ROZLYTREK Hard capsule Ref.[10280] Active ingredients: Entrectinib

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 Warnings and Precautions (5.6)].

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 6.

Table 6. Pharmacokinetic Parameters for Entrectinib and Metabolite M5:

* Geometric mean

Absorption

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 Specific Populations (8.4)].

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 AUC_0-INF by 6-fold and C_max by 1.7-fold [see Drug Interactions (7.1)]. Coadministration of a moderate CYP3A inhibitor with ROZLYTREK is predicted to increase entrectinib AUC_0-Tau by 3-fold and C_max 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 AUC_0-INF by 77% and C_max by 56% [see Drug Interactions (7.1)]. Coadministration of a moderate CYP3A inducer with ROZLYTREK is predicted to reduce entrectinib AUC_0-Tau by 56% and C_max 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 C_max 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 C_max by 21% [see Drug Interactions (7.1)].

Effect of Entrectinib on Transporters: Coadministration of a single 600 mg ROZLYTREK dose with digoxin [a sensitive P-glycoprotein (P-gp) substrate] increased digoxin C_max 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.

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.

14.1 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, ≥12 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) or next-generation sequencing (NGS) laboratory-developed test. 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 51 patients with ROS1-positive NSCLC. The median age was 53 years (range: 27 to 72); female (67%); White (57%), Asian (37%), and Black (6%); and Hispanic or Latino (3.9%); never smoked (57%); and ECOG performance status 0 or 1 (88%). Ninety-four percent of patients had metastatic disease, including 43% with CNS metastases; 94% had adenocarcinoma; 69% received prior platinum-based chemotherapy for metastatic or recurrent disease or had progressed in less than 6 months following adjuvant or neoadjuvant therapy. ROS1 positivity was determined by NGS in 71% and by FISH in 29%. Fifty-five percent had central laboratory confirmation of ROS1 positivity using an analytically validated NGS test.

Efficacy results are summarized in Table 7.

Table 7. Efficacy Results in ROS1-Positive NSCLC Patients per BICR Assessment:

Confidence Interval (CI) calculated using the Clopper-Pearson method.
Response duration were based on additional 5 months' follow-up after the primary analysis of ORR.
* Observed DOR
^† denotes ongoing resp

Among the 51 patients, 7 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 5 of these 7 patients.

14.2 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 6 months of follow-up after the first dose of ROZLYTREK; 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 57 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). Thirty-four patients (63%) 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 8, 9, and 10.

Table 8. Efficacy Results for Patients with Solid Tumors Harboring NTRK Gene Fusions:

Response duration were based on additional 5 months' follow-up after the primary analysis of ORR.
* Observed DOR
^† denotes ongoing response

Table 9. Efficacy by Tumor Type:

MASC: mammary analogue secretory carcinoma; NA = not applicable; PR = partial response.
* Censored

Table 10. Efficacy Results by NTRK Gene Fusion Partner:

PR = partial response; PD = progressive disease; SD = stable disease; NA = not applicable; NE = not evaluable.
* Censored

Among 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.