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G.J. Weiss



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    MO07 - NSCLC - Targeted Therapies II (ID 114)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO07.06 - Updated results of a first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies (ID 2400)

      16:15 - 17:45  |  Author(s): G.J. Weiss

      • Abstract
      • Presentation
      • Slides

      Background
      AP26113 is a novel tyrosine kinase inhibitor (TKI) that exhibits pan-ALK inhibitory activity against all 9 clinically-identified crizotinib-resistant mutants, including the L1196M gatekeeper, in preclinical experiments. AP26113 also inhibits ROS1 and selectively inhibits mutant EGFR (EGFRm) in preclinical experiments, including the T790M resistance mutation, without affecting the native receptor.

      Methods
      We report data from the dose finding component (3+3 design) of a phase 1/2 open-label, multicenter study in patients with advanced malignancies (except leukemia) refractory to available therapies or for whom no standard treatment exists. Dosing was once daily (QD) or twice daily.

      Results
      As of 17 April 2013, 55 patients were enrolled: 30mg (daily dose) n=3, 60mg n=3, 90mg n=8, 120 mg n=15, 180mg n=15, 240mg n=9, 300mg n=2; 62% female, median age 58 yrs; diagnoses: non-small cell lung cancer (NSCLC, n=47), other (n=8). 33 patients discontinued: 22 disease progression, 6 adverse event (AE), 4 deaths (2 possibly related: sudden death, hypoxia), 1 withdrawal by subject. The most common AEs included fatigue (40%), nausea (36%), and diarrhea (33%), which were generally grade 1/2 in severity. The most common grade 3/4 AE was pneumonia (5%). Two patients experienced dose limiting toxicities: grade 3 ALT increase in 1 patient (240mg QD); grade 4 dyspnea and grade 3 hypoxia in 1 patient (300mg QD). Twenty-eight patients had ALK+ history (24 NSCLC, 4 other). Among 24 evaluable ALK+ patients, 15 responded. Responses were observed in 2/4 (50%) ALK+ TKI-naïve patients and 13/17 (76%) ALK+ patients with prior crizotinib therapy and no other ALK inhibitor exposure. Among ALK+ NSCLC patients with prior crizotinib only, 12/16 (75%) responded. The longest response is 40+ weeks (ongoing). 4 of 5 ALK+ patients with untreated or progressing CNS lesions at baseline and with follow-up scans had evidence of radiographic improvement in CNS, including 1 patient resistant to crizotinib and LDK378 (overall response = stable disease). CNS lesion improvements in all 4 patients are ongoing, with durations ranging from 15+ to 28+ weeks. Twenty patients had EGFRm history (19 NSCLC, 1 SCLC); 18 had ≥1 prior EGFR TKI. Of 18 evaluable EGFRm patients, 1 patient (prior erlotinib) responded at 120mg QD (duration 26+ weeks, ongoing), 7 patients had stable disease, including 4 with T790M by history (1 ongoing at 240mg QD, duration 16+ weeks). The maximum tolerated dose has not been defined; however, based on safety, efficacy, and pharmacokinetics, the recommended phase 2 dose (RP2D) is 180mg QD. Updated data will be presented.

      Conclusion
      AP26113 has promising anti-tumor activity in patients with ALK+ NSCLC and other ALK+ tumors, with initial evidence of activity in EGFRm patients, and is generally well tolerated. Five phase 2 cohorts are enrolling at the RP2D (180mg QD): 1) ALK inhibitor-naïve ALK+ NSCLC, 2) crizotinib-resistant ALK+ NSCLC, 3) single EGFR TKI-resistant NSCLC with documented T790M, 4) other tumors with AP26113 targets, 5) crizotinib-naïve or –resistant ALK+ NSCLC with active CNS metastases. Further phase 1 testing at 240mg QD will occur in EGFRm patients with documented T790M. NCT01449461

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-049 - TSR-011: A Potent Inhibitor of ALK Including Crizotinib-Resistant Mutations in Phase 1-2 Development for ALK+ NSCLC (ID 3466)

      09:30 - 16:30  |  Author(s): G.J. Weiss

      • Abstract

      Background
      Significant progress has been made in the identification of subsets of non-small cell lung cancer (NSCLC) driven by tyrosine kinase gene fusions (including gene fusions of ALK, RET, ROS1 and NTRK1). Despite approval of crizotinib for ALK+ NSCLC there are still significant challenges and high unmet need to develop new agents with durable efficacy against these kinase gene fusions that initiate NSCLCs. In order to address limitations of crizotinib, and to provide treatment option with increased activity against crizotinib resistance mutations and amplified EML4-ALK, TSR-011, a potent, small molecule, second generation ALK inhibitor is undergoing clinical evaluation. TSR-011 was designed using X-ray structure based drug design, and hence has high affinity for the ALK kinase domain (Kd = 0.36 nanomolar, [nM]). TSR-011 inhibits wild type, recombinant ALK kinase activity with an IC50 value of 0.7 nM and exhibits sustained potent inhibition of EML4-ALK-dependent tumor growth in mice. ALK amplification and mutations that are important drivers of tumor cell growth or crizotinib resistance are inhibited by TSR-011 at low nM (IC50 values of 0.1 to 2.2 nM) concentrations. TSR-011 is a similarly potent inhibitor of recombinant TRK kinases including suppressing proliferation of a NTRK1-rearranged colorectal cancer cell line in vitro. Collectively, the selective and potent activity of TSR-011 against ALK, and clinically observed crizotinib resistance mutations, coupled with pharmacologic properties that predict a low clearance, minimal risk for drug interactions, wide distribution and long half life, make TSR-011 a promising 2[nd] generation ALK inhibitor.

