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Christine M Lovly



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    EP1.01 - Advanced NSCLC (ID 150)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.01-108 - EGFR Exon 18 Mutations in NSCLC: Frequent Co-Occurrence of Multiple EGFR Mutations and Assessment of Cis/Trans Status (ID 2747)

      08:00 - 18:00  |  Author(s): Christine M Lovly

      • Abstract

      Background

      A subset of EGFR exon 18 (ex18) mutations including G719X are known drivers in NSCLC. However, the sensitivity profile of other ex18 mutations and frequently occurring dual ex18/ex18 and ex18/non-ex18 combinations has not been well described.

      Method

      Hybrid-capture based comprehensive genomic profiling was performed on 46,296 FFPE tissue samples from patients with NSCLC. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA and reported as mut/Mb. Configuration was determined by analyzing sequencing reads that spanned both loci. The number of reads that harbored mutations at one or both positions was tabulated and used to infer cis or trans status. Patient ancestry was determined by single nucleotide polymorphism (SNP) microarray data, ancestry informative markers, and principal component analysis (PCA)..

      Result

      EGFR ex18 mutations (point mutations and indels) were identified in 1.1% (522/46,296) of NSCLCs. The median patient age was 67 years (range 30-96) and 67% of patients were female. This subset was also enriched for patients of East Asian descent when compared to EGFR wildtype NSCLC (17% v 3.9%; p < 0.001), similar to ex19del and L858R populations (19% and 24%, respectively). Median TMB was 4.35 mut/mb (range 0-70). Co-occurring EGFR mutations were identified in 69% (362/522) of cases, including most commonly S768I (20%, 103/522) and L858R (12%,61/522). T790M was detected in 6.1% (32/522) of ex18 cases. Multiple EGFR ex18 mutations occurred in 15% (76/522) of cases including 2 cases with 3 and a single case with 4 such mutations. The most commonly observed missense pairs were E709A/G719S (17/76) and E709A/G719A (16/76). Other combinations of E709X/G719X made up an additional 42% (32/76), with the remaining 14% of cases consisting of rare combinations (n<4 for all). All ex18 mutations in all cases (76/76) were in cis. Preliminary evidence from paired cases and assessment of mutant allele frequencies suggests that ex18 mutations found together in cis arise de novo. Results of in vitro studies to determine the sensitivity of single ex18 mutations as well as common pairs to all generations of EGFR inhibitors will be presented.

      Conclusion
      EGFR ex18 mutations co-occur at a high frequency with both ex18 and non-ex18 EGFR mutations, unlike classic EGFR mutations (L858R, ex19del). Female gender, East Asian ancestry, and low TMB were common in ex18 cases, similar to populations with classic EGFR mutations. In all cases with multiple EGFR ex18 mutations these mutations were always found to occur in cis. Further work to understand the evolution of these co-occurring EGFR mutations and to determine the best therapeutic strategy or strategies for this NSCLC patient population is warranted

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-25 - Real-World Outcomes of Advanced NSCLC Patients with Common and Uncommon/Complex EGFR Mutation Profiles (ID 2387)

      09:45 - 18:00  |  Author(s): Christine M Lovly

      • Abstract

      Background

      In patients with advanced non-small cell lung cancer (aNSCLC) with non-squamous histology, the evaluation of EGFR mutations is standard of care and informs treatment selection. EGFR mutations are well-defined and can be classified into common, uncommon/complex mutation subtypes that are known to have different response rates to approved EGFR tyrosine kinase inhibitors (TKIs).

      Method

      We used data from the nationwide Flatiron Health electronic health record-derived database in this study. Our retrospective cohort included patients diagnosed in the US from Jan-2014 to Mar-2018 who had a positive EGFR test at time of first-line (1L) therapy initiation. Patients with baseline EGFR T790M mutations (n=44) or variants of unknown significance were excluded. Demographics, clinical characteristics, 1L treatment duration, and overall survival outcomes were compared between patients with common (Exon 19 E746-A750 del, Exon 19 del other, or Exon 21 L858R) vs. uncommon/complex EGFR mutations (all other EGFR mutations [i.e. Exon 18 G719X, Exon 20 insertions, Exon 21 L861Q], and/or concomitant mutations [KRAS, BRAF]). Minimum follow-up after initiation of 1L therapy was 4 months.

