The FDA has approved entrectinib for patients with any solid tumor bearing NTRK fusions, making it the second TRK inhibitor to receive a tissue-agnostic approval; larotrectinib was the first. How the drugs compare to each other remains unknown. Entrectinib was also approved to treat metastatic non–small cell lung cancer with ROS1 rearrangements.

The FDA has issued a tissue-agnostic approval to entrectinib (Rozlytrek; Genentech) to target multiple solid tumor types bearing NTRK fusions, making it the second such approval for a TRK inhibitor. The drug was also greenlighted for the treatment of metastatic ROS1-positive non–small cell lung cancer (NSCLC).

Entrectinib targets the kinases TRKA, TRKB, TRKC, ROS1, and ALK. The genes encoding these proteins can undergo rearrangements in a several types of cancer, producing overactive enzymes that spur tumor growth.

The FDA's decision drew on three studies: the phase I STARTRK-1 and ALKA-372-001 trials, along with the phase II STARTRK-2 trial. The results of these studies suggest that the drug is safe, with only 4% of patients withdrawing due to side effects, says Robert Doebele, MD, PhD, of the University of Colorado Anschutz Medical Campus in Aurora, who participated in the trials. Side effects that occurred in at least 20% of patients included fatigue, dizziness, sensory disruptions such as altered taste and vision, and weight gain.

The three trials included 54 adults with tumors harboring NTRK fusions, including colorectal, breast, and thyroid tumors. The overall response rate (ORR) for this group was 57%, and responses lasted at least 12 months in 45% of the patients. In addition, 51 adults with NSCLC and ROS1 rearrangements received the drug. Their ORR was 78%. The responses lasted 12 months or longer in 55% of patients.

Patients with NSCLC commonly develop brain metastases. Combined results from the two phase I trials, published in 2017, revealed that entrectinib produced responses in five of eight patients with brain metastases (four of the responders had NSCLC and the fifth had colorectal cancer). Entrectinib's central nervous system (CNS) activity sets it apart from crizotinib (Xalkori; Pfizer), which is also approved for patients with NSCLC, says Doebele. Crizotinib has poor CNS penetration, however, so entrectinib's approval is significant. “Having an option for patients with brain metastases or who are at risk for them is critical,” Doebele says.

Anna Farago, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, who also took part in trials of the drug, agrees. “It's exciting to see a new approval for ROS1-rearranged NSCLC, especially one with CNS activity.”

The FDA granted tissue-agnostic approval to larotrectinib (Vitrakvi; Bayer), another drug that works against NTRK fusion–positive tumors, in November 2018. No head-to-head trials have compared the two, however, and Farago says that whether there are any significant differences between them is not clear. “Time will tell if one rises to the top.” –Mitch Leslie