The FDA has granted an accelerated approval to larotrectinib (Vitrakvi) for the treatment of adult and pediatric patients with solid tumors that have an
gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.
The approval is based on findings from patients with TRK-positive tumors enrolled across 3 clinical trials. In results published in the
) in February 2018, larotrectinib induced an objective response rate (ORR) of 75% (95% CI, 61-85) by independent review and 80% (95% CI, 67-90) by investigator assessment in 55 evaluable patients. Per the independent assessment, there were 7 (13%) complete responses, 34 (62%) partial responses, and 7 (13%) patients with stable disease (SD).
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.
"Today’s approval marks another step in an important shift toward treating cancers based on their tumor genetics rather than their site of origin in the body. This new site-agnostic oncology therapy isn’t specific to a cancer arising in a particular body organ, such as breast or colon cancer. Its approval reflects advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine. We now have the ability to make sure that the right patients get the right treatment at the right time," FDA Commissioner Scott Gottlieb, MD, said in statement.
This type of drug development program, which enrolled patients with different tumors but a common gene mutation, wouldn’t have been possible a decade ago because we knew a lot less about such cancer mutations. Using our breakthrough therapy designation and accelerated approval processes, we support innovation in precision oncology drug development and the evolution of more targeted and effective treatments for cancer patients. This is especially true when it comes to pediatric cancers. We’re committed to continuing to advance a more modern framework of clinical trial designs that support more targeted innovations across disease types based on our growing understanding of the underlying biology of diseases like cancer," added Gottlieb.
The FDA reviewed data from 55 adult and pediatric patients with TRK
fusion–positive cancers enrolled across a phase I adult trial (LOXO-TRK-14001), the phase II NAVIGATE trial, and the phase I/II SCOUT pediatric trial. In the studies, adult patients received oral larotrectinib at 100 mg orally twice daily and pediatric patients (aged ≤18 years) were treated with larotrectinib at 100 mg/m2
up to a maximum of 100 mg orally twice daily. Treatment was received until disease progression or unacceptable toxicity. The data cutoff for the NEJM
findings was July 17, 2017.
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 patient age 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.
The ORR by tumor type was salivary gland tumor (83%), other soft-tissue sarcoma (91%), infantile fibrosarcoma (100%), thyroid tumor (100%), colon cancer (25%), lung cancer (75%), melanoma (50%), GIST (100%), cholangiocarcinoma (best response, SD), appendix tumor (best response, SD), breast cancer (progressive disease), and pancreatic cancer (best response, SD).
The most common all-grade treatment-related adverse events (TRAEs) were increased ALT/AST level (38%), dizziness (25%), fatigue (16%), nausea (16%), constipation (16%), vomiting (11%), increased body weight (11%), anemia (9%), decreased neutrophil count (9%), and diarrhea (5%).
Grade 3 TRAEs included increased ALT/AST level (5%), anemia (2%), decreased neutrophil count (2%), nausea (2%), and dizziness (2%). There were no grade 4/5 TRAEs. Dose reductions were required in 8 of the 55 patients.
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 FDA approval of larotrectinib marks an important milestone in how we treat cancers that have an NTRK
gene fusion—a rare driver of cancer. I have seen firsthand how treatment with larotrectinib, which is designed specifically for this oncogenic driver, can deliver clinically meaningful responses in patients with TRK fusion cancer, regardless of patient age or tumor type," David Hyman, MD, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center and a global principal investigator for a larotrectinib clinical trial, said in a statement. "We now have the first therapy approved for this genomic alteration, regardless of cancer type."
The accelerated approval of larotrectinib in this setting is contingent on the results of a confirmatory trial.
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.