Roche Gains Entrectinib Through Ignyta Merger

Daniel O'Day, CEO

Roche has announced plans to acquire the ROS1/TRK inhibitor entrectinib, through an all-cash $1.7 billion-dollar merger with Ignyta. Roche will pay $27.00 per share for Ignyta, representing a 71% premium. The transaction was approved by both companies and Roche has begun acquiring outstanding shares. The transaction is expected to close in early 2018.

“Cancer is a highly complex disease and many patients suffer from mutations which are difficult to detect and treat,” Daniel O’Day, CEO Roche Pharmaceuticals, said in a statement. "The agreement with Ignyta builds on Roche’s strategy of fitting treatments to patients and will allow Roche to broaden and strengthen its oncology portfolio globally.”

The pivotal open-label phase II STARTRK-2 basket study is currently exploring entrectinib for patients with locally advanced or metastatic solid tumors and a gene rearrangement in NTRK1/2/3, ROS1, or ALK (NCT02568267). The key solid tumors being explored in the trial are non—small cell lung cancer (NSCLC) and metastatic colorectal cancer (mCRC). The primary endpoint of the study is objective response rate (ORR).

Based on earlier studies, in May 2017, entrectinib was granted a breakthrough therapy designation by the FDA as a treatment for adult and pediatric patients with NTRK-positive, locally advanced or metastatic solid tumors who have either progressed following prior therapies or who have no acceptable standard therapies.

In addition to entrectinib, Ignyta is also exploring RXDX-105, a VEGFR-sparing RET inhibitor. This agent is currently being studied in a phase Ib basket study. Additionally, the company is also exploring the Hh/SMO inhibitor taladegib for ovarian cancer and RXDX-106, a TYR03, AXL, and MER inhibitor, which is in late stage preclinical development.

“Ignyta has been singularly focused on developing precisely targeted therapeutics guided by diagnostics for patients with rare cancers," Jonathan E. Lim, Ignyta’s Chairman, CEO, and Co-Founder, said in a statement. "We are excited that Roche, the global leader in both oncology and personalized healthcare, recognizes this powerful approach and shares our passion for advancing entrectinib for the benefit of patients.”

The only currently FDA-approved agent for the treatment of ROS1 fusion-positive NSCLC is crizotinib (Xalkori); although a head-to-head comparison is unlikely, in preclinical work, entrectinib was found to be 30 times more potent against ROS1 than crizotinib. Moreover, entrectinib was designed to cross the blood-brain barrier, a trait that crizotinib lacks.

In October, promising results for entrectinib were presented for patients with ROS1-positive NSCLC at the World Conference on Lung Cancer (WCLC).¹ In this trial, the ORR with entrectinib was 68.8% by blinded independent central review (BICR), which included 2 complete responses (6.3%). Entrectinib also demonstrated activity in the central nervous system (CNS), with an intracranial ORR by BICR of 83.3% for those with measurable CNS lesions at baseline (95% CI, 35.9%-99.6%).

In combined results from 2 phase I trials entrectinib demonstrated similar efficacy.² Of the 119 patients in the trial, the most common tumor types were NSCLC (60%) and gastrointestinal cancers (15%). Patients in this analysis were not all specifically selected based on mutation status, with 60 having a gene rearrangement in NTRK1/2/3, ROS1, or ALK, with 30 meeting the criteria for the phase II study and 25 evaluable for efficacy.

Of those with NTRK alterations (n = 3), the ORR was 100% (95% CI, 44%-100%). In patients with ROS1 rearrangements, the ORR was 86% (95% CI, 60%-96%), which included 2 complete responses. In the ALK-rearranged cohort, the ORR was 57% (95% CI, 25%-84%).

The median progression-free survival (PFS) for those with NTRK alterations was not yet reached. In the ROS1 group, the median PFS was 19.0 month (95% CI, 6.5-not reached), and for those with ALK rearrangements the median PFS was 8.3 months (95% CI, 4.6-112.0). Median overall survival was not reached across mutations, with 89.4% of patients alive at 12 months.

Several studies continue to enroll patients to investigate entrectinib. Based on communications with the FDA, Ignyta, which plans to continue operating out of San Diego, anticipates submission of a new drug application for the treatment in 2018.

References

1. Ahn M-J, Cho BC, Siena S, et al. Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC). Presented at: IASLC 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract 8564.
2. Drilon A, Siena S, Ou SI, et al. Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7(4):400-409.