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S.N. Waqar



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    MA 07 - ALK, ROS and HER2 (ID 673)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 07.02 - Response to Ensartinib in TKI Naïve ALK+ NSCLC Patients (ID 10247)

      15:45 - 17:30  |  Author(s): S.N. Waqar

      • Abstract
      • Presentation
      • Slides

      Background:
      Ensartinib is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1, and SLK. Ensartinib has demonstrated significant anti-tumor activity in both ALK TKI-naïve and crizotinib-resistant NSCLC patients. We report on data from ALK TKI treatment naïve patients.

      Method:
      Pts with advanced solid tumors and ECOG PS 0-1 were treated with ensartinib 225 mg qd on a continuous 28-day schedule. In expansion phase, pts were required to have measurable ALK+ NSCLC with tissue confirmed centrally via FISH or IHC. Asymptomatic brain metastases were allowed. Targeted NGS of cfDNA was performed retrospectively at baseline and on study and compared with tissue results.

      Result:
      As of 01Apr2017, 102 pts enrolled. In the ALK TKI naïve cohort, 15 (8 female, 7 male) ALK+ NSCLC pts treated at doses ≥ 200 mg evaluable for response. 4 pts had received prior chemotherapy. Median age 59 (34-80) yrs, 60% had ECOG PS 1. Partial response (PR) achieved in 13 pts (87%). Six pts had ALK detected via plasma NGS. In two patients who did not respond to ensartinib, tissue was positive via FISH and plasma was negative. Seven patients had insufficient plasma for NGS evaluation. Median PFS in the initial 13 evaluable ALK+ pts was 25.6 mos with the longest being 44+ mos. The PFS for all patients is still maturing. In 3 pts with central nervous system (CNS) target lesions and no prior radiation, 1 had a complete response (CR) and 2 had PR for an ORR of 100%. Most common drug-related AEs (>20% of pts) included rash (54%), nausea (34%), pruritus (26%), vomiting (25%), and fatigue (21%). Most AEs were Grade (G) 1-2. Most common G3 tx-related AE was rash (12 pts).

      Conclusion:
      Ensartinib was well-tolerated and induced responses in ALK TKI naïve ALK+ NSCLC pts, including pts with CNS lesions. Enrollment is ongoing in the phase 3 study of ensartinib vs. crizotinib in ALK TKI naïve NSCLC patients.

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    OA 14 - New Paradigms in Clinical Trials (ID 681)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      OA 14.07 - Progress in Lung Squamous Cell Carcinoma from the Lung-MAP Master Protocol (S1400) Sub-Studies S1400A, S1400B, S1400C and S1400D (ID 9593)

      11:00 - 12:30  |  Author(s): S.N. Waqar

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung-MAP (S1400) is a master umbrella protocol designed to establish genomic screening for previously treated squamous cell lung cancer patients (SqCCA), and independently evaluate targeted therapies with matching biomarkers and alternative therapies (designated non-match therapy) in patients without putative markers. The protocol opened June 16, 2014 with four biomarker-driven sub-studies and one non-match sub-study.

      Method:
      Eligibility stipulated advanced SqCCA, progressing after at least one prior platinum-based chemotherapy, PS 0–2, and EGFR/ALK wild-type. Tumor samples were required and analyzed for gene alterations by FoundationOne NGS assay (Foundation Medicine). The original biomarker and non-match studies were: S1400B evaluating taselisib for PI3K mutations, S1400C evaluating palbociclib for cell cycle gene alterations (CCGA), S1400D evaluating AZD4547 for FGFR mutations, S1400E evaluating rilotumumab and erlotinib for c-MET positive tumors, and S1400A evaluating durvalumab in patients with no matching biomarkers. The original design included randomization to a control arm, but was amended to a single-arm phase 2 design. The primary endpoint for each modified sub-study was response.

      Result:
      As of June 16, 2017 all original sub-studies have been closed to accrual; 1298 patients registered to the screening component of the trial and 486 patients have registered to a sub-study. Two new sub-studies have been launched and are currently accruing. Details of the completed sub-studies are included in the table.