      Result

      23,321 patients had non-squamous or NOS histology. 1,315 patients had EGFR mutations detected prior to or during 1L treatment. Of those, 1,000 (82% common, 18% uncommon/complex mutations) had 1L EGFR TKI therapy initiated (median age 70 years, 70% women, 57% Caucasian, 47% smokers). In this population, 1L median treatment duration was longer for patients with common mutations than for those with uncommon/complex mutation profiles (11 vs 7 months; p<0.0001). Median overall survival was also affected by mutation status (24 vs 15 months; unadjusted HR 1.6; 95% CI 1.3–2.1; p<0.001). Among 315 patients (59% common, 41% uncommon/complex mutations) who initiated 1L treatment with non-EGFR TKI systemic therapies (median age 68 years, 59% women, 57% Caucasian, 53% smokers), median overall survival also improved with common vs uncommon/complex mutations (30 vs 17 months; unadjusted HR 1.7; 95% CI 1.3–2.4; p<0.001). However, there were no significant differences in median 1L (non-EGFR TKI) treatment duration (4 months common vs 6 months uncommon/complex mutations). Notably, 60% of patients with a common mutation treated with other 1L systemic therapies went on to receive a 2L EGFR TKI.

      Conclusion

      Uncommon/complex mutations were present in over 20% of aNSCLC patients with any EGFR mutations. Increased overall survival and 1L treatment duration with EGFR TKI therapy were observed in patients with common mutation subtypes vs. uncommon/complex mutation subtypes.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-20 - Tarloxotinib as a Novel Therapeutic Strategy for Oncogenic Alterations Across the ErbB Family of Receptors (ID 2607)

      09:45 - 18:00  |  Author(s): Christine M Lovly

      • Abstract

      Background

      The ErbB family of receptors tyrosine kinases (EGFR, HER2, HER3, and HER4) have been implicated in multiple different tumor types. The implementation of comprehensive next generation sequencing has allowed the identification of diverse gene alterations that function as oncogene drivers in these receptors. Some of the non-common gene alterations identified are resistant to marketed EGFR/HER2 inhibitors. Tarloxotinib is a prodrug that generates a potent and irreversible pan-HER inhibitor (tarloxotinib-E) under hypoxic conditions associated with tumors. In this study we evaluated the effect of tarloxotinib on several types of oncogenic mutations and fusions that involve the ErbB family of receptors.

      Method

      cDNAs encoding EGFR kinase domain duplications (EGFR-EGFR), EGFR-RAD51 gene fusion, EGFR-ERBB4, ERBB2-GRB7 and EZR-ERBB4 gene fusion were expressed in Ba/F3 cells. Using spheroid assays we evaluated the proliferation of A172 glioblastoma cell line treated with tarloxotinib, tarloxotinib-E or 1st, 2ndor 3rdgeneration EGFR/HER2 TKIs. We analyze the on target and signaling effects elicited by tarloxotinib-E via immunoblots. Using a nude mice xenograft model of the human derived cell line CUTO17 wi the EGFR exon 20 insertion p.N771_H773dupNPH, we evaluated tumor, tissue and blood drug levels by mass spectrometry and the effect of tarloxotinib on tumor growth.

      Result

      Our results demonstrate that tarloxotinib-E inhibits phosphorylation of EGFR with a kinase duplication and inhibits proliferation in a spheroid invasion assay in A172 cells. In the CUTO17 EGFR exon 20 model, treatment with tarloxotinib inhibited tumor growth. Intratumor levels of tarloxotinib-E were ~20 times higher than skin and ~50 times higher than plasma demonstrating selective tumor conversion of tarloxotinib. Cell growth inhibition (EC50) of novel HER family fusions (EGFR-EGFR, EGFR-RAD51, EGFR-ERBB4, ERRB2-GRB7 and EZR-ERBB4) will be presented.

      Conclusion

      Tarloxotinib is a potent irreversible inhibitor in vitro for cells that harbor oncogenic alterations across the ERBB gene family, including EGFR kinase domain duplications, ErbB fusions and exon-20 insertions. Tarloxotinib is selectively activated in hypoxic tumor regions demonstrating a novel mechanism to generate a therapeutic window and avoid on-target EGFR-related toxicities.

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      P1.14-29 - Disrupting the Paradigm: Partnering with Oncogene-Focused Patient Groups to Propel Research (ID 1498)

      09:45 - 18:00  |  Author(s): Christine M Lovly

      • Abstract
      • Slides

      Background

      Genomic alterations drive more than 60% of adenocarcinoma cases of non-small cell lung cancer (NSCLC). About 20% of cases will have an oncogenic driver (EGFR, ALK, ROS1, BRAF, NTRK, etc.) that can be treated with approved targeted therapy drugs, and more (RET, Exon 20 insertions, etc.) have clinical trial options. Patients and caregivers dealing with these cancers have organized globally into oncogene-focused groups (“Groups”—see Table 1) and are building partnerships that seek to provide support, increase awareness and education, accelerate and fund research, and improve access to effective diagnosis and treatment.

      table 1 oncgene-focused patient and caregiver groups..png

      Method

      We partnered in a variety of ways to accelerate research. While each Group sets its own research priorities, we’ve found successful collaborative research has the following seven characteristics. It includes patients from the start, in all aspects of the project. It addresses questions meaningful to patients. It develops patient-centered measurements. It accommodates patients’ clinical realities. It leverages social media and patient groups. It shares progress with participants frequently. It makes results rapidly and freely available.

