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)

Alexander Drilon, Salvatore Siena, Sai Hong Ignatius Ou, Manish Patel, Myung Ju Ahn, Jeeyun Lee, Todd M. Bauer, Anna F. Farago, Jennifer J. Wheler, Stephen V. Liu, Robert Doebele, Laura Giannetta, Giulio Cerea, Giovanna Marrapese, Michele Schirru, Alessio Amatu, Katia Bencardino, Laura Palmeri, Andrea Sartore-Bianchi, Angelo VanzulliSara Cresta, Silvia Damian, Matteo Duca, Elena Ardini, Gang Li, Jason Christiansen, Karey Kowalski, Ann D. Johnson, Rupal Patel, David Luo, Edna Chow-Maneval, Zachary Hornby, Pratik S. Multani, Alice T. Shaw, Filippo G. De Braud

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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 languageEnglish
Pages (from-to)400-409
Number of pages10
JournalCancer Discovery
Volume7
Issue number4
DOIs
Publication statusPublished - Apr 1 2017

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Gene Fusion
Safety
Central Nervous System Diseases
Neoplasms
Gene Targeting
Renal Cell Carcinoma
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Colorectal Neoplasms
Melanoma
Lung Neoplasms
Therapeutics
Central Nervous System
entrectinib
Breast Neoplasms

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 journalArticle

Drilon, A, Siena, S, Ou, SHI, Patel, M, Ahn, MJ, Lee, J, Bauer, TM, Farago, AF, Wheler, JJ, Liu, SV, Doebele, R, Giannetta, L, Cerea, G, Marrapese, G, Schirru, M, Amatu, A, Bencardino, K, Palmeri, L, Sartore-Bianchi, A, Vanzulli, A, Cresta, S, Damian, S, Duca, M, Ardini, E, Li, G, Christiansen, J, Kowalski, K, Johnson, AD, Patel, R, Luo, D, Chow-Maneval, E, Hornby, Z, Multani, PS, Shaw, AT & De Braud, FG 2017, '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)', Cancer Discovery, vol. 7, no. 4, pp. 400-409. https://doi.org/10.1158/2159-8290.CD-16-1237
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. / 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). In: Cancer Discovery. 2017 ; Vol. 7, No. 4. pp. 400-409.
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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, na{\"i}ve 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",
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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

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