      Sub-study Final Accrual Biomarker prevalence/% of sub-study registrations Closure Date Response to investigational therapy N (%) Status
      S1400A (non-match) Total: 116 Durvalumab: 78 Docetaxel: 38 NA/59% 12/18/15 Docetaxel arm closed: 4/22/15 11 (16%) Administratively closed to enable activation of new non-match study.
      S1400B PI3K Total: 39 taselisib: 31 Docetaxel: 8 8%/9% 12/12/16 Docetaxel arm closed: 12/18/15 1 (4%) Closed at interim futility analysis.
      S1400C (CCGA+) Total: 54 Palbociclib: 37 Docetaxel: 17 19%/15% 09/01/16 Docetaxel arm closed: 12/18/15 2 (6%) Closed at interim futility analysis.
      S1400D (FGFR+) Total: 45 AZD4547: 35 Docetaxel: 10 16%/12% 10/31/16 Docetaxel arm closed: 12/18/15 2 (7%) Closed at interim futility analysis.
      S1400E (MET+) Total: 9 R+E: 4 E: 5 N/A (closed too early) 11/26/2014 N/A Closed d/t discontinuation of development of rilotumumab


      Conclusion:
      Lung-MAP as a master genomic screening protocol has demonstrated feasibility with respect to accrual and evaluation of targeted therapies in lower prevalence patient populations. This dynamic, centralized, single-IRB platform is well positioned to efficiently assess multiple novel therapeutics for advanced SqCCA patients.

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    P3.03 - Chemotherapy/Targeted Therapy (ID 719)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P3.03-007 - LCMC2: Expanded Profiling of Lung Adenocarcinomas Identifies ROS1 and RET Rearrangements and TP53 Mutations as a Negative Prognostic Factor (ID 8338)

      09:30 - 16:00  |  Author(s): S.N. Waqar

      • Abstract
      • Slides

      Background:
      The Lung Cancers Mutation Consortium (LCMC) is a multi-institutional effort where 16 sites identify oncogenic drivers and pool data to assess the impact of targeted therapies in patients with lung adenocarcinomas. We now report the results of the second patient cohort (LCMC2) with an expanded multiplex molecular panel to include RET and ROS1 and tumor suppressors.

      Method:
      904 patients with centrally confirmed stage IV lung adenocarcinomas who were candidates for therapy had at least one of 14 oncogenic drivers assessed in a CLIA-compliant laboratory using genotyping, FISH, massively parallel sequencing (NGS), and immunohistochemistry (IHC) analyses.

      Result:
      Among 423 patients tested for all 14 targets, we found a driver in 65%. Mutated KRAS was found in 31%, sensitizing EGFR in 14%, MET amplification in 5%, ALK rearrangements in 4%, BRAF V600E in 3%, and HER2 in 3%. Rearrangements in RET and ROS1 were each found in 2% (CI 1 to 3%). Using IHC, PTEN loss was found in 8% (CI 6 to 11%) and MET expression in 58% (CI 55 to 61%). Use of targeted therapies in patients with EGFR, HER2, or BRAF mutations, ALK, ROS1, or RET rearrangements, and MET amplification was associated with a gain in overall survival of 1.5 years relative to those with the same drivers not receiving targeted therapy and a gain of 1 year relative to those without an actionable driver. Current and former cigarette smokers derived a survival benefit from targeted therapies similar to never smokers (p=0.975). Among 154 patients who had all drivers assessed and NGS testing in addition, any TP53 mutation was associated with poorer survival among those with EGFR, ALK, or ROS1 (p=0.014). STK11 was detected in 11%, all in patients with KRAS mutations.

      Conclusion:
      Using an expanded testing panel, LCMC2 demonstrates the survival benefit of matching targeted treatments to oncogenic drivers in patients with lung adenocarcinomas, identifies additional prognostic factors, and supports the performance of multiplex molecular testing on specimens from all individuals with lung adenocarcinomas irrespective of clinical characteristics. We detected either MET amplifications or HER2 mutations in 7%, together more than the 4% with ALK. A targeted drug is available in the United States for 35% of patients with lung adenocarcinomas. The routine use of massively parallel sequencing (NGS) detects both targetable drivers and tumor suppressor genes that have significance for therapy selection and prognosis. Supported by Free to Breathe

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