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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.
Entrectinib demonstrated steady-state brain-to-plasma concentration ratios of 0.4-2.2 in multiple animal species (mice, rats, and dogs) and demonstrated in vivo anti-tumor activity in mice with intracranial implantation of TRKA- and ALK-driven tumor cell lines.
Pharmacodynamics: Entrectinib exposure-response relationships and the time course of pharmacodynamic responses are unknown.
Cardiac Electrophysiology: Across clinical trials, 3.1% of 355 patients, who received ROZLYTREK at doses ranging from 100 mg to 2600 mg daily under fasting or fed conditions (75% received 600 mg orally once daily) and had at least one post-baseline ECG assessment, experienced QTcF interval prolongation of >60 ms after starting ROZLYTREK and 0.6% had a QTc interval >500 ms [see QT Interval Prolongation under Precautions].
Clinical Studies: ROS1-Positive Non-Small Cell Lung Cancer: The efficacy of ROZLYTREK was evaluated in a pooled subgroup of patients with ROS1-positive metastatic NSCLC who received ROZLYTREK at various doses and schedules (90% received ROZLYTREK 600 mg orally once daily) and were enrolled in one of three multicenter, single-arm, open-label clinical trials: ALKA, STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267). To be included in this pooled subgroup, patients were required to have histologically confirmed, recurrent or metastatic, ROS1-positive NSCLC, ECOG performance status ≤2, measurable disease per RECIST v 1.1, ≥18 months of follow-up from first post-treatment tumor assessment, and no prior therapy with a ROS1 inhibitor. Identification of ROS1 gene fusion in tumor specimens was prospectively determined in local laboratories using either a fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), or polymerase chain reaction (PCR) laboratory-developed tests. All patients were assessed for CNS lesions at baseline. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) according to RECIST v1.1 as assessed by blinded independent central review (BICR). Intracranial response according to RECIST v1.1 was assessed by BICR. Tumor assessments with imaging were performed every 8 weeks.
Efficacy was assessed in 92 patients with ROS1-positive NSCLC. The median age was 53 years (range: 27 to 86); female (65%); White (48%), Asian (45%), and Black (5%); and Hispanic or Latino (2.4%); never smoked (59%); and ECOG performance status 0 or 1 (88%). Ninety-nine percent of patients had metastatic disease, including 42% with CNS metastases; 96% had adenocarcinoma; 65% received prior platinum-based chemotherapy for metastatic or recurrent disease and no patient had progressed in less than 6 months following platinum-based adjuvant or neoadjuvant therapy. ROS1 positivity was determined by NGS in 79% FISH in 16%, and PCR in 4%. Twenty-five percent had central laboratory confirmation of ROS1 positivity using an analytically validated NGS test.
Efficacy results are summarized in Table 1. (See Table 1.)
Click on icon to see table/diagram/imageAmong the 92 patients, 10 had measurable CNS metastases at baseline as assessed by BICR and had not received radiation therapy to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 7 of these 10 patients.
NTRK Gene Fusion-Positive Solid Tumors: The efficacy of ROZLYTREK was evaluated in a pooled subgroup of adult patients with unresectable or metastatic solid tumors with a NTRK gene fusion enrolled in one of three multicenter, single-arm, open-label clinical trials: ALKA, STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267). To be included in this pooled subgroup, patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery causing significant morbidity for locally advanced disease; measurable disease per RECIST v1.1; at least 2 years of follow-up from first post-treatment tumor assessment; and no prior therapy with a TRK inhibitor. Patients received ROZLYTREK at various doses and schedules (94% received ROZLYTREK 600 mg orally once daily) until unacceptable toxicity or disease progression. Identification of positive NTRK gene fusion status was prospectively determined in local laboratories or a central laboratory using various nucleic acid-based tests. The major efficacy outcome measures were ORR and DOR, as determined by a BICR according to RECIST v1.1. Intracranial response according to RECIST v1.1 as evaluated by BICR. Tumor assessments with imaging were performed every 8 weeks.
Efficacy was assessed in the first 54 adult patients with solid tumors with an NTRK gene fusion enrolled into these trials. The median age was 58 years (range: 21 to 83); female (59%); White (80%), Asian (13%) and Hispanic or Latino (7%); and ECOG performance status 0 (43%) or 1 (46%). Ninety-six percent of patients had metastatic disease, including 22% with CNS metastases, and 4% had locally advanced, unresectable disease. All patients had received prior treatment for their cancer including surgery (n=43), radiotherapy (n=36), or systemic therapy (n=48). Forty patients (74%) received prior systemic therapy for metastatic disease with a median of 1 prior systemic regimen and 17% (n=9) received 3 or more prior systemic regimens. The most common cancers were sarcoma (24%), lung cancer (19%), salivary gland tumors (13%), breast cancer (11%), thyroid cancer (9%), and colorectal cancer (7%). A total of 52 (96%) patients had an NTRK gene fusion detected by NGS and 2 (4%) had an NTRK gene fusion detected by other nucleic acid-based tests. Eighty-three percent of patients had central laboratory confirmation of NTRK gene fusion using an analytically validated NGS test.
Efficacy results are summarized in Tables 2, 3, and 4. (See Tables 2, 3 and 4.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageAmong the subset of patients who received prior systemic therapy for metastatic disease, the ORR was 53%, similar to that seen in the overall population. Among the 54 adult patients, 4 had measurable CNS metastases at baseline as assessed by BICR and had not received radiation therapy to the brain within 2 months of study entry. Responses in intracranial lesions were observed in 3 of these 4 patients.
