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Robert C. Doebele



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    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA14.02 - Entrectinib in Patients with ROS1-Positive NSCLC or NTRK Fusion-Positive Solid Tumors with CNS Metastases (Now Available) (ID 1631)

      15:45 - 17:15  |  Author(s): Robert C. Doebele

      • Abstract
      • Presentation
      • Slides

      Background

      Entrectinib potently inhibits kinases encoded by NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated analysis data (31 May 2018 data cut-off) from three Phase 1/2 entrectinib trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]) for a large cohort of adult patients with NTRK fusion-positive solid tumors (NTRK+) or ROS1 fusion-positive NSCLC (ROS1+), with baseline CNS metastases.

      Method

      Patients had locally advanced/metastatic NTRK+ solid tumors or ROS1+ NSCLC by nucleic acid-based assays confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were performed at baseline, week 4, and then every 8 weeks by blinded independent central review (RECIST v1.1). Primary endpoints were overall response rate (ORR), duration of response (DOR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy in patients with CNS metastases, safety.

      Result

      Most patients were treated first-line or after one line of prior therapy; baseline characteristics relating to measurable CNS metastases for patients with NTRK+ solid tumors and ROS1+ NSCLC are presented (Table). Intracranial outcomes for the NTRK+ solid tumors (n=54; 18% NSCLC) and ROS1+ NSCLC (n=53) efficacy evaluable populations are reported (Table). Durability of treatment effect and potential delayed progression in the CNS was observed; time to CNS progression was 17.0 months (95% CI: 14.3–NE) for NTRK+ solid tumor patients and NE (95% CI: 15.1–NE) for ROS1+ NSCLC. In the subset of patients with NTRK+ NSCLC (n=10), 6 patients had CNS metastases at baseline (by BICR); IC-ORR was 66.7% (4/6), 2 CR; IC-DOR was NE. In both the NTRK+ and ROS1+ populations, entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2.

      Conclusion

      Entrectinib induced clinically meaningful durable responses in patients with NTRK+ solid tumors or ROS1+ NSCLC with CNS disease at baseline.

      Funding: This study was funded by F. Hoffmann-La Roche

      table.jpg

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 3
    • Now Available
    • 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): Robert C. Doebele

      • 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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      P1.01-83 - Comparative Efficacy Analysis Between Entrectinib Trial and Crizotinib Real-World ROS1 Fusion-Positive (ROS1+) NSCLC Patients (ID 2215)

      09:45 - 18:00  |  Presenting Author(s): Robert C. Doebele

      • Abstract

      Background

      Entrectinib is an oral tyrosine kinase inhibitor for ROS1 fusion-positive (ROS1+) NSCLC. Three phase 1/2 single-arm studies showed entrectinib efficacy in this population (Doebele WCLC 2018). Due to the rarity of ROS1+ patients generating direct comparative evidence in prospective randomized trials is difficult. We identified a retrospective real-world cohort of ROS1+ NSCLC patients from electronic health records (EHR), to compare crizotinib, the current standard of care, to entrectinib as reported in clinical trials

      Method

      Crizotinib-treated patients with advanced ROS1+ NSCLC diagnosed 1 Jan 2011 to 30 Jun 2018, were identified with technology-enabled abstraction in the Flatiron Health EHR-derived database (>2.1 million cancer patients from US oncology practice). Entrectinib trial inclusion/exclusion criteria were applied to match the crizotinib cohort as closely as possible. Primary endpoint: time to treatment discontinuation (TTD), adapted from Gong (ASCO 2018); real-world progression-free survival (rwPFS; physician/scan report) and overall survival (OS) were secondary outcomes. Time-to-event analyses used Kaplan-Meier survival curves and Cox proportional hazard models on propensity score weighted populations; age, gender, race/ethnicity, smoking status, brain metastasis and previous lines of therapy were prognostic factors.

      Result

      We analyzed 53 entrectinib and 69 crizotinib ROS1+ NSCLC patients. Median weighted TTD: entrectinib, 14.6 months (95% CI: 8.3–23.8); crizotinib, 8.8 months (95% CI: 8.2–9.9). When rwPFS from crizotinib was compared to trial PFS, entrectinib had longer PFS vs crizotinib (weighted HR: 0.44; 95% CI: 0.27–0.74). Median OS with entrectinib was not reached (median follow-up: 15.5 months); weighted median OS with crizotinib was 18.5 months (95% CI: 15.1–19.9). Findings were consistent across multiple sensitivity analyses.