      Methods
      A Phase 1-2a dose escalation and cohort expansion study is underway to evaluate safety, tolerability, PK, and preliminary efficacy of TSR-011. Phase 1 is evaluating unselected patients with advanced solid tumors and lymphomas. The recommended Phase 2 dose will be evaluated in Phase 2a in patients required to have ALK+ tumors (defined by immunohistochemistry or fluorescent in-situ hybridization) including those with NSCLC progressing on, or naïve to, ALK inhibitor therapy.

      Results
      As of June 2013, patients have been enrolled at oral doses between 30 and 480 mg. Pharmacokinetic parameters have been dose responsive and human drug exposures in excess of that associated with efficacy in murine xenograft models are maintained for the entire dosing interval. Two of the first five patients have SD. A patient with EML4-ALK+ NSCLC with metastatic pericardial thickening and symptomatic disease, who progressed on crizotinib showed clinical improvement in symptoms and thinning of the pericardium by 6 weeks of treatment and continues on study.

      Conclusion
      Based on tight binding to ALK, potency at inhibiting enzymatic activity, as well as activity against crizotinib resistant mutations and early clinical data, TSR-011 is a promising agent for both ALK-dependent and crizotinib resistant NSCLC.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-009 - Paradoxical increase in Ki67 with neoadjuvant chemotherapy in NSCLC (ID 1143)

      09:30 - 16:30  |  Author(s): G.J. Weiss

      • Abstract

      Background
      Neoadjuvant chemotherapy is used to help downstage cancer, and is widely used in locally-advanced breast cancer. Studies of Ki67 proliferation index in breast cancer have been fairly extensively evaluated. Comparison of core and surgical specimens in breast cancers without exposure to chemo- or radiotherapy revealed technical variation of up to 20% in the Ki67 index score. In non-small cell lung cancer (NSCLC), however, little is known about the association of rate of change of Ki67 after neoadjuvant chemotherapy with radiographic response and clinical outcomes. We surveyed NSCLC from patients treated with neoadjuvant chemotherapy.

      Methods
      NSCLC patients treated with neoadjuvant chemotherapy were identified from 3 Hungarian hospitals and 1 community hospital in the United States. Matched pre-chemotherapy and post-surgical resection formalin-fixed, paraffin-embedded (FFPE) tumor specimens were collected and the Ki67 index was scored under an IRB exemption. We set an absolute difference of 20% between pre-chemotherapy and post-resection Ki67 scores as “meaningful” to avoid possible technical variation reported in the literature. Radiographic response to neoadjuvant chemotherapy by RECIST 1.0 criteria was also measured. Fisher’s exact test was used to measure the relationship between gender, histology, and type of chemo with “meaningful” Ki67 index. Logistic regression was used to test the relationship between Ki67 index decline rate and outcome subgroup (response/no response). Decline rate was defined as a ratio of decrease of Ki67 to its level at baseline.

      Results
      63 matched cases were identified. 46 cases were analyzable for pre-chemotherapy and post-operative Ki67, and chemotherapy regimen; 40 cases also had response criteria by RECIST. Of the 46 cases, the median patient age was 59 years (range 40-77), 23 were men, and 30 of 34 had a smoking history. There were 24 adenocarcinomas and 22 squamous cell carcinomas. Stages I, II, III, and IV were 2, 9, 31, and 4; respectively. All but two patients received a platinum-doublet, with 24 containing gemcitabine. 5 patients also received neoadjuvant radiotherapy. The mean Ki67 index scores were 35% (range 1-100%) pre-chemotherapy and 32% (0-100%) post-resection. 9 patients (19.6%) had a paradoxical “meaningful” increase in Ki67 index after neoadjuvant chemotherapy. Of the 40 patients with RECIST response data, there was 1 complete response, 34 partial responses, 4 stable diseases, and 1 disease progression. There were no statistically significant differences between gender, histology subtype, or type of platinum doublet administered associated with this paradoxical increase. There was no statistically significant difference in Ki67 decline rate between responders and nonresponders.

      Conclusion
      In this cohort of patients, there was a paradoxical “meaningful” increase in Ki67 index after neoadjuvant chemotherapy in ~20% of patients, without a clear association between histology or platinum doublet administered. For patients receiving neoadjuvant chemotherapy, the Ki67 index decline rate was not associated with radiographic response. Approximately 1/5 of NSCLC may have selection of tumor cells for a higher proliferative index when undergoing neoadjuvant platinum-based chemotherapy. The effect of this on progression-free and overall survival is being evaluated.