Entrectinib: Potent Inhibitor of NTRK, ROS1, and ALK fusions

Entrectinib (RXDX-101) is the first Ignyta therapy to move through clinical development from Phase I to a global pivotal Phase II clinical trial. In recently reported results from two ongoing Phase I trials (ALKA-372-001 and STARTRK-1), consisting of a total of 119 patients with a range of solid tumor types, entrectinib demonstrated the following features:

  • The Phase I clinical trial database contains the largest patient safety experience of any Trk inhibitor in clinical development, consisting of a total of 119 patients with a range of solid tumor types, which showed entrectinib appeared to be well tolerated, with no evidence to date of cumulative toxicity or of renal, hepatic, or QTc toxicity.
  • By selectively inhibiting altered proteins arising from oncogenic rearrangements to the NTRK, ROS1, and ALK genes, entrectinib has achieved an overall response rate of 79% in patients with extracranial disease (n = 24) and significant tumor regression (45% by volumetric assessment) in a patient with an NTRK1+ primary brain tumor.
  • This potentially best-in-class small molecule has also demonstrated clinically significant activity in the central nervous system (CNS), achieving both complete and durable responses in patients with CNS disease in these Phase I studies.

But in order to fully grasp the effectiveness of Ignyta’s pipeline therapies in development, it’s crucial to start with the role that gene fusions play in development of cancers and move to the Phase I responses and information on the current Phase II basket study, STARTRK-2.

For more detailed scientific information on the specific gene fusions targeted by entrectinib, please see the following pages through the links below.

Gene Fusions and Cancer Development

The journey from normal cell to neoplasm doesn’t happen overnight. Over the past three decades, researchers have identified key genomic players in the transformation of healthy cells, including NTRK1, NTRK2, NTRK3 (collectively referenced as NTRK), RET, and AXL.1,2

Under normal conditions, these oncogenes are gatekeepers regulating the flow of cellular growth signaling. However, when mutations or chromosome instability affect their DNA sequences, the resulting fusion proteins or other molecular alterations can be overactive, setting off a signal cascade that drives uncontrolled proliferation. These abnormal cells then form localized tumors and eventually may acquire additional genomic events that enable them to spread to other parts of the body.

Precision therapeutics have the potential to selectively target the protein products of these altered genes, representing an important leap forward in cancer care.2,3 Specificity to the exact molecular process driving a patient’s cancer gives this class of drugs a degree of potency and selectivity that is hard to match with traditional therapies.

Learn more about these specific gene fusions and the cancers they are associated with:

Entrectinib – Phase I Trials and Clinical Responses as of March 2016

Entrectinib (RXDX-101) is a selective inhibitor for all three Trk receptor tyrosine kinases encoded by the three NTRK genes, as well as the ROS1 and ALK receptor tyrosine kinases.6 This investigational drug is active at low nanomolar concentrations, allowing for once-daily oral administration to patients whose tumors have been shown to have gene rearrangements in NTRK, ROS1, or ALK.7 The investigational drug is designed to be orally administered once daily and is being studied in patients whose tumors have tested positive for gene rearrangements in NTRK, ROS1, or ALK.7 As a ROS1 inhibitor, entrectinib has been demonstrated in cellular anti-proliferative studies to have 36-fold greater potency against ROS1 compared to another commercially available ROS1 inhibitor, crizotinib.8

In recently reported results from two ongoing Phase I trials (ALKA-372-001 and STARTRK-1), consisting of a total of 119 patients with a range of solid tumor types, entrectinib appeared to be well tolerated, with the most frequent adverse events reported as mild to moderate fatigue, altered taste, abnormal sensations in the nerves, nausea, and muscle aches. The Phase I clinical trial database contains the largest patient safety experience of any Trk inhibitor in clinical development, with no evidence to date of cumulative toxicity or of renal, hepatic, or QTc toxicity. It is notable that no responders have discontinued entrectinib due to tolerability issues at the time of publication.7

“Oncogene addiction” can develop in tumors carrying such gene fusions, as they may become dependent on overactive signaling for survival and proliferation. Small molecule tyrosine kinase inhibitor drugs exploit this molecular weakness when it is present in cancer cells and disable the aberrant proteins.2 Most tyrosine kinase fusions studied in vitro can be shown to function as oncogenic drivers capable of singlehandedly causing transformation of cultured cells. This phenomenon results from the manipulation of the internal signaling pathways to produce a malignant phenotype.2 Some of the most important kinases that have been shown to undergo rearrangement in human cancers include the anaplastic lymphoma kinase (ALK), ROS1 kinase, and the family of neurotrophic tyrosine receptor kinases (NTRKs).2,3,4,5

In these Phase I trials, there were four patients with NTRK fusions, consisting of patients with non-small cell lung cancer (NSCLC), colorectal cancer (CRC), salivary gland cancer, and astrocytoma.7 All four of these patients demonstrated tumor regression (three confirmed responses by RECIST (Response Evaluation Criteria In Solid Tumors is a set of published rules that define how to measure and determine when tumors shrink (“respond”), stay the same (“stable”) or grow (“progression”) during treatments) and one by volumetric assessment). Two of these Trk patients remained on study, one of whom has been on study for longer than 12 months. In addition, there was an 86% confirmed response rate (12 of 14 patients) to entrectinib in patients with ROS1 fusions and a 57% response rate for patients with ALK fusions (4 of 7 patients).7 Many of these responses occurred rapidly, within the first four weeks of entrectinib treatment. Seventeen of the patients remained on study treatment, with the longest at 27 months.7 In these Phase I studies, entrectinib has also demonstrated clinically significant activity in the central nervous system (CNS), achieving both complete and durable responses in patients with CNS disease.7

“Many of these responses occurred rapidly, within the first four weeks of entrectinib treatment.”

