A Curated Selection of the Latest Advances in Cancer Research
Peer Reviewed Publications
Safety and Antitumor Activity of the Multi-Targeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib (RXDX-101): Combined Results from Two Phase 1 Trials (ALKA-372-001 and STARTRK-1). Drilon, A., Siena, S. et al. Cancer Discovery. 2017. Feb 9. doi: 10.1158/2159-8290 PMID: 28183697
CONCLUSIONS: Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in NSCLC, colorectal cancer, mammary analog secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as > 2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer.
Clinical and radiographic response following targeting of BCAN-NTRK1 fusion in glioneuronal tumor. Alvarez-Breckenridge, C. et al. npj Precision Oncology. 2017;1(1):5.
CONCLUSIONS: The patient was treated for 11 months and during this time volumetric analysis of the lesion demonstrated a maximum reduction of 60% in the contrast-enhancing tumor compared to his pre-treatment magnetic resonance imaging study. The radiologic response was associated with resolution of his clinical symptoms and was maintained for 11 months on treatment. This report of a BCAN-NTRK1 fusion in glioneuronal tumors highlights its clinical importance as a novel, targetable alteration.
Response to Entrectinib in a Differentiated Thyroid Cancer With a ROS1 Fusion. Liu, S.V. et al. JCO Precision Oncology. 2017 :1, 1-5
CONCLUSIONS: This patient case provides additional confirmation that ROS1 fusions are actionable targets even when observed outside of NSCLC and supports the ongoing development of small-molecule, CNS-active ROS1 inhibitors such as entrectinib in basket study designs across multiple solid tumors.
Activity of Entrectinib in a Patient With the First Reported NTRK Fusion in Neuroendocrine Cancer. Sigal, D. et al. J Natl Compr Canc Netw. 2017;15(11):1317–1322
CONCLUSIONS: This is the first report of an NTRK fusion in NETs. Our patient's response to entrectinib suggests that NTRK fusions can be important in the pathogenesis of NETs. Recent DNA-based genomic analyses of NETs may have missed NTRK fusions due its large gene rearrangement size and multiple fusion partners. The tumor's initial pseudoprogression may represent a unique response pattern for TRK-targeted therapies. An effort to characterize the prevalence of NTRK fusions in NETs using optimal sequencing technology is important.
Acral Lentiginous Melanoma Harboring a ROS1 Gene Fusion With Clinical Response to Entrectinib. Couts, K.L. et al. JCO Precision Oncology. 2017. DOI: 10.1200/PO.16.00013
CONCLUSIONS: ROS1 fusions occur and can respond to targeted therapy in cutaneous melanoma; however, they may be specific to ALM subtype. This report expands knowledge of ROS1 inhibitor response outside of NSCLC and identifies new therapeutic options for a subset of patients with ALM.
What Hides Behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma. Drilon, A. et al. Ann Oncol. 2016 Feb; PMID 26884591
CONCLUSIONS: This first report of clinical activity with TrkC inhibition and the development of acquired resistance in an NTRK3-rearranged cancer emphasize the utility of comprehensive molecular profiling and targeted therapy for rare malignancies (NCT02097810).
Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer. Farago, A.F. et al. Journal of Thoracic Oncology. 2015;10(12):1670-1674. doi:10.1097/01.JTO.0000473485.38553.f0.
CONCLUSIONS: Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases.
Sensitivity to Entrectinib Associated with a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer. Sartore-Bianchi, A. et al. JNCI J Natl Cancer Inst. 2016; 108(1): djv306
CONCLUSIONS: We identified abnormal expression of the TRKA protein in tumor and liver metastases of a CRC patient refractory to standard therapy. Molecular characterization unveiled a novel LMNA-NTRK1 rearrangement within chromosome 1 with oncogenic potential, and the patient was treated with the pan-TRK inhibitor entrectinib, achieving partial response with decrease in hepatic target lesions from 6.8 and 8.2 cm in longest diameter to 4.7 and 4.3 cm, respectively. To our knowledge, this is the first clinical evidence of efficacy for therapeutic inhibition of TRKA in a solid tumor, illuminating a genomic-driven strategy to identify CRCs reliant on this oncogene to be clinically targeted with entrectinib.
Entrectinib, a Pan-TRK, ROS1 and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications. Ardini, E. et al. Mol Cancer Ther; 15(4); 628-39
CONCLUSIONS: Entrectinib is currently showing great promise in phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC. The drug is, thus, potentially suited to the therapy of multiple molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available.
Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model. Iyer, R. et al. Cancer Lett. 2016 Mar 28;372(2):179-86. PMID: 26797418
CONCLUSIONS: We show that entrectinib inhibits growth of TrkB expressing NB cells in vitro and in vivo, and that it enhances the efficacy of conventional chemotherapy in in vivo models. Our data suggest that entrectinib is a potent Trk inhibitor and should be tested in clinical trials for NBs and other Trk-expressing tumors
NTRK1 rearrangement in colorectal cancer patients: evidence for actionable target using patient-derived tumor cell line. Lee, SJ. et al. Oncotarget. 2015: 6(36): 39028-35 PMID: 26472021
CONCLUSIONS: TrkA IHC is an effective, initial screening method for NTRK1 rearrangement detection in the clinic. Inhibition of the TrkA kinase is a promising targeted therapy for cancer patients whose tumors harbor a NTRK1 rearrangement.
