FDA Approves ROZLYTREK® for NTRK Positive tumors and ROS1 Positive Non Small Cell Lung Cancer

SUMMARY: The FDA on August 15, 2019, granted accelerated approval to ROZLYTREK® (Entrectinib) for adults and pediatric patients 12 years 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 progressed following treatment or have no satisfactory standard therapy. The FDA on the same day approved ROZLYTREK® for adults with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors are ROS1-positive.

Next-Generation Sequencing (NGS) has enabled the detection of Neurotrophic Tropomyosin Receptor Kinase (NTRK) gene fusions, which was first discovered in Colon cancer in 1982. The three TRK family of Tropomyosin Receptor Kinase (TRK) transmembrane proteins TRK A, TRK B, and TRK C are encoded by Neurotrophic Tropomyosin Receptor Kinase genes NTRK1, NTRK2, and NTRK3, respectively. These Receptor Tyrosine Kinases are expressed in human neuronal tissue and are involved in a variety of signaling events such as cell differentiation, cell survival and apoptosis of peripheral and central neurons. They therefore play an essential role in the physiology of development and function of the nervous system. There are over 50 different partner genes that fuse with NTRK genes. Chromosomal fusion involving NTRK genes arise early in cancer development and remain so as tumors grow and metastasize. Gene fusions involving NTRK genes lead to transcription of chimeric TRK proteins which can confer oncogenic potential by increasing cell proliferation and survival. Early clinical evidence suggests that these gene fusions lead to oncogene addiction regardless of tissue of origin. (Oncogene addiction is the dependency of some cancers on one or a few genes for the maintenance of the malignant phenotype). It is estimated that gene fusions involving NTRK genes occurs in about 0.5% to 1% of many common malignancies and have been identified in a broad range of solid tumor types including Non-Small Cell Lung Cancer (NSCLC), Cholangiocarcinoma, Colorectal, Gynecological, Neuroendocrine, Pancreatic tumors and in more than 90% of certain rare tumor types, such as Salivary gland tumors, a type of juvenile Breast cancer, and infantile Fibrosarcoma.

Approximately 1-2% of lung adenocarcinomas harbor ROS1 gene rearrangements. ROS1 gene is located on chromosome 6q22 (long arm of chromosome 6) and plays an important role in cell growth and development. ROS1 gene fusion with another gene results in a mutated DNA sequence which then produces an abnormal protein responsible for unregulated cell growth and cancer. ROS1 gene rearrangement has been identified as a driver mutation in Non Small Cell Lung Cancer with adenocarcinoma histology. This is more common in nonsmokers or in light smokers (<10 pack years), who are relatively young (average age of 50 years) and thus share similar characteristics with ALK-positive patients. ROS1 mutations have been also been associated with Cholangiocarcinoma (Bile duct cancer) and Glioblastoma multiforme. ROS1 rearrangements are mutually exclusive with other oncogenic mutations found in NSCLC such as EGFR mutations, KRAS mutations and ALK rearrangement. The presence of a ROS1 rearrangement can be detected by Fluorescence In Situ Hybridization (FISH), ImmunoHistoChemistry (IHC), Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and Next Generation-Sequencing.

ROZLYTREK® is a pan-TRK, ROS1 and ALK Tyrosine Kinase Inhibitor (TKI), designed to inhibit the kinase activity of the TRK A/B/C and ROS1 proteins, whose activating fusions drive proliferation in certain types of malignancies. ROZLYTREK® has potent anti-neoplastic activity in various neoplastic conditions, particularly NSCLC, by blocking ROS1 and NTRK kinase activity and may result in the death of cancer cells with ROS1 or NTRK gene fusions.

The FDA approvals were based on results from the integrated analysis of the pivotal 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 pediatric patients. ROZLYTREK®, was studied in several solid tumor types, including NSCLC, Breast cancer, Mammary analogue secretory carcinoma, Cholangiocarcinoma, Colorectal, Gynecological, Neuroendocrine, Salivary gland, Pancreatic, Thyroid cancers and Sarcoma. Patients were enrolled across 15 countries and more than 150 sites, and safety was assessed from an integrated analysis of 355 patients across these four trials. The Primary endpoints included Overall Response Rate (ORR), Duration of Response (DoR) and Secondary endpoints include Progression Free Survival (PFS), Overall Survival (OS) in patients with and without baseline CNS disease, and Safety.

The efficacy of ROZLYTREK® in NTRK gene fusion-positive, locally advanced or metastatic solid tumors was evaluated in 54 adult patients, who received ROZLYTREK® at various doses and schedules in one of three multicenter, single-arm, clinical trials. About 94% of patients received ROZLYTREK® 600 mg orally once daily. The median age was 58 years, about 60% of the patients were women and more than 40% of the patients had received 2 or more prior lines of therapy. Positive NTRK gene fusion status was determined in local laboratories or a central laboratory using nucleic acid-based tests prior to enrollment. The Overall Response Rate as determined by independent review was 57%, and the Duration of Response (DoR) was 6 months or longer for 68% of patients and 12 months or longer for 45% of patients. Objective responses to ROZLYTREK® were seen in people, with CNS metastases at baseline.

The efficacy of ROZLYTREK® in ROS1-positive metastatic NSCLC was evaluated in 51 adult patients who received ROZLYTREK® at various doses and schedules in the same three trials and 90% of patients received ROZLYTREK® 600 mg orally once daily. The Overall Response Rate was 78% and the Duration of Response (DoR) was 12 months or longer for 55% of patients. The most common adverse reactions (20% or more) with ROZLYTREK® were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, arthralgia and vision disorders.

It was concluded that based on this multicenter, pooled analysis of global clinical trials, ROZLYTREK® was well tolerated and induced clinically meaningful, durable systemic responses in patients with NTRK-fusion positive solid tumors, with or without CNS disease. This is the third tissue agnostic cancer therapy (cancer treatment based on a common biomarker across different tumor types rather than the location in the body where the tumor originated) approved by the FDA. The previous tissue agnostic cancer therapies approved by the FDA were KEYTRUDA® (Pembrolizumab) for tumors with MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR) tumors in 2017 and VITRAKVI® (Larotrectinib) for NTRK gene fusion tumors in 2018. Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Demetri GD, Paz-Ares L, Farago AF, et al. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA17.