NTRK gene fusions involving either NTRK1, NTRK2 or NTRK3 (encoding the neurotrophin receptors TRKA, TRKB and TRKC, respectively) are oncogenic drivers of various adult and paediatric tumour types. ...These fusions can be detected in the clinic using a variety of methods, including tumour DNA and RNA sequencing and plasma cell-free DNA profiling. The treatment of patients with NTRK fusion-positive cancers with a first-generation TRK inhibitor, such as larotrectinib or entrectinib, is associated with high response rates (>75%), regardless of tumour histology. First-generation TRK inhibitors are well tolerated by most patients, with toxicity profiles characterized by occasional off-tumour, on-target adverse events (attributable to TRK inhibition in non-malignant tissues). Despite durable disease control in many patients, advanced-stage NTRK fusion-positive cancers eventually become refractory to TRK inhibition; resistance can be mediated by the acquisition of NTRK kinase domain mutations. Fortunately, certain resistance mutations can be overcome by second-generation TRK inhibitors, including LOXO-195 and TPX-0005 that are being explored in clinical trials. In this Review, we discuss the biology of NTRK fusions, strategies to target these drivers in the treatment-naive and acquired-resistance disease settings, and the unique safety profile of TRK inhibitors.
Attempts to develop MET-targeted therapies have historically focused on MET-expressing cancers, with limited success. Thus, MET expression in the absence of a genomic marker of MET dependence is a ...poor predictor of benefit from MET-targeted therapy. However, owing to the development of more sensitive methods of detecting genomic alterations, high-level MET amplification and activating MET mutations or fusions are all now known to be drivers of oncogenesis. MET mutations include those affecting the kinase or extracellular domains and those that result in exon 14 skipping. The activity of MET tyrosine kinase inhibitors varies by MET alteration category. The likelihood of benefit from MET-targeted therapies increases with increasing levels of MET amplification, although no consensus exists on the optimal diagnostic cut-off point for MET copy number gains identified using fluorescence in situ hybridization and, in particular, next-generation sequencing. Several agents targeting exon 14 skipping alterations are currently in clinical development, with promising data available from early-phase trials. By contrast, the therapeutic implications of MET fusions remain underexplored. Here we summarize and evaluate the utility of various diagnostic techniques and the roles of different classes of MET-targeted therapies in cancers with MET amplification, mutation and fusion, and MET overexpression.
Activating receptor tyrosine kinase RET (rarranged during transfection) gene alterations have been identified as oncogenic in multiple malignancies. RET gene rearrangements retaining the kinase ...domain are oncogenic drivers in papillary thyroid cancer, non-small-cell lung cancer, and multiple other cancers. Activating RET mutations are associated with different phenotypes of multiple endocrine neoplasia type 2 as well as sporadic medullary thyroid cancer. RET is thus an attractive therapeutic target in patients with oncogenic RET alterations. Multikinase inhibitors with RET inhibitor activity, such as cabozantinib and vandetanib, have been explored in the clinic for tumors with activating RET gene alterations with modest clinical efficacy. As a result of the nonselective nature of these multikinase inhibitors, patients had off-target adverse effects, such as hypertension, rash, and diarrhea. This resulted in a narrow therapeutic index of these drugs, limiting ability to dose for clinically effective RET inhibition. In contrast, the recent discovery and clinical validation of highly potent selective RET inhibitors (pralsetinib, selpercatinib) demonstrating improved efficacy and a more favorable toxicity profile are poised to alter the landscape of RET-dependent cancers. These drugs appear to have broad activity across tumors with activating RET alterations. The mechanisms of resistance to these next-generation highly selective RET inhibitors is an area of active research. This review summarizes the current understanding of RET alterations and the state-of-the-art treatment strategies in RET-dependent cancers.
The proto-oncogene ROS1 encodes a receptor tyrosine kinase with an unknown physiological role in humans. Somatic chromosomal fusions involving ROS1 produce chimeric oncoproteins that drive a diverse ...range of cancers in adult and paediatric patients. ROS1-directed tyrosine kinase inhibitors (TKIs) are therapeutically active against these cancers, although only early-generation multikinase inhibitors have been granted regulatory approval, specifically for the treatment of ROS1 fusion-positive non-small-cell lung cancers; histology-agnostic approvals have yet to be granted. Intrinsic or extrinsic mechanisms of resistance to ROS1 TKIs can emerge in patients. Potential factors that influence resistance acquisition include the subcellular localization of the particular ROS1 oncoprotein and the TKI properties such as the preferential kinase conformation engaged and the spectrum of targets beyond ROS1. Importantly, the polyclonal nature of resistance remains underexplored. Higher-affinity next-generation ROS1 TKIs developed to have improved intracranial activity and to mitigate ROS1-intrinsic resistance mechanisms have demonstrated clinical efficacy in these regards, thus highlighting the utility of sequential ROS1 TKI therapy. Selective ROS1 inhibitors have yet to be developed, and thus the specific adverse effects of ROS1 inhibition cannot be deconvoluted from the toxicity profiles of the available multikinase inhibitors. Herein, we discuss the non-malignant and malignant biology of ROS1, the diagnostic challenges that ROS1 fusions present and the strategies to target ROS1 fusion proteins in both treatment-naive and acquired-resistance settings.
