Dataset Information

Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1).

ABSTRACT: Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer.Significance: Gene fusions of NTRK1/2/3, ROS1, and ALK (encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease. Cancer Discov; 7(4); 400-9. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 339.

SUBMITTER: Drilon A

PROVIDER: S-EPMC5380583 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1).

Drilon Alexander A Siena Salvatore S Ou Sai-Hong Ignatius SI Patel Manish M Ahn Myung Ju MJ Lee Jeeyun J Bauer Todd M TM Farago Anna F AF Wheler Jennifer J JJ Liu Stephen V SV Doebele Robert R Giannetta Laura L Cerea Giulio G Marrapese Giovanna G Schirru Michele M Amatu Alessio A Bencardino Katia K Palmeri Laura L Sartore-Bianchi Andrea A Vanzulli Angelo A Cresta Sara S Damian Silvia S Duca Matteo M Ardini Elena E Li Gang G Christiansen Jason J Kowalski Karey K Johnson Ann D AD Patel Rupal R Luo David D Chow-Maneval Edna E Hornby Zachary Z Multani Pratik S PS Shaw Alice T AT De Braud Filippo G FG

Cancer discovery 20170209 4

Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring <i>NTRK1/2/3, ROS1</i>, or <i>ALK</i> gene fusions, naïve to prior TKI treatment targeting the specific gene, and who wer ...[more]

PMID: 28183697

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Project description:Abstract The STARTRK-NG (Studies of Tumor Alterations Responsive to Targeting Receptor Kinases - Next Generation) trial is a Phase 1/1b study of entrectinib in pediatric patients with cancer, including primary brain tumors, neuroblastoma, and other non-neuroblastoma, extracranial solid tumors harboring NTRK, ROS1, or ALK gene fusions (NCT02650401). Entrectinib is a potent oral, CNS-penetrant, inhibitor of the tyrosine kinases TRKA/B/C (encoded by the genes NTRK1/2/3, respectively), ROS1, and ALK with IC50s < 2?nM (biochemical kinase assay). Overall, gene fusions are rare in the cancer population (<3%); however, they have been seen in over 40 solid tumor histologies, including non-small cell lung cancer, salivary gland cancers, soft tissue sarcomas and glioneuronal tumors. A survey of two pediatric cancer databases, St. Jude pediatric cancer database (PeCan; total n=1,604) and the University of Michigan database (Peds-MiOncoSeq; total n=91), identified malignancies with gene fusions in all three NTRK genes, including infantile fibrosarcoma, juvenile breast cancer, mesoblastic nephroma, intrinsic pontine gliomas, acute leukemias and anaplastic lymphoma. Previously, we reported an objective response rate of 79% was seen in 24 tyrosine kinase inhibitor-naïve patients with solid tumors harboring NTRK, ROS1, or ALK gene fusions, who were treated at doses consistent with the RP2D (Drilon et al, AACR 2016). The most common (>10% incidence) treatment-related adverse events have been fatigue/asthenia, dysgeusia, paresthesia, nausea, myalgia, diarrhea, dizziness, arthralgia, vomiting, and constipation; importantly, there has been no evidence of cumulative toxicity. In addition, we have treated a 20-month-old boy presenting with infantile fibrosarcoma metastatic to the brain, which harbored an ETV6-NTRK3 fusion. Tumor restaging following 1 month of therapy showed a significant tumor regression of CNS metastases accompanied by significant clinical improvement. Together, these data provide compelling evidence to identify pediatric patients harboring NTRK, ROS1, or ALK fusions for enrollment in the STARTRK-NG trial.

Dataset Information

Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1).

Publications

Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1).

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