EMA Committee Recommends Approval of Bristol Myers Repotrectinib

EMA Committee Recommends Approval of Bristol Myers Repotrectinib

By, Admin 18 November 2024

EMA committee recommends approval of Bristol Myers’ repotrectinib to treat advanced ROS1-positive NSCLC & NTRK-positive solid tumours

Overview

Bristol Myers Squibb announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval for repotrectinib, a next-generation tyrosine kinase inhibitor (TKI), as a treatment for adult patients with ROS1 -positive advanced non-small cell lung cancer (NSCLC) and for the treatment of adult and paediatric patients 12 years of age and older with advanced solid tumours expressing a NTRK gene fusion, and who have received a prior NTRK inhibitor, or have not received a prior NTRK inhibitor and treatment options not targeting NTRK provide limited clinical benefit, or have been exhausted. The European Commission (EC), which has the authority to approve medicines for the European Union (EU), will now review the CHMP recommendation. The final EC decision is expected in January 2025.

Stantment from Bristol Myers Squibb

  • Patients in the EU with ROS1 -positive non-small cell lung cancer and NTRK -positive solid tumours face a great unmet need for new therapies that may improve their outcomes and address or delay the difficult issue of treatment resistance,” said Joseph Fiore, vice president, global program lead, repotrectinib, Bristol Myers Squibb. 
  • We look forward to the EC’s upcoming decision and to potentially bringing this next-generation treatment to patients with tumours harbouring ROS1 or NTRK fusions in the EU.

The TRIDENT-1 & CARE Trials

  • The positive opinion is based on results from the TRIDENT-1 and CARE trials, in which repotrectinib demonstrated clinically meaningful response rates in patients across ROS1 -positive NSCLC and NTRK -positive solid tumour cohorts, both as an initial targeted treatment or after progression on a prior targeted treatment. 
  • Durability of response was robust and intracranial responses were observed in both settings, as well as in patients whose tumours harbour common resistance mutations. 
  • The safety profile of repotrectinib was well characterized and generally manageable with routine standard-of-care treatments. 
  • The study remains ongoing to assess long-term outcomes and additional endpoints across patient populations with ROS1 -positive advanced NSCLC and NTRK -positive advanced solid tumours.

FDA Approval for Augtyro

  • In November 2023 the US Food and Drug Administration approved Augtyro (repotrectinib) for the treatment of adult patients with locally advanced or metastatic ROS1 -positive NSCLC. 
  • In June 2024 the US Food and Drug Administration approved Augtyro for the treatment of patients with NTRK-positive locally advanced or metastatic solid tumours.

Thanks to the volunteers- Bristol Myers Squibb thanks the patients and investigators involved in the TRIDENT-1 and CARE clinical trials.

About the Trial: TRIDENT-1

  • TRIDENT-1 is a global, multicenter, single-arm, open-label, multi-cohort phase 1/2 clinical trial evaluating the safety, tolerability, pharmacokinetics and anti-tumour activity of repotrectinib in patients with advanced solid tumours, including non-small cell lung cancer (NSCLC). 
  • Phase 1/2 includes patients with locally advanced or metastatic solid tumours harbouring ROS1 and NTRK fusions. 
  • Additional analyses of the trial are still being conducted; asymptomatic central nervous system (CNS) metastases are allowed. 
  • The trial excludes patients with symptomatic brain metastases, among other exclusion criteria. 
  • Phase 1 of the trial included the dose escalation that determined the recommended phase 2 dose.

About Phase 2 Trial

  • Phase 2 of the trial has a primary endpoint of overall response rate (ORR). 
  • Key secondary endpoints include duration of response (DOR) according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) as assessed by Blinded Independent Central Review (BICR), progression-free survival (PFS), and intracranial response in six distinct expansion cohorts, including tyrosine kinase inhibitor (TKI)-naïve and TKI-pretreated patients with ROS1 -positive locally advanced or metastatic NSCLC and NTRK -positive locally advanced or metastatic solid tumours.

CARE Trial

  • CARE is a phase 1/2 open-label, safety, tolerability, pharmacokinetics and anti-tumour activity clinical trial evaluating repotrectinib in paediatric and young adult patients with locally advanced or metastatic solid tumors harbouring ALK, ROS1 or NTRK1-3 gene alterations.
  • About the phase I

- Phase 1 of the study aims to evaluate the safety and tolerability at different dose levels. 

- Phase 1 of the trial has primary endpoints of dose limiting toxicities (DLTs) and paediatric recommended phase 2 dose (RP2D). 