MET exon 14 alterations are oncogenic drivers of non-small-cell lung cancers (NSCLCs)
. These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition
. ...Crizotinib is a multikinase inhibitor with potent activity against MET
. The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations. Objective response rate was 32% (95% confidence interval (CI), 21-45) among 65 response-evaluable patients. Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by splice-site region and mutation type of the MET exon 14 alteration, concurrent increased MET copy number or the detection of a MET exon 14 alteration in circulating tumor DNA. The median duration of response was 9.1 months (95% CI, 6.4-12.7). The median progression-free survival was 7.3 months (95% CI, 5.4-9.1). MET exon 14 alteration defines a molecular subgroup of NSCLCs for which MET inhibition with crizotinib is active. These results address an unmet need for targeted therapy in people with lung cancers with MET exon 14 alterations and adds to an expanding list of genomically driven therapies for oncogenic subsets of NSCLC.
•EGFR-TKI osimertinib inhibits EGFR-TKI sensitizing and T790 M resistance mutations.•Assessing appropriate EGFR-TKI (monotherapy or in combination) sequencing is needed.•The role of sequencing for ...maximal benefit in EGFRm advanced NSCLC is explored here.
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 80–85% of cases. Epidermal growth factor receptor (EGFR) mutations are observed in approximately 40% and 20% of patients with NSCLC in Asian and non-Asian populations, respectively.
First-generation (gefitinib, erlotinib) and second-generation (afatinib, dacomitinib) EGFR-tyrosine kinase inhibitors (TKIs) have been standard-of-care (SoC) first-line treatment for patients with sensitizing EGFR mutation positive advanced NSCLC following Phase III trials versus platinum-based doublet chemotherapy. However, most patients treated with first-line first- or second-generation EGFR-TKIs develop resistance. Osimertinib, a third-generation, central nervous system active EGFR-TKI which potently and selectively inhibits both EGFR-TKI sensitizing (EGFRm) and the most common EGFR T790 M resistance mutations, has shown superior efficacy versus first-generation EGFR-TKIs (gefitinib / erlotinib). Osimertinib is now a treatment option for patients with advanced NSCLC harboring EGFRm in the first-line setting, and treatment of choice for patients with T790 M positive NSCLC following disease progression on first-line EGFR-TKIs. The second-generation EGFR-TKI dacomitinib has also recently been approved for the first-line treatment of EGFRm positive metastatic NSCLC.
There remains a need to determine appropriate sequencing of EGFR-TKIs in this setting, including EGFR-TKIs as monotherapy or in combination with other TKIs / signaling pathway inhibitors. This review considers the evolving role of sequencing treatments to maximize benefits for patients with EGFRm positive advanced NSCLC.
Ras-GTPase-activating proteins (RasGAP), notably NF1 and RASA1, mediate negative control of the RAS/MAPK pathway. We evaluated clinical and molecular characteristics of non-small cell lung carcinoma ...(NSCLC) with
mutations in comparison with
-mutated cases.
Large genomic datasets of NSCLC MSK-IMPACT dataset at MSKCC (
= 2,004), TCGA combined lung cancer dataset (
= 1,144) were analyzed to define concurrent mutations and clinical features of
-mutated NSCLCs. Functional studies were performed using immortalized human bronchial epithelial cells (HBEC) and NSCLC lines with truncating mutations in
, or both.
Overall, approximately 2% of NSCLCs had
-truncating mutations, and this alteration was statistically, but not completely, mutually exclusive with known activating
(
= 0.02) and
(
= 0.02) mutations. Unexpectedly,
-truncating mutations had a strong tendency to co-occur with
-truncating mutations (
< 0.001). Furthermore, all patients (16/16) with concurrent
-truncating mutations lacked other known lung cancer drivers. Knockdown of RASA1 in HBECs activated signaling downstream of RAS and promoted cell growth. Conversely, restoration of RASA1 expression in
-mutated cells reduced MAPK and PI3K signaling. Although growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK or PI3K, cells with concurrent
mutations were profoundly more sensitive (IC
: 0.040 μmol/L trametinib). Finally, simultaneous genetic silencing of
and
sensitized both HBECs and NSCLC cells to MEK inhibition.
Cancer genomic and functional data nominate concurrent
loss-of-function mutations as a strong mitogenic driver in NSCLC, which may sensitize to trametinib.
.
Summary Squamous-cell carcinomas of the lung (SQCLCs) are defined by unique clinicopathological and molecular characteristics that have evolved substantially over time. Historically, these neoplasms ...were the most common subtype of non-small-cell lung cancers and were regarded as central tumours with high molecular complexity without targetable genetic abnormalities. Today, the incidence of SQCLCs is surpassed by adenocarcinomas of the lung with a shift towards peripheral squamous tumours. Differential responses to cytotoxic and biological treatments have reshaped our approach to standard therapies. Additionally, evidence of unique biology has emerged with the discovery of SOX2 amplification, NFE2L2 and KEAP1 mutations, PI3K pathway changes, FGFR1 amplification, and DDR2 mutations. These discoveries have ushered in a new era of targeted therapeutic agents for patients with this disease. This Review draws attention to the distinct clinical and pathological characteristics of SQCLCs, summarises present experience with existing cytotoxic and targeted therapies, and discusses emerging treatments based on new insights into the biology of this disease.
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