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
| Original language | English |
|---|---|
| Pages (from-to) | 400-409 |
| Number of pages | 10 |
| Journal | Cancer Discovery |
| Volume | 7 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 1 2017 |
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ASJC Scopus subject areas
- Oncology
Cite this
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; Siena, Salvatore; Ou, Sai Hong Ignatius; Patel, Manish; Ahn, Myung Ju; Lee, Jeeyun; Bauer, Todd M.; Farago, Anna F.; Wheler, Jennifer J.; Liu, Stephen V.; Doebele, Robert; Giannetta, Laura; Cerea, Giulio; Marrapese, Giovanna; Schirru, Michele; Amatu, Alessio; Bencardino, Katia; Palmeri, Laura; Sartore-Bianchi, Andrea; Vanzulli, Angelo; Cresta, Sara; Damian, Silvia; Duca, Matteo; Ardini, Elena; Li, Gang; Christiansen, Jason; Kowalski, Karey; Johnson, Ann D.; Patel, Rupal; Luo, David; Chow-Maneval, Edna; Hornby, Zachary; Multani, Pratik S.; Shaw, Alice T.; De Braud, Filippo G.
In: Cancer Discovery, Vol. 7, No. 4, 01.04.2017, p. 400-409.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib
T2 - Combined results from two phase I trials (ALKA-372-001 and STARTRK-1)
AU - Drilon, Alexander
AU - Siena, Salvatore
AU - Ou, Sai Hong Ignatius
AU - Patel, Manish
AU - Ahn, Myung Ju
AU - Lee, Jeeyun
AU - Bauer, Todd M.
AU - Farago, Anna F.
AU - Wheler, Jennifer J.
AU - Liu, Stephen V.
AU - Doebele, Robert
AU - Giannetta, Laura
AU - Cerea, Giulio
AU - Marrapese, Giovanna
AU - Schirru, Michele
AU - Amatu, Alessio
AU - Bencardino, Katia
AU - Palmeri, Laura
AU - Sartore-Bianchi, Andrea
AU - Vanzulli, Angelo
AU - Cresta, Sara
AU - Damian, Silvia
AU - Duca, Matteo
AU - Ardini, Elena
AU - Li, Gang
AU - Christiansen, Jason
AU - Kowalski, Karey
AU - Johnson, Ann D.
AU - Patel, Rupal
AU - Luo, David
AU - Chow-Maneval, Edna
AU - Hornby, Zachary
AU - Multani, Pratik S.
AU - Shaw, Alice T.
AU - De Braud, Filippo G.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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
AB - 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
UR - http://www.scopus.com/inward/record.url?scp=85017161079&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85017161079&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-16-1237
DO - 10.1158/2159-8290.CD-16-1237
M3 - Article
C2 - 28183697
AN - SCOPUS:85017161079
VL - 7
SP - 400
EP - 409
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 4
ER -