      Conclusion

      Entrectinib was associated with longer TTD and PFS in ROS1+ NSCLC patients vs a matched real-world crizotinib population. Control populations derived from real-world cohorts can supplement evidence from clinical trials in settings where new standards of care are needed, but where only limited data are available and randomization is not feasible.

      Funding: This study was funded by F. Hoffmann-La Roche

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      P1.01-87 - Acquired Resistance Mechanisms and Clinical Outcomes for Patients with Epidermal Growth Factor Receptor (EGFR) Positive Non-Small Cell Lung Cancer (NSCLC) Treated with Osimertinib (Now Available) (ID 2960)

      09:45 - 18:00  |  Author(s): Robert C. Doebele

      • Abstract
      • Slides

      Background

      Osimertinib is a 3rd generation TKI approved for stage IV EGFR+ NSCLC in the first line or post-progression with T790M. The spectrum of osimertinib resistance mutations and clinical outcomes post-osimertinib progression are not well described.

      Method

      Single-center retrospective review of patients with stage IV EGFR+ NSCLC treated with osimertinib was conducted. Resistance mutations were determined via tissue biopsy or circulating tumor DNA (Guardant) prior to and at time of progression on osimertinib. PFS was calculated using Kaplan-Meier method. PFS1 is start of osimertinib to radiographic progression. PFS2 is start of next therapy after osimertinib to next radiographic progression.

      Result

      We identified 95 patients with stage IV EGFR+ lung adenocarcinoma treated with osimertinib detected via NGS (56/95), real-time PCR (29/95), Sanger sequencing (8/95), and other techniques (2/95). Most patients were female (63/95) and never smokers (72/95). Osimertinib resistance and post-progression patterns are shown in Table 1. Potentially targetable mutations were found in 55% (26/47) samples and 14% (6/47) samples had oncogenes targetable with available TKIs. TP53 mutations prior to osimertinib did not significantly influence PFS (36 weeks vs 39 weeks; p = 0.13). MET amplification was only seen in the setting of undetectable T790M or in patients who received first line osimertinib. Median PFS1 for 1st line EGFR TKI (n=17), 2nd line EGFR TKI (n=41), 3rd or greater line EGFR TKI (n=29) was 36, 45 and 39 weeks respectively (p=0.268) with median follow up of 59, 81, and 64 weeks. 10 patients received locally ablative radiotherapy for oligoprogressive disease (defined as ≤ 3 progressive sites) and continued osimertinib post-progression with median PFS2 of 49 weeks.

      resistance table.png

      Conclusion

      There is utility to repeat biopsy after progression on osimertinib as targetable oncogenes can be found. Presence of TP53 prior to starting osimertinib did not influence PFS1. Continuing osimertinib and adding radiotherapy for oligoprogressive disease does increase post-progression PFS.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-03 - HLA Affinity for Mutant EGFR Derived Peptides Identifies a Group of Patients with EGFR Driven NSCLC and Favorable Prognosis (ID 965)

      09:45 - 18:00  |  Author(s): Robert C. Doebele

      • Abstract

      Background

      Tumor mutations generate neopeptides with the potential to elicit T cell responses. Most commonly, passenger mutations are involved in this process, whereas driver mutations are restricted by the HLA genotype. Here, we hypothesized that peptides derived from mutant EGFR with ability to be presented by the host HLA molecules might elicit T cell responses against EGFR mutation positive tumors.

      Method

      We used the NETMHCpan platform to predict HLA A, B and C alleles that bind to peptides derived from EGFR p.L858R and EGFR p.E746_A750del but not to the closest wild type peptides. We termed the identified alleles as “protective alleles” based on their potential to elicit T cell responses against mutant EGFR. Further, we classified patients with EGFR mutation positive lung adenocarcinoma in the TCGA database with known HLA genotype into having at least one protective allele (“protected” group) or having none of these alleles (“non-protected” group).

