General Information

Rozlytrek (entrectinib) is a kinase inhibitor.

Rozlytrek is specifically indicated for the following:

• the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive. 
• the treatment of adult and pediatric patients 1 month of age and older with solid tumors that:
  • have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation,
  • are metastatic or where surgical resection is likely to result in severe morbidity, and 
  • have either progressed following treatment or have no satisfactory alternative therapy. 

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Rozlytrek is supplied as capsules or pellets for oral administration. Patients should be selected for treatment based on the presence of ROS1 rearrangement(s) or NTRK gene fusion.

Recommended Dosage for ROS1-Positive Non-Small Cell Lung Cancer

• 600 mg orally once daily

Recommended Dosage for NTRK Gene Fusion-Positive Solid Tumors:

• Adults: 600 mg orally once daily.
• Pediatric Patients 12 Years and Older: Recommended dosage is based on body surface area (BSA) as shown:
  • BSA greater than 1.50 m2: 600 mg once daily
  • BSA 1.11 to 1.50 m2: 500 mg once daily
  • BSA 0.91 to 1.10 m2: 400 mg once daily 
• Pediatric patients > 1 month to ≤ 6 months of age: 250 mg/m2 orally once daily. 

Mechanism of Action

Rozlytrek (entrectinib) is an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2, and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK) with IC50 values of 0.1 to 2 nM. Entrectinib also inhibits JAK2 and TNK2 with IC50 values > 5 nM. The major active metabolite of entrectinib, M5, showed similar in vitro activity against TRK, ROS1, and ALK. Fusion proteins that include TRK, ROS1, or ALK kinase domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumor types harboring NTRK, ROS1, and ALK fusion genes.

Side Effects

Adverse effects associated with the use of Rozlytrek may include, but are not limited to, the following:

• fatigue
• constipation
• altered sense of taste (dysgeusia)
• swelling (edema)
• dizziness
• diarrhea
• nausea
• nervous system disorders (dysesthesia)
• shortness of breath (dyspnea)
• muscle pain (myalgia)
• cognitive impairment
• increased weight
• cough
• vomiting
• fever (pyrexia)
• joint pain (arthralgia)
• vision disorders

Clinical Trial Results

The FDA approval of Rozlytrek was based on the integrated analysis of the Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials, and data from the Phase I/II STARTRK-NG study. In the integrated analysis, Rozlytrek was studied in several solid tumor types, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers. In ROS1-positive, metastatic NSCLC, Rozlytrek shrank tumors in 78% of people with the disease (overall response rate [ORR]; N=51) and the duration of response (DoR) ranged from 1.8 to 36.8+ months (N=40 out of 51). Rozlytrek also shrank tumors in more than half of people with NTRK gene fusion-positive, locally advanced or metastatic solid tumors (ORR=57%; N=54), and objective responses were observed across 10 tumor types (DoR ranged from 2.8 to 26.0+ months; N=31 out of 54). Objective responses to Rozlytrek were seen in people with central nervous system (CNS) metastases at baseline.

FDA approval in pediatric infants with NTRK-positive tumors was investigated in 33 pediatric patients who received entrectinib based on body surface area (20 mg to 600 mg orally or via enteral feeding tube once daily) in one of two multicenter, single-arm clinical trials: STARTRK-NG or TAPISTRY. 

The major efficacy outcome measure was overall response rate (ORR), as assessed by Blinded Independent Central Review (BICR) according to RECIST v1.1 for extracranial tumors and Response Assessment in Neuro-Oncology (RANO) for primary central nervous system tumors. An additional efficacy outcome measure was duration of response (DOR). Among the 33 pediatric patients, the ORR was 70% and median DOR was 25.4 months.