In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On August 15, 2019, the oral TRK, ROS1, and ALK kinase inhibitor entrectinib was granted accelerated approval for treatment of adult patients and pediatric patients 12 years of age or older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK)-gene fusion without a known acquired resistance mutation, are metastatic or if surgical resection is likely to result in severe morbidity, and have experienced disease progression following treatment or have no satisfactory standard therapy.1,2 Entrectinib also was approved for the treatment of adults with ROS1-positive metastatic non–small cell lung cancer (NSCLC).1,2
Supporting Efficacy Data: NTRK-Positive Solid Tumors
Efficacy data on entrectinib in NTRK-positive solid tumors come from a pooled subgroup of 52 patients in the single-arm ALKA, STARTRK-1 (ClinicalTrials.gov identifier NCT02097810), and STARTRK-2 (NCT02568267) studies. Patients had to have disease progression after systemic therapy, if available, or would have required surgery causing significant morbidity for locally advanced disease. Entrectinib was given at various doses and schedules, with 94% of patients receiving 600 mg once daily until disease progression or unacceptable toxicity.
The median age of patients was 57 years (range = 21–83 years); 59% were female; 80% were white; 96% had metastatic disease (22% with central nervous system [CNS] metastases); Eastern Cooperative Oncology Group (ECOG) performance status was 0 or 1 for 89%; all had received prior treatment including surgery (n = 43), radiotherapy (n = 36), or systemic therapy (n = 48); and 63% had received prior systemic therapy for metastatic disease with a median of one prior systemic regimen. The most common cancers were sarcoma (24%), lung cancer (19%), salivary gland tumors (13%), breast cancer (11%), thyroid cancer (9%), and colorectal cancer (7%).
Objective response on blinded independent central review using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was observed in 31 patients (57%, 95% confidence interval [CI] = 43%–71%), with a complete response in 4 patients (7.4%). The duration of response ranged from 2.8 to 26+ months, with responses of at least 6 months in 68% of responders, at least 9 months in 61%, and at least 12 months in 45%. Response rates in those with the most common cancer types were 46% for sarcoma, 70% for NSCLC, 86% for salivary gland cancer, 83% for breast cancer, 20% for thyroid cancer, and 25% for colorectal cancer. Responses in intracranial lesions were observed in three of four patients with measurable CNS metastases who had not received radiotherapy to the brain within 2 months of study entry.
Supporting Efficacy Data: ROS1-Positive NSCLC
Efficacy data on entrectinib in ROS1-positive NSCLC come from a pooled subgroup of 51 patients in the same three single-arm trials. The entrectinib dose was 600 mg once daily in 90% of patients. The median age of patients was 53 years (range = 27–72 years); 67% were female; 57% were white; 37% Asian; 57% were never smokers; blinded independent central review performance status was 0 or 1 for 88%; 94% had metastatic disease (43% with CNS metastases); 94% had adenocarcinoma; and 69% received prior platinum-based chemotherapy for metastatic or recurrent disease or had disease progression in less than 6 months after adjuvant or neoadjuvant therapy.
Entrectinib has warnings or precautions for congestive heart failure, CNS effects, skeletal fractures, hepatotoxicity, hyperuricemia, QT interval prolongation, vision disorders, and embryofetal toxicity.
Objective response on blinded independent central review using RECIST version 1.1 was observed in 40 patients (78%, 95% CI = 65%–89%), including a complete response in 3 (6%). The duration of response ranged from 1.8 to 36.8+ months, with responses lasting at least 9 months in 70% of responders, at least 12 months in 55%, and at least 18 months in 30%. Responses in intracranial lesions were observed in five of seven patients with measurable CNS metastases who had not received radiotherapy to the brain within 2 months of study entry.
How It Works
Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases TRKA, TRKB, and TRKC (encoded by the NTRK genes NTRK1, NTRK2, and NTRK3, respectively), the proto-oncogene tyrosine protein kinase ROS1, and the anaplastic lymphoma kinase (ALK). Entrectinib also inhibits JAK2 and TNK2. The major active metabolite of entrectinib, M5, showed similar in vitro activity as the parent compound against TRK, ROS1, and ALK. Fusion proteins that include TRK, ROS1, or ALK kinase domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways, leading to unconstrained cell proliferation. Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumor types harboring NTRK, ROS1, and ALK-fusion genes. It also exhibited in vivo antitumor activity in mice with intracranial implantation of TRKA- and ALK-driven tumor cell lines.
How It Is Used
Patients must be selected for treatment of locally advanced or metastatic solid tumors based on the presence of NTRK-gene fusion. A U.S. Food and Drug Administration (FDA)-approved test for the detection of NTRK-gene fusion in solid tumors for selecting patients for entrectinib treatment is not available.
Patients must be selected for treatment of metastatic NSCLC based on the presence of ROS1 rearrangement(s) in tumor specimens. An FDA-approved test for detection of ROS1 rearrangement(s) in NSCLC for selecting patients for entrectinib treatment is not available.