      Result

      We identified HLA alleles A*31:01, A*33:01, A*68:01 and B*08:01 as protective for EGFR p.L858R and alleles A*03:01 and A*11:01 as protective for EGFR p.E746_A750del. These alleles with the exception of A*11:01 are found more common in European compared to Asian populations. In the TCGA population, we identified 20 patients with EGFR p.L858R and 14 patients with EGFR p.E746_A750del positive lung adenocarcinoma and complete follow up and HLA data. Among them, 11 classified in the “protected” and 23 in the “non-protected” group. There were no significant differences in the two groups with respect to gender, age or stage at diagnosis. Patients in the “protected” group had longer overall survival (p value=0.0011) and disease-free survival (p value=0.0047) compared to the “non-protected” group. Presence of the same alleles did not affect prognosis in patients from the TCGA with KRAS mutation positive adenocarcinoma. Difference in overall survival remained significant after controlling for stage, gender and age at diagnosis in a Cox proportional hazards model (risk ratio 0.01, 95% CI 0.001-0.34).

      Conclusion

      Here, we present a methodology to identify HLA alleles with the potential to elicit EGFR directed T cell responses against mutant EGFR. Interestingly, the identified alleles are more common in European populations, known to carry less risk for EGFR mutations compared to Asian populations. Presence of such alleles predicts better prognosis in an early stage EGFR mutation positive lung cancer population, consistent with our hypothesis that they might drive adaptive immunity against mutant EGFR.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 6
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-09 - Unveiling Hidden MET-Mediated Primary Alectinib Resistance in ALK-Positive Non-Small Cell Lung Cancer (Now Available) (ID 1989)

      09:45 - 18:00  |  Author(s): Robert C. Doebele

      • Abstract
      • Slides

      Background

      Alectinib is an ALK inhibitor that is currently used for the treatment of ALK-positive NSCLC. This next generation ALK inhibitor was initially used as second-line therapy following resistance to crizotinib. More recently, alectinib has superseded crizotinib, an ALK/ROS1/MET inhibitor, as a first-line therapy due to its superiority in phase III trials. Although patients enjoy durable responses to alectinib, they eventually develop resistance. Here we describe four cases of primary resistance to alectinib in which the patients show little to no response to alectinib when administered as first or second-line therapy.

      Method

      In order to investigate primary resistance to alectinib, tissue was obtained during re-biopsy and subjected to routine clinical genetic analyses including gene fusion detection and genetic mutation analysis using the Archer FusionPlex and VariantPlex assays, respectively. Concurrently, at the time of biopsy, additional fresh tissue was procured for cell line derivation. The primary cell line was then used to assess ALK and other inhibitors’ potency by cell viability assays. Targeted analysis of signaling pathways was performed in the cell lines via western blot analysis and proximity ligation assays to determine resistance mechanisms.

      Result

      We present 4 cases of ALK patients with primary resistance to alectinib when used as either first (n=3) or second-line therapy (n=1). In 3 of the 4 cases, routine clinical resistance testing revealed no additional ALK or non-ALK related genetic abnormalities (e.g.; ALK kinase domain mutations, other oncogenic gain-of-function mutations, or gene amplification). However, examination of targeted gene expression data indicated elevated RNA transcripts of MET alone or combined MET and AXL. Analysis of the cell lines derived from these 4 patients further implicates MET in alectinib resistance alone or together with AXL or ERBB3. Signaling analysis shows that MET provides a prosurvival effect, signaling through the PI3K/AKT pathway. In the case where MET was the sole identified bypass mechanism of alectinib resistance, the patient also rapidly progressed through brigatinib, but a regimen of crizotinib plus brigatinib resulted in rapid tumor shrinkage.

      Conclusion

      Here, we document cases of primary resistance to alectinib therapy using human-derived cell lines to expose novel resistance mechanisms not identified by routine clinical testing. We show that MET is a critical component and serves as a bypass mechanism of alectinib resistance either alone or in combination with AXL or ERBB3. We also demonstrate that crizotinib could overcome MET-mediated ALK resistance in a patient.

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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): Robert C. Doebele

      • 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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      P1.14-25 - Targeting NRG1-Fusions in Lung Adenocarcinoma: Afatinib as a Novel Potential Treatment Strategy (ID 1805)

      09:45 - 18:00  |  Author(s): Robert C. Doebele

      • Abstract
      • Slides

      Background

      Neuregulin 1 (NRG1) gene fusions result in activation of ErbB2-/ErbB3-mediated signaling pathways, and may function as oncogenic drivers. NRG1 fusions have emerged as a potential therapeutic target across multiple tumor types, including non-small-cell lung cancer (NSCLC). Afatinib, a pan-ErbB-family blocker, may be a treatment option for patients with NRG1+ NSCLC, as supported by preclinical evidence and seven published case reports (Table).