- Secondary endpoints include overall response rate (ORR), clinical benefit rate (CBR), time to response (TTR), duration of response (DOR) and intracranial ORR (IC-ORR). 

- Patients less than 12 years of age will initially be enrolled in phase 1 to determine the RP2D for this age group.

Phase II Enrollment

  • Once the paediatric RP2D is determined, patients less than 12 years of age may be enrolled into phase 2 of the study. 
  • Patients ages 12 to 25 years will be directly enrolled into phase 2 concurrent with phase 1 enrollment. 
  • Phase 2 of the study will seek to demonstrate the efficacy and anti-tumour activity of repotrectinib in paediatric and young adult patients. 
  • The primary endpoint of phase 2 is ORR and secondary endpoints include CBR, TTR, DOR, IC-ORR, progression-free survival (PFS), central nervous system PFS (CNS-PFS) and overall survival (OS).

About Lung Cancer

  • Lung cancer is the leading cause of cancer deaths in the United States. The two main types of lung cancer are non-small cell and small cell. 
  • Non-small cell lung cancer (NSCLC) represents up to 85% of diagnoses. 
  • Survival rates vary depending on the stage and type of the cancer when diagnosed. 
  • ROS1 fusions are rare and occur in about 1-2% of patients with NSCLC. 
  • With a median age of 50, patients with tumours that are ROS1-positive tend to be younger than the average lung cancer patient, more often female than male and may have little to no smoking history. 
  • ROS1 -positive lung cancer tends to be aggressive and can often spread to the brain. 
  • ROS1 tyrosine kinase inhibitor (TKI) therapy is the current standard of care for patients with a tumour harbouring this gene alteration.

About Neurotrophic Tropomyosin Receptor Kinase

  • Neurotrophic tropomyosin receptor kinase (NTRK) are a family of receptors involved in neural development. 
  • An NTRK gene fusion is an alteration that occurs when a piece of the chromosome containing the NTRK gene breaks off and joins with a gene on another chromosome. 
  • These fusions lead to abnormal proteins, which may cause cancer cells to grow. 
  • While NTRK gene fusions are rare in patients with solid tumours, testing for NTRK gene fusions allows for the identification of patients who may benefit from TRK inhibitor therapy.

About Bristol Myers Squibb

  • Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. 
  • The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. 
  • Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. 
  • Deep understanding of causal human biology, cutting-edge capabilities and differentiated research programs uniquely position the company to approach cancer from every angle.

Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

About the Drug: Repotrectinib

  • Repotrectinib (TPX-0005, BMS-986472) is a next-generation tyrosine kinase inhibitor (TKI) targeting ROS1- or NTRK -positive advanced solid tumours, including non-small cell lung cancer (NSCLC), where there remain significant unmet medical needs for patients. 
  • Repotrectinib was designed to improve durability of response and with favourable properties for human brain penetration to enhance intracranial activity. 
  • It is being studied in a registrational phase 1/2 trial primarily in adults and a Phase 1/2 trial in paediatric patients.

Repotrectinib: Approvals

  • In June 2017, repotrectinib was granted an Orphan Drug designation by the U.S. Food and Drug Administration (FDA). 
  • Since then, repotrectinib has demonstrated clinically meaningful results and was granted three Breakthrough Therapy Designations (BTDs) by the FDA for the treatment of patients with: 

- ROS1 -positive metastatic NSCLC who have not been treated with a ROS1 TKI; 
- ROS1 -positive metastatic NSCLC who have been previously treated with one ROS1 TKI and who have not received prior platinum-based chemotherapy; 
- and advanced solid tumours that have an NTRK gene fusion who have progressed following treatment with one or two prior tropomyosin receptor kinase (TRK) TKIs (with or without prior chemotherapy) and have no satisfactory alternative treatments.

Repotrectinib: Previously Approvals

  • Repotrectinib was also previously granted four fast-track designations in patients with: 

- ROS1 -positive advanced NSCLC who have been treated with disease progression following one prior line of platinum-based chemotherapy and one prior line of a ROS1 TKI; 
- ROS1 -positive advanced NSCLC who have not been treated with a ROS1 TKI; 
- ROS1 -positive advanced NSCLC who have been previously treated with one ROS1 TKI and who have not received prior platinum-based chemotherapy; and 
- advanced solid tumours that have an NTRK gene fusion who have progressed following treatment with at least one prior line of chemotherapy and one or two prior TRK TKIs and have no satisfactory alternative treatments.

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