Detecting Gene Rearrangements in Patient Populations Through a 2-Step Diagnostic Test Comprised of Rapid IHC Enrichment Followed by Sensitive Next-Generation Sequencing. Murphy, D. et al. Appl Immunohistochem Mol Morphol 2016;00:000–000
CONCLUSIONS: The 2-step diagnostic test presented in this paper demonstrates a method to rapidly screen a large population of patients to identify a small percentage who harbor gene rearrangements. This method allows for the screening of negative patient specimens quickly and inexpensively and reflexes putatively positive samples to higher resolution multiplexed NGS based testing.
ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer. Pietrantonio, F. et al. JNCI J Natl Cancer Inst (2017) 109(12): djx089
CONCLUSIONS: ALK, ROS1, and NTRK rearrangements define a new rare subtype of mCRC with extremely poor prognosis. Primary tumor site, MSI-high, and RAS and BRAF wild-type status may help to identify patients bearing these alterations. While sensitivity to available treatments is limited, targeted strategies inhibiting ALK, ROS, and TrkA-B-C provided encouraging results. ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer.
Identification and characterization of a novel SCYL3-NTRK1 rearrangement in a colorectal cancer patient. Milione, M. et al. Oncotarget. 2017;8(33): 55353-55360
CONCLUSIONS: Here we report the identification and functional characterization of a new SCYL3- NTRK1 fusion gene in a 61-year-old colorectal cancer patient. To our knowledge, this fusion protein has never been previously documented in oncological patients. We show that this novel fusion is oncogenic and sensitive to TRKA inhibitors.
A multiplexed immuno-histochemistry test to screen for protein overexpression of ROS1, TrkA, TrkB and TrkC in multiple tumor tissue types. Boomer, A. et al. Proceedings of the Annual Meeting of the American Association for Cancer Research 2015; Apr 18-22, Philadelphia (PA), abstract number 3389.
Monitoring activity of RXDX-101 in Phase 1/2 patients using a pharmacodynamic assay for TrkA activation. Murphy, D. et al. European Journal of Cancer 50:143-144 · October 2014 DOI: 10.1016/S0959-8049(14)70562-3
A novel, statistical-based method to determine RNA expression by next-generation sequencing in clinical FFPE samples. Shoemaker, R. et al. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5274.
Improved efficacy response attributed to diagnostic selection – Interim results of the phase 1 experience from ALKA-372-001. Christiansen, J. et al. Ann Oncol (2016) 27 (suppl 6): doi: 10.1093/annonc/mdw363.86
Novel Entrectinib Trial Focuses on Gene Rearrangements Across Many Tumor Types Berberabe, Tony. OncologyLive 17.7 2016 Apr. pp 24
Entrectinib Will Likely Play an Increasing Role in Treating Brain Tumors, Other Cancers, Expert Says Connelly, S. Targeted Oncology. 2016 Nov.
NTRK gene fusions as novel targets of cancer therapy across multiple tumour types Amatu et al. ESMO Open 2016; 1:e000023. DOI: 10.1136/esmoopen-2015-000023. Mar2016
Tropomyosin-Related Kinases making Headway in Head and Neck Cancer. Sciavolino P. Targeted Therapies in Onc. 2015 Dec; pp69, 72
Precision Medicine in Sarcoma Pinpoints Tropomyosin-Related Kinases Sciavolino P. Targeted Therapies in Onc. 2015 Oct; pp40, 41
Cholangiocarcinoma: New Targeted Therapies on the Horizon Darcy Lewis. Precision Medicine in Oncology. 2016 Jul. pp48,49
Tropomyosin Receptor Kinase (TRK): Another Promising Target in Metastatic Colorectal Cancer Sciavolino P. Targeted Therapies in Onc. 2015 Dec; pp34, 37
Treatment Strategies with NTRK Gene Rearrangements Emerge in Lung and Other Solid Tumors Sciavolino P. Targeted Therapies in Onc. 2015 Sep; pp30, 31
Entrectinib Shows Dramatic Response in Rare Salivary Gland Tumor Otrompke J. Targeted Oncology. 2016 May.
NTRK Fusions in Papillary Thyroid Cancer: Expanding Targetable Treatment Options Sciavolino P. Targeted Oncology. 2016 Oct.
Metastatic Colorectal Cancer Target May Prove Promising for Subset of Patients Sciavolino P. Targeted Oncology. 2015 Dec.
A new agent is being explored in Brain cancer Connelly S. Cure Today. 2016 Nov.
Basket studies: Changing the way cancer is treated Sadick B. Cure Today. 2016 Apr.