CLINICAL TRIALS PROFILE FOR REPOTRECTINIB

All Clinical Trials for Repotrectinib

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT03093116 ↗	A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements	Recruiting	TP Therapeutics, Inc.	Phase 1/Phase 2	2017-02-27	Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose (RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. Midazolam DDI substudy will examine effect of of repotrectinib on CYP3A induction. Phase 2 will determine the confirmed Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR) of repotrectinib in each subject population expansion cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. The secondary objective will include the duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and clinical benefit rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
NCT03093116 ↗	A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements	Recruiting	Turning Point Therapeutics, Inc.	Phase 1/Phase 2	2017-02-27	Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose (RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. Midazolam DDI substudy will examine effect of of repotrectinib on CYP3A induction. Phase 2 will determine the confirmed Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR) of repotrectinib in each subject population expansion cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. The secondary objective will include the duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and clinical benefit rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
NCT04094610 ↗	A Study of Repotrectinib in Pediatric and Young Adult Subjects Harboring ALK, ROS1, OR NTRK1-3 Alterations	Recruiting	Turning Point Therapeutics, Inc.	Phase 1/Phase 2	2020-03-20	Phase 1 will evaluate the safety and tolerability at different dose levels of repotrectinib in pediatric and young adult subjects with advanced or metastatic malignancies harboring anaplastic lymphoma kinase (ALK), receptor tyrosine kinase encoded by the gene ROS1 (ROS1), or neurotrophic receptor kinase genes encoding TRK kinase family (NTRK1-3) alterations to estimate the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) and select the Pediatric Recommended Phase 2 Dose (RP2D). Phase 2 will determine the anti-tumor activity of repotrectinib in pediatric subjects with advanced or metastatic malignancies harboring ALK, ROS1, or NTRK1-3 alterations.
NCT04772235 ↗	Phase I Study of Repotrectinib and Osimertinib in NSCLC Patients	Not yet recruiting	Turning Point Therapeutics, Inc.	Phase 1	2021-04-01	This is a Phase I study of repotrectinib in combination with osimertinib in patients with advanced or metastatic EGFR mutant non small cell lung cancer (NSCLC). The study will be conducted in 2 parts, Part Ia and Part Ib, and its purpose will be to find the incidence of dose-limiting toxicities (DLTs) as defined by the primary safety and tolerability endpoint. The Phase Ia study will also determine the impact of repotrectinib on osimertinib pharmacokinetics (PK) and the maximum tolerated dose (MTD), if reached, of repotrectinib given in combination with osimertinib and the recommended Phase II dose (RP2D). Dose escalation will be conducted according to a 'Rolling-6' based study design with 3 dose levels for repotrectinib: 80 mg once a day (QD), 160 mg QD or 160 mf QD during 14 days followed by 160 mg twice a day (BID); in combination with 80 mg QD of osimertinib. A total of 6 patients will be enrolled in each dose level cohort. In addition, this Phase Ib study will test early drug activity (efficacy) of the proposed combination treatment in an expansion cohort at the RP2D.
NCT04772235 ↗	Phase I Study of Repotrectinib and Osimertinib in NSCLC Patients	Not yet recruiting	Instituto Oncológico Dr Rosell	Phase 1	2021-04-01	This is a Phase I study of repotrectinib in combination with osimertinib in patients with advanced or metastatic EGFR mutant non small cell lung cancer (NSCLC). The study will be conducted in 2 parts, Part Ia and Part Ib, and its purpose will be to find the incidence of dose-limiting toxicities (DLTs) as defined by the primary safety and tolerability endpoint. The Phase Ia study will also determine the impact of repotrectinib on osimertinib pharmacokinetics (PK) and the maximum tolerated dose (MTD), if reached, of repotrectinib given in combination with osimertinib and the recommended Phase II dose (RP2D). Dose escalation will be conducted according to a 'Rolling-6' based study design with 3 dose levels for repotrectinib: 80 mg once a day (QD), 160 mg QD or 160 mf QD during 14 days followed by 160 mg twice a day (BID); in combination with 80 mg QD of osimertinib. A total of 6 patients will be enrolled in each dose level cohort. In addition, this Phase Ib study will test early drug activity (efficacy) of the proposed combination treatment in an expansion cohort at the RP2D.
NCT05004116 ↗	A Study of Repotrectinib in Combination With Chemotherapy in Children and Young Adults With Solid Tumor Cancer	Recruiting	Memorial Sloan Kettering Cancer Center	Phase 1/Phase 2	2021-08-09	This study will test the safety of the study drug, repotrectinib, in combination with chemotherapy (irinotecan and temozolomide) in children and young adults who have advanced or metastatic solid tumors. We researchers will try to find the highest dose of the study drug that causes few or mild side effects in study participants. When the researchers find this dose, we will evaluate it in a different group of participants to find out whether repotrectinib in combination with chemotherapy is an effective treatment for children and young adults who have advanced/metastatic solid tumors. Another purpose of the study is to look at the way the body absorbs, distributes, and gets rid of repotrectinib.
NCT05071183 ↗	A Study of Repotrectinib in Combination With Other Anticancer Therapies for the Treatment of Subjects With KRAS-Mutant Solid Tumors	Recruiting	Turning Point Therapeutics, Inc.	Phase 1/Phase 2	2021-10-01	A Phase 1b/2 Study of Repotrectinib in Combination with Other Anticancer Therapies for the Treatment of Subjects with KRAS-Mutant Advanced Solid Tumors (TRIDENT-2)

