Larotrectinib Granted Priority Review for NTRK-Positive Cancers

The FDA has granted a priority review to a new drug application (NDA) for larotrectinib for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors with an NTRK gene fusion, according to Bayer and Loxo Oncology, the codevelopers of the pan-TRK inhibitor.

The NDA is based on findings from patients with TRK-positive tumors enrolled across phase I or II clinical trials. In results published in the New England Journal of Medicine (NEJM) in February 2018, larotrectinib induced an objective response rate of 75 percent by independent review and 80 percent by investigator assessment in 55 evaluable patients. Per the independent assessment, there were seven (13 percent) complete responses, 34 (62 percent) partial responses and five (9 percent) patients with stable disease.¹

At one year, 71 percent of responses were ongoing. More than half (55 percent) of patients remained progression-free at 1 year. The median duration of response had not been reached after a median follow-up of 8.3 months. The same was true for median progression-free survival after a median follow-up of 9.9 months.

Under the Prescription Drug User Fee Act, the FDA is scheduled to make its decision on the NDA by Nov. 26, 2018.

“TRK fusion cancer is not limited to any organ or site of the body and occurs in both adults and children,” Scott Fields, M.D., senior vice president and head of Oncology Development at Bayer’s Pharmaceutical Division, said in a statement. “The priority review designation for larotrectinib may help bring this treatment option to patients, facing a high unmet medical need, as soon as possible.”

In a recent interview with OncLive, Anna Farago, M.D., Ph.D., a coinvestigator on the pivotal phase 1/2 research, commented on the potential implications of larotrectinib receiving an FDA approval.

“In some cancer types, TRK fusions are very rare. I am primarily a thoracic oncologist and, in lung cancer, these fusions occur at a frequency of well under 1 percent. In less common cancer types, they are more common. For example, these are fusions that are commonly seen in pediatric fibrosarcoma. The total number of patients who may benefit is slightly difficult to predict at this point, but for patients whose cancer has a TRK fusion, these drugs can be tremendously effective,” said Farago, an instructor of Medicine at Harvard Medical School, and assistant in Medicine in the Division of Hematology/Oncology at Massachusetts General Hospital.

“We see a very high response rate of 75 percent by central review and a median progression-free survival that was not yet reached at a median follow-up of 9.4 months. Like other targeted therapies where you find the right drug for the right oncogenic driver, this drug will be tremendously attractive for those patients with TRK fusions,” Farago added.

The NEJM data included an additional three months of patient follow-up to data presented at the 2017 ASCO Annual Meeting. The data presented at ASCO came from the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancers from across a phase I adult trial, the phase 2 NAVIGATE trial, and the phase 1/2 SCOUT pediatric trial. The data cutoff for the NEJM findings was July 17, 2017.

TRK fusion—positive adult and pediatric patients with advanced solid tumors representing 17 unique cancer types were enrolled across the three phase 1/2 clinical trials. The breakdown by tumor type included salivary gland tumor (12 patients), other soft-tissue sarcoma (11 patients), infantile fibrosarcoma (seven patients), thyroid tumor (five patients), colon cancer (four patients), lung cancer (four patients), melanoma (four patients), GIST (three patients), cholangiocarcinoma (two patients), appendix tumor (one patient), breast cancer (one patient), and pancreatic cancer (one patient).

The median age of patients was 45 years, with 56 percent of patients 40 years of age or older. A third of patients (35 percent) had received three or more prior systemic chemotherapies. Twenty-four patients had an ECOG performance status of 0, 27 had a status of 1, and four had a status of 2. Patients were assigned to 100 mg of larotrectinib twice daily.

Investigators did not notice a trend toward better results in one tumor type versus another with larotrectinib. Additionally, outcomes appeared similar regardless of the age of patients or the type of NTRK alteration (1, 2 or 3) or fusion partner.

Most patients (93 percent) experienced grade 1 or 2 adverse events (AEs). There were no grade 4 AEs related to treatment and the most common treatment-related grade 3 AEs were increased ALT or AST (5 percent), anemia (2 percent), decreased neutrophil count (2 percent), nausea (2 percent) and dizziness (2 percent).

The most common grade 3 AEs (at least 5 percent) regardless of attribution were anemia (11 percent), increased ALT or AST (7 percent), decreased neutrophil count (7 percent) and increased body weight (7 percent).

TRK gene fusions are genetic alterations that appear across a wide range of tumors—including breast and colorectal cancer, infantile fibrosarcoma, lung cancer, melanoma and various sarcomas—and lead to uncontrolled TRK signaling and tumor growth. Such fusions are rare, but they are expressed in dozens of adult and pediatric tumor types. To date, researchers have identified more than 50 different partner genes that fuse with 1 of 3 TRK genes (NTRK 1, 2 and 3).