Actrectinib (Rozlytrek, Genentech) is a tyrosine kinase inhibitor of the tropomyosin kinase (Trk) -A, TrkB and TrkC receptor isoforms (which are encoded by the neurotrophic receptor kinase (NTRK) genes NTRK1, NTRK2, and NTRK3 respectively), the proto-oncogenic tyrosine kinase 1 receptor (ROS1) and anaplastic lymphoma kinase (ALK).1 Alterations to these molecular targets are present in a variety of different solid tumors.1 In August 2019, the FDA approved entrectinib for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) which is ROS1-positive. In addition, it has been approved for adult and pediatric patients 12 years of age and older with solid tumors who NTRK gene fusion with no known acquired resistance mutation, is metastatic when surgical resection is not a safe option and has progressed after treatment or does not have an appropriate alternative treatment.2.3
The accelerated approval of entrectinib was based on the combined results of the STARTRK-1 phase 1 trial, the STARTRK-2 phase 2 basket trial and the ALKA-372-001 phase 1 trial , as well as data from phase 1/2 STARTRK- NG test.2 Fifty-one patients ROS1-NSCLC metastatic positive experienced tumor shrinkage, resulting in an overall response rate (ORR) of 78%, and the duration of this response (DUR) ranged from 1.8 to 36.8 months.2 In 54 patients who had NTRK advanced or metastatic solid tumors positive for gene fusion proteins, an ORR of 57% was observed in 10 types of tumors, including those with metastases of the central nervous system (CNS) at the start.2 The DUR for this group of patients ranged from 2.8 to 26.0 months.2
The most commonly reported adverse reactions (ARs) (> 20%) were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, weight gain, cough, vomiting, pyrexia, arthralgia, vision impairment and cognitive impairment.3 Interruptions and dose reductions were necessary due to adverse reactions in 46% and 29%, respectively. In addition, congestive heart failure (CHF) occurred in 3.4% of patients studied, with a median time to onset of 2 months, and resolution occurred in approximately 50% of patients after interruption / discontinuation of treatment with medical care. Therefore, caution should be used in patients with preexisting CHF and an assessment of left ventricular function is recommended before initiation.3 In addition, CNS effects such as cognitive impairment (27%), mood disorder (10%), dizziness (38%) and sleep disturbance (14%) may occur. The incidence of these CNS effects was similar in patients regardless of the CNS involvement in disease progression.3
Entrectinib has also been shown to increase the risk of fractures, with a median fracture delay of 3.8 months.3 QT prolongation has also been reported in 3.1% of patients.3 Finally, laboratory results suggesting abnormalities, including anemia, lymphopenia, neutropenia, increased serum creatinine, hyperuricemia, increased ALT and AST were observed during treatment.3
Entrectinib has a hepatic metabolism via cytochrome P450 (CYP) 3A and therefore interacts with moderate to strong inhibitors and inducers of CYP3A.3 In addition, due to its effects on the QTcF interval, the use of entrectinib should be avoided with other drugs known to prolong the QT / QTc interval.3
Dosage and cost
The recommended dosage for both ROS1NSCLC positive and NTRK solid tumors positive for gene fusion are 600 mg orally once daily with or without food until disease progression or intolerable AEs occur.3 Currently, no dose adjustment is recommended in patients with mild to moderate renal impairment (CrCl 30 ml / min to <90 ml / min) or mild hepatic impairment (total bilirubin < 1.5 times ULN) and the drug has not been studied in patients with severe impairment.3 If a dose is missed, patients should be informed that they should take their daily dose as soon as possible, unless the next dose is due within 12 hours.3 The dose should be repeated if a patient vomits immediately after administration.3 In response to side effects, for the first occurrence, the dose should be reduced to 400 mg per day, and further reduced to 200 mg per day during the second occurrence.3 Entrectinib should be permanently discontinued in patients still unable to tolerate after 2 dose reductions.3 The cost per month of treatment with entrectinib is estimated at $ 17,050, pending insurance coverage.4
1. Hoffman-La Roche. Study of oral RXDX-101 in adult patients with locally advanced or metastatic cancer NTRK1, NTRK2, NTRK3, ROS1, or ALK molecular alterations (STARTRK-1). March 27, 2014. Accessed October 23, 2019. https://clinicaltrials.gov/ct2/show/NCT02097810.
2. The FDA approves Roche’s Rozlytrek (entrectinib) for people with ROS1-positive metastatic non-small cell lung cancer and solid tumors of the NTRK gene fusion protein. Update for investors. Rock; August 16, 2019. Accessed October 24, 2019. https://www.roche.com/investors/updates/inv-update-2019-08-16.htm.
3. Entrectinib [package insert]. Genentech USA; August 2019. Accessed October 24, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf.
4. Pagliarulo, N. Roche cancer medicine 3rd approved for pan-tumor use. BioPharmaDive. Published August 15, 2019. Accessed October 24, 2019. https://www.biopharmadive.com/news/roche-rozlytrek-cancer-drug-approval-tumor-agnostic/561027/.