Pharmacokinetics: The pharmacokinetics for entrectinib and its pharmacologically active major circulating metabolite M5 were characterized in adult patients with ROS1-positive NSCLC, NTRK gene fusion-positive solid tumors, and healthy subjects. The pharmacokinetics of entrectinib and M5 are linear and are not dose-dependent or time-dependent. Steady state is achieved within one week for entrectinib and two weeks for M5 following daily administration of ROZLYTREK. The pharmacokinetic parameters for entrectinib and M5 are described in Table 5. (See Table 5.)
Click on icon to see table/diagram/imageAbsorption: The maximum entrectinib plasma concentration was reached 4-6 hours after oral administration of a 600 mg dose.
Effect of Food: A high-fat (approximately 50% of total caloric content), high-calorie (approximately 800 to 1000 calories) meal did not have a significant effect on entrectinib exposure.
Distribution: Entrectinib and its active major metabolite M5 are both >99% bound to human plasma proteins in vitro.
The estimated apparent volume of distribution (V/F) was 551 L and 81.1 L for entrectinib and M5, respectively.
Elimination: The estimated apparent clearance (CL/F) was 19.6 L/h and 52.4 L/h for entrectinib and M5, respectively. The elimination half-lives of entrectinib and M5 were estimated to be 20 and 40 hours, respectively.
Metabolism: Entrectinib is metabolized primarily by CYP3A4 (~76%). The active metabolite M5 (formed by CYP3A4) is the only major active circulating metabolite identified. M5 has similar pharmacological potency to entrectinib in vitro and circulating M5 exposures at steady-state in patients were 40% of the corresponding entrectinib exposure.
Excretion: Following oral administration of a single oral dose of [14C]-labeled entrectinib, 83% of radioactivity was excreted in feces (36% of the dose as unchanged entrectinib and 22% as M5) with minimal excretion in urine (3%).
Specific Populations: No clinically significant differences in the pharmacokinetics of entrectinib were observed based on age (12 years to 86 years), sex, race (White, Asian and Black), body weight (32 to 130 kg), mild to moderate renal impairment (CLcr 30 to <90 mL/min) and mild hepatic impairment (total bilirubin ≤1.5 times ULN). The impact of moderate to severe hepatic impairment or severe renal impairment on the pharmacokinetics of entrectinib is unknown.
Pediatric Patients: The predicted systemic exposures for body surface area-based doses of 600 mg (BSA >1.50 m2), 500 mg (BSA of 1.11 to 1.50 m2) and 400 mg (BSA of 0.91 to 1.10 m2) in pediatric patients 12 years and older are comparable to the exposure in adults at the 600 mg dose [see Use in Children under Precautions].
Drug Interaction Studies: Clinical Studies: Effect of CYP3A Inhibitors on Entrectinib: Coadministration of itraconazole (a strong CYP3A inhibitor) with a single 100 mg ROZLYTREK dose increased entrectinib AUC0-INF by 6-fold and Cmax by 1.7-fold [see Effect of Other Drugs on ROZLYTREK under Interactions]. Coadministration of a moderate CYP3A inhibitor with ROZLYTREK is predicted to increase entrectinib AUC0-Tau by 3-fold and Cmax by 2.9-fold.
Effect of CYP3A Inducers on Entrectinib: Coadministration of rifampin (a strong CYP3A inducer) with a single 600 mg ROZLYTREK dose reduced entrectinib AUC0-INF by 77% and Cmax by 56% [see Effect of Other Drugs on ROZLYTREK under Interactions]. Coadministration of a moderate CYP3A inducer with ROZLYTREK is predicted to reduce entrectinib AUC0-Tau by 56% and Cmax by 43%.
Effect of Gastric Acid Reducing Drugs on Entrectinib: Coadministration of a proton pump inhibitor (PPI), lansoprazole with a single 600 mg ROZLYTREK dose reduced entrectinib AUC by 25% and Cmax by 23%.
Effect of Entrectinib on CYP Substrates: Coadministration of ROZLYTREK 600 mg once daily with oral midazolam (a sensitive CYP3A substrate) in patients increased the midazolam AUC by 50% but reduced midazolam Cmax by 21% [see Effect of Other Drugs on ROZLYTREK under Interactions].
Effect of Entrectinib on Transporters: Coadministration of a single 600 mg ROZLYTREK dose with digoxin [a sensitive P-glycoprotein (P-gp) substrate] increased digoxin Cmax by 28% and AUC by 18%.
In Vitro Studies: Entrectinib is not a substrate of P-gp or BCRP, but M5 is a substrate of P-gp and BCRP. Entrectinib and M5 are not substrates of OATP1B1 or OATP1B3.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were not conducted with entrectinib. Entrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay; however, an in vitro assay in cultured human peripheral blood lymphocytes did demonstrate a potential for abnormal chromosome segregation (aneugenicity). Entrectinib was not clastogenic or aneugenic in the in vivo micronucleus assay in rats and did not induce DNA damage in a comet assay in rats.
Dedicated fertility studies were not conducted with entrectinib. With the exception of dose-dependent decreases in prostate weight in male dogs, there were no effects on male and female reproductive organs observed in general toxicology studies conducted in rats and dogs at doses resulting in exposures of up to approximately 3.2 fold the human exposure (AUC) at the 600 mg dose.