      Method

      Here, we report clinico-pathological and molecular characteristics of four new cases of NRG1 fusion-positive lung adenocarcinoma treated with afatinib. Afatinib activity is reported.

      Result

      Case 1 is a 70-year-old, female, never-smoker, diagnosed with pan-wildtype, non-mucinous, adenocarcinoma. She received afatinib in the fifteenth-line setting and experienced a partial response (PR) for 24 months. Following further progression on chemotherapy, NRG1-fusion was identified using NanoString analysis (re-biopsy was performed to find an explanation for afatinib efficacy). The patient was re-challenged with afatinib (best response: PR [3 months]), before switching to atezolizumab (best response: progressive disease).

      Case 2 is a 66-year-old female, never-smoker, diagnosed with metastatic, non-mucinous adenocarcinoma. A CD74-NRG1 fusion was identified by Oncomine™ Comprehensive Assay, and fifth-line afatinib treatment was initiated. She experienced a PR, ongoing after 14 months of treatment.

      Case 3 is a 68-year-old male diagnosed with lung adenocarcinoma. A SDC4-NRG1 fusion was subsequently identified using Next Generation Sequencing and the patient initiated second-line afatinib treatment. He achieved stable disease as best response, lasting for four months.

      Case 4 is a 43-year-old, female, non-smoker, diagnosed with advanced invasive mucinous adenocarcinoma. A CD74-NRG1 fusion was subsequently identified by RNA sequencing and the patient initiated third-line afatinib treatment; PR is ongoing.

      Conclusion

      These findings add to a growing body of evidence suggesting afatinib activity in NRG1-fusion positive NSCLC. Prospective study of a larger cohort of patients with NRG1-fusion positive NSCLC treated with afatinib is warranted to better evaluate this potential activity.

      Patient

      Tumor type

      NRG1 fusion partner

      Best response

      Duration of response (months)

      Reference

      i

      Non-mucinous lung adenocarcinoma

      SLC3A2

      PR

      12

      Gay, et al. J Thoracic Oncol 2017

      ii

      IMA

      CD74

      PR

      10

      Gay, et al. J Thoracic Oncol 2017

      iii

      Non-mucinous lung adenocarcinoma

      SDC4

      PR

      12

      Jones, et al. Ann Oncol 2017

      iv

      IMA

      CD74

      PR

      6.5

      Cheema, et al. J Thoracic Oncol 2017

      v

      IMA

      CD74

      SD

      3

      Drilon, et al. Cancer Discov 2018

      vi

      IMA

      SDC4

      PD

      -

      Drilon, et al. Cancer Discov 2018

      vii

      IMA

      CD74

      PD

      -

      Drilon, et al. Cancer Discov 2018

      IMA, invasive mucinous lung adenocarcinoma; PD, progressive disease; SD, stable disease

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      P1.14-27 - Duration of Targeted Therapy in Advanced NSCLC (aNSCLC) with Drivers Identified by Circulating Tumor DNA (ctDNA) Analysis (ID 953)

      09:45 - 18:00  |  Author(s): Robert C. Doebele

      • Abstract

      Background

      Identifying targetable genomic drivers is critical for optimal first-line treatment planning in aNSCLC. ctDNA testing can aid treatment selection when tissue specimens are inadequate for complete genotyping or when a rapid turnaround time is advantageous. Targeted therapy (TT) outcomes for ctDNA-detected drivers have not been widely reported in the first-line setting given the relatively recent adoption of this technology into clinical practice.

      Method

      We conducted a multicenter retrospective review of patients with aNSCLC who received matched TT following identification of a driver on a validated commercial ctDNA assay (Guardant360). Eligible patients were tested per regular clinical care between March 2014-October 2018 and must not have received a TT prior to ctDNA testing (prior chemotherapy or immunotherapy was permitted). Kaplan-Meier analysis was used to estimate median duration of TT (DTT) for both the first and all subsequent sequential targeted therapies where applicable (e.g. osimertinib following erlotinib). Patients still on TT were censored at last follow-up.

      Result

      76 patients met inclusion criteria. Median age of diagnosis of aNSCLC was 64.5 years (range 31-87y), 67% were female, 74% were never smokers, and 97% had adenocarcinoma histology. 21/76 (28%) patients received chemotherapy (n=17), immunotherapy (5), and/or a biologic (4) prior to receiving TT. 41/76 (54%) patients remain on TT at the time of data analysis, 32 of whom are still on their first TT. 38/41 patients still on TT have at least 6 months follow-up. Treatment outcomes are summarized in Table 1.

