Ignyta Announces Updated Data from Entrectinib Phase 1 Clinical Trials at the 2016 AACR Annual Meeting

Excerpt:

“Ignyta, Inc. (RXDX),a precision oncology biotechnology company, today announced that updated results of its Phase 1 clinical trials of entrectinib, the company’s proprietary oral tyrosine kinase inhibitor targeting solid tumors harboring activating alterations to NTRK1, NTRK2, NTRK3, ROS1 or ALK, were presented in an oral plenary session at the 2016 Annual Meeting of the American Association for Cancer Research (AACR) in New Orleans, Louisiana.

“ ‘We continue to be excited by entrectinib’s ability to help patients with advanced cancer,’ said Jonathan Lim, M.D., Chairman and CEO of Ignyta. ‘With respect to efficacy, in the 25 patients in the Phase 1 trials who would meet the eligibility criteria for our Phase 2 clinical trial, we saw tumor regression in 20 patients, or 80%. Nineteen out of 24 patients with extracranial solid tumors had a confirmed RECIST response, representing a 79% overall response rate; and one patient with an astrocytoma had evidence of substantial tumor regression by volumetric measurement. These responses were observed in patients with each of NTRK, ROS1 and ALK rearrangements, and across six tumor histologies, including complete and/or durable responses in both primary and metastatic tumors of the central nervous system.’ ”

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Novel Entrectinib Trial Focuses on Gene Rearrangements Across Many Tumor Types

Excerpt:

“A decade ago, researchers believed molecular alterations occurred in only one or two cancer types. That way of thinking has changed, however, with the understanding that the same alterations, especially gene fusions, can occur across many different tumor types.

“As a result, researchers have designed a recently launched clinical study into entrectinib, a first-inclass inhibitor of tropomyosin receptor kinases (Trk), as a basket trial in which the drug can be evaluated simultaneously for activity against three gene alterations and multiple tumor types.

“STARTRK-2 (NCT02568267) is an open-label, phase II study in which patients with locally advanced or metastatic solid tumors are assigned to different baskets according to whether their tumors harbor rearrangements in one of three key genes—NTRK1/2/3, ROS1, or ALK.”

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Ignyta Announces Collaboration with UCSF For Clinical Trial of Entrectinib

“Ignyta, Inc. (Nasdaq: RXDX),a precision oncology biotechnology company, today announced a clinical collaboration with the University of California, San Francisco (UCSF), under which UCSF will study entrectinib in a proof-of-concept clinical trial in cancer patients with metastatic melanoma that is positive for activating alterations to NTRK1/2/3 (encoding TrkA/TrkB/TrkC) or ROS1.

“ ‘We are excited to collaborate with UCSF, a world-renowned academic research institution,’ said Jonathan Lim, M.D., Chairman and CEO of Ignyta. ‘The focus on melanoma in this study will complement the broader range of indications on which we are focused in our own clinical trials, and we expect the findings to accelerate our understanding of the potential role of entrectinib in treating patients with NTRK-positive and ROS1-positive cancers.’

“Under the terms of the collaboration agreement, Ignyta will contribute $1 million toward the funding of the clinical trial, as well as per-patient fees based on enrollment of NTRK-positive or ROS1-positive patients and their participation in the trial. Ignyta will also provide UCSF with sufficient supply of entrectinib for use in the clinical trial. In addition to the safety and efficacy data from the trial, UCSF will provide Ignyta with tumor samples and genetic sequencing data for patients screened for inclusion in the trial for further genomic analysis.”


New Guideline Will Expand List of Lung Cancer Molecular Tests Doctors Can Use to Help Make Treatment Decisions

The gist: A new guideline will expand the list of tumor abnormalities that doctors can test for to help their lung cancer patients make treatment decisions. Different drugs have been developed to treat patients with different tumor abnormalities, such as mutations in the ALK and EGFR genes. Molecular testing lets doctors see which abnormalities a patient might have, and suggest the best-fitting treatments. The new guidelines will include recommendations for molecular testing of abnormalities in the  ROS1, MET, ERBB2, RET, NTRK1, ALK, and EGFR genes.

“The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) are teaming to revise the evidence-based guideline, “Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors.”

“The updated guideline will include new recommendations for ALK testing by IHC, ALK-EGFR resistance, and a number of emerging target molecular targets which will include, but is not limited to, ROS1, MET, ERBB2, RET, NTRK1. Multiplexed “Next Generation Sequencing” multigene panels and the reassessment of immunohistochemistry will be reviewed. The role of rebiopsy and repeat analysis in the setting of post-treatment relapse, along with testing of blood samples for mutations in circulating tumor cells, cell free tumor DNA, or exosomes will be considered.

“The revision of the guideline will again be based on evidence from unbiased review of published experimental literature. The revisions will be recommended by an expert panel made up of renowned worldwide leaders in the field. The revision will start in early 2015, taking around 18 months to complete.

” ‘Although only one year has passed since the molecular testing guideline was published, rapid accumulation of scientific knowledge and new evidence in this field indicate that the guidelines should be updated. Thus, an update has begun that includes an expanded list of genes and new methods that are clinically relevant,’ said Yasushi Yatabe, MD, PhD, chief, Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan and IASLC member.”


Prevalence of New Genetic Driver in Lung Cancer Shown in Study

“A line has been drawn from mutation of the gene NTRK1, to its role as an oncogene in non-small cell lung cancer, to treatment that targets this mutation. ‘Everything we know about lung cancer points to the idea that when we find one of these genetic drivers and can target it with a drug, patients will respond and tend to have a good amount of time on drug before it becomes ineffective. Obviously we can’t guarantee the effectiveness of targeting the NTRK1 mutation at this point, but everything we know about these kinds of genes makes us extremely hopeful,’ says one researcher.”

Editor’s note: A new targeted therapy treatment may be on the horizon for some lung cancer patients. Targeted therapies work by targeting specific molecules inside cancer cells. Often, these molecules are proteins that are mutated and cause cancer cells to multiply rapidly, contributing to tumor growth. There are several mutated proteins commonly found in non-small cell lung cancer (NSCLC) tumors. For a given patient, these can be detected by molecular testing, and based on the results, doctors can prescribe certain targeted therapy drugs. A newly discovered mutation called NTRK1 is being explored as a potential target for a new targeted therapy. To test the new drug, called LOXO-101, scientists have started a new clinical trial and are enrolling patients whose tumors have NTRK1 mutations.


Genetic Mutation May Offer New Treatment Target for Some Lung Cancers

DNA analyses of lung adenocarcinomas, a type of non-small cell lung cancer (NSCLC), found that some tumors contain a kind of mutation called a gene fusion in a gene called NTRK1. The mutation consists of NTRK1, which is involved in cell growth, merging with a different gene. As a result, the gene’s product, a protein called TRKA, is continuously ‘switched on,’ independent of the signals that normally activate it. Treating cell cultures of lung cancer cells containing the NTRK1 gene fusion with TRKA inhibitors suppressed their growth. Patients with gene fusions in another gene, ALK, experience tumor shrinkage in response to treatment with the ALK inhibitor crizotinib (Xalkori). Similarly, TRKA inhibitors may act as targeted therapies for lung adenocarcinoma patients with NTRK1 mutations.


Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer : Nature Medicine : Nature Publishing Group

We identified new gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the high-affinity nerve growth factor receptor (TRKA protein). Both the MPRIPNTRK1 and CD74NTRK1 fusions lead to constitutive TRKA kinase activity and are oncogenic. Tumor samples from patients with lung cancer (3.3%) without known oncogenic alterations assayed by next-generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions.