Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Bristol-Myers Squibb Pharma EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors
ATC code: L01EX28
Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1, the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, TRKC, and anaplastic lymphoma kinase (ALK) with IC50 values of 0.05 to 1.04 nM.
Fusion proteins that include ROS1 or TRK domains can drive tumourigenic potential through hyperactivation of downstream signalling pathways leading to unconstrained cell proliferation. Repotrectinib has demonstrated in vitro and in vivo inhibition of cell lines expressing the targeted fusion oncogenes ROS1, TRKA, TRKB, TRKC, and corresponding mutations (ROS1G2032R, ROS1D2033N, TRKAG595R, TRKBG639R, TRKCG623R). Repotrectinib binds inside the boundary of the ATP-binding pocket and avoids steric interference from both solvent front and gatekeeper mutations.
Analysis of ECG data from 334 patients in the TRIDENT-1 phase 2 study, who received AUGTYRO at the recommended dose (unknown prandial state), demonstrated that the upper limit of 90% confidence interval (CI) of the mean QTcF change from baseline (ΔQTcF) exceeded 10 milliseconds (ms) for a few time point estimates but remained <20 ms.
Patients with increased risk of QTc prolongation were not enrolled in TRIDENT-1.
The efficacy of repotrectinib was evaluated in adult patients with solid tumours harboring ROS1 or NTRK1-3 rearrangements in a phase I/II, multicentre, single-arm, open-label, multi-cohort clinical study (TRIDENT-1). Patients received various doses and schedules of repotrectinib (156 [91%] received repotrectinib 160 mg orally once daily for the first 14 days of treatment followed by 160 mg orally twice daily until disease progression or unacceptable toxicity).
The primary efficacy endpoint was overall response rate (ORR) by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. The secondary endpoints were duration of response (DOR), progression free survival (PFS) by BICR according to RECIST v1.1 and overall survival (OS). Intracranial response according to modified RECIST v1.1 was assessed by BICR. Tumour assessments with imaging were performed at least every 8 weeks.
The efficacy of repotrectinib was evaluated in a subgroup of adult patients with locally advanced or metastatic ROS1-positive NSCLC pooled from phase I/II of TRIDENT-1. Patients were required to have ECOG performance status ≤1, measurable disease per RECIST v 1.1, ≥8 months follow-up rom first dose. Identification of ROS1 fusions in tumour specimens was prospectively determined in local laboratories using next-generation sequencing (NGS), polymerase chain reaction (PCR) or fluorescence in situ hybridisation (FISH) tests. All ROS1-positive tumours by local FISH testing required central laboratory confirmation using an analytically validated NGS test. ROS1 fusions were identified by NGS in 57%, FISH in 22%, and PCR in 21% of patients. All patients were assessed for CNS lesions at baseline.
Among the 121 ROS1 inhibitor naïve patients, the median age was 57 years (range: 28–93), 23% and 5% were 65 years or older and 75 years or older respectively. The majority were female (56%) Asian (60%) or White (30%); and never smoked (63%). Baseline ECOG performance status was 0 (38%) and 1 (62%). At baseline, 92% of patients had metastatic disease, 25% of patients had CNS metastases by BICR; 97% of patients had adenocarcinoma; 26% of patients had prior platinum-based chemotherapy for locally advanced or metastatic disease.
Among the 107 patients who had received 1 prior ROS1 TKI (crizotinib 77%, entrectinib 21%, and ceritinib 3%) with no prior platinum-based chemotherapy, the median age was 57 years, (range: 33-81), 29% and 8% were 65 years or older and 75 years or older, respectively. The majority were female (74%), Asian (42%) or White (49%); never smoked (68%); and ECOG performance status of 0 (34%) and 1 at baseline (66%). At baseline, 98% patients had metastatic disease, 40% had CNS metastases by BICR, and 96% had adenocarcinoma. Efficacy results are summarised in Table 5.
Table 5. Efficacy results in ROS1-positive NSCLC patients per BICR assessment:
| Efficacy parameters | ROS1 inhibitor naïve patients (N=121) | ROS1 inhibitor pretreated patients (N=107) |
|---|---|---|
| Confirmed Overall Response Rate, (95 CI) | 77 (68, 84) | 49 (39, 59) |
| Complete Response Rate N (%) | 15 (12) | 8 (8) |
| Partial Response Rate N (%) | 78 (65) | 44 (41) |
| Median Duration of Response (mDOR) in Months (95% CI) | 33.6 (25.5, NE) | 14.8 (7.6, NE) |
| Range (months) | 1.4+ – 49.7+ | 1.8+ – 31.4 |
| 12-months durable response % (95% CI) | 77 (68, 86) | 53 (38, 68) |
| 18-months durable response % (95% CI) | 70 (60, 80) | 44 (27, 61) |
| 24-months durable response % (95% CI) | 64 (52, 75) | 38 (19, 56) |
DOR landmarks are by K-M estimates.
Minimum follow up was 7 months.
+denotes ongoing response.
NE : Not Estimated
The median time to response was 1.84 (range 1.5, 7.4) months for TKI-naïve patients and 1.84 (range 1.6, 22.1) months for TKI pretreated patients.
Among the 121 TKI naive patients, 14 had measurable CNS metastases at baseline as assessed by BICR (4 patients had CNS intervention within 60 days of first dose of study treatment), and intracranial response was observed in 12 patients (3 CR and 9 PR), for an intracranial ORR of 86% (95% CI: 57, 98). Among the 107 TKI pretreated patients with no prior platinum-based chemotherapy,23 had measurable CNS metastases at baseline as assessed by BICR (7 patients had CNS intervention within 60 days of first dose of study treatment), and intracranial response was observed in 10 patients (2 CR and 8 PR), for an intracranial ORR of 44% (95% CI: 23, 66).
In35 ROS1 TKI pretreated patients with solvent front mutation, ORR was 51.4% (95% CI: 34.0, 68.6).
The efficacy of repotrectinib was evaluated in a population of patients with locally advanced (not eligible for surgery, radiation or multimodality therapy) or metastatic NTRK gene fusion positive solid tumours pooled from phase I/II. Patients were required to have ECOG performance status ≤1, and measurable disease per RECIST v 1.1 and ≥8 months follow-up from first dose. Identification of NTRK gene fusions in tumour specimens was prospectively determined in local laboratories using NGS, PCR or FISH tests. All NTRK 1-3 gene fusion positive tumours by local FISH testing required central laboratory confirmation using an analytically validated NGS test. NTRK fusions were identified by NGS in 96%, FISH in 2.5%, and PCR in 1.7% of patients. All patients were assessed for CNS lesions at baseline.
Among the 51 TKI-naive patients in phase I/II, the median age was 61 years (range: 25–84); 41% and 12% were 65 years or older and 75 years or older respectively. The majority were female (53%); Asian (51%) or White (25%). Baseline ECOG performance status was 0 (45%) and 1 (55%). At baseline, 96% of patients had metastatic disease and 20% patients had CNS metastases by BICR. The most common tumours were NSCLC 53%, thyroid cancer 12%, salivary gland cancer 10%, and soft tissue sarcoma 6%.
Among the 69 TKI-pretreated patients in phase I/II, 17% of patients had received 2 prior TKI therapies, 52% of patients had received larotrectinib and 46% entrectinib, the median age was 56 years (range: 18–81); 36% and 7% were 65 years or older and 75 years or older respectively. The patients were female (48%); Asian (30%) or White (58%). Baseline ECOG performance status was 0 (39%) and 1 (61%). At baseline, 91% of patients had metastatic disease and 23% of patients had CNS metastases by BICR. The most common tumours were NSCLC 25%, salivary gland cancer 17%, soft tissue sarcoma 15%, and thyroid cancer 10%.
ORR and DOR were assessed by BICR and according to RECIST v1.1. Intracranial response according to modified RECIST v1.1 was assessed by BICR. Tumour assessments with imaging were performed at least every 8 weeks. The primary efficacy populations included 51 TKI inhibitor naïve patients and 69 patients who had received 1 prior TKI inhibitor. Efficacy results with a minimum follow-up of 8 months are summarised in Table 6.
Table 6. Overall efficacy by BICR in adults with NTRK gene fusion-positive tumours:
| Efficacy parameters | TKI naïve patients (n=51) | TKI pretreated patients (n=69) |
|---|---|---|
| Confirmed Overall Response Rate, (95 CI) | 59 (44, 72) | 48 (36, 60) |
| Complete Response N (%) | 8 (16) | 2 (3) |
| Partial Response N (%) | 22 (43) | 31 (45) |
| Median Duration of Response in Months (95% CI) | NE (NE, NE) | 9.8 (7.36, 12.98) |
| Range (months) | 0.0+, 43.9+ | 1.8, 26.5+ |
| 6-months durable response % (95% CI) | 92.9 (83.3, 100.0) | 72.7 (57.5, 87.9) |
| 9-months durable response % (95% CI) | 89.1 (77.5, 100.0) | 62.8 (46.0, 79.6) |
| 12-months durable response % (95% CI) | 89.1 (77.5, 100.0) | 41.6 (23.8, 59.3) |
95% CIs are based on Kaplan-Meier methodology using the Greenwood variance estimate
DOR landmarks are by K-M estimates
Minimum follow up was 8 months
+denotes ongoing response
NE: Not Estimated
The median time to response was 1.8 (range 1.6, 7.3) months for TKI-naïve patients and 1.9 (range 1.7, 3.7) months for TKI pretreated patients.
In 30 NTRK TKI pretreated patients with solvent front mutation at baseline, ORR was 53% (95% CI: 34.3,71.7).
ORR and DOR by tumour type in adult patients with NTRK gene fusion-positive solid tumours are presented in Table 7 below.
Table 7. Efficacy results in TKI naive NTRK gene fusion-positive solid tumours:
| Tumour type | Patients (N=51) | ORR | DOR | |
|---|---|---|---|---|
| n (%) | 95% CI | Range (months) | ||
| NSCLC | 27 | 17 (63.0) | 42.4, 80.6 | 0.0+, 31.3+ |
| Thyroid Cancer | 6 | 6 (100.0) | 54.1, 100.0 | 4.7, 43.9+ |
| Salivary Gland Cancer | 5 | 4 (80.0) | 28.4, 99.5 | 12.9+, 31.4+ |
| Sarcoma, Soft tissue | 3 | 1 (33.3) | 0.8, 90.6 | 14.7+ |
| Other* | 3 | SD, SD, SD | NA | NA |
| Colorectal cancer | 2 | CR, SD | NA | 7.5+ |
| Breast Cancer | 2 | PD, PD | NA | NA |
| Glioblastoma | 1 | SD | NA | NA |
| Cholangiocarcinoma | 1 | PD | NA | NA |
| Peripheral Nerve Sheath Tumour | 1 | PR | NA | 23.0+ |
* Includes oesophageal cancer, prostate cancer and head and neck cancer
PD: progressive disease; PR: partial response; SD: stable disease; NA: not applicable
+denotes ongoing response
Table 8. Efficacy results in TKI pretreated NTRK gene fusion-positive solid tumours:
| Tumour type | Patients (N=69) | ORR | DOR | |
|---|---|---|---|---|
| n (%) | 95% CI | Range (months) | ||
| NSCLC | 17 | 9 (52.9) | 27.8, 77.0 | 1.9, 23.0+ |
| Salivary Gland Cancer | 12 | 9 (75.0) | 42.8, 94.5 | 3.7, 26.5+ |
| Sarcoma, Soft tissue | 10 | 1 (10.0) | 0.3, 44.5 | 5.6 |
| Thyroid Cancer | 7 | 2 (28.6) | 3.7, 71.0 | 2.0, 9.6 |
| Other* | 5 | 2 (40.0) | 5.3, 85.3 | 11.0+, 14.8+ |
| Colorectal cancer | 4 | 2 (50.0) | 6.8, 93.2 | 9.2, 17.5 |
| Glioblastoma | 3 | 1 (33.3) | 0.8, 90.6 | 23.5 |
| Neuroendocrine Tumour | 3 | 3 (100.0) | 29.2, 100.0 | 5.5, 9.1 |
| Pancreatic Cancer | 3 | PD, PD, SD | NA | NA |
| Cholangiocarcinoma | 2 | PR, PD | NA | 1.8 |
| Peripheral Nerve Sheath Tumour | 2 | PR, PR | NA | 5.5, 11.1 |
| Breast Cancer | 1 | PR | NA | 15.6+ |
* Include gallbladder cancer, cervical cancer, gastrointestinal stromal tumour, mucoepidermoid and unknown primary cancer
PD: progressive disease; PR: partial response; SD: stable disease; NA: not applicable
+denotes ongoing response
Due to the rarity of NTRK gene fusion-positive cancers, patients were studied across multiple tumour types with limited numbers of patients in some tumour types, causing uncertainty in the ORR estimate per tumour type. The ORR in the total population may not reflect the expected response in a specific tumour type.
AUGTYRO was evaluated in paediatric patients with locally advanced or metastatic tumours harbouring NTRK alteration in the phase I/II, open-label, single-arm, multicentre, multicohort CARE study. Efficacy was evaluated in patients who received AUGTYRO orally either as 160 mg once daily or 160 mg once daily for 14 days followed by 160 mg twice daily or adult equivalent dose, until disease progression or unacceptable toxicity.
Patients were required to have Lansky (<16 years) or Karnofsky (≥16 years) score of at least 50, and measurable disease per RECIST v1.1 or Response Assessment in Neuro-Oncology Criteria (RANO). Patients with a primary CNS tumour or CNS metastases were required to be neurologically stable and on a stable or decreasing dose of steroids for at least 14 days prior to enrolment.
Identification of NTRK1-3 gene fusions in tumour specimens was prospectively determined in local laboratories using NGS, PCR or FISH tests. All NTRK gene fusion positive tumours by local FISH testing require retrospective central laboratory confirmation using an analytically validated NGS test.
Primary efficacy endpoints were ORR by BICR according to RECIST v1.1 or RANO and secondary efficacy endpoints were DOR and PFS by BICR according to RECIST v1.1 or RANO and OS. Tumour assessments with imaging were performed at least every 8 weeks.
Thirteen NTRK positive paediatric patients (age range: 1 year to 15 years old; 5 were 12-17 years of age), had measurable disease at baseline per BICR and at least one post baseline scan were evaluated in CARE study. Of these, 5 were NTRK TKI naive (3 CNS tumours and 2 solid tumours) and 8 had received prior NTRK TKI therapy (3 CNS tumours and 5 solid tumours).
Of the 5 TKI naïve patients, 1 complete response and 2 partial responses were observed. Among the 8 TKI-pretreated patients, there were 2 partial responses.
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
The European Medicines Agency has deferred the obligation to submit the results of studies with AUGTYRO in one or more subsets of the paediatric population in the treatment with NTRK gene fusion-positive locally advanced or metastatic solid tumours (see section 4.2 for information on paediatric use).
The pharmacokinetic (PK) parameters for repotrectinib have been characterised in patients with NTRK gene fusion-positive solid tumours, ROS1-positive NSCLC, and in healthy subjects. Repotrectinib maximum concentration (Cmax) and area under the curve over time to infinity (AUC0-inf) increases were 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. Steady state PK was time-dependent due to autoinduction of CYP3A4. The steady-state average concentration (Cavg) of 160 mg twice daily dosing regimen is similar to Cavg following 160 mg single dose administration.
Repotrectinib estimated steady state geometric mean (CV%) Cmax is 572 ng/mL (38.3%), Cmin is 158 ng/mL (57.7%), and Cavg (AUC0-12h divided by dosing interval) is 347 ng/mL (42.3%) for 160 mg twice a day.
Following oral administration of ascending single doses of repotrectinib ranging from 40 mg to 240 mg, repotrectinib exhibited rapid absorption with Cmax occurring at approximately 2-3 hours post dose under fasted conditions. The geometric mean (CV%) absolute bioavailability of repotrectinib is 45.7% (19.6%).
A high-fat, high-calorie meal (916 calories, 56% fat) increased repotrectinib AUC0-inf by 56% and Cmax by 149% following a single 160 mg oral dose (administered as 40 mg capsules). In another study, a high-fat, high-calorie meal increased AUC0-inf by 42% and Cmax by 110% following a single 160 mg oral dose (administered as 160 mg capsules). Similar increases (AUC0-inf by 36% and Cmax by 124%) were observed with a low-fat, low-calorie meal.
Repotrectinib peak concentration occurred at approximately 4 to 6 hours post a single oral dose of 40 mg to 160 mg under fed conditions (high-fat meal).
Binding of repotrectinib to human plasma protein was 95.4% in vitro. The blood-to-plasma ratio was 0.56 in vitro. The geometric mean (CV%) apparent volume of distribution (Vz/F) was 432 L (55.9%) in cancer patients following a single 160 mg oral dose of repotrectinib.
Repotrectinib is primarily metabolised by CYP3A4 to form hydroxylated metabolites followed by secondary glucuronidation. No metabolite exceeded 10% of total circulating drug-related radioactivity.
Repotrectinib elimination is time-dependent due to autoinduction of CYP3A4.