      Table 1. Duration of Targeted Therapy

      Driver

      Therapy

      n, total patients/discontinued therapy

      Median (95% CI) DTT in weeks1

      EGFR

      Erlotinib

      Osimertinib

      Afatinib

      Gefitinib

      Any EGFR TKI2

      21 / 19

      23 / 6

      3 / 2

      1 / 1

      48 / 20

      33 (23-54)

      NR

      3, 13, 93*

      63

      86 (48-197)

      ALK fusion

      Alectinib

      Crizotinib

      Any ALK TKI3

      7 / 2

      2 / 2

      9 / 2

      NR

      20, 44

      NR

      BRAF V600E

      Dabrafenib + Trametinib

      10 / 7

      51 (13-88)

      MET exon 14 skipping

      Crizotinib

      Investigational

      3 / 2

      1 / 1

      4, 77, 63*

      14

      ROS1 fusion

      Investigational

      2 / 1

      50, 79*

      ERBB2 exon 20 insertion

      Ado-trastuzumab emtansine

      2 / 1

      46, 14*

      RET fusion

      Investigational

      1 / 1

      47

      1 – individual data rather than median provided for counts <5

      2 – includes 15 patients receiving sequential EGFR TKIs

      3 – includes 3 patients receiving sequential ALK TKIs

      * indicates therapy is ongoing for individual data points

      Abbreviations: NR – not reached; TKI – tyrosine kinase inhibitor

      Conclusion

      This study provides interim data on targeted therapy outcomes for aNSCLC patients with Guardant360-detected drivers treated in everyday clinical practice. Outcomes are in line with what is expected for tissue-detected drivers in the TT naïve setting and this cohort will continue to be followed. Identification of NSCLC driver mutation using well-validated ctDNA assays can be used for clinical decision-making.

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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): Robert C. Doebele

      • 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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      P1.14-58 - A Phase II Study to Evaluate Neoadjuvant Osimertinib for Surgically Resectable, EGFR-Mutant Non-Small Cell Lung Cancer (ID 580)

      09:45 - 18:00  |  Author(s): Robert C. Doebele

      • Abstract
      • Slides

      Background

      The third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is well-tolerated and effective for first-line treatment of metastatic EGFR-mutant non-small cell lung cancer (NSCLC). The efficacy of osimertinib in the treatment of early stage EGFR-mutant NSCLC, however, is unknown, and cytotoxic chemotherapy is considered the standard of care when systemic therapy is necessary for these patients. Neoadjuvant chemotherapy is an established therapeutic modality in locally-advanced NSCLC, in which a major pathologic response is associated with improved survival. Neoadjuvant use of targeted therapies in oncogene-driven NSCLC may offer the dual advantages of increased response rates and of more favorable toxicity profiles compared to cytotoxic chemotherapy, and also provides the opportunity to identify mechanisms underlying tumor cell persistence despite optimal oncogene-targeted therapy.

      Method

      This ongoing phase II, multi-institution study aims to enroll 27 patients with surgically resectable stage I-IIIA EGFR-mutant NSCLC. Patients are treated with one to two months of osimertinib 80 mg orally daily followed by surgical resection. The primary endpoint is major pathologic response (mPR) rate, defined as less than 10% residual viable tumor at surgical resection. Secondary endpoints include safety assessment, unanticipated delays to surgery, surgical complication rate, pathological complete response rate (pCR), unconfirmed objective response rate (ORR), rate of lymph node downstaging, disease-free survival, and overall survival. Tumor biopsies are obtained prior to osimertinib treatment in order to permit comparative correlative studies between pre- and post-osimertinib treated tumors. This includes genomic and transcriptomic analyses, evaluation of tumor immune cell infiltrates, and development of patient-derived model systems for functional validation studies.

      Result

      As of March 2019, five patients with EGFR-mutant NSCLC (2 stage IIIA, 1 stage IB, 2 Stage IA) have been enrolled and treated with osimertinib for an average of 56 days prior to surgical resection. Restaging imaging prior to surgical resection demonstrated an unconfirmed radiographic partial response in three patients (60% ORR) and stable disease in two patients (100% disease control rate). The mPR rate is 20% (1 of 5). No pCR’s were observed. One patient demonstrated lymph node downstaging from N2 to N0. Treatment was well-tolerated without SAEs and all patients proceeded to surgical resection without unscheduled delay or surgical complications. Genomic and immunophenotyping analyses are underway and will be reported.

