FDA Approves Roche's NTRK Fusion Therapy for Solid Tumors

Key Takeaways

• FDA granted accelerated approval to entrectinib on August 15, 2019 for NTRK fusion-positive solid tumors in patients 12 years and older.
• Integrated analysis of four trials (STARTRK-2, STARTRK-1, ALKA-372-001, STARTRK-NG) demonstrated a 57% overall response rate with durable responses lasting up to 26+ months.
• Common adverse events include fatigue (46%), constipation (46%), and dysgeusia (44%), with most toxicities manageable through dose modification.
• Recommended adult dose is 600 mg orally once daily; pediatric dosing is 300 mg/m² (maximum 600 mg).

What Did the FDA Approve?

The FDA approved entrectinib (marketed as Rozlytrek) under the accelerated approval pathway for two distinct indications. First, for adult and pediatric patients 12 years and older with solid tumors harboring NTRK gene fusions without known acquired resistance mutations, that are metastatic or where surgical resection would cause severe morbidity, and who have progressed following prior treatment or have no satisfactory alternatives. Second, for adults with ROS1-positive metastatic non-small cell lung cancer (NSCLC).

This approval marked Roche's first FDA-approved tumor-agnostic medicine and the first treatment designed to target both ROS1 and NTRK gene fusions that also demonstrates activity in cancers that have spread to the brain, according to Roche's announcement.

Which Clinical Trials Supported the Approval?

The FDA's approval was based on an integrated analysis of data from four clinical trials: STARTRK-2 (NCT02568267), STARTRK-1 (NCT02097810), ALKA-372-001 (EudraCT 2012-000148-88), and STARTRK-NG (NCT02650401). These trials collectively enrolled over 1,000 patients across 15 countries.

For the NTRK fusion-positive indication, the efficacy population included 54 adult and pediatric patients with solid tumors harboring NTRK gene fusions. The most common tumor types in this population were sarcoma, lung cancer, salivary gland tumors, breast cancer, thyroid cancer, and colorectal cancer.

What Were the Efficacy Results?

The FDA-approved label reports the following efficacy data for entrectinib in NTRK fusion-positive solid tumors:

Entrectinib Efficacy in NTRK Fusion-Positive Solid Tumors

Endpoint	Result	95% Confidence Interval
Overall Response Rate (ORR)	57%	43-71
Complete Response	7%	-
Partial Response	50%	-
Responses lasting ≥6 months	68%	-
Responses lasting ≥12 months	45%	-

The duration of response ranged from 2.8 months to 26.0+ months. Responses were observed across 10 different tumor types, demonstrating the tissue-agnostic nature of this targeted therapy.

What Is the Safety Profile?

The safety analysis included 355 patients who received entrectinib across the four clinical trials. The most common adverse reactions occurring in at least 20% of patients are summarized below:

• Fatigue: 46%
• Constipation: 46%
• Dysgeusia (altered taste): 44%
• Edema: 40%
• Dizziness: 38%
• Nausea: 34%
• Diarrhea: 31%
• Dysesthesia: 29%
• Weight gain: 26%
• Vomiting: 23%
• Arthralgia: 22%
• Vision disorders: 21%

Grade 3-4 adverse reactions occurred in 34% of patients. Dose interruptions due to adverse reactions were required in 47% of patients, dose reductions in 27%, and permanent discontinuation in 7%. The most common reasons for dose modification were cognitive adverse reactions, ataxia, and increased weight.

How Is Entrectinib Dosed?

According to the FDA prescribing information, the recommended dosage for adult patients is 600 mg orally once daily. For pediatric patients 12 years and older, the recommended dosage is 300 mg/m² orally once daily, with a maximum dose of 600 mg.

Entrectinib is available as 100 mg and 200 mg capsules. Patients should take the medication once daily with or without food at approximately the same time each day. Treatment should continue until disease progression or unacceptable toxicity.

What Makes This Approval Significant?

Entrectinib represents a significant advancement in precision oncology as a tumor-agnostic therapy. Unlike traditional cancer treatments that target specific tumor types, entrectinib targets the underlying genetic driver—NTRK gene fusions—regardless of where the cancer originated in the body.

Additionally, entrectinib demonstrated the ability to cross the blood-brain barrier and showed activity in patients with central nervous system metastases, a population often excluded from or underserved by existing therapies.

What Should Patients Know About NTRK Testing?

NTRK gene fusions are rare, occurring in less than 1% of most solid tumors but at higher frequencies in certain rare cancers. Testing can be performed using next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), or immunohistochemistry (IHC). NGS is preferred as it can identify the fusion partner and detect other actionable alterations simultaneously.

Patients with advanced solid tumors should discuss comprehensive biomarker testing with their oncologist to determine if they may benefit from entrectinib or other targeted therapies.

Frequently Asked Questions

Primary Sources

1. U.S. Food and Drug Administration. Approval Letter for Rozlytrek (entrectinib). August 15, 2019.
2. U.S. Food and Drug Administration. Rozlytrek (entrectinib) Prescribing Information. August 2019.
3. Roche. FDA approves Roche's Rozlytrek (entrectinib) for people with ROS1-positive, metastatic non-small cell lung cancer and NTRK fusion-positive solid tumours. August 16, 2019.
4. ClinicalTrials.gov. Entrectinib trials in NTRK fusion-positive cancers.