The recommended entrectinib dose for adults with NTRK gene fusion–positive solid tumors or with ROS1-positive NSCLC is 600 mg orally once daily until progression or unacceptable toxicity. For pediatric patients aged 12 and older (adolescents) with NTRK gene fusion–positive solid tumors, the daily dose is 600 mg, 500 mg, and 400 mg in those with a body surface area (BSA) greater than 1.50 m2, 1.11 to 1.50 m2, and 0.91 to 1.10 m2, respectively. Two dose reductions are permitted for adverse reactions: to 400 mg and then 200 mg once daily for adults and pediatric patients with a BSA greater than 1.50 m2 or 1.11 to 1.50 m2, and to 300 mg and then 200 mg once daily for pediatric patients with a BSA of 0.91 to 1.10 m2. Treatment should be discontinued in patients unable to tolerate entrectinib after two dose reductions.
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
Prescribing information provides recommended dosage modifications, including dose reduction, interruption, and discontinuation, for adverse reactions, including congestive heart failure, CNS effects, hepatotoxicity, hyperuricemia, QT interval prolongation, vision disorders, anemia or neutropenia, and any grade 3 or 4 adverse reactions.
For adult and pediatric patients with a BSA greater than 1.50 m2, the entrectinib dose should be reduced to 200 mg once daily if concomitant use of moderate CYP3A inhibitors cannot be avoided and to 100 mg orally once daily if concomitant use of strong CYP3A inhibitors cannot be avoided. Coadministration of entrectinib with moderate or strong CYP3A inhibitors should be avoided in pediatric patients with a BSA of up to 1.50 m2. Coadministration of entrectinib with moderate or strong CYP3A inducers should be avoided.
Safety data come from 355 patients who received entrectinib in the single-arm ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG studies. Most adults (75%) received 600 mg orally once daily. Doses ranged from 100 mg/m2 to 1,600 mg/m2 once daily in adults and 250 mg/m2 to 750 mg/m2 once daily in pediatric patients. A total of 5% of patients were up to age 18. The most common tumors were lung cancer (56%), sarcoma (8%), and colon tumors (5%).
The most common adverse events of any grade (≥ 20%) were fatigue (48%), constipation (46%), dysgeusia (44%), edema (40%), dizziness (38%), diarrhea (35%), nausea (34%), dysesthesia (34%), dyspnea (30%), myalgia (28%), cognitive impairment (27%), increased weight (25%), cough (24%), vomiting (24%), pyrexia (21%), arthralgia (21%), and vision disorders (21%). Grade 3 or 4 adverse events occurred in 60% of patients, with the most common being increased weight (7%), dyspnea (6%), lung infection (5%), fatigue/asthenia (5%), cognitive disorders (4.5%), pulmonary embolism (3.4%), hypoxia (3.4%), and pleural effusion (3.1%). The most common grade 3 or 4 laboratory abnormalities were lymphopenia (12%), hyperuricemia (10%), anemia (9%), and neutropenia (7%).
Serious adverse events occurred in 39% of patients, with the most common being pneumonia (3.9%), dyspnea (3.7%), pleural effusion (3.4%), sepsis (2.5%), pulmonary embolism (2.3%), respiratory failure (2%), and pyrexia (2%). One patient developed grade 4 myocarditis after one dose of entrectinib, which resolved after treatment discontinuation and administration of high-dose corticosteroids. Adverse events led to discontinuation of entrectinib in 9% of patients, with the most common causes being pneumonia, cardiorespiratory arrest, dyspnea, and fatigue (< 1% each). Adverse events led to treatment interruption in 46% of patients, with the most common causes being increased blood creatinine (4%) and fatigue (3.7%), and to dose reductions in 29%, with the most common causes being dizziness (3.9%) and increased blood creatinine (3.1%). Fatal events included dyspnea (0.6%), pneumonia (0.6%), sepsis (0.6%), suicide (0.3%), large intestine perforation (0.3%), and tumor-lysis syndrome (0.3%).
Entrectinib has warnings/precautions for congestive heart failure, CNS effects (including cognitive impairment and mood disorders), skeletal fractures, hepatotoxicity, hyperuricemia, QT interval prolongation, vision disorders, and embryofetal toxicity. Patients should have liver function tests monitored every 2 weeks during the first month of treatment, monthly thereafter, and as clinically indicated. Serum uric acid levels should be assessed prior to treatment initiation and periodically during treatment. Left-ventricular ejection fraction should be assessed prior to treatment in patients with symptoms or known risk factors for congestive heart failure. Patients who have or who are at risk for QTc interval prolongation should be monitored. QT interval and electrolytes should be monitored at baseline and periodically during treatment. Patients should be advised not to breastfeed while receiving entrectinib. ■
1. U.S. Food and Drug Administration: FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclc. Accessed September 19, 2019.
2. Rozlytrek (entrectinib) capsules prescribing information, Genentech, August 2019. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf. Accessed September 19, 2019.