      Conclusion

      Preliminary data from this phase II study indicates that neoadjuvant osimertinib treatment in surgically-resectable, EGFR-mutant NSCLC is well-tolerated and can induce pathological responses and downstaging of disease prior to surgery.

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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): Robert C. Doebele

      • 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

      +

      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)

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-06 - Detection of ctDNA and Correlation with Tumor Mutation Testing in Early Stage NSCLC (ID 2950)

      10:15 - 18:15  |  Author(s): Robert C. Doebele

      • Abstract

      Background

      In advanced disease, circulating tumor (ctDNA) has proven a viable alternative to tissue based molecular testing to identify patients with lung adenocarcinoma (LUAD) eligible for targeted therapies. ctDNA is under investigation for utility in early cancer detection and non-invasive companion diagnostics to allow for identification of targetable biomarkers in patients who may benefit from neoadjuvant targeted therapy. However, in the early stage cancer setting, ctDNA has been limited by reliance on interrogation of genomic alterations alone resulting in low detection rates (13% stage I, 22% stage II, 40% stage III, Abbosh et al, Nature 2017). Herein, we test the ability of the novel ctDNA-based assay to detect ctDNA in patients with early stage LUAD, and secondarily, to identify targetable oncogenes in these patients.

      Method

      Eligible patients had stage IA-IIIA LUAD deemed surgically resectable. Following consent, plasma samples were collected prior to surgery or neoadjuvant therapy. Circulating free DNA (cfDNA) was analyzed for ctDNA with the LUNAR assay (Guardant Health), which utilizes an integrated genomic and epigenomic ctDNA assessment at a tumor allelic fraction down to 0.01% to report “ctDNA detected” or “ctDNA not detected”. This single blood sample cfDNA assay utilizes a variant filter to distinguish tumor from non-tumor derived cfDNA alterations in the absence of other genomic DNA (e.g. tissue sequencing or peripheral blood mononuclear cells). Molecular analysis of paired FFPE primary tumor specimens was performed using the Illumina TruSight Tumor 26 or ArcherDx VariantPlex Solid Tumor library preparation kits followed by next-generation sequencing (NGS) on the Illumina platform in a CLIA-certified laboratory. Sensitivity for tumor driver mutation detection is evaluated by comparing tumor drivers identified in ctDNA with those identified in corresponding paired primary tumor specimens.

      Result

      We enrolled 31 patients with early stage LUAD who ultimately underwent surgical resection, 29 of whom completed LUNAR testing (19 with stage I, 4 with stage II and 6 with stage IIIA). Analysis of tumor tissue identified a driver mutation in 83% (24/29) of cases (KRAS=11, EGFR=10, MET=3, ALK=1). A genomic cancer-associated mutation was identified in 16%, 25% and 67% in stage I, II, and III, respectively. The LUNAR assay demonstrated 100% specificity for EGFR and KRAS mutations. The incorporation of the epigenomic classifier enhanced pre-operative ctDNA detection to 26% of Stage I, 50% of stage II, and 67% of stage III patients.

      Conclusion

      The majority of patients with early stage LUAD had an identifiable oncogene alteration, consistent with data from advanced disease. Utilizing a plasma only, integrated genomic and epigenomic ctDNA assay demonstrated improved performance over tumor informed approaches. The ctDNA detection rate increased with disease stage, consistent with increased tumor burden. With 100% tissue concordance of EGFR and KRAS alterations identified in ctDNA, ctDNA may prove an option for not only identification of early stage LUAD, but also identifying biomarker positive LUAD eligible for clinical trials utilizing targeted therapy in the neoadjuvant setting.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-88 - Surgical Outcomes of a Multicenter Phase II Trial of Neoadjuvant Atezolizumab in Resectable Stages IB-IIIB NSCLC: Update on LCMC3 Clinical Trial (ID 1817)

      10:15 - 18:15  |  Author(s): Robert C. Doebele

      • Abstract
      • Slides

      Background

      The role of immune checkpoint inhibitors in resectable NSCLC remains undefined. We report the updated safety results of the first multicenter trial assessing neoadjuvant atezolizumab (a PD-L1 inhibitor) for resectable NSCLC.

