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Entrectinib shows promise for gene-mutated cancers
NEW ORLEANS — The oral anticancer drug entrectinib appeared safe and effective for the treatment of patients with several types of cancer who harbored NTRK, ROS1 and ALK alterations and were not previously treated with targeted therapies, according to data presented at the American Association for Cancer Research Annual Meeting.
“Recurrent gene rearrangements are appealing targets for the small molecule world,” Alexander Drilon, MD, assistant attending physician in developmental therapeutics clinic and thoracic oncology service at Memorial Sloan Kettering Cancer Center, said during a press conference.
Alexander Drilon
“Recurrent gene fusions are oncogenic drivers across a variety of cancers.”
Entrectinib (RXDX-101, Ignyta) is an oral inhibitor of the tyrosine kinases TrkA, TrkB and TrkC — encoded by the genes NTRK1, NTRK2 and NTRK3 — as well as ROS1 and ALK.
Two phase 1 studies of patients with advanced or metastatic cancers harboring these alterations, with or without central nervous system disease, showed an objective response rate of 72% in 18 tyrosine kinase inhibitor-naive patients and led to a recommended phase 2 dose of 600 mg per day.
Drilon and colleagues used a 3 + 3 dose escalation to assess the safety and pharmacokinetics of entrectinib.
Eleven of 18 patients remained on study after a median follow-up of 11 months. The researchers observed objective responses in 75% (n = 3) of patients with NTRK 1/2/3 mutations, 75% (n = 6) of patients with ROS1 mutations and 67% (n = 4) patients with ALK mutations. One patient with a NTRK mutation achieved a complete response.
Patients who responded to treatment had several types of solid tumors, including non–small cell lung cancer, colorectal cancer and mammary analog secretory carcinoma.
Responses were observed as early as the first treatment cycle, and some responses lasted as long as 2 years.
One patient — a man aged 46 years with SQSTM1– and NTRK1–rearranged NSCLC previously treated with four lines of chemotherapy and immunotherapy — achieved an overall partial response with a complete response in the brain.
“This patient was actually on hospice,” Drilon said. “Within a few weeks, he experienced a dramatic clinical response to therapy. Approaching 1 year, we have seen 80% shrinkage of the tumor burden, and he remains on treatment.”
Drilon further reported on a boy aged 20 months who presented with recurrent, metastatic infantile fibrosarcoma harboring an ETV6-NTRK3 gene rearrangement.
The boy had a left leg mass at birth that required through-the-knee amputation. He received 24 weeks of chemotherapy for a left lung metastasis identified at age 4 months, followed by five chemotherapy cycles at age 12 months for a resected large right frontal intracranial tumor.
When he joined the entrectinib trial in February 2016, he had recurrent central nervous system disease, with lesions on the right front and temporal lobes.
“This boy has resumed eating and crawling,” Drilon said.
The most frequent treatment-related adverse events included fatigue or asthenia (47%), dysgeusia (32%), constipation (26%), dizziness (21%), paresthesia (21%), diarrhea (16%), myalgia (16%) and weight gain (16%).
Three patients — including two patients dosed above the recommended phase 2 dose — experienced treatment-related serious adverse events. However, all were resolved with dose alterations.
“The majority of patients have responses that are ongoing, and the responses can be very rapid and durable,” Drilon said. “Dramatic intracranial activity has also been demonstrated. The drug continues to be explored in a global phase 2 basket study.” – by Cameron Kelsall
Reference:
Drilon A, et al. Abstract CT007. Presented at: American Association for Cancer Research Annual Meeting; April 16-20, 2016; New Orleans.
Disclosure: Ignyta funded this study. Drilon reports honoraria, travel expenses and a speakers bureau position with Ignyta, as well as research funding or other compensation from AstraZeneca, Exelixis, Foundation Medicine and Genentech/Roche.
Perspective
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Progress in this area with the development of therapeutics targeting the unique fusions found in the tumors is a great example of where the field of precision medicine is going. Patients whose tumors harbor the NTRK fusion genes can be identified by diagnostic tests and referred for clinical trials, such as those that are now sharing preliminary results. The drugs appear to be active in the treated patients and some dramatic responses have been noted. Interestingly, these fusions can occur in a small percentage in common tumor types such as breast, lung, colorectal, or head and neck cancer, or much more commonly in some rare tumors. The excitement around the approach is that it is now possible to provide the right treatment with drugs like entrectinib (RXDX-101, Ignyta) to the right patients, and it is looking like at least some of the patients treated thus far can have long-lasting responses. Importantly, in the era of precision medicine, recognizing such fusions through genomic testing is very important as the drugs may be active even for patients who have advanced disease and who may have entered into hospice care.
Because the fusions are not very common, various clinical trials have opened to provide opportunity for patients to be treated while capturing the clinical outcomes of the therapy for all patients. This will maximize potential benefit to patients while allowing the scientific community to learn as much as possible about how best to use these new treatments.