Larotrectinib
In November last year, the Food and Drug Administration granted accelerated approval to larotrectinib (Vitrakvi®) for adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment.
In the phase I trial larotrectinib showed a dramatic antitumor effect in all cancers harboring a TRK fusion mutation in three clinical trials, demonstrating that it works in the vast majority of both adults and children who have tumors with the mutation. Data from the three multisite clinical trials were shared at the 2017 annual meeting of the American Society of Clinical Oncology.
The three studies involved a total of 55 people with TRK fusion cancers, ranging in age from four months to 76 years. Larotrectinib was used to treat 17 tumor types. The overall response rate was 76 percent, with the longest recipient still on the treatment after 25 months. Among responders, 89 percent remained progression free at the time the data were analyzed.
Notably, while many study participants had durable responses, a few developed resistance over time, providing an opportunity to test a second-generation inhibitor called LOXO-195 in adults and children with previously treated NTRK fusion cancers in another phase I study.
Entrectinib
Entrectinib targets five gene fusions: NTRK1, NTRK2, NTRK3, ROS1, and ALK. Memorial Sloan Kettering medical oncologist Alexander Drilon presented the combined results of two phase I trials with entrectinib at the 2017 annual meeting of the American Society of Clinical Oncology.
Researchers observed rapid (within one month of treatment) and durable (lasting more than two years) responses in five cancer types: non-small cell lung cancer, metastatic colorectal cancer, mammary analogue secretory carcinoma (a rare cancer of the salivary gland), renal cell carcinoma, and melanoma. Entrectinib is designed to penetrate the blood-brain barrier. It demonstrated activity against cancers originating in or spreading to the central nervous system.
Researchers determined the optimal dose to test in a more-limited phase II basket trial, where each “mini basket” will enroll up to 62 people with cancer that has one of the five gene fusions. Investigators will recruit participants from more than 120 institutions worldwide.
HDM201
A phase I trial of the oral agent HDM201 is investigating the highest dose that can be administered safely in people with advanced solid tumors and normal TP53, a gene that governs the production of the p53 protein, which plays a role in controlling cell growth.
Memorial Sloan Kettering is one of 14 international sites conducting the study, which seeks to recruit a total of 225 participants. Eligible participants have advanced solid tumors, blood cancer, and normal TP53. Examples of tumor types include colorectal cancer, melanoma, soft tissue sarcoma, osteosarcoma, testicular cancer, renal cell carcinoma, acute myeloid leukemia, myelodysplastic syndromes, and acute lymphoblastic leukemia.