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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

Partial response to entrectinib. Horizontal (A) and coronal (B) images of the chest at day -7 (baseline scan), day 26 (C, D), and day 155 (E, F) on entrectinib.
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Figure 2: Partial response to entrectinib. Horizontal (A) and coronal (B) images of the chest at day -7 (baseline scan), day 26 (C, D), and day 155 (E, F) on entrectinib.

Mentions: Restaging CT scans at 26 days demonstrated RECIST partial response of -47% (Figure 2 A–D). There was resolution of the prior right-sided pleural effusion, marked interval re-expansion of the left upper and lower lobes, and partial resolution of the previous diffuse consolidative opacity in the left lung. There was decreased ground glass and septal thickening of the tumor in other areas of the left upper lobe, thought to represent improvement of lymphangitic spread of disease. There was decreased pleural thickening on the left. In the mediastinum, there was significant interval regression of previous bulky bilateral lymphadenopathy. In the abdomen, there was significant improvement of previous para-aortic lymphadenopathy. There was increased sclerosis of previously visualized bone metastases, consistent with treatment response. The left-sided chest wall mass was smaller and flatter on exam, and the satellite nodules were no longer palpable. The radiographic response was confirmed and ongoing in subsequent scans. At day 155, restaging scans demonstrated further tumor reduction, -77% compared to baseline (Figure 2 E, F). There was ongoing improvement of the left lower lobe consolidation and ongoing decreased size of mediastinal lymph nodes. The previous left chest wall mass was no longer palpable or visible on scans. He had no new sites of disease involvement.


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)

Partial response to entrectinib. Horizontal (A) and coronal (B) images of the chest at day -7 (baseline scan), day 26 (C, D), and day 155 (E, F) on entrectinib.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Partial response to entrectinib. Horizontal (A) and coronal (B) images of the chest at day -7 (baseline scan), day 26 (C, D), and day 155 (E, F) on entrectinib.
Mentions: Restaging CT scans at 26 days demonstrated RECIST partial response of -47% (Figure 2 A–D). There was resolution of the prior right-sided pleural effusion, marked interval re-expansion of the left upper and lower lobes, and partial resolution of the previous diffuse consolidative opacity in the left lung. There was decreased ground glass and septal thickening of the tumor in other areas of the left upper lobe, thought to represent improvement of lymphangitic spread of disease. There was decreased pleural thickening on the left. In the mediastinum, there was significant interval regression of previous bulky bilateral lymphadenopathy. In the abdomen, there was significant improvement of previous para-aortic lymphadenopathy. There was increased sclerosis of previously visualized bone metastases, consistent with treatment response. The left-sided chest wall mass was smaller and flatter on exam, and the satellite nodules were no longer palpable. The radiographic response was confirmed and ongoing in subsequent scans. At day 155, restaging scans demonstrated further tumor reduction, -77% compared to baseline (Figure 2 E, F). There was ongoing improvement of the left lower lobe consolidation and ongoing decreased size of mediastinal lymph nodes. The previous left chest wall mass was no longer palpable or visible on scans. He had no new sites of disease involvement.

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