The geometric mean (CV%) apparent oral clearance (CL/F) was 15.9 L/h (45.5%) in cancer patients following a single 160 mg oral dose of repotrectinib. Based on the population PK (popPK) analysis, the single dose mean (SD) terminal half-life (t½) was estimated to be 68.6 (29.6) hours, and the steady state terminal t½ was estimated to be 44.5 (20.8) hours in cancer patients.
Following a single oral 160 mg dose of [14C] repotrectinib, 4.84% (0.56% as unchanged) of the radioactivity was recovered in urine and 88.8% (50.6% as unchanged) in faeces.
In the popPK analysis, mild (eGFR-CKD-EPI 60 to 90 mL/min, n=139) or moderate (eGFR-CKD-EPI 30 to 60 mL/min, n=27) renal impairment did not influence the clearance of repotrectinib. Repotrectinib has not been studied in patients with severe renal impairment (eGFR- CKD-EPI <30 mL/min).
In the popPK analysis, mild hepatic impairment (total bilirubin >1.0 to 1.5 times ULN or AST >ULN, n=59) did not influence the clearance of repotrectinib. Pharmacokinetics of repotrectinib have not been established in patients with moderate (total bilirubin >1.5 to 3 times ULN) or severe (total bilirubin >3 times ULN) hepatic impairment.
In the popPK analysis, no clinically relevant differences in the pharmacokinetics of repotrectinib were identified based on gender, age (18 years to 93 years), body weight (39.5 kg to 169 kg), or race (Asian and White) in adults.
PK data was available from paediatric patients 12 years and older (n=13, age 13 to 15 years, body weight 46.4 to 76.7 kg). Based on popPK simulations, adolescents 12 years and older have similar systemic exposure as that of adults when administered the adult dose of 160 mg once daily for 14 days, followed by 160 mg twice daily.
CYP Enzymes: Repotrectinib induces CYP3A4, CYP2B6, CYP2C8, CYP2C19, CYP2C9 and inhibits CYP3A4/5 (GI tract), CYP2C8 and CYP2C9.
Other Metabolic Pathways: Repotrectinib inhibits UGT1A1.
Transporter Systems: Repotrectinib inhibits P-gp, BCRP, OATP1B1, MATE1 and MATE2-K. Repotrectinib is a substrate for P-gp and a potential substrate for MATE2-K and BCRP.
Carcinogenicity studies with repotrectinib were not conducted.
Repotrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.
Repotrectinib caused micronuclei formations via an aneugenic mechanism in human lymphoblastoid TK6 cells in vitro, and in bone marrow of rats in vivo at doses >100 mg/kg nominal dose. The exposure of animals at the no observed effect level (NOEL) for aneugenicity was approximately 3.4-fold human exposure at the recommended clinical dose (based on AUC).
In a preliminary embryo-foetal development study in rats, teratogenic and embryo-foetal effects (foetal external malformation of malrotated hindlimbs and decreased foetal weight) and maternal effects (skin scabbing and abrasions in cervical and thoracic regions and increased body weight) were observed in pregnant rats at exposures that were less than 2-fold human exposure at the recommended clinical dose.
Dedicated fertility studies were not conducted with repotrectinib. There were no effects on male and female reproductive organs observed in general toxicology studies conducted in rats and monkeys at any dose level tested, which equated to exposures in rats of up to 2-fold and 2.6-fold in males and females, respectively, and exposures in monkeys that were below the human exposure at the recommended clinical dose.
Following repeat-dose oral administration of repotrectinib daily for up to 3 months, the main toxicities observed in rats at exposure levels <3-fold human exposure were skin scabs/ulcerations, CNS effects (i.e. ataxia, tremors), decreased RBC parameters, and bone marrow hypocellularity.
The main toxicities observed in monkeys at exposure margins below clinical exposure were emesis, watery faeces, minimal subacute/chronic inflammation and/or minimal to mild mucosal gland hyperplasia in the large intestines, and decreased RBC parameters. The skin ulcerations were considered secondary to NTRK inhibition resulting in loss of sensation and bodily injury.
Overall, juvenile rats were dosed and evaluated up to 58 days (starting on postnatal day [PND] 12 through PND 70) in repeat-dose toxicity studies. CNS-related mortality was observed at PND 13 to PND 15 (approximately equivalent to infant) at exposure levels ≥1.5-fold adolescent human exposure.
Decreased effects on growth (decreased body weight, food consumption and femur length) were observed at exposure levels ≥0.1-fold the adolescent human exposure.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.