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D.M. Jackman



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    MINI 30 - New Kinase Targets (ID 157)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI30.09 - Clinical Response to Entrectinib in a Patient with NTRK1-Rearranged Non-Small Cell Lung Cancer (NSCLC) (ID 2913)

      18:30 - 20:00  |  Author(s): D.M. Jackman

      • Abstract
      • Presentation
      • Slides

      Background:
      Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in less than 1% of NSCLCs. Cell-based assays have demonstrated that NTRK1 rearrangement leads to expression of an oncogenic TrkA fusion protein. While inhibition of TrkA in preclinical models reduces TrkA auto-phosphorylation and cell proliferation, the clinical activity of TrkA inhibitors in NSCLCs harboring an NTRK1 fusion is not known. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor of TrkA, TrkB, TrkC, ROS1, and ALK, with IC50 values for kinase inhibition ≤ 2 nM.

      Methods:
      We used an anchored multiplex polymerase chain reaction (AMP) assay to screen for NTRK1 rearrangements (Zheng et al., Nature Medicine 2014). Among over 663 NSCLC cases screened, we identified one positive case in which the 3’ end of SQSTM1 exon 6 was fused to the 5’ end of NTRK1 exon 10, leading to an SQSTM1-NTRK1 fusion transcript. We enrolled the patient onto the Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). The dose of entrectinib was 400 mg/m[2] (750 mg) once daily. We assessed safety of entrectinib and response to treatment using RECIST 1.1.

      Results:
      The patient is a 46 yo male with a 30 pack year smoking history who was first diagnosed with metastatic NSCLC in November 2013. Prior therapies included carboplatin/pemetrexed, pembrolizumab, docetaxel, and vinorelbine. At the time of study enrollment, the patient had an ECOG performance status of 2 and required supplemental oxygen at a rate of 3 liters per minute by nasal cannula. He reported significant pain and dyspnea due to widely metastatic disease, including a large left hilar mass narrowing the left upper lobe bronchus and obstructing the left lower lobe bronchus, extensive and palpable neck and chest lymphadenopathy, and a palpable expansile left chest wall mass. Staging head CT also revealed numerous (15 to 20) asymptomatic brain metastases measuring up to 1.7 cm that had not been previously treated. The patient was started on entrectinib and tolerated the study medication well, with one adverse event of grade 1 dysgeusia, which resolved after two weeks. Within three weeks of starting treatment, the patient reported resolution of dyspnea and pain, and improvement in energy and appetite. He no longer required supplemental oxygen and all sites of palpable disease had improved or resolved. At four weeks of treatment, restaging CT scans demonstrated a partial response by RECIST of -47%, with significant regression or resolution of lymphadenopathy, reduction in size of the chest wall mass, and marked reexpansion of the left lung. Restaging of the CNS by head CT demonstrated near complete resolution of previously visualized brain metastases.

      Conclusion:
      In a heavily pre-treated patient with NSCLC harboring an NTRK1 gene fusion, entrectinib therapy resulted in rapid clinical improvement and a radiologic partial response at 4 weeks with minimal toxicity. This preliminary report suggests that entrectinib may be an effective therapy for patients with NTRK1-rearranged NSCLC.

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    P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P3.01-023 - A Phase II Trial of AUY922, a Heat Shock Protein 90 (HSP90) Inhibitor, in ALK-Positive Lung Cancer Patients Previously Treated with ALK Inhibitors (ID 1739)

      09:30 - 17:00  |  Author(s): D.M. Jackman

      • Abstract
      • Slides

      Background:
      Anaplastic lymphoma kinase (ALK) fusions are key oncogenic drivers in non-small cell lung cancer (NSCLC) that confer sensitivity to treatment with ALK tyrosine kinase inhibitors (TKIs), such as crizotinib. Despite this activity, ALK-positive patients ultimately develop resistance to ALK TKIs. In preclinical models, ALK fusion proteins are HSP90 clients and remain sensitive to HSP90 inhibition despite acquired resistance to ALK TKIs. We therefore designed a phase II trial of the HSP90 inhibitor AUY922 in patients with previously treated, ALK-positive NSCLC.

      Methods:
      In this single-arm, multicenter, open-label study, we enrolled patients with advanced, ALK-positive NSCLC who had failed at least one prior ALK inhibitor. Key eligibility criteria included ECOG PS 0-2, measurable disease based upon RECIST version 1.1, and presence of an ALK rearrangement by FISH. Participants were treated with AUY922 at a dose of 70 mg/m[2 ]IV once weekly until disease progression, unacceptable toxicity, or death. The primary endpoint was objective response rate (ORR) according to RECIST version 1.1. Key secondary endpoints included safety, progression-free survival (PFS), and disease control rate (DCR). The planned sample size was 20 patients.

      Results:
      Between December 2012 and December 2014, 6 patients were enrolled. Median age was 52.5 years (range 42-54 years). A majority of patients (83%) were female. The median number of prior lines of therapy was 3 (range 2-4). All patients had previously received at least 1 ALK TKI (crizotinib n=5, alectinib n=1), and 2 patients had received a second ALK inhibitor (ceritinib n=2). Most patients (n=4) had received an ALK inhibitor as the last line of therapy prior to enrollment. Among the 6 patients enrolled, no objective responses were observed (ORR 0%). Three patients (50%) had a best response of stable disease (SD), but none remained on therapy beyond 3 months from the time of enrollment (Table). The median PFS was 1.43 months (95% CI 1.3-2.8 months). Common adverse events (AEs) included grade 1-2 diarrhea (83%), vision disorders (50%), fatigue (50%), and constipation (33%). The only treatment-related grade 3 AE was alkaline phosphatase elevation in 1 patient. The study was closed due to poor accrual in December 2012. Table 1

      Patient Best Response RECIST v1.1. Progression-Free Survival (months)
      1 -4.9% 2.80
      2 36.5 0.73
      3 5.1 1.03*
      4 121.9 1.43
      5 11 2.60
      6 69.5 1.30
      * Censored (Discontinued due to toxicity)


      Conclusion:
      Although limited by a small sample size and premature closure, this study suggests that AUY922 is associated with minimal anti-tumor activity in ALK-positive patients previously treated with ALK inhibitors. Combinations of ALK TKIs and HSP90 inhibitors may represent an alternative strategy, and several such studies are now ongoing.

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