AUGTYRO Capsule Ref.[107392] Active ingredients: Repotrectinib

Repotrectinib exposure-response relationships and the time course of pharmacodynamic responses are not fully characterized.

Cardiac Electrophysiology

AUGTYRO does not cause a mean increase in the QTc interval >20 milliseconds (ms) at 160 mg QD followed by 160 mg BID, the approved recommended dosage.

The geometric mean (CV%) of repotrectinib steady state peak concentration (C_max,ss) is 713 (32.5%) ng/mL and the area under the time concentration curve (AUC_0-24h,ss) is 7210 (40.1%) ng•h/mL following the approved recommended twice daily dosage in patients with cancer. Repotrectinib C_max and AUC_0-inf increases approximately dose proportional (but less than linear with estimated slopes of 0.78 and 0.70, respectively) over the single dose range of 40 mg to 240 mg (0.25 to 1.5 times the approved recommended dosage). Steady state PK was time-dependent with an autoinduction of CYP3A4. Steady state is achieved within 14 days of daily administration of 160 mg.

Absorption

The geometric mean (CV%) absolute bioavailability of repotrectinib is 45.7% (19.6%). Peak repotrectinib concentration occurred at approximately 2 to 3 hours post a single oral dose of 40 mg to 240 mg (0.25 to 1.5 times the approved recommended dosage) under fasted conditions.

Effect of Food

No clinically significant differences in repotrectinib pharmacokinetics were observed in patients with cancer following administration of a high-fat meal (approximately 800-1000 calories, 50% fat).

Distribution

The geometric mean (CV%) apparent volume of distribution (Vz/F) was 432 L (55.9%) in patients with cancer following a single 160 mg oral dose of AUGTYRO.

AUGTYRO binding to plasma protein was 95.4% in vitro. The blood-to-plasma ratio was 0.56 in vitro.

Elimination

Repotrectinib elimination is time-dependent due to autoinduction of CYP3A4.

The repotrectinib mean terminal half-life is approximately 60.7 h for patients with cancer following a single dose. The steady state repotrectinib terminal half-life is approximately 40.3 h for patients with cancer.

The geometric mean (CV%) apparent oral clearance (CL/F) was 15.9 L/h (45.5%) in patients with cancer following a single 160 mg oral dose of AUGTYRO.

Metabolism

Repotrectinib is primarily metabolized by CYP3A4 followed by secondary glucuronidation.

Excretion

Following a single oral 160 mg dose of radiolabeled repotrectinib, 4.84% (0.56% as unchanged) was recovered in urine and 88.8% (50.6% unchanged) in feces.

Specific Populations

No clinically significant differences in the pharmacokinetics of repotrectinib were observed based on age (12 to 93 years), sex, race (White 50%, Asian 38%, Black 7%), mild to moderate renal impairment (eGFR 30 to <90 mL/min), or mild hepatic impairment (total bilirubin >1 to 1.5 times ULN or AST > ULN). The effect of moderate (total bilirubin >1.5 to 3 times ULN with any AST) or severe (total bilirubin >3 x ULN with any AST) hepatic impairment, severe renal impairment, kidney failure (eGFR <30 mL/min), or dialysis on repotrectinib pharmacokinetics is unknown or not fully characterized.

Drug Interaction Studies

Clinical Studies

Strong CYP3A and P-gp inhibitors: Repotrectinib AUC_0-inf increased by 5.9-fold and C_max by 1.7-fold following concomitant use with itraconazole (strong CYP3A and P-gp inhibitor).

Strong CYP3A and P-gp inducers: Repotrectinib AUC_0-inf decreased by 92% and C_max by 79% following concomitant use with rifampin (strong CYP3A and P-gp inducer).

CYP3A substrates: Midazolam (CYP3A substrate AUC_0-inf decreased by 69% and C_max by 48% following concomitant use in subjects who were previously administered 160 mg repotrectinib once daily for 14 days followed by 160 mg twice daily for 7 days.

In vitro Studies

CYP Enzymes: Repotrectinib induces CYP3A4, CYP2B6, CYP2C8, CYP2C19, CYP2C9 and inhibits CYP3A4/5 (GI tract). Repotrectinib does not induce CYP1A2.

Other Metabolic Pathways: Repotrectinib inhibits UGT1A1.

Transporter Systems: Repotrectinib inhibits P-gp, BCRP, OATP1B1, and MATE2-K. Repotrectinib is a substrate for P-gp.