      Result

      These methods have enabled the Groups to collaborate successfully with clinicians, researchers, advocacy organizations, and industry to generate ideas for next steps in research for their disease, forge new studies and clinical trials for a specific oncogenic driver, create new patient-derived models of oncogene-driven cancers to study acquired resistance, develop registry-based studies to collect real-world data, and guide patients to clinical trials.

      Conclusion

      Oncogene-focused patient-caregiver groups are creating new paradigms across the research continuum. They have demonstrated that their partnerships with advocacy organizations, clinicians, researchers, and industry, can increase available patient-derived models, patient data, and specimens among geographically distributed, oncogene-driven cancer populations.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-04 - NCI-NRG Oncology ALK PROTOCOL (NRG-LU003): A Biomarker-Driven Protocol for Previously Treated ALK-Positive Non-Squamous NSCLC Patients      (ID 2021)

      10:15 - 18:15  |  Author(s): Christine M Lovly

      • Abstract

      Background

      Currently, the 1stgeneration ALK inhibitor crizotinib and 2ndgeneration ALK inhibitors ceritinib, alectinib and brigatinib are FDA-approved for the treatment of advanced ALK-positive NSCLC. The 3rdgeneration ALK inhibitor lorlatinibrecentlyreceived accelerated approval for patients after failure of a 2ndgeneration inhibitor.

      2ndgeneration ALK inhibitors are widely used in crizotinib-resistant patients and have recently replaced crizotinib as first-line therapy for newly diagnosed patients. There is an urgent need to define the optimal therapy for patients who have become resistant to a second-generation ALK inhibitor. Pre-clinical data and small case series suggest that the presence/absence of ALK resistance mutations or the specigic ALK mutation may serve as a critical biomarker to guide selection of therapy, particularly in the setting of relapse on a 2ndgeneration ALK inhibitor when ALK resistance mutations are more common,

      Method

      NRG-LU003 proposes to study ALK-positive non-squamous NSCLC patients who develop resistance to a second-generation ALK inhibitor, in order to establish a treatment algorithm for these patients based on resistance mechanisms.Patients will undergo tissue biopsy along with blood sampling for cfDNA analysis. One of the aims of the study is to establish the concordance between tissue and liquid biopsies; liquid biopsy may replace tissue biopsy after the first 200 patients enrolled, depending on the concordance and in consultation with CDRH/FDA. Treatments will be selected based on preclinical and clinical data demonstrating activity of treatment particular inhibitor against the specific ALK mutation or resistance mechanism identified. If no ALK resistance mutations are identified, patients will be randomized to receive either a next-generation ALK inhibitor they have not previously received or pemetrexed-based therapy with cisplatin or carboplatin.

      Target accrual is 660 patients and primary objective is to assess whether ALK kinase domain mutations (e.g., G1202/C1156/I1171/L1196/V1180/F1174 mutations) associated with drug resistance are predictive of objective response to subsequent ALK inhibitor therapy, to assess whether subsequent pemetrexed based chemotherapy improves objective response compared to ALK inhibitor therapy for patients with no ALK resistance mutations, and to evaluate objective responses of patients with specific genetic alterations (e.g., ALK L1198F, compound mutations, or high-level MET amplification) treated with crizotinib.

      Mutation

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      G1202, G1202del, G1202R

      lorlatinib

      brigatinib

      C1156Y

      lorlatinib

      alectinib

      brigatinib

      I1171

      lorlatinib

      ceritinib

      brigatinib

      L1196, L1196M

      lorlatinib

      ceritinib

      alectinib

      brigatinib

      ensartinib

      V1180

      lorlatinib

      ceritinib

      brigatinib

      F1174

      lorlatinib

      alectinib

      brigatinib

      Compound mutation

      lorlatinib

      ALK L1198F (alone/ in combination with another ALK mutation)

      crizotinib

      MET amplification

      crizotinib

      No ALK-resistance mutations*

      lorlatinib

      ceritinib

      alectinib

      brigatinib

      ensartinib

      Pemetrexed

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      Cisplatin or Carboplatin

      Result

      "Section not applicable"

      Conclusion

      This study has been approved and is open for enrollment through the National Clinical Trials Network (NCTN).

      This project is supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC) from the National Cancer Institute (NCI)