Clinical Trial Conditions for Repotrectinib

Condition Name

Condition Name for Repotrectinib
Intervention	Trials
Metastatic Solid Tumor	4
Metastatic Solid Tumors	2
Advanced Solid Tumor	2
Locally Advanced Solid Tumors	2

Condition MeSH

Condition MeSH for Repotrectinib
Intervention	Trials
Neoplasms	6
Carcinoma, Non-Small-Cell Lung	2
Central Nervous System Neoplasms	1
Lymphoma, Non-Hodgkin	1

Clinical Trial Locations for Repotrectinib

Trials by Country

Trials by Country for Repotrectinib
Location	Trials
United States	51
China	38
Spain	11
France	9
Japan	9

Trials by US State

Trials by US State for Repotrectinib
Location	Trials
Ohio	4
New York	4
Massachusetts	3
Colorado	3
Texas	3

Clinical Trial Progress for Repotrectinib

Clinical Trial Phase

Clinical Trial Phase for Repotrectinib
Clinical Trial Phase	Trials
Phase 3	1
Phase 1/Phase 2	4
Phase 1	3

Clinical Trial Status

Clinical Trial Status for Repotrectinib
Clinical Trial Phase	Trials
Recruiting	7
Not yet recruiting	1

Clinical Trial Sponsors for Repotrectinib

Sponsor Name

Sponsor Name for Repotrectinib
Sponsor	Trials
Turning Point Therapeutics, Inc.	6
TP Therapeutics, Inc.	1
Instituto Oncológico Dr Rosell	1

Sponsor Type

Sponsor Type for Repotrectinib
Sponsor	Trials
Industry	9
Other	2

Repotrectinib: A Breakthrough in Targeted Cancer Therapy

Introduction to Repotrectinib

Repotrectinib, marketed as Augtyro by Bristol Myers Squibb, is a next-generation tyrosine kinase inhibitor (TKI) that has garnered significant attention in the oncology community. This drug has shown promising results in treating patients with locally advanced or metastatic cancers, particularly those with ROS1-positive non-small cell lung cancer (NSCLC) and NTRK-positive solid tumors.

Clinical Trials Overview

The approval and ongoing evaluation of repotrectinib are largely based on the results from two pivotal clinical trials: TRIDENT-1 and CARE.

TRIDENT-1 Trial

The TRIDENT-1 trial is a multicenter, single-arm, open-label study designed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of repotrectinib. This trial includes multiple cohorts of patients with ROS1-positive NSCLC and NTRK-positive solid tumors.

• ROS1-Positive NSCLC: In the TRIDENT-1 trial, patients who were ROS1 TKI naïve showed an objective response rate (ORR) of 79% (95% CI, 68–88%) and a median duration of response (DOR) of 34.1 months (95% CI, 26–NE)[1][4].
• Patients with Prior ROS1 TKI: For patients who had received prior ROS1 TKI therapy, the ORR was 38% (95% CI, 25–52%) with a median DOR of 14.8 months (95% CI, 7.6–NE)[1][4].

CARE Trial

The CARE trial, another phase 1/2 study, further supports the efficacy of repotrectinib in patients with NTRK-positive solid tumors. This trial demonstrated clinically meaningful and durable responses in both adult and pediatric patients[2].

FDA and Regulatory Approvals

FDA Approval for ROS1-Positive NSCLC

On November 15, 2023, the FDA granted traditional approval to repotrectinib for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC. This approval was based on the robust efficacy data from the TRIDENT-1 trial[1][4].

