FDA Grants Entrectinib Breakthrough Designation for NTRK+ Solid Tumors

Jonathan Lim, MD

The FDA has granted a breakthrough therapy designation to entrectinib for use 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, according to Ignyta, the manufacturer of the multikinase inhibitor.

Breakthrough therapy designation is meant to expedite the development of promising medications that have shown preliminary signs of clinical efficacy. Under the program, the FDA will be more accessible, in order to provide advice on the design and conduct of the clinical development program.

“The granting of breakthrough therapy designation enables us to continue high quality engagement with the FDA during the development of entrectinib, and we greatly appreciate the commitment by the FDA to move this investigational drug forward,” Jonathan Lim, MD, Chairman and CEO of Ignyta, said in a statement. "We believe this designation validates the broad potential of entrectinib as a novel treatment for patients, regardless of age, with TRK-positive tumors, a group of cancers for which there currently is no approved treatment and which represents a clear unmet medical need.”

Entrectinib is an orally available, ATP-competitive tyrosine kinase inhibitor that has demonstrated low to subnanomolar efficacy against 5 kinases (TrkA, B, and C; ROS1 and ALK). The agent has exhibited in vitro and in vivo activity against NTRK1/2/3-, ROS1-, and ALK-rearranged cancers.

Data presented at the 2016 AACR Annual Meeting showed that entrectinib achieved objective responses in 79% of patients with solid tumors associated with NTRK, ROS-1, or ALK rearrangements. Of 24 evaluable patients in the study, 19 had objective responses to entrectinib. The agent also achieved durable responses in primary brain tumors and brain metastases, including 1 complete response.

Findings were reported from the phase I development program of entrectinib, involving the STARTRK-1 and ALKA-372-001 trials. In the STARTRK-1 trial, entrectinib was given continuously to 65 patients in the United States, Europe, and Asia. ALKA-372-001 involved 54 Italian patients treated with intermittent and continuous dosing. All 119 patients in both studies had tumors with NTRK/ROS1/ALK alterations.

The 19 patients whose tumors responded to entrectinib represented diverse malignancies: non—small cell lung cancer (NSCLC), colorectal cancer, melanoma, gastrointestinal stromal tumor, and mammary analog secretory carcinoma (MASC). Patients with NTRK1/2/3, ROS1, and ALK gene fusions responded to the agent.

In a subgroup with ROS1-rearranged tumors and no prior exposure to a tyrosine kinase inhibitor (n = 14), treatment with entrectinib led to objective responses in 12 patients (86%). Two patients had complete responses. Eleven of the responding patients had NSCLC and the other had melanoma. In the ALK-mutated group (n = 7), 57% of patients experienced a response. The majority of patients in this group had NSCLC (n = 5).

In the subgroup of NTRK-rearranged cancers (n = 5), 100% of patients with various tumor histologies and fusion types responded to entrectinib. The agent resulted in “dramatic intracranial activity” in all three patients with central nervous system disease (CNS).

The most common treatment-related adverse events at the 600 mg daily dose were fatigue/asthenia (47%), dysgeusia (32%), constipation (26%), dizziness (21%), paresthesia (21%), diarrhea (16%), myalgia (16%), and weight gain (16%).

Patient accrual has already begun in the larger phase II STARTRK-2 trial (NCT02568267), designed to confirm the results observed in the STARTRK-1 and ALKA-1 trials. The recommended phase II dose from the earlier studies was identified as 600 mg daily. The study is enrolling those with NTRK1/2/3, ROS-1, and ALK rearrangements.

Drilon A, De Braud FG, Siena S, et al. Entrectinib, an oral pan-Trk, ROS1, and ALK inhibitor in TKI-naïve patients with advanced solid tumors harboring gene rearrangements. Presented at the 2016 AACR Annual Meeting; April 16-20, New Orleans, Louisiana. Abstract CT007.