Enctrectinib (Rozlytrek, Genentech) is a tyrosine kinase inhibitor of the isoforms of tropomyosin receptor kinase (Trk)-A, TrkB, and TrkC (which are encoded by neurotrophic receptor kinase (NTRK) genes NTRK1, NTRK2, and NTRK3 respectively), receptor tyrosine kinase proto-oncogene 1 (ROS1), and anaplastic lymphoma kinase (ALK).1 Alterations in these molecular targets are present in a variety of different solid tumors.1 In August 2019, the FDA approved entrectinib for treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) that is ROS1-positive. Additionally it was approved for adult and pediatric patients 12 years and older with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic where surgical resection is not a safe option and have progressed following treatment or have no appropriate alternative therapy.2,3
The accelerated approval of entrectinib was based on the pooled results from the phase 1 STARTRK-1 trial, phase 2 basket trial STARTRK-2, and phase 1 ALKA-372-001 trial, as well as data from the phase 1/2 STARTRK-NG trial.2 Fifty-one patients with ROS1-positive metastatic NSCLC experienced shrinkage of tumors, 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 locally NTRK gene-fusion protein positive advanced or metastatic solid tumors, an ORR of 57% was observed in 10 tumor types, including those with central nervous system (CNS) metastases at baseline.2 DUR for this group of patients ranged from 2.8 to 26.0 months.2
The most common reported adverse effects (AEs) (> 20%) were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, increased weight, cough, vomiting, pyrexia, arthralgia, vision disorders, and cognitive impairment.3 Dose interruptions and reductions were required because of AEs in 46% and 29%, respectively. Additionally, congestive heart failure (CHF) occurred in 3.4% of patients studied, with median time to onset of 2 months, and resolution occurring in approximately 50% of patients following therapy interruption/discontinuation with medical management. Therefore, caution should be used in patients with preexisting CHF and assessment of left ventricular function is recommended before initiation.3 Additionally, CNS effects such as cognitive impairment (27%), mood disorders (10%), dizziness (38%), and sleep disturbances (14%), can occur. The incidence of these CNS effects was similar in patients regardless of CNS involvement in disease progression.3
Entrectinib was also shown to increase the risk of fractures, with a median time to fracture was 3.8 months.3 QT interval prolongation was also reported in 3.1% of patients.3 Lastly, laboratory results suggesting abnormalities including anemia, lymphopenia, neutropenia, increased serum creatinine, hyperuricemia, increased ALTs, and ASTs were observed during therapy.3
Entrectinib exhibits hepatic metabolism through cytochrome P450 (CYP) 3A and therefore interacts with moderate-strong CYP3A inhibitors and inducers.3 In addition, due to its effects on the QTcF interval, 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 ROS1-positive NSCLC and NTRK gene fusion-positive solid tumors is 600 mg by mouth once daily with or without food until disease progression or intolerable AEs occur.3 Currently, no dosage adjustments are recommended for 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 instructed to 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 adverse reactions, for first occurrence, the dose should be reduced to 400 mg daily, and further reduced to 200 mg daily upon the second occurrence.3 Entrectinib should be permanently discontinued in patients still unable to tolerate following 2 dose reductions.3 The cost per month of treatment with entrectinib is estimated to be $17,050, pending insurance coverage.4
1. Hoffman-La Roche. Study of oral RXDX-101 in adult patients with locally advanced or metastatic cancer targeting NTRK1, NTRK2, NTRK3, ROS1, or ALK molecular alterations (STARTRK-1). March 27, 2014. Accessed October 23, 2019. https://clinicaltrials.gov/ct2/show/NCT02097810.
2. FDA approves Roche’s Rozlytrek (entrectinib) for people with ROS1-positive, metastatic non-small cell lung cancer and NTRK gene fusion-protein solid tumours. Investor Update. Roche; 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 drug the 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/.