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Ignyta to Seek Entrectinib Approval in ROS1-Positive Lung Cancer, Tissue-Agnostic Indication

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NEW YORK (GenomeWeb) – Next year, precision medicine company Ignyta will submit two applications for its lead therapeutic product entrectinib — one in ROS1-positive non-small cell lung cancer, and another for patients with any kind of solid tumor characterized by NTRK-fusions.

Ignyta not only plans to garner near concurrent review and approval entrectinib for the two indications, but also aims to introduce a multimarker NGS-based companion diagnostic on the market alongside the drug, which can identify patients who have these biomarkers and are most likely to respond.

In a webcast call with investors this week during the European Society for Medical Oncology's meeting in Madrid, Ignyta CEO Jonathan Lim discussed the company's communications with the US Food and Drug Administration regarding the development of entrectinib and the Trailblaze Pharos companion diagnostic.

Following the agency's feedback, "we're in a position to confirm that we've now completed enrollment of a sufficient number of patients necessary to support an NDA filing for [entrectinib] with a tissue-agnostic indication, just as we have for the ROS1 non-small cell lung cancer indication," Lim said during the call.

Ignyta acquired entrectinib less than four years ago, when the agent was in early Phase I development, before any proof-of-concept studies had established the indications for the drug, Lim recalled. "We're now in an unprecedented position where we're preparing registration submissions for two independent, high unmet need, molecularly defined populations in NTRK and ROS1, as well as a [CDx premarket approval application] to support both those Rx indications," he said.

The FDA has granted entrectinib orphan drug status in the ROS1-positive, locally advanced or metastatic NSCLC, and orphan and breakthrough therapy status for the tissue-agnostic NTRK-fusion indication. Approximately 1 percent of NSCLC tumors harbor ROS1 tumors. Ignyta estimates that NTRK show up in 15 percent of NSCLC tumors and even rarely in more than 30 other solid tumors types.

In order to garner approval for entrectinib in ROS1-positive NSCLC, Ignyta will submit pooled data from three studies — STARTRK-1, STARTRK-2 and ALKA — across which it has treated more than 70 patients with the drug. The company said it has completed enrollment of the registration efficacy data drawn from more than 50 patients, which will be included in the new drug application submission in the second half of 2018.

The agency has asked to see the overall response rate of patients receiving the drug and to follow responding patients for a year or more to assess their duration of response. Additionally, the agency is interested in the activity of the drug in staving off brain metastases, particularly since patients with this type of NSCLC commonly experience metastases to the brain.

Earlier this year, Ignyta shared interim data for entrectinib in 32 ROS1-positive NSCLC patients and reported a median progression-free survival of 19.1 months. Within the 75 percent of patients who responded to the drug, median duration of response was 17.2 months.

As of April, one patient has been on the drug for three years, two others are going on two-and-a-half years, and 63 percent of patients were still on the study. Of the 11 patients with brain metastases, five out of the seven patients with measurable lesions responded to the drug.

Lim highlighted that Ignyta's drug appears to have better duration of response than Pfizer's Xalkori (crizotinib), the first-generation therapy for ROS1-positive NSCLC, and appears to stave off brain metastasis. Ignyta is planning to update this data at an upcoming lung cancer conference next month.

The FDA also provided feedback on Ignyta's plan to advance entrectinib in locally advanced or metastatic solid tumors characterized by NTRK fusions in adults and children. The regulatory submission will include pooled data from the STARTRK-2 basket study, STARTRK-1, ALKA, and STARTRK-NG studies.

Ignyta said it plans to present data in this indication in the first half of next year. Similar to the ROS1-indication, the agency wants Ignyta to report the overall response rate, track responders for six months or more to gauge their durability of response, and the impact of the drug on brain metastases. 

The plan to advance entrectinib in a tissue-agnostic, molecularly guided indication follows the recent FDA approval for Keytruda (pembrolizumab) for the treatment of any advanced solid tumors characterized by high microsatellite instability or mismatch repair deficiency. This was the first time the FDA approved a drug in a pan-cancer setting, and is hoping to embrace regulatory policies that enable advancement of many other therapies, according to recent comments from the agency's new commissioner Scott Gottlieb.

He recently noted that the agency is seeing increased use of seamless trials, where instead of conducting three separate (Phase I/II/III) studies, one large, continuous adaptive study is done. Drugmakers have filed more than 40 investigational new drug applications for cancer drugs that employ these seamless strategies, which he said saves time and costs compared to the traditional three-phase study paradigm.

Seamless trials are particularly useful when developing drugs "that intervene on common elements found across multiple kinds of diseases states," Gottlieb said yesterday at the RAPS 2017 Regulatory Convergence Conference. "If we had to stop and start formal Phase II trials in each different organ system where a cancer arose, it could have been a protracted process."

In the development program for entrectinib and other drugs in its pipeline, Ignyta is making use of pooled data from different trials and employing innovative approaches, such as basket studies, suggesting a kind of seamless, adaptive approach.

Entrectinib will be launched with a companion diagnostic called Trailblaze Pharos, an NGS test that detects gene fusions, which the agency has agreed to review on an expedited timeframe. The company recently held a joint meeting with FDA's drug and device divisions to ensure that the regulatory plan for the test will allow it to be launched in parallel with the approval of the two indications for entrectinib.

Ignyta will run the tests in its lab, which is CLIA-certified, CAP-accredited, and awaiting approval from the New York State Department of Health. However, despite investing in the launch of a CDx, the company is expecting to face competition from other lab-developed NGS tests on the market.

"Post-launch we expect that the majority of patients will be identified via commercially available NGS tests," Lim said. "We are working with a number of diagnostic partners to ensure that TRK is on these panels."