Carcinogenicity studies with repotrectinib were not conducted.

Repotrectinib was genotoxic in an in vitro assay in human lymphoblastoid TK6 cells and in an in vivo rat bone marrow micronucleus assay via an aneugenic mechanism of action. Repotrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.

Dedicated fertility studies were not conducted with repotrectinib. There were no effects on male and female reproductive organs observed in general repeat-dose toxicology studies of up to 3 months in duration in rats and monkeys at any dose level tested, which equated to exposures of up to approximately 3 times the human exposure at the 160 mg twice daily dose based on AUC.

14.1 Locally Advanced or Metastatic ROS1-Positive NSCLC

The efficacy of AUGTYRO was evaluated in TRIDENT-1, a multicenter, single-arm, open-label, multi-cohort clinical trial (NCT03093116). Patients were required to have ROS1-positive locally advanced or metastatic NSCLC, ECOG performance status ≤1, measurable disease per RECIST v 1.1, and ≥8 months from first dose. All patients were assessed for CNS lesions at baseline, and patients with symptomatic brain metastases were excluded from the trial. Patients received AUGTYRO 160 mg orally once daily for 14 days, then increased to 160 mg twice daily until disease progression or unacceptable toxicity. Tumor assessments were performed at least every 8 weeks. Identification of ROS1 gene fusions in tumor specimens was prospectively determined in local laboratories using next-generation sequencing (NGS), polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) tests. All ROS1-positive patients by local FISH testing required central laboratory confirmation of ROS1 fusion using an analytically validated NGS test. ROS1 fusions were identified by NGS in 51%, FISH in 26%, and PCR in 23%. 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 modified RECIST v1.1 was assessed by BICR. Tumor assessments with imaging were performed every 8 weeks. The efficacy populations included 71 ROS1 TKI-naïve patients who received up to 1 prior line of platinum-based chemotherapy and/or immunotherapy and 56 patients who received 1 prior ROS1 TKI with no prior platinum-based chemotherapy or immunotherapy.

Among the 71 ROS1 TKI-naïve patients, the median age was 57 years (range: 28 to 80); female (60.6%); Asian (67.6%), White (25.4%), Hispanic or Latino (4.2%), Black or African American (1.4%); never smoked (63.4%); and ECOG performance status of 1 at baseline (66.2%). At baseline, 94.4% of patients had metastatic disease, 25.4% of patients had CNS metastases by BICR; 97.2% had adenocarcinoma; and 28.2% patients had prior chemotherapy consisting of platinum-based chemotherapy and/or immunotherapy for locally advanced or metastatic disease.

Among the 56 patients who had received 1 prior ROS1 TKI (including crizotinib [82%] and entrectinib [16%]) with no prior platinum-based chemotherapy or immunotherapy, the median age was 57 years (range: 33-78); female (67.9%); Asian (48.2%), White (44.6%), Black or African American and Hispanic or Latino (1.8% each); never smoked (64.3%); and ECOG performance status of 1 at baseline (67.9%). At baseline, 98.2% patients had metastatic disease, 42.9% with CNS metastases by BICR, and 94.6% had adenocarcinoma.

Efficacy results are summarized in Table 5.

Table 5. Efficacy Results for Patients with ROS1-Positive NSCLC in TRIDENT-1:

Abbreviations: CI = confidence interval; NE = not evaluable; “+” indicates ongoing response
^a DOR results are based on the updated data as of 19 December 2022.
^b Median DOR (95% CI) are based on Kaplan-Meier estimates.
^c DOR landmark analysis is based on the observed DOR.

Among TKI-naïve patients, 8 had measurable CNS metastases at baseline as assessed by BICR; responses in intracranial lesions were observed in 7 of these 8 patients. Among the TKI pretreated patients with no prior platinum-based chemotherapy, 12 had measurable CNS metastases at baseline as assessed by BICR; responses in intracranial lesions were observed in 5 of these 12 patients.

Among the 56 ROS1 inhibitor-pretreated patients, 8 had resistance mutations following TKI therapy. Responses were observed in 6 of these 8 patients; responders included patients with solvent front (ROS1^G2032R), gatekeeper (ROS1^L2026M), and other mutations (ROS1^S1986F/Y).