      Method

      Eligible patients with clinical stage IB-IIIB resectable NSCLC received 2 cycles of neoadjuvant atezolizumab (1200 mg, days 1, 22) followed by surgical resection (day 40±10). Pre- and post-treatment PET/CT, pulmonary function tests (PFT), and bio-specimens were obtained. Adverse events (AE) were recorded according to CTCAEv.4.0. Preoperative treatment-related TRAE (preop-TRAE) and postoperative TRAE (postop-TRAE) defined as AE onset on, or after date of surgery, were analyzed.

      Result

      Follow-up data to post-surgery visit were analyzed for 101 patients out of planned 180: mean age: 64.6 years; male: 47/101(46.5%); current smokers: 23/101(22.8%); non-squamous histology: 66/101(65.3%); and clinical stages IB(10.9%), IIA(15.8%), IIB(27.7%), IIIA(38.6%), and IIIB(6.9%). Two cycles of atezolizumab were not completed in 5/101(5.0%) patients due to grade 1 or 2 AEs. Surgery was not performed in 11/101(10.9%) patients: 5 demonstrated disease progression, and 6 for ‘other’ reasons. 6/101(5.9%) patients were deemed unresectable. Surgery was delayed (outside of 10-day window) in 10/90(11.1%) patients by an average of 11(1-39) days. Two of these delays were due to TRAEs (hypothyroidism and pneumonitis), 3 were patient-elected delays, 2 were surgeon-related, and 3 for ‘other’ reasons. Intraoperative vascular complications occurred in 2/90(2.2%) and extensive hilar fibrosis was noted in 20/90(22.2%) patients. Overall, there was insignificant mean change in the PFTs pre- vs. post-atezolizumab therapy. Only 3/101(3.0%) patients had treatment-related dyspnea, dyspnea on exertion, or pneumonitis.

      Table 1

      Treatment Related Adverse Events

      (TRAE)

      Preoperative TRAE

      (N = 101)

      Postoperative TRAE

      (N = 90)

      All AEs

      Any grade

      55 (54.5%)

      20 (22.2%)

      Grade 1

      29 (28.7%)

      7 (7.8%)

      Grade 2

      24 (23.8%)

      9 (10.0%)

      Grade 3

      2 (2.0%)

      4 (4.4%)

      Grade 4

      0

      0

      Grade 5

      0

      0

      Specific AEs

      Dyspnea

      1 (1.0%; grade 2)

      3 (3.3%; grade 1)

      Dyspnea on exertion

      1 (1.0%; grade 1)

      0

      Myalgia

      4 (4.0%; grade 1 or 2)

      0

      Hyperthyroidism

      3 (3.0%; grade 1 or 2)

      1 (1.1%; grade 1)

      Hypothyroidism

      0

      1 (1.1%; grade 2)

      Pneumonitis

      1 (1.0%; grade 3)

      3 (3.3%; grade 2 or 3)

      Transaminitis (AST or ALT)

      8 (7.9%; grade 1 or 2)

      3 (3.3%; grade 1 or 2)

      Post-atezolizumab Change in Pulmonary Function Tests

      PFT factor

      Mean change (95% Confidence Interval)

      FEV1 (N = 72)

      -0.6% (-2.6% to 1.3%)

      FVC (N = 72)

      0.0% (-1.8% to 1.8%)

      DCLO (N = 64)

      -1.2% (-4.1% to 1.7%)

      Conclusion

      Treatment with neoadjuvant atezolizumab in resectable stage IB-IIIB NSCLC was well tolerated, with minimal delay to surgery, and few treatment associated AEs. This trial continues to accrue and assess MPR, survival, and other long-term endpoints.

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    PL01 - New Questions with Imaginative Answers (ID 88)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • +

      PL01.01 - Tumor-Agnostic Biologically Driven Treatments: An Endless Dream? (Now Available) (ID 3580)

