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).
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 harboringNTRK1/2/3, ROS1, orALKgene 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 withSQSTM1-NTRK1-rearranged lung cancer.Significance:Gene fusions ofNTRK1/2/3, ROS1, andALK(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.
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York. drilona@mskcc.org.
Alexander
A
Drilon
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.|Dipartimento di Oncologia e Emato-Oncologia, Università degli Studi di Milano, Milan, Italy.
Salvatore
S
Siena
Chao Family Comprehensive Cancer Center, University of California, Irvine, California.
Sai-Hong Ignatius
SI
Ou
Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota, Florida.
Manish
M
Patel
Samsung Medical Center, Seoul, Korea.
Myung Ju
MJ
Ahn
Samsung Medical Center, Seoul, Korea.
Jeeyun
J
Lee
Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, Tennessee.
Todd M
TM
Bauer
Massachusetts General Hospital, Boston, Massachusetts.
Anna F
AF
Farago
The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jennifer J
JJ
Wheler
Georgetown Lombardi Comprehensive Cancer Center, Washington, DC.
Stephen V
SV
Liu
University of Colorado Cancer Center, Aurora, Colorado.
Robert
R
Doebele
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Laura
L
Giannetta
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Giulio
G
Cerea
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Giovanna
G
Marrapese
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Michele
M
Schirru
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Alessio
A
Amatu
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Katia
K
Bencardino
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Laura
L
Palmeri
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Andrea
A
Sartore-Bianchi
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.|Dipartimento di Oncologia e Emato-Oncologia, Università degli Studi di Milano, Milan, Italy.
Angelo
A
Vanzulli
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Sara
S
Cresta
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Silvia
S
Damian
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Matteo
M
Duca
Nerviano Medical Sciences s.r.l, Milan, Italy.
Elena
E
Ardini
Ignyta, Inc., San Diego, California.
Gang
G
Li
Ignyta, Inc., San Diego, California.
Jason
J
Christiansen
Ignyta, Inc., San Diego, California.
Karey
K
Kowalski
Ignyta, Inc., San Diego, California.
Ann D
AD
Johnson
Ignyta, Inc., San Diego, California.
Rupal
R
Patel
Ignyta, Inc., San Diego, California.
David
D
Luo
Ignyta, Inc., San Diego, California.
Edna
E
Chow-Maneval
Ignyta, Inc., San Diego, California.
Zachary
Z
Hornby
Ignyta, Inc., San Diego, California.
Pratik S
PS
Multani
Massachusetts General Hospital, Boston, Massachusetts.
Alice T
AT
Shaw
Dipartimento di Oncologia e Emato-Oncologia, Università degli Studi di Milano, Milan, Italy.|Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Filippo G
FG
De Braud
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077547:Crizotinib; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D000069295:Mammary Analogue Secretory Carcinoma / Q000188:drug therapy* / Q000235:genetics; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000235:genetics; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000235:genetics; D020812:Receptor, trkC / Q000037:antagonists & inhibitors / Q000235:genetics; D000071456:Sequestosome-1 Protein / Q000235:genetics
D001549:Benzamides; D007191:Indazoles; D008562:Membrane Glycoproteins; C000611485:NTRK1 protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC; C000591259:tropomyosin-related kinase-B, human; C000607349:entrectinib