FDA Approves Entrectinib for ROS1+ NSCLC and NTRK+ Solid Tumors


The FDA has approved entrectinib for the treatment of adult patients with <em>ROS1</em>-positive metastatic non&ndash;small cell lung cancer. An accelerated approval was also granted to entrectinib for the treatment of adult and adolescent patients with solid tumors harboring an <em>NTRK </em>gene fusion and who have no alternative, effective therapies available.

The FDA has approved entrectinib (Rozlytrek) for the treatment of adult patients withROS1-positive metastatic non—small cell lung cancer (NSCLC). An accelerated approval was also granted to entrectinib for the treatment of adult and adolescent patients with solid tumors harboring anNTRKgene fusion and who have no alternative effective therapies available.1

These 2 indications are based on the results of pooled data from the phase II STARTRK-2 trial, the phase I STARTRK-1 trial, and the phase I ALKA-372-001 trial, as well as data from the phase I/II STARTRK-NG trial. Together these studies demonstrate the efficacy for entrectinib across a variety of solid tumor types.

&ldquo;We are in an exciting era of innovation in cancer treatment as we continue to see development in tissue agnostic therapies, which have the potential to transform cancer treatment. We&rsquo;re seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine,&rdquo; FDA Acting Commissioner Ned Sharpless, MD, said in a press release. &ldquo;Using the FDA&rsquo;s expedited review pathways, including breakthrough therapy designation and accelerated approval process, we&rsquo;re supporting this innovation in precision oncology drug development and the evolution of more targeted and effective treatments for cancer patients. We remain committed to encouraging the advancement of more targeted innovations in oncology treatment and across disease types based on our growing understanding of the underlying biology of diseases.&rdquo;

In the integrated analysis from the phase II STARTRK-2 trial, the phase I STARTRK-1 trial, and the phase I ALKA-372-001 trial, 54 patients with solid tumors harboringNTRKgene fusions were analyzed and demonstrated an overall response rate (ORR) of 57.4% and a median duration of response (DOR) of 10.4 months.2

STARTRK-2 is an international, multicenter, open-label, basket trial that enrolled patients with solid tumors harboring anNTRK1/2/3,ROS1, orALKgene fusion. STARTRK-1 is a multicenter, open-label, dose-escalation trial that evaluated a daily continuous dosing schedule of entrectinib in patients with solid tumors withNTRK1/2/3,ROS1,orALKgene fusions in the United States and South Korea. Investigators evaluated the safety and tolerability of entrectinib via a standard dose escalation and determined the recommended phase II dose of entrectinib to be 400 mg/m2daily. And the ALKA-372-001 trial is a multicenter, open-label, dose-escalation trial that valuated an intermittent and continuous entrectinib dosing schedule in patients in Italy with advanced or metastatic solid tumors with TRKA/B/C,ROS1,orALKgene fusions.

The trials included patients with 10 tumor types and more than 19 histopathologies, including breast cancer, cholangiocarcinoma, colorectal cancer, gynecological cancer, neuroendocrine tumors, NSCLC, salivary gland cancer, pancreatic cancer, sarcoma, and thyroid cancer. Many of the patients also had central nervous system (CNS) metastases at baseline. The median age across the trials was 57.5 and approximately 60% of the patient population were women. More than 40% of the patients had received &ge;2 prior lines of therapy, and 37% had previously untreated cancers.

Results from the integrated analysis showed that the intracranial ORR was 54.5%, with more than one-quarter of these patients achieving a complete response.

The responses were also consistent in several subgroup analyses, including CNS metastases at baseline (50.0%, n = 12) versus none (59.5%, n = 42); andNTRKgene type—NTRK1(59.1%, n = 22),NTRK2(0%, n = 1), andNTRK3(58.1%, n = 31). Furthermore, the median progression-free survival (PFS) was 11.2 months and the median overall survival (OS) was 20.9 months.

The most commonly reported adverse events reported with entrectinib were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, pain, anemia, cognitive disorders, increased weight, vomiting, cough, blood creatinine increase, arthralgia, pyrexia, and myalgia.

The studies also included data for 53 patients withROS1-activating gene fusions. Among the patients with locally advanced or metastaticROS1-positive NSCLC, the ORR was 77.4% with a median DOR of 24.6 months, and the intracranial ORR was 55.0%.

Also contributing to the supporting data were results from the STARTRK-NG trial, a dose-escalation and expansion study of entrectinib in pediatric and adolescent patients with no curative first-line treatment option, recurrent or refractory extracranial solid tumors or primary CNS tumors with or withoutNTRK,ROS1,orALKfusions.

In findings presented at the 2019 ASCO Annual Meeting, 100% of the pediatric patients with CNS and solid tumors that harbored anNTRK1/2/3,ROS1, orALKgene fusion or mutation achieved a response to treatment with entrectinib.3One complete response was observed in a patient with CNS tumors and anETV6-NTRK3gene fusion, a second was observed in a patient with no CNS tumors and aDCTN1-ALKgene fusion, and a third in a patient with neuroblastoma harboring anALKF1174L mutation.

&ldquo;Today&rsquo;s approval includes an indication for pediatric patients, 12 years of age and older, who haveNTRKfusion—positive tumors by relying on efficacy information obtained primarily in adults. The FDA continues to encourage the inclusion of adolescents in clinical trials. Traditionally, clinical development of new cancer drugs in pediatric populations is not started until development is well underway in adults, and often not until after approval of an adult indication,&rdquo; Richard Pazdur, MD, director of the FDA&rsquo;s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA&rsquo;s Center for Drug Evaluation and Research, said in the press release. &ldquo;Efficacy in adolescents was derived from adult data and safety was demonstrated in 30 pediatric patients.&rdquo;

Previously, entrectinib had received priority review, breakthrough therapy, and orphan drug designations from the FDA.

This accelerated approval marks the FDA&rsquo;s third tissue-agnostic cancer drug approval based on a biomarker observed across different tumor types. The prior tissue-agnostic approvals were for pembrolizumab (Keytruda) for tumors with microsatellite instability—high or mismatch repair deficient tumors and for larotrectinib (Vitrakvi) for the treatment of tumors postitive for anNTRKgene fusion.


  1. FDA approves third oncology drug that targets a key genetic driver of cancer, rather than a specific type of tumor [press release]. FDA website. Posted August 15, 2019. https://bit.ly/2TDORX1. Accessed August 15, 2019.
  2. Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA17.
  3. Robinson GW, Gajjar AJ, Gauvain KM, et al. Phase 1/1B trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system (CNS) tumors.J Clin Oncol.2019;37(suppl; abstr 10009). doi: 10.1200/JCO.2019.37.15_suppl.10009.
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