Larotrectinib Update Shows Durable Responses in TRK-positive Cancers

David Hyman, MD

Larotrectinib (LOXO-101) induced durable responses in patients with TRK fusion—positive solid tumors, according to updated results for the novel pan-TRK inhibitor published in the New England Journal of Medicine (NEJM).¹

Among 55 evaluable patients, the objective response rate was 75% (95% CI, 61-85) by independent review and 80% (95% CI, 67-90) by investigator assessment. Per the independent assessment, there were 7 (13%) complete responses, 34 (62%) partial responses, and 5 (9%) patients with stable disease.

At 1 year, 71% of responses were ongoing. More than half (55%) 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.

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).

The newly published data include an additional 3 months of patient follow-up to data presented at the 2017 ASCO Annual Meeting.² 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 II NAVIGATE trial, and the phase I/II 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 3 phase I/II clinical trials. The breakdown by tumor type included salivary gland tumor (n = 12), other soft-tissue sarcoma (n = 11), infantile fibrosarcoma (n = 7), thyroid tumor (n = 5), colon cancer (n = 4), lung cancer (n = 4), melanoma (n = 4), GIST (n = 3), cholangiocarcinoma (n = 2), appendix tumor (n = 1), breast cancer (n = 1), and pancreatic cancer (n = 1).

The median age of patients was 45 years (range, 0.3-76.0), with 56% of patients ≥40 years of age. A third of patients (35%) had received ≥3 prior systemic chemotherapies. Twenty-four patients had an ECOG performance status of 0, 27 had a status of 1, and 4 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%) 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%), anemia (2%), decreased neutrophil count (2%), nausea (2%), and dizziness (2%).

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

“In this series of studies, larotrectinib had rapid, potent and durable antitumor activity in children and adults who had solid tumors with TRK fusions without regard to patient age, tumor tissue, and fusion status,” David Hong, MD, co-principal investigator on the paper published in NEJM and professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, said in a statement.

“Our data not only validated TRK fusions as therapeutic targets, but also showed the potential for larotrectinib as a therapeutic agent for TRK fusion—positive cancers,” added Hong.

In December, Loxo Oncology and Bayer filed a rolling new drug application with the FDA for the treatment of adult and pediatric patients based on these findings. Bayer expects to file a Marketing Authorization Application with the European Union this year.

References

1. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion—positive cancers in adults and children. N Engl J Med. 2018; 378:731-739. doi: 10.1056/NEJMoa1714448.
2. Hyman DM, Laetsch TW, Kummar S, et al. The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers. J Clin Oncol. 2017;35 (suppl; abstr LBA2501).

“The data outlined in the NEJM publication show the potential that larotrectinib has for patients who have TRK fusion cancers,” David Hyman, MD, senior study author and chief of the Early Drug Development service at Memorial Sloan Kettering Cancer Center, said in a statement. “These data warrant screening for TRK fusions in patients of all ages with advanced solid tumors.”