On September 11, 2017 Ignyta, Inc. (Nasdaq:RXDX), a biotechnology company focused on precision medicine in oncology, provided an update on entrectinib—an orally bioavailable, CNS-active tyrosine kinase inhibitor being developed in tumors that harbor NTRK fusions or ROS1 fusions, currently being studied in a registration-enabling Phase 2 clinical trial known as STARTRK-2—and RXDX-105—an investigational, VEGFR-sparing, potent RET inhibitor (Press release, Ignyta, SEP 11, 2017, View Source [SID1234520465]).
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"Building on last week’s announcement of the completion of enrollment of the entrectinib efficacy data set for NDA submission in ROS1 fusion-positive non-small cell lung cancer, we are equally excited to also have completed enrollment of the efficacy data set for NDA submission in the NTRK tissue-agnostic indication," said Jonathan Lim, M.D., chairman and CEO of Ignyta. "We look forward to dual registration submissions in 2018 for these two independent, high unmet need, molecularly defined populations."
Entrectinib program updates:
Based on written feedback from the FDA, Ignyta confirms completion of enrollment of the efficacy data sets for both the NTRK tissue-agnostic (i.e., fusion-positive solid tumor) cohort and the ROS1 NSCLC cohort to support dual NDA submissions in 2018.
No additional studies were requested for these submissions.
Entrectinib was intentionally designed to cross the blood-brain barrier and has demonstrated CNS activity. Specific guidance was provided by FDA on inclusion of entrectinib CNS efficacy data in future prescribing information for both NTRK and ROS1.
An update on data from STARTRK-2 on entrectinib in ROS1 NSCLC, including an additional six months of follow-up, will be presented at the International Association for the Study of Lung Cancer (IASLC) 18th World Conference on Lung Cancer (WCLC) in Yokohama, Japan October 18, 2017. Previous interim data were shared in an investor update call in April 2017.
Additionally, a recent joint meeting with the Center for Devices and Radiological Health (CDRH) and the Center for Drug Evaluation Research (CDER) on companion diagnostic strategy for entrectinib confirms the premarket approval submission plan and timeline for Trailblaze Pharos are tracking with the dual NDA submissions in NTRK and ROS1.
RXDX-105 program updates:
New Phase 1b clinical data on RXDX-105 presented this week at the ESMO (Free ESMO Whitepaper) 2017 Congress in Madrid, Spain demonstrated clinical activity in RET fusions and compelling response rate in an ultra-rare lung cancer population.
Safety –
A total of 152 patients, with a range of solid tumors, have been treated in the Phase 1/1b clinical trial, including 74 patients treated at the recommended Phase 2 dose of 275mg daily in the fed state, and 43 patients treated at a dose of 350mg daily in the fed state.
RXDX-105 continues to be well tolerated, with the most common treatment-related adverse events Grade 1 or 2 and reversible with dose modifications. The most common Grade 3 treatment-related adverse events ( > 5 percent) were rash (10 percent), hypophosphatemia (7 percent) and elevated ALT (7 percent).
Importantly, toxicities commonly associated with VEGFR inhibition, such as hypertension, hypothyroidism, proteinuria and neurotoxicity were rarely observed ( < 5 percent); and RXDX-105 was not associated with Qt/QTc prolongation.
Efficacy –
Of those treated, 22 patients had NSCLC harboring RET fusions and were RET inhibitor naïve, making them evaluable for response.
A preliminary objective response rate of 75 percent was observed in patients with non-KIF5B-RET fusions, with six of eight patients achieving a confirmed partial response. In contrast, those with KIF5B-RET fusions (14 patients) did not demonstrate a RECIST response. These data are consistent with previous studies that suggest that KIF5B-RET fusions may be less susceptible to RET inhibition.
The longest duration of response (DOR) in a responding patient with non-KIF5B-RET fusion was 10.2 months and ongoing; two-thirds of responding patients currently continue on treatment in active response; median DOR therefore has not yet been reached.
Development plan –
This robust clinical trial design has employed next generation sequencing to identify the precise patient populations most likely to benefit from RXDX-105 – those with non-KIF5B-RET fusions – which is estimated to be approximately 800 new patients per year in the United States.
The RXDX-105 Phase 1b study will be concluded with no further enrollment. Those currently receiving treatment will remain on study.
Ignyta will continue discussing RXDX-105 with potential partners and will provide an update on this program in the first half of 2018.