Selected Examples of Patients with Responses:

  1. In a 46-year-old NSCLC patient with a SQSTM1NTRK1 fusion who was enrolled in the entrectinib Phase I trial (STARTRK-1), after progressing on multiple lines of standard therapy (including immunotherapy), entrectinib was well tolerated, and AEs possibly related to treatment were grade 1 dysgeusia, grade 1 paresthesia, and grade 2 fatigue, all of which subsequently resolved.9 The patient’s clinical status improved within three weeks of entrectinib initiation, and within 26 days, a partial tumor reduction of 47% was observed by RECIST criteria. A restaging scan conducted after 317 days revealed 79% tumor shrinkage relative to baseline, along with a complete response of all brain metastases.9 This patient has remained on study for over a year.7
  2. Another patient with refractory metastatic colorectal cancer (mCRC) driven at least in part by a novel fusion of the lamin A/C gene (LMNA) with NTRK1 was enrolled in the entrectinib Phase I trial (ALKA-372-001).10 A partial response was observed after four weeks on therapy, with a collective 30% reduction across all observed target lesions, which was confirmed by computed tomography (CT) scan four weeks later. Hepatic lesions, as well as adrenal and peritoneal metastases, also decreased in size in this patient. AEs were not reported, and the duration of response was greater than five months at the time of publication.10
  3. Clinical experience with entrectinib includes a patient with metastatic CRC and an ALK rearrangement who had failed prior therapies.11 After four weeks of therapy, the patient showed a partial response, with a 38% decrease in target lesions. Drug-related adverse events (AEs) were not observed in this patient, and the duration of response was at least four months at the time of publication.11

About the STARTRK-2 Basket Study

The favorable preliminary results seen with entrectinib in Phase I clinical trials of patients with NTRK, ROS1, or ALK gene rearrangements laid the foundation for an open-label, multicenter, global, Phase 2 basket study STARTRK-2 to examine the use of entrectinib in patients living with tumors driven by these gene rearrangements.12 The study will enroll any patient with a solid tumor that tests positive for an NTRK, ROS1, or ALK fusion, assuming that the patient meets all other entry criteria (Box 1). Examples of such tumor types include NSCLC, mCRC, salivary gland cancer, sarcoma, melanoma, thyroid cancer, glioblastoma, astrocytoma, cholangiocarcinoma, lymphoma, and others.

The website www.startrktrials.com has further information on the STARTRK-2 trial for patients with NTRK, ROS1, and ALK fusions.

Box 1: STARTRK-2 Main Inclusion Criteria for patients with NTRK, ROS1, and ALK fusions 12
  • Histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumor that harbors an NTRK1, NTRK2, NTRK3, ROS1, or ALK gene rearrangement
  • Measurable or evaluable disease
  • Prior anticancer therapy is allowed (excludes approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements)
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  • Adequate organ function as defined by protocol
  • Ability to swallow oral entrectinib capsules


  1. Puig de la Bellacasa R, Karachaliou N, Estrada-Tejedor R, Teixidó J, Costa C, Borrell JI. ALK and ROS1 as a joint target for the treatment of lung cancer: a review. Transl Lung Cancer Res. 2013; 2(2):72-86.
  2. Shaw AT, Hsu PP, Awad MM, Engelman JA. Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer. 2013; 13(11):772-787.
  3. Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun. 2014; 5:4846. doi: 10.1038/ncomms5846.
  4. Wiesner T, He J, Yelensky R, et al. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun. 2014; 5:3116. doi: 10.1038/ncomms4116.
  5. Berge EM, Doebele RC. Targeted therapies in non-small cell lung cancer: emerging oncogene targets following the success of epidermal growth factor receptor. Semin Oncol. 2014; 41(1):110-125.
  6. Iyer R, Wehrmann L, Golden RL, et al. Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model. Cancer Lett. 2016; 372(2):179-186.
  7. Drilon A. Entrectinib, an oral pan-Trk, ROS1, and ALK inhibitor in TKI-naïve patients with advanced solid tumors harboring gene rearrangements – updated Phase I results. (Abstract number CT007) Presented at 2016 Annual Meeting of the American Association of Cancer Research. Available at: https://ignyta.com/wp-content/uploads/2016/04/160417-Drilon-AACR-2016-vF.pdf Accessed: June 23, 2016.
  8. Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, Ballinari D, Ciomei M, Texido G, Degrassi A, Avanzi N, Amboldi N, Saccardo MB, Casero D, Orsini P, Bandiera T, Mologni L, Anderson D, Wei G, Harris J, Vernier JM, Li G, Felder E, Donati D, Isacchi A, Pesenti E, Magnaghi P, Galvani A. Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications. Mol Cancer Ther. 2016 Apr;15(4):628-39. doi: 10.1158/1535-7163.MCT-15-0758. Epub 2016 Mar 3. PubMed PMID: 26939704.
  9. Farago AF, Le LP, Zheng Z, et al. Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer. J Thorac Oncol. 2015;10(12):1670-1674.
  10. Sartore-Bianchi A, Ardini E, Bosotti R, et al. Sensitivity to Entrectinib Associated with a Novel LMNANTRK1 Gene Fusion in Metastatic Colorectal Cancer. J Natl Cancer Inst. 2015;108(1). pii: djv306. doi: 10.1093/jnci/djv306.
  11. Amatu A, Somaschini A, Cerea G, et al. Novel CADALK gene rearrangement is drugable by entrectinib in colorectal cancer. Br J Cancer. 2015; 113(12):1730-1734.
  12. Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK1/2/3, ROS1, or ALK Gene Rearrangements (Fusions) (STARTRK-2). Available at: https://clinicaltrials.gov/ct2/show/NCT02568267?term=entrectinib&rank=1 Accessed: March 15, 2016

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