2 p.Asp769Tyr mutation. This finding can provide an insight into the optimal treatment of lung adenocarcinoma patients with novel mutations. Additionally, we summarized the efficacy of targeted therapy for HER2 mutant lung cancer in this article.

NUTM1-Rearranged Neoplasms: A Heterogeneous Group of Primitive Tumors with Expanding Spectrum of Histology and Molecular Alterations: An Updated Review

Nuclear protein of testis (NUT), a protein product of the NUTM1 gene (located on the long arm of chromosome 15) with highly restricted physiologic expression in post-meiotic spermatids, is the oncogenic driver of a group of emerging neoplasms when fused with genes involved in transcription regulation. Although initially identified in a group of lethal midline carcinomas in which NUT forms fusion proteins with bromodomain proteins, NUTM1-rearrangement has since been identified in tumors at non-midline locations, with non-bromodomain partners and with varied morphology. The histologic features of these tumors have also expanded to include sarcoma, skin adnexal tumors, and hematologic malignancies that harbor various fusion partners and are associated with markedly different clinical courses varying from benign to malignant. Most of these tumors have nondescript primitive morphology and therefore should be routinely considered in any undifferentiated neoplasm. The diagnosis is facilitated by the immunohistochemical use of the monoclonal C52 antibody, fluorescence in situ hybridization (FISH), and, recently, RNA-sequencing. The pathogenesis is believed to be altered expression of oncogenes or tumor suppressor genes by NUT-mediated genome-wide histone modification. NUTM1-rearranged neoplasms respond poorly to classical chemotherapy and radiation therapy. Targeted therapies such as bromodomain and extraterminal domain inhibitor (BETi) therapy are being developed. This current review provides an update on NUTM1-rearranged neoplasms, focusing on the correlation between basic sciences and clinical aspects.

Leveraging Pathway-Interference to Overcome Drug-Resistance in Acute Lymphoblastic Leukemia

Background: The concept of multi-step carcinogenesis (Fearon and Vogelstein 1990) suggests that acquisition of mutations in addition to an existing set of mutations invariably accelerates tumor-progression. In colorectal cancer and many other cancer types, activation of multiple distinct oncogenic pathways is required for the development of invasive cancer. Here, we examined this paradigm for genetic lesions in B-ALL and 13 other cancer types. Bioinformatic approaches: To broadly study how oncogenic drivers across multiple signaling pathways interact, we developed a bioinformatic platform to map interactions between genetic lesions that cause oncogenic activation of eight oncogenic pathways, including PI3K, STAT5, NF-κB, Hippo, Notch, WNT, RAS-ERK and TGFβ-Smad pathways. Plotting of interaction scores between 56 pathway pairs in a matrix for 14 cancer types revealed that 12 of the 14 cancer types showed a pattern of globally synergistic pathway interactions, consistent with the Fearon and Vogelstein model of cooperation of multiple pathways to drive malignant transformation. Strikingly, B-ALL and gliomas showed the opposite behavior with largely antagonistic pathway interactions. Results. Unlike the vast majority of cancer types, B-ALL and gliomas are driven by one principal oncogenic pathway at a time. While the reasons for negative pathway interactions in glioma are unknown, we focused on functional analyses on pathway interference patterns in 1,148 cases of B-ALL. Genetic lesions leading to STAT5- or ERK-pathway activation are frequently found in B-ALL. Interestingly, activating lesions of both pathways co-occurred in only 3% of the cases studied, suggesting that co-activation of STAT5- and ERK-occurs much less frequently than expected by chance (odds ratio 0.13, P=2e-16, Figure, left). Unbiased interaction mapping analyses of mutational co-occurrence indicated strong negative selection for dual activation of both STAT5- and ERK-pathways (Figure, middle). Importantly this inter-pathway aversion is much stronger than intra-pathway effects, reflecting incompatibility rather than redundancy. Even in rare cases of co-occurrence in the same sample, single-cell mutation and phosphoprotein analyses revealed that STAT5- and ERK-activating mutations were mutually exclusive and reflected two competing clones. STAT5- and ERK-pathways engage conflicting transcriptional and biochemical programs, resulting in "friction", when both pathways are concurrently activated. In agreement with pathway interference, we demonstrated that Cre-mediated deletion of divergent pathway components - Erk2 fl/fl in a STAT5-driven model of B-ALL and Stat5 fl/fl in an ERK-driven B-ALL model - dramatically accelerated initiation of fatal leukemia in vivo. While Cre-mediated deletion of divergent pathway components precipitated leukemia-initiation, these findings suggest that reactivation of divergent signaling pathways represents a powerful barrier against malignant transformation. Interestingly, our preclinical studies suggested that pharmacological reactivation of divergent (suppressed) pathways can be leveraged for therapeutic benefit: The DUSP6 small molecule inhibitor BCI-215 functions as powerful activator of ERK and suppresses STAT5-phosphorylation, i.e. the principal pathway in STAT5-driven B-ALL (Figure, right). Likewise, DPH, a small molecule STAT5-agonist interferes with ERK-phosphorylation, the principal oncogenic driver in RAS-pathway B-ALL (Figure, right). Both BCI-215 and DPH significantly prolonged overall survival of NSG mice transplanted with refractory STAT5- and ERK-driven B-ALL PDX, respectively. Conclusions: We propose that a diverse spectrum of signaling input reflects interactions of normal cells with their environment, while convergence on one centralized pathway is a hallmark of cancer. Tracking early stages of leukemia-initiation, we identified convergence on one principal oncogenic driver and inactivation of diverging pathways as an early critical step. Pharmacological reactivation of divergent signaling pathways to subvert transformation was achievable by STAT5- and ERK-agonists. Proof-of-concept studies in patient-derived B-ALL cells revealed that pharmacological reactivation of suppressed divergent circuits can be leveraged as a previously unrecognized strategy to overcome drug-resistance. Figure 1 Figure 1. Disclosures Izraeli: Roche: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; sightDx: Consultancy. Weinstock: ASELL: Consultancy; SecuraBio: Consultancy; Bantam: Consultancy; AstraZeneca: Consultancy; Abcuro: Research Funding; Verastem: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Travera: Other: Founder/Equity; Ajax: Other: Founder/Equity.