14.2 Locally Advanced or Metastatic NTRK Gene Fusion-Positive Solid Tumors

The efficacy of AUGTYRO was evaluated in TRIDENT-1 (NCT03093116), a multi-center, single-arm, open-label, multi-cohort clinical trial in 88 adult patients with locally advanced or metastatic NTRK gene fusion-positive (NTRK1/2/3) solid tumors who had either received a prior TKI treatment or were TKI-naïve. All patients were assessed for CNS lesions at baseline, and patients with symptomatic brain metastases were excluded from the trial. Patients received AUGTYRO 160 mg orally once daily for 14 days, then increased to 160 mg twice daily until disease progression or unacceptable toxicity. Tumor assessments were performed every 8 weeks. NTRK gene fusions were identified prospectively using NGS in 94%, FISH in 5%, and PCR in 1%. NTRK gene fusion-positive tumors identified by local FISH testing required central laboratory confirmation using an analytically validated NGS test. The major efficacy outcome measures were ORR and DOR according to RECIST v1.1 as assessed by BICR. Intracranial response according to modified RECIST v1.1 was assessed by BICR.

Among the 40 TRK TKI-naïve patients, the median age was 61 years (range: 25 to 84); 60% were female patients; race was Asian 53%, White 25%, Black or African American 5%, and other or not reported 18%; ethnicity was Hispanic or Latino 5%, not Hispanic or Latino 87%, and not reported 8%; and ECOG performance status of 1 at baseline was 55%. At baseline, 98% of patients had metastatic disease and 23% of patients had CNS metastases by BICR. Seventy percent (n=28) of patients received prior systemic therapy with a median of one prior systemic regimen, and 7.5% (n=3) received three or more prior systemic regimens.

Among the 48 TRK TKI-pretreated patients, the median age was 58 years (range: 20 to 81); 48% were female patients; race was White 65%, Asian 25%, Black or African American 2%, and not reported 8%; ethnicity was not Hispanic or Latino 92%, and missing 8%; and ECOG performance status of 1 at baseline was 60%. At baseline, 96% of patients had metastatic disease and 25% of patients had CNS metastases by BICR. Seventy-seven percent (n=37) of patients received 2 or more prior systemic regimens, and 46% (n=22) received three or more prior systemic regimens, and 7 patients (15%) received 2 prior TKI therapies.

Efficacy results are summarized in Table 6.

Table 6. Efficacy Results for Patients with NTRK Gene Fusion-Positive Tumors in
TRIDENT-1:

NE = not evaluable; “+” indicates ongoing response
^a Median DOR (95% CI) are based on Kaplan-Meier estimates.
^b DOR landmark analysis is based on the observed DOR.

Among the 88 patients, 5 had measurable CNS metastases at baseline as assessed by BICR. Responses were seen in 2 (100%) TKI-naïve patients and 3 (100%) TKI-pretreated patients. One out of 2 TKI-naïve and 2 out of 3 TKI-pretreated patients received prior radiotherapy to the brain, all more than 2 months prior to study entry.

Twenty-six of the TRK TKI-pretreated patients had a resistance mutation at baseline, including 24 and NTRK3^G623L/R/E/V with solvent front mutations (NTRK1^G595R mutations), one with both a solvent front mutation and a gatekeeper mutation (NTRK1^F589L), and one with another mutation (NTRK1^G667C). In the 25 TKI-pretreated patients with solvent front mutations at baseline, ORR was 60% (95% CI: 39, 79).

ORR and DOR by tumor type in adult patients with NTRK gene fusion-positive solid tumors are presented in Tables 7 and 8 below.

Table 7. Efficacy Results by Tumor Type in TKI-naïve NTRK Gene Fusion Patients:

^* Includes esophageal cancer and head and neck cancer
PD: progressive disease; PR: partial response; SD: stable disease; NA: not applicable
⁺ indicates ongoing response

Table 8. Efficacy Results by Tumor Type in TKI-pretreated NTRK Gene FusionPositive Patients:

^* Includes gallbladder cancer and unknown primary cancer
PD: progressive disease; PR: partial response; SD: stable disease; NA: not applicable
⁺ indicates ongoing response

ORR and DOR in adult patients are presented by NTRK gene fusion partner Tables 9 and 10 below.

Table 9. Efficacy Results by NTRK Gene Fusion Partner in TRK TKI-Naïve Patients:

PD: progressive disease; PR: partial response; SD: stable disease; NA: not applicable
⁺ indicates ongoing response

Table 10. Efficacy Results by NTRK Gene Fusion Partner in TRK TKI-Pretreated Subjects:

PR = partial response; PD = progressive disease; SD = stable disease; NA = not applicable; NE = not evaluable
⁺ indicates ongoing response