FDA Approves Entrectinib for Multiple Solid Tumor Indications

The FDA approved entrectinib (Rozlytrek) for the treatment of adults and pediatric patients who are 12 years of age and older with NTRK fusion-positive, locally advanced/metastatic solid tumors who either progressed on previous therapies or as a frontline therapy for those who have no other acceptable therapies.

"NTRK-positive NSCLC can be hard to treat and not as responsive to chemotherapy and immunotherapy, so a targeted drug with little toxicity is an attractive option for treatment and should be used," said Beth Eaby-Sandy, MSN, CRNP, thoracic oncology nurse practitioner, Abramson Cancer Center, University of Pennsylvania.

The drug was also approved for patients with metastatic, ROS1-positvie non-small cell lung cancer (NSCLC).

"For ROS1 in particular, this drug has shown good clinical activity with little in the way of side effects. ROS1-positive NSCLC is rare; it is only around 1-2% of NSCLC, and more common in younger, never smoking patients," Eaby-Sandy said. "However, given that there is currently only 1 [other] drug approved for ROS-1 positive NSCLC, which is crizotinib, this is an area where we need more drug approvals, especially targeted agents, before providers are left to resort to traditional chemotherapy."

“Rozlytrek’s FDA approval for 2 rare types of cancer is an important advance for patients, combining a targeted medicine and genomic testing to bring this new treatment option to patients who are waiting,” Sandra Horning, MD, chief medical officer and head of global product development at Genentech, said in a press release.

The approval was based on findings from an integrated analysis, including the following studies:

• STARTRK-2, a global, open-label basket study for patients with solid tumors that harbor an NTRK1/2/3-, ROS1-, or ALK-positive gene fusion.
• STARTRK-1, a phase I, multi-center, open-label dose escalation study of daily continuous dosing schedule in patients with solid tumors with NTRK1/2/3, ROS1, or ALK gene fusions.
• ALKA-372-001, a phase I, multicenter, open-label, dose escalation trial of intermittent and continuous entrectinib for patients with advanced or metastatic solid tumors that harbor TRKA/B/C, ROS1, or ALK gene fusions.
• STARTRK-NG, a phase I/IIb dose escalation and expansion study that evaluated the safety and efficacy of the drug in children and adolescent patients who had no curative first-line treatment options, recurrent or refractory extracranial solid tumors or primary CNS tumors, with or without TRK, ROS1, or ALK fusions.

The integrated analysis included data of 53 patients with ROS1-activating gene fusions and 54 patients with locally advanced or metastatic NTRK fusion—positive solid tumors from the phase II STARTRK-2, phase I STARTRK-1 and phase I ALKA-372-001 trials—comprising 10 tumor types with more than 19 histopathologies. Tumor types included breast cancer, cholangiocarcinoma, colorectal cancer, gynecological cancer, neuroendocrine tumors, NSCLC, salivary gland cancer, pancreatic cancer, sarcoma and thyroid cancer.

Results from the integrated analysis showed that the responses were observed across 10 solid tumor types, including in patients with and without CNS metastases at baseline. Moreover, the intracranial ORR (IC ORR) was 54.5%, with more than one-quarter of these patients achieving a complete response.

The responses were consistent in several subgroup analyses, including CNS metastases at baseline (50.0%, n=12) versus none (59.5%, n=42); and NTRK gene type—NTRK1 (59.1%, n=22), NTRK2 (0%, n=1), and NTRK3 (58.1%, n=31). Furthermore, the median PFS was 11.2 months and the median OS was 20.9 months.

Additionally, the pooled findings from STARTRK-2, STARTRK-1, and ALKA-372-001, showed that entrectinib demonstrated a 77.4% ORR and a median DOR of 24.6 months in patients locally advanced or metastatic ROS1-positive NSCLC; the IC ORR was 55.0%.

"As with all therapies, these drugs can have some side effects. Patients may experience dizziness, altered taste, fatigue and other side effects. Often these improve with time, but if they are more severe they can be managed with a reduction of the dose. It is important to know that patients may temporarily experience aches and pains when holding or stopping the drug but this will last only a few days or will stop when the drug is resumed," said clinical investigator Robert Doebele, MD, PhD, of University of Colorado- Denver.

Adverse events (AEs) with entrectinib were consistent with that seen in prior studies. The most commonly reported AEs included fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, pain, anemia, cognitive disorders, weight increased, vomiting, cough, blood creatinine increase, arthralgia, pyrexia, and myalgia.

“Rozlytrek is the first FDA-approved treatment that selectively targets both ROS1 and NTRK fusions, and, importantly, has also shown responses in these rare cancer types that have spread to the brain.”