Limits...
Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer.

Farago AF, Le LP, Zheng Z, Muzikansky A, Drilon A, Patel M, Bauer TM, Liu SV, Ou SH, Jackman D, Costa DB, Multani PS, Li GG, Hornby Z, Chow-Maneval E, Luo D, Lim JE, Iafrate AJ, Shaw AT - J Thorac Oncol (2015)

Bottom Line: We assessed safety and response to treatment.Entrectinib was well tolerated, with no grade 3-4 adverse events.Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases.

View Article: PubMed Central - PubMed

Affiliation: *Department of Medicine, Massachusetts General Hospital, Boston, MA; †Department of Pathology, Massachusetts General Hospital, Boston, MA; ‡Memorial Sloan Kettering Cancer Center, New York, NY; ‖Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota, FL; §Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; ¶Department of Medicine, Georgetown University Medical Center, Washington, DC; #University of California Irving Health, Orange, CA; **Dana-Farber Cancer Institute, Boston, MA; ††Beth Israel Deaconess Medical Center, Boston, MA; and ‡‡Ignyta, Inc., San Diego, CA.

ABSTRACT

Introduction: Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in a subset of non-small cell lung cancers (NSCLCs) and other solid tumor malignancies, leading to expression of an oncogenic TrkA fusion protein. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor, including TrkA. We sought to determine the frequency of NTRK1 rearrangements in NSCLC and to assess the clinical activity of entrectinib.

Methods: We screened 1378 cases of NSCLC using anchored multiplex polymerase chain reaction (AMP). A patient with an NTRK1 gene rearrangement was enrolled onto a Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). We assessed safety and response to treatment.

Results: We identified NTRK1 gene rearrangements at a frequency of 0.1% in this cohort. A patient with stage IV lung adenocrcinoma with an SQSTM1-NTRK1 fusion transcript expression was treated with entrectinib. Entrectinib was well tolerated, with no grade 3-4 adverse events. Within three weeks of starting on treatment, the patient reported resolution of prior dyspnea and pain. Restaging CT scans demonstrated a RECIST partial response (PR) and complete resolution of all brain metastases. This patient has continued on treatment for over 6 months with an ongoing PR.

Conclusions: Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases.

No MeSH data available.


Related in: MedlinePlus

Complete response of brain metastases to entrectinib. (A-C) Baseline head CT scan at day -7 demonstrating metastases (green arrows) in the right thalamus (A), left occipital lobe (B) and left cerebellum (C). (D-I) Restaging head CT scans at day 26 (D-F) and day 155 (G-I) on entrectinib.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4643748&req=5

Figure 3: Complete response of brain metastases to entrectinib. (A-C) Baseline head CT scan at day -7 demonstrating metastases (green arrows) in the right thalamus (A), left occipital lobe (B) and left cerebellum (C). (D-I) Restaging head CT scans at day 26 (D-F) and day 155 (G-I) on entrectinib.

Mentions: The patient also had a complete response of all brain metastases on entrectinib. Fifteen to 20 baseline brain metastases had been identified, the largest of which were in the left occipital region, the right thalamus, and the left cerebellum. These measured up to 1.7 cm in diameter (Figure 3A–C). At day 26, a head CT with contrast demonstrated near resolution of these metastases (Figure 3 D–F), and by day 155 the patient continued to have a complete response of all brain metastases (Figure 3 G–I). To date, the patient has continued on entrectinib for over 6 months with ongoing partial response and current duration of response 4.1 months.


Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer.

Farago AF, Le LP, Zheng Z, Muzikansky A, Drilon A, Patel M, Bauer TM, Liu SV, Ou SH, Jackman D, Costa DB, Multani PS, Li GG, Hornby Z, Chow-Maneval E, Luo D, Lim JE, Iafrate AJ, Shaw AT - J Thorac Oncol (2015)

Complete response of brain metastases to entrectinib. (A-C) Baseline head CT scan at day -7 demonstrating metastases (green arrows) in the right thalamus (A), left occipital lobe (B) and left cerebellum (C). (D-I) Restaging head CT scans at day 26 (D-F) and day 155 (G-I) on entrectinib.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4643748&req=5

Figure 3: Complete response of brain metastases to entrectinib. (A-C) Baseline head CT scan at day -7 demonstrating metastases (green arrows) in the right thalamus (A), left occipital lobe (B) and left cerebellum (C). (D-I) Restaging head CT scans at day 26 (D-F) and day 155 (G-I) on entrectinib.
Mentions: The patient also had a complete response of all brain metastases on entrectinib. Fifteen to 20 baseline brain metastases had been identified, the largest of which were in the left occipital region, the right thalamus, and the left cerebellum. These measured up to 1.7 cm in diameter (Figure 3A–C). At day 26, a head CT with contrast demonstrated near resolution of these metastases (Figure 3 D–F), and by day 155 the patient continued to have a complete response of all brain metastases (Figure 3 G–I). To date, the patient has continued on entrectinib for over 6 months with ongoing partial response and current duration of response 4.1 months.

Bottom Line: We assessed safety and response to treatment.Entrectinib was well tolerated, with no grade 3-4 adverse events.Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases.

View Article: PubMed Central - PubMed

Affiliation: *Department of Medicine, Massachusetts General Hospital, Boston, MA; †Department of Pathology, Massachusetts General Hospital, Boston, MA; ‡Memorial Sloan Kettering Cancer Center, New York, NY; ‖Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota, FL; §Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; ¶Department of Medicine, Georgetown University Medical Center, Washington, DC; #University of California Irving Health, Orange, CA; **Dana-Farber Cancer Institute, Boston, MA; ††Beth Israel Deaconess Medical Center, Boston, MA; and ‡‡Ignyta, Inc., San Diego, CA.

ABSTRACT

Introduction: Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in a subset of non-small cell lung cancers (NSCLCs) and other solid tumor malignancies, leading to expression of an oncogenic TrkA fusion protein. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor, including TrkA. We sought to determine the frequency of NTRK1 rearrangements in NSCLC and to assess the clinical activity of entrectinib.

Methods: We screened 1378 cases of NSCLC using anchored multiplex polymerase chain reaction (AMP). A patient with an NTRK1 gene rearrangement was enrolled onto a Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). We assessed safety and response to treatment.

Results: We identified NTRK1 gene rearrangements at a frequency of 0.1% in this cohort. A patient with stage IV lung adenocrcinoma with an SQSTM1-NTRK1 fusion transcript expression was treated with entrectinib. Entrectinib was well tolerated, with no grade 3-4 adverse events. Within three weeks of starting on treatment, the patient reported resolution of prior dyspnea and pain. Restaging CT scans demonstrated a RECIST partial response (PR) and complete resolution of all brain metastases. This patient has continued on treatment for over 6 months with an ongoing PR.

Conclusions: Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases.

No MeSH data available.


Related in: MedlinePlus