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Zofia Piotrowska



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    OA 07 - Biomarker for Lung Cancer (ID 659)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      OA 07.05 - Serial Biopsies in Patients with EGFR-Mutant NSCLC Highlight the Spatial and Temporal Heterogeneity of Resistance Mechanisms (ID 10181)

      16:40 - 16:50  |  Presenting Author(s): Zofia Piotrowska

      • Abstract
      • Presentation
      • Slides

      Background:
      Resistance to EGFR tyrosine kinase inhibitors (TKIs) limits treatment outcomes among patients with EGFR-mutant NSCLC. Resistance mechanisms have previously been conceptualized as binary “positive/negative” variables, but emerging evidence suggests resistant cancers are heterogeneous, and subclones may be appreciated through multiple biopsies.

      Method:
      We retrospectively analyzed 221 EGFR mutant pts at MGH who had >1 biopsy after progression on their initial EGFR inhibitor. Data on acquired resistance (AR) mechanisms observed at each biopsy, adverse events, and treatment were collected.

      Result:
      Among 221 pts with a total of 355 post-AR tissue biopsies, median age was 59 (range, 28-88), 69% were female, 64% had EGFR del19, 33% L858R and 3% other activating mutations. Median number of biopsies per patient was 1 (range, 1-4). Biopsies at first resistance to EGFR TKI showed 61% T790M, 5% MET amplification (amp), 3% SCLC transformation, 2% acquired PIK3CA and 1% acquired BRAF mutations. 83 pts had two biopsies during their post-resistance course; 43/83 (52%) had heterogeneity between biopsy 1 and 2. In particular, 20% “lost” T790M, while 11% “gained” T790M. Among 17 pts who lost T790M, 3 gained a separate resistance mechanism, including MET amp and BRAF V600E. In some cases, synchronous biopsies identified spatial heterogeneity. For example, an osimertinib-resistant patient had a T790M/C797S lung nodule, while a concurrent mediastinal lymph node was wild-type at both loci (both sites retained the activating EGFR mutation). Similarly, another osimertinib-resistant patient with MET amp in a pleural effusion cell block had a lung nodule biopsy which lacked MET amp; the patient was treated with combination EGFR and MET inhibitors with a partial response. Additional details regarding concurrent liquid biopsies, treatment histories and clinical outcomes will be presented.

      Conclusion:
      In this large cohort of EGFR mutant NSCLC patients, we frequently observed variations in resistance mechanisms in patients with > 1 post-AR biopsy. Our data highlights the heterogeneity of resistant cancers and the limitations of a single biopsy in fully capturing the spectrum of resistance mechanisms in each patient. Serial biopsies or non-invasive methods may be required to characterize resistance and identify potential therapeutic targets.

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    OA 09 - EGFR TKI Resistance (ID 663)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA 09.01 - Characterizing the Genomic Landscape of EGFR C797S in Lung Cancer Using ctDNA Next-Generation Sequencing (ID 10213)

      11:00 - 11:10  |  Presenting Author(s): Zofia Piotrowska

      • Abstract
      • Presentation
      • Slides

      Background:
      Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) active in T790M-positive lung cancer. Acquired resistance to osimertinib is driven by EGFR C797S in ~20-30% of cases. Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) can be used to identify resistance mechanisms. The allelic configuration (cis vs. trans) of C797S with respect to T790M has therapeutic implications, but the relative frequency of each and other co-occurring genomic alterations are not well defined in clinical samples.

      Method:
      We queried the Guardant Health database for lung adenocarcinoma patients and an EGFR C797S mutation. All patients had comprehensive ctDNA testing using the Guardant360 NGS assay between June 2015 and June 2017. Cis/trans configuration for T790M and C797S was determined using Integrated Genomics Viewer software.