FDA Approval for NTRK-Positive Solid Tumors

In June 2024, the FDA approved repotrectinib for adult and pediatric patients 12 years of age and older with NTRK-positive locally advanced or metastatic solid tumors, where surgical resection is likely to result in severe morbidity, or in patients who have progressed after treatment or have no satisfactory alternative therapy[2][4].

European Medicines Agency (EMA) Recommendation

The EMA's Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of repotrectinib for both ROS1-positive NSCLC and NTRK-positive solid tumors. This recommendation is currently under review by the European Commission, with a final decision expected in January 2025[5].

Safety and Tolerability

Repotrectinib has been shown to have a manageable safety profile. The most common adverse reactions (>20%) include dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness[1].

Market Analysis and Projections

Unmet Medical Need

Repotrectinib addresses a significant unmet medical need, particularly for patients with ROS1-positive NSCLC and NTRK-positive solid tumors who have limited treatment options. The drug's ability to induce durable responses, including in patients with CNS metastases and those who have developed resistance mutations, positions it as a valuable addition to the treatment landscape[1][2][4].

Market Potential

Given its approvals and positive clinical trial results, repotrectinib is expected to capture a substantial share of the market for targeted therapies in NSCLC and other solid tumors. The drug's efficacy in both adult and pediatric patients further expands its market potential.

Competitive Landscape

Repotrectinib competes with other TKIs such as crizotinib (Xalkori) and entrectinib (Rozlytrek) but stands out due to its next-generation design, which offers improved efficacy and tolerability. The robust evidence of its efficacy in patients who have progressed on prior TKIs is a key differentiator[1][3].

Future Directions and Ongoing Research

Post-Marketing Commitments

The FDA has issued a post-marketing commitment (PMC) to provide final results from the ongoing clinical studies, ensuring continuous monitoring and evaluation of repotrectinib's long-term efficacy and safety[1].

Expanding Indications

Repotrectinib is under priority review for additional indications, including its use in patients with NTRK-positive solid tumors. The positive outcomes from the TRIDENT-1 and CARE trials suggest potential for further approvals in other tumor types[2][4].

Key Takeaways

• Robust Efficacy: Repotrectinib has demonstrated high ORRs and durable responses in patients with ROS1-positive NSCLC and NTRK-positive solid tumors.
• Manageable Safety Profile: The drug has a generally manageable safety profile with common adverse reactions that are consistent with other TKIs.
• Regulatory Approvals: FDA approvals for ROS1-positive NSCLC and NTRK-positive solid tumors, with EMA recommendation pending.
• Market Potential: Significant market potential due to unmet medical needs and competitive advantages over existing therapies.
• Ongoing Research: Continuous monitoring and evaluation through post-marketing commitments and potential expansion into new indications.

FAQs

What is repotrectinib and how does it work?

Repotrectinib is a next-generation tyrosine kinase inhibitor that targets specific genetic mutations, such as ROS1 and NTRK, in cancer cells, inhibiting their growth and proliferation.

Which cancers is repotrectinib approved for?

Repotrectinib is approved for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC and for adult and pediatric patients 12 years of age and older with NTRK-positive locally advanced or metastatic solid tumors.

What are the common side effects of repotrectinib?

Common adverse reactions include dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness.

How effective is repotrectinib in patients who have received prior TKI therapy?

In patients who have received prior ROS1 TKI therapy, repotrectinib showed an ORR of 38% with a median DOR of 14.8 months, indicating its efficacy even in patients with resistance to previous treatments.

What is the current regulatory status of repotrectinib in Europe?

The EMA's CHMP has recommended the approval of repotrectinib for both ROS1-positive NSCLC and NTRK-positive solid tumors, with a final decision expected from the European Commission in January 2025.

Sources

1. FDA Approval Summary: Repotrectinib for Locally Advanced or Metastatic ROS1-Positive Non–Small Cell Lung Cancer. Clinical Cancer Research, 2024.
2. FDA Grants Priority Review to Repotrectinib for NTRK+ Solid Tumors. Onclive, 2024.
3. Repotrectinib Induces Durable Responses in ROS1+ NSCLC Subsets. Onclive, 2023.
4. Repotrectinib Garners Positive CHMP Opinion for ROS1+ NSCLC and NTRK+ Solid Tumors. Onclive, 2024.
5. EMA Committee Recommends Repotrectinib for Lung Cancer. Investing.com, 2024.