We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

The somatic genomic landscape of glioblastoma

Important advancements in the treatment of non-small cell lung cancer (NSCLC) have been achieved over the past two decades, increasing our understanding of the disease biology and mechanisms of tumour progression, and advancing early detection and multimodal care. The use of small molecule tyrosine kinase inhibitors and immunotherapy has led to unprecedented survival benefits in selected patients. However, the overall cure and survival rates for NSCLC remain low, particularly in metastatic disease. Therefore, continued research into new drugs and combination therapies is required to expand the clinical benefit to a broader patient population and to improve outcomes in NSCLC.

The biology and management of non-small cell lung cancer

Background Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. Methods We enrolled patients with consecutively and prospectively identified TRK fusion–positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1–2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety. Results A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion–positive tumor types. The overall response rate was 75% (95% confidence ...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1714448

Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children

The problem of resistance to therapy in cancer is multifaceted. Here we take a reductionist approach to define and separate the key determinants of drug resistance, which include tumour burden and growth kinetics; tumour heterogeneity; physical barriers; the immune system and the microenvironment; undruggable cancer drivers; and the many consequences of applying therapeutic pressures. We propose four general solutions to drug resistance that are based on earlier detection of tumours permitting cancer interception; adaptive monitoring during therapy; the addition of novel drugs and improved pharmacological principles that result in deeper responses; and the identification of cancer cell dependencies by high-throughput synthetic lethality screens, integration of clinico-genomic data and computational modelling. These different approaches could eventually be synthesized for each tumour at any decision point and used to inform the choice of therapy. A review of drug resistance in cancer analyses each biological determinant of resistance separately and discusses existing and new therapeutic strategies to combat the problem as a whole.

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A view on drug resistance in cancer

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.

NTRK fusion-positive cancers and TRK inhibitor therapy

Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers While responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance LOXO-195 is a novel, selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models As clinical proof of concept, the first two patients with TRK fusion-positive cancers that developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients

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A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors.

Efforts to develop genomically targeted therapy for glioblastoma (GBM) have been unsuccessful to date. Fusions involving the tropomyosin receptor kinases (TrkA/B/C) encoded by NTRK1/2/3 represent a potential therapeutic target in diffuse gliomas. Novel TRK inhibitors have shown remarkable efficacy in patients with TRK fusions in a myriad of solid tumor types; however, there is little clinical data on TRK inhibitor efficacy in diffuse gliomas. Here, we report the case of a 35 year-old woman with recurrent GBM whose NTRK3 fusion tumor was treated to response with larotrectinib. The patient was initially diagnosed with an IDH1 R132H-mutant, 1p/19q intact anaplastic astrocytoma of the right temporal lobe. Three years later, she developed a local recurrence treated with temozolomide with disease progression. Resection identified transformation to GBM for which she received temozolomide and an IDO inhibitor with rapid tumor growth. Urgent piecemeal debulking was performed and confirmed recurrent GBM in both the central and hippocampal components. She was started on CCNU and bevacizumab. Prospective clinical sequencing of the central tumor and matched normal DNA confirmed clonal IDH1 R132H and a mutational signature of temozolomide-induced hypermutation. Multi-region custom RNA sequencing of her disease utilizing the Archer Anchored multiplex technology revealed an in-frame EML4-NTRK3 fusion in the dominant clone of the central tumor that was absent from the hippocampal specimen, indicating intratumoral heterogeneity of a potential therapeutically sensitizing alteration. After further clinical deterioration due to progressive disease involving multiple other brain regions, the patient received larotrectinib via expanded access under an emergency single patient use protocol. A partial response was achieved after only three weeks, the degree of which was radiologically discrepant between disease sites, consistent with the subclonality of the fusion oncoprotein. While there was significant periventricular tumor shrinkage (67x52mm to 8x4mm), there was no shrinkage in the right frontal and occipital lobes. A repeat MRI 1 month later showed disease progression with increasing tumor in the latter sites, but ongoing response of periventricular tumor. This led to clinical deterioration and ultimate discontinuation of lacrotrectinib. In summary, the observed mixed response persisting even at the time of drug discontinuation suggests that while heterogeneous, the EML4-NTRK3-mutant subclone was sensitive and responded to larotrectinib therapy, highlighting larotrectinib’s potential role in TRK fusion CNS disease. TRK fusions may therefore be therapeutic targets in GBM. Patients with TRK fusion CNS tumors are eligible for the ongoing NAVIGATE Phase 2 larotrectinib trial to further understand this biological effect. Citation Format: Alison M. Schram, Barry S. Taylor, Jaclyn F. Hechtman, Ryma Benayed, Lu Wang, Bethany Hanusch, Robert Young, Christian Grommes, Nora Ku, David M. Hyman, Thomas Kaley, Alexander Drilon. Potential role of larotrectinib (LOXO-101), a selective pan-TRK inhibitor, in NTRK fusion-positive recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-302. doi:10.1158/1538-7445.AM2017-LB-302

Abstract LB-302: Potential role of larotrectinib (LOXO-101), a selective pan-TRK inhibitor, in NTRK fusion-positive recurrent glioblastoma

Glioblastoma is the most common malignant primary brain tumor in adults. Despite aggressive initial treatment, recurrence is inevitable and almost always fatal. Treatment options for recurrent disease are limited and do not substantially improve survival. In recent years, molecular characterization of gliomas has revealed recurrent somatic mutations, structural rearrangements, and epigenetic alterations. These genomic alterations have implications for prognosis and response to treatment. IDH1/2 mutations are associated with a more favorable prognosis among glioblastomas, whereas tumors with MGMT promoter hypermethylation are more likely to respond to treatment with alkylating agents.1,2 The pattern of genomic alterations can also provide insight into the origin and evolution of the tumor. For example, the presence of coexistent mutations in IDH1 and ATRX suggest a secondary glioma that has progressed from a lower-grade glioma.3-5 In addition to informing prognosis and diagnostic classification, some genomic alterations in glioma represent potential therapeutic targets. Specifically, recurrent alterations in one of several receptor tyrosine kinases (RTKs), including EGFR, PDGFRA, MET, and FGFR1/2/3, have been observed in the majority of glioblastomas.6 Unfortunately, efforts to develop genomically targeted therapy for the treatment of glioblastoma have been unsuccessful to date.7 It remains unknown the extent to which the lack of activity of targeted therapy may be attributed to so-called key alterations that do not represent true clonal drivers that are critical to tumor growth and progression compared with the simple inability of existing drugs to achieve therapeutic exposures within the CNS.

In addition to these more common genomic alterations, less common fusions that involve the kinase domain of tropomyosin receptor kinases (TRKs; A/B/C) encoded by the genes, NTRK1, NTRK2, and NTRK3 have also been identified in gliomas.8-11 In other cancer types, selective inhibition of these TRK fusions has resulted in remarkable efficacy12; however, it remains unknown whether this therapeutic strategy is effective in primary brain tumors. Here, we report the case of a young woman with recurrent glioblastoma treated with larotrectinib, a first-in-class, potent, highly selective TRK inhibitor. To our knowledge, this is the first report of the use of a TRK inhibitor in a patient with a TRK fusion–positive glioblastoma.

Bethany Hanusch

Papers

A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors.

Abstract LB-302: Potential role of larotrectinib (LOXO-101), a selective pan-TRK inhibitor, in NTRK fusion-positive recurrent glioblastoma

Genomic Heterogeneity Underlies Mixed Response to Tropomyosin Receptor Kinase Inhibition in Recurrent Glioma