In late October, Ignyta presented the results from a Phase 2 study of Entrectinib
in patients with ROS1-positive non-small cell lung cancer (NSCLC) at the International Association for the Study of Lung Cancer (IASLC) 18th
World Conference on Lung Cancer in Yokohoma, Japan.
The recent data showed a 78% overall response rate (ORR) that led the company to believe that the drug could be a best-in-class therapeutic option as a first-line targeted therapy for patients with ROS1-
positive non-small cell lung cancer.
Rare Disease Report
recently spoke with Jonathan Lim, M.D., the Chairman and CEO of Ignyta about the exciting results and next steps for Entrectinib.
Rare Disease Report:
Can you speak to your study of entrectinib in patients with ROS1-positive non-small cell lung cancer? What specifically makes this data so impressive?
The data that were presented at World Lung showed that entrectinib is a compelling future therapeutic option as a first-line targeted therapy for patients with ROS1 positive non-small cell lung cancer, and this belief is based on areas in which we believe entrectinib is demonstrating compelling differentiation.
The data comes from a dataset formed from 3 different studies, namely STARTRK-2, which is the global phase 2, potentially registration-enabling study in more than 150 sites across 15 countries. It’s also based on the 2 phase 1 studies: STARTRK-1 and ALKA372001. The objective response rates, or the ability to shrink tumor size, showed that it was 78% by local assessment and 69% by central assessment. Right now, there’s only 1 approved ROS1 inhibitor, crizotinib, which demonstrated 72% ORR by local assessment and 66% ORR by central assessment.
Entrectinib was intentionally designed to cross the blood-brain barrier, and has shown compelling CNS (central nervous system) activity. The CNS response rates for intracranial ORR in this population was 83%, and 5 out of 6 patients with measurable CNS lesions had a confirmed resist response in the brain. This is important for 2 main reasons: first, it addresses preexisting CNS lesions in patients who already have brain metastasis. With the ability to cross the blood-brain barrier, we believe that the compound has the potential to also prevent or slow down new metastasis to the brain, which is one of the most frequent sites of progression in patients with non-small cell lung cancer who are treated with current standard of care therapies that do not cross the blood-brain barrier.
Why is it so important for novel therapies like yours to be active throughout the CNS? Does crizotinib also express CNS activity?
Often times, because patients today do not have CNS active ROS1 targeted inhibitors available as approved drugs, they might need radiation therapy which can lead to cognitive side effects like memory impairment, slurred speech or headaches. It’s very important for novel therapies to be able to have CNS activity, but also a good tolerability that can preserve the patients’ core self. If the CNS activity of novel compounds can address CNS lesions and can prevent or slow down other lesions from developing in the brain, the hope is that this could translate into prolonged durability. In the interim dataset presented in Yokohoma, the median duration response was about 29 months and the median PFS was about 30 months. We found that this was compelling, as well, based on the interim data. There is an analog in the ALK lung space where Alectinib, which is a CNS-active compound, demonstrated 25 months of PFS, which was longer than the 10 months PFS of Crizotinib, which has lower CNS activity. A lot of this PFS advantage was driven by significantly fewer patients progressing in the brain while on treatment.
Is entrectinib safe and tolerable for patients?
Those are the final dimensions that we think are important for differentiation; safety and tolerability. We actually reported a dataset of more than 200 patients treated at the recommended phase 2 dose and most of entrectinib’s AEs were grade 1 or 2 and reversible. Only 3% of patients discontinued treatment due to a lack of tolerability.
What is the mechanism of action of entrectinib, and what is it targeting?
Entrectinib is a tyrosine kinase inhibitor, so it basically targets receptor tyrosine kinases which are proteins that can be changed by mutations or genetic rearrangements to the DNA that encode those proteins which then lead to aberrant signaling. For instance, when you get a mutation that arises in ROS1 or in TRK, then it can turn on self-signaling such that abnormal growth occurs and cancer gets turned on. The targets that entrectinib go after are the tyrosine kinases called TRK and ROS1. When either of those get turned on, you need to shut down the signaling by blocking the protein that is abnormally turned on. That’s how the drug works – It specifically goes after these abnormal proteins that are turned on by the genetic rearrangements.
“A good analogy would be a light switch that is left in the “on” position as a result of the genetic rearrangement. What entrectinib and other tyrosine kinase inhibitors essentially try to do is go in and mechanically shut off the on switch,” added Ignyta CFO Jacob Chacko, who was also present for the interview.
: What are the hopes of Ignyta, as entrectinib moves through the pipeline?
Our hopes for the drug are that it can be an attractive therapeutic option for patients with non-small cell lung cancer that’s driven by ROS1 gene rearrangements. Why we’re hopeful that it will become an option is based on the early signs of activity, both in patients with preexisting brain metastasis, as well as patients with systemic disease driven by ROS1. We think that the objective response rates are compelling and the interim data on durability as exemplified by median duration of response and median PFS are compelling. If these data continue to hold true to the registration dataset, which will be submitted to the FDA in the second half of 2018, we believe that Entrectinib has a really good shot to be an alternative for NSCLC patients.
: Are any additional studies being required of Ignyta and Entrectinib by the U.S. Food and Drug Administration (FDA)?
STARTRK-2 is designed to be the registration-enabling study, and we have not been requested to do any additional studies.
We have been requested by the FDA, though, to follow the last patient enrolled in the registration dataset for at least 12 months after response, which brings us into the second half of next year. We’ll also be completing all of the chemistry manufacturing controls, as well as the non-clinical and diagnostic activity to support registration, in addition to the clinical data.
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