      Result:
      We identified 50 unique patients with a total of 66 samples which were C797S positive. All had a co-existent EGFR activating mutation (del19 74%, L858R 24%, other 2%). 60/66 (91%) C797S+ samples were also T790M+. In the 6 samples with C797S but without T790M in ctDNA, 4 were from patients who were T790M+ on a prior Guardant360 assay, 1 never had T790M in blood or tissue and developed C797S while on 1[st]-line afatinib, and 1 had no further clinical details available. T790M and C797S were on the same allele (cis configuration) in 44/46 evaluable patients (98%); 1 (2%) was in trans. One sample had two different C797S mutations, one cis and one trans to T790M. 13 C797S+/T790M+ samples (22%) had multiple C797X mutations detected and 12 samples carried other mutations in or adjacent to the EGFR ATP-binding pocket (e.g. L792, F795, G796, etc). The most common non-EGFR mutations co-occurring with C797S were BRAF amplification/mutation (20%), MET amplification (17%), PIK3CA mutation/amplification (15%), CCNE1 amplification 14% and MYC amplification (14%).

      Conclusion:
      Understanding EGFR TKI resistance mechanisms is critical to developing more effective therapies. ctDNA offers a non-invasive method to characterize the resistance landscape. Our data suggests C797S most commonly occurs with T790M in cis (98%), a state associated with resistance to all currently available EGFR TKIs. The trans configuration, which may respond to combined 1[st]/3[rd]-gen EGFR TKIs, is rare (2%). Moreover, C797S is frequently detected along with other resistance mechanisms in ctDNA, underscoring the heterogeneity of resistant cancers. New treatments targeting C797S/T790M are needed, as is a deeper understanding of therapeutic targeting of heterogeneity in resistant cancers.

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    OA 12 - Emerging Genomic Targets (ID 679)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA 12.02 - Final Results of a Phase 2 Study of the hsp90 Inhibitor Luminespib (AUY922) in NSCLC Patients Harboring EGFR Exon 20 Insertions (ID 10182)

      11:10 - 11:20  |  Presenting Author(s): Zofia Piotrowska

      • Abstract
      • Presentation
      • Slides

      Background:
      EGFR exon 20 insertions (ins20) comprise 4-10% of EGFR mutations in NSCLC and are refractory to 1[st]/2[nd] generation EGFR TKIs. No effective targeted therapies exist for patients with EGFR ins20. EGFR is a client protein of the molecular chaperone Heat Shock Protein 90 (hsp90). Here, we present the final results of a phase II investigator-initiated trial to assess the activity of the Hsp90 inhibitor luminespib (AUY922) in NSCLC patients with EGFR ins20 (NCT01854034).

      Method:
      Between 8/2013 and 10/2016, the study enrolled 29 patients with stage IV NSCLC, EGFR ins20 identified on local testing, ECOG PS 0-2, at least one prior line of therapy and no untreated brain metastases. The study was closed on 2/28/17 when the available drug supply was exhausted. Luminespib was given at 70mg/m2 IV weekly. Response was assessed by RECIST 1.1 every 6 weeks; treatment beyond progression was allowed. Dose interruptions and dose reductions were allowed as needed for toxicity management. Primary endpoint was ORR with a target disease control rate (DCR; PR/CR plus SD lasting > 3 mos) of > 20%. Secondary endpoints were PFS, OS, safety and response by EGFR ins20 subtype.

      Result:
      29 patients (18 female/11 male, median age 60 (range, 31-79)) were enrolled. Median number of prior therapies = 1 (range, 1-5.) 4/29 achieved PR and 1 CR (ORR 5/29; 17%). 15 patients had SD and 9 had PD as their best response. mPFS was 2.9 mos (95% CI, 1.4-5.6,) mOS was 13 mos (95% CI, 4.9-19.5.) DCR was 11/29 (38%). Among 19 patients with baseline PS 0-1 and < 2 prior therapies, ORR = 21% and mPFS = 5.1 mos (95% CI, 2.1-11.8.) The most common luminespib-related toxicities were visual changes (22/29; 76%) diarrhea (21/29; 72%) and fatigue (13/29; 45%). Treatment-related grade 3 toxicities included ocular toxicity (1/29; 3%), hypertension (3/29; 10%) and hypophosphatemia (1/29; 3%). All study treatment was stopped on 2/28/17 due to lack of drug availability; 3 patients were on treatment without progression at study termination.

      Conclusion:
      The study met its primary endpoint and suggests that luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of luminespib and other Hsp90 inhibitors in this population is warranted, as are novel systems to continue drug supply for benefitting patients when availability of experimental compounds is limited.

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