Repotrectinib Demonstrates Durable Activity in NTRK Fusion-Positive Solid Tumors with Promising Outcomes in TKI-Pretreated Patients
核心洞察
Repotrectinib achieved a 59% confirmed response rate in TKI-naive patients with NTRK fusion-positive solid tumors (搜索), with 85% of responders maintaining their response for at least 24 months.
In TKI-pretreated patients, repotrectinib demonstrated a 48% confirmed response rate with a median duration of response of 9.8 months, marking the first trial to show clinical efficacy in this population.
The drug showed intracranial activity and maintained responses regardless of tumor type, NTRK (搜索) gene, or presence of resistance mutations, with mostly low-grade adverse events.
Repotrectinib (Augtyro) has demonstrated enduring clinical activity in patients with NTRK fusion-positive solid tumors (搜索), including those previously treated with tyrosine kinase inhibitors (TKIs), according to updated findings from the phase 1/2 TRIDENT-1 trial published in Nature Medicine. The results represent the first demonstration of clinical efficacy in TKI-pretreated patients with NTRK (搜索) fusion-positive tumors.
Efficacy in Treatment-Naive Patients
Among 51 patients with no prior TKI therapy, repotrectinib achieved a confirmed response rate of 59% (95% CI, 44%-72%) after a median follow-up of 25.7 months. The responses included complete responses in 16% of patients and partial responses in 43%. Notably, the median duration of response was not evaluable, with approximately 85% (95% CI, 70%-99%) of patients with a response sustaining their response for a minimum of 24 months.
The median progression-free survival in the TKI-naive cohort reached 30.3 months (95% CI, 9.0-NE), with an estimated 24-month PFS rate of 60% (95% CI, 46%-74%). The estimated overall survival rate at 24 months was 68% (95% CI, 54%-83%).
Breakthrough in TKI-Pretreated Population
In a significant clinical advancement, repotrectinib showed substantial activity in 69 patients previously treated with TKIs, with a median follow-up of 21.3 months. This cohort achieved confirmed responses in 48% (95% CI, 36%-60%) of patients, including complete responses in 3% and partial responses in 45%. The median time to first response was 1.9 months, and the median duration of response was 9.8 months (95% CI, 7.4-13.0).
Among TKI-pretreated patients, 42% (95% CI, 24%-59%) of responders sustained their responses for 12 months or longer. The median PFS was 7.4 months (95% CI, 3.9-9.7), with an estimated 12-month PFS rate of 26% (95% CI, 14%-37%). The median overall survival reached 18.6 months (95% CI, 11.6-25.3).
Activity Against Resistance Mutations
The trial demonstrated repotrectinib's ability to overcome resistance mechanisms that limit current TRK inhibitors. Among the 69 TKI-pretreated patients, 30 (43%) had NTRK (搜索) solvent front mutations at baseline. Of these patients with resistance mutations, 16 (53%; 95% CI: 34%-72%) achieved confirmed responses, with a median duration of response of 8.6 months and median PFS of 7.4 months.
"Repotrectinib, a next-generation TKI, showed durable clinical activity in adult patients with [NTRK (搜索) fusion-positive] solid tumors, including in patients with previous TKI treatment, with or without NTRK solvent front mutations, across multiple NTRK genes and fusion partners and in patients with or without intracranial disease," wrote lead study author Benjamin Besse, MD, PhD, director of Clinical Research at the Gustave Roussy Institute (搜索).
Intracranial Activity
Repotrectinib demonstrated notable intracranial activity, addressing a critical unmet need in NTRK (搜索) fusion-positive cancers. Among patients with measurable intracranial disease at baseline, intracranial responses occurred in 2 of 3 patients in the TKI-naive cohort and 4 of 6 patients in the TKI-pretreated group. The intracranial duration of response ranged from 17.5 to 24.0 months in TKI-naive patients and 5.5 to 10.6 months in TKI-pretreated patients.
For patients without intracranial disease at baseline, the intracranial PFS rates were 87% at 24 months for TKI-naive patients and 67% at 12 months for those with prior TKI therapy.
Safety Profile
The safety analysis included 144 patients with NTRK (搜索) fusion-positive disease, showing that any-grade treatment-emergent adverse effects occurred in 99% of patients, with treatment-related adverse events in 97%. However, grade 3 or higher treatment-related adverse events affected only 34% of the population.
The most common adverse events included dizziness (63%), dysgeusia (56%), and constipation (41%). Treatment-related adverse events led to treatment discontinuation in only 3% of patients, dose reduction in 44%, and dose interruption in 42%. Notably, no patients discontinued treatment due to dizziness, the most common side effect.
Diverse Tumor Types
The trial enrolled patients with 18 different NTRK (搜索) fusion-positive tumor types. Non-small cell lung cancer (搜索) was the most common at 53% in TKI-naive patients and 25% in TKI-pretreated patients, followed by thyroid cancer (搜索) (12% and 10%), salivary gland cancer (搜索) (10% and 17%), and soft tissue sarcoma (搜索) (6% and 14%). Responses were observed across all tumor types, NTRK genes, and fusion partners.
Regulatory Approval
Based on these findings, the FDA granted accelerated approval to repotrectinib in June 2024 for patients 12 years and older with NTRK fusion-positive solid tumors (搜索). The approval represents a significant advancement for patients with these rare cancers, particularly those who have exhausted other TKI options.
The TRIDENT-1 trial continues to enroll patients, with ongoing assessment of long-term efficacy and safety outcomes. The study's single-arm design and the rarity of NTRK (搜索) fusion-positive tumors present limitations, but the consistent responses across diverse tumor types and treatment histories support repotrectinib's broad therapeutic potential in this patient population.