New Drug Shows Enduring Efficacy Against ROS1+ Non-Small Cell Lung Cancer

Augtyro (repotrectinib), a next-generation tyrosine kinase inhibitor (TKI) drug, displayed swift and long-lasting efficacy against a certain type of lung cancer, according to the results of a long-term trial published today in the New England Journal of Medicine.

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Non-small cell lung cancer (NSCLC) represents the most common type of lung cancer. In about 2% of cases, a mutation called ROS1 fusion occurs. It’s a genetic anomaly that contributes to the cancer’s development and aggressiveness.

Such ROS1-positive (ROS1+) cases require more targeted therapy than other types of NSCLC. Currently, healthcare practitioners use a specific class of drugs known as ROS1 tyrosine kinase inhibitors (TKIs). This class consists of two “early-generation” TKIs: Xalkori (crizotinib) and Rozlytrek (entrectinib).

However, these early-generation TKIs have two main limitations. The main problem is drug resistance, with over 50% of those treated eventually developing resistance and disease progression. Also, this type of lung cancer tends to spread to the brain—an area of the body that early-generation TKIs cannot penetrate well.

Ultimately, gaps in effective options for patients with ROS1+ NSCLC drove the development of a new, next-generation TKI: repotrectinib. The oral drug became FDA-approved on November 15, 2023, under the brand Augtyro (Turning Point Therapeutic/Bristol Myers Squibb).

Augtyro is indicated for locally advanced or metastatic ROS1+ NSCLC. This medication has two unique features: a binding site designed to act on NSCLC cells with or without fusion mutations, as well as a molecular structure for improved intracranial activity.

The approval was based on the TRIDENT-1 study, a combination Phase 1–2 trial designed to establish dosing parameters, safety expectations, and efficacy results for repotrectinib in individuals with NSCLC. The data collected in Phase 1 helped to determine the dosing regimen for Phase 2, in which a total of 426 patients received 160 milligrams (mg) once daily for two weeks, followed by 160 mg twice daily. The Phase 2 study design was longer-term, looking at the participants’ duration of response based on follow-up scans, progression-free survival, and safety.

In this trial, Augtyro was effective in treating NSCLC patients with ROS1 fusion and its antitumor activity was long-lasting. Of those without prior TKI treatment, 79% of participants responded well to Augtyro. The median duration of response was 34.1 months, and the median progression-free survival was 35.7 months. The response was quick, with a median time to respond of 1.8 months.

Augtyro also proved effective in participants who previously took an early-generation ROS1 TKI, with 38% experiencing a response. The median duration of response in this group was 14.8 months, with a median progression-free survival of 9 months. Of the patients with a confirmed mutation representing resistance to early-generation TKI, 59% responded to Augtyro.

The results also reflected the drug’s intracranial action. In patients with known brain metastasis at baseline, 83% of those who hadn't received a ROS1 TKI before and 60% of those who had previously received a ROS1 TKI had an intracranial response lasting at least 12 months.

The most common side effects were mild, including dizziness (58% of participants), taste changes (50%), and numbness/tingling (30%). Only 3% of participants discontinued the trial due to adverse events.

The trial was funded by Turning Point Therapeutics, which was acquired by Bristol Myers Squibb.