      08:15 - 09:45  |  Presenting Author(s): Robert C. Doebele

      • Abstract
      • Presentation
      • Slides

      Abstract

      The identification of several oncogenes in non-small cell lung cancer (NSCLC) along with the development of cognate, targeted tyrosine kinase inhibitors (TKIs) has revolutionized the treatment approach for patients with this disease. Several oncogene targets have been successfully deployed in other malignancies, including melanoma (BRAF), GIST (KIT), CML (BCR-ABL) and other malignancies. However, until recently, the conventional wisdom has said that targeted therapies will not have similar efficacy for the same class of oncogenes across different tumor histologies. This point of view was likely largely grounded in two perceptions: 1) certain oncogenes are heavily associated with certain tumor histologies (e.g., BCR-ABL in CML or EGFR in NSCLC) and 2) based on the differential activity of BRAF/MEK inhibition in melanoma compared to colorectal cancers (CRC) harboring BRAF V600E mutations. Since then, BRAF +/- MEK inhibition has demonstrated remarkable response rates in NSCLC, anaplastic thyroid cancer, and hairy cell leukemia suggesting that CRC may be the exception rather than the rule. In 2012, we identified the first NTRK1 fusion in NSCLC,1 and while prior reports of NTRK gene fusions existed,2 there were no therapies developed for this oncogene. Preclinical in vitro and in vivo models suggested that ATP-competitive inhibitors had activity irrespective of NTRK1/2/3 gene (TRKA/B/C kinases) and also irrespective of tumor histology.3 Clinical trial data with the two lead TRK inhibitors, larotrectinib4 and entrectinib,5 confirmed both of these preclinical findings of activity in NTRK1/2/3 across tumor histologies, validating the concept of tumor (or tissue) agnostic therapeutic strategies in cancer. Similar to NTRK gene fusions, ALK, ROS1 and RET gene fusions have not only been identified in NSCLC, but also in other tumor histologies. Clinical data suggest similar opportunities for these oncogene targets. For examples, entrectinib generated a robust and durable response in a patient with GOPC-ROS1 fusion melanoma6 and similar responses have been noted in ROS1 fusion IMT.7 Basket clinical trials of ROS1 inhibitors are now ongoing. RET gene fusions are targetable alterations in NSCLC as well as other malignancies, and now improved, highly RET-selective inhibitors under development with encouraging activity.8 NRG1 gene fusions represent another opportunity for a tumor agnostic development. Although first described in NSCLC (specifically, invasive mucinous adenocarcinomas),9 these novel fusion genes that signal via HER2/HER3 heterodimers have been described across numerous tumor types, including pancreatic, ovarian, and other cancers, albeit at a low estimated frequency of 0.2%.10 This low frequency is a common reason cited to not pursue such strategies, but given the immense heterogeneity of cancer it is likely that we will further fragment cancer types based on their underlying biology. Additional tumor agnostic targets include ALK gene fusions, HER2 mutations, EGFR mutations (including exon 20 insertions), FGFR1/2/3 fusions, BRAF fusions, MET (exon 14 skipping, gene amplification, and fusions), and others. Indeed, several KRAS mutant selective inhibitors are under development and may open the flood gates for tumor agnostic trials given the frequency of mutations in this oncogene. Success of tumor agnostic strategies will be dictated by appropriate biomarker selection, which may differ for each tumor types, robust testing methods that capture the majority of oncogenic variants (NRG1 is a good example that is not currently covered on many assays), and implementation of panel-based next generation sequencing applications in more routine practice. While it is likely that we already have the testing capability and even the appropriate drugs to to target these tumor agnostic oncogenes, infrastructure changes at institutions may need to be enacted to allow for clinical trial teams that enroll from many disease types, similar to existing phase I teams. The NSCLC community of oncologists, researchers, pathologists, patient advocates, and commercial partners has had immense success in realizing the dream of precision oncology strategies and can lead the way to distribute the knowledge gained over the last decade in precision oncology strategies.tumor agnostic.png

      References

      1. Vaishnavi A, Capelletti M, Le AT, et al: Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med 19:1469-1472, 2013

      2. Vaishnavi A, Le AT, Doebele RC: TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 5:25-34, 2015

      3. Doebele RC, Davis LE, Vaishnavi A, et al: An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer Discov 5:1049-57, 2015

      4. Drilon A, Laetsch TW, Kummar S, et al: Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 378:731-739, 2018

      5. Drilon A, Siena S, Ou SI, et al: Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov 7:400-409, 2017

      6. Couts KL, McCoach CE, Murphy D, et al: Acral Lentiginous Melanoma Harboring a ROS1 Gene Fusion With Clinical Response to Entrectinib. JCO Precision Oncology:1-7, 2017

      7. Lovly CM, Gupta A, Lipson D, et al: Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions. Cancer Discov 4:889-95, 2014

      8. Subbiah V, Gainor JF, Rahal R, et al: Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discov 8:836-849, 2018

      9. Fernandez-Cuesta L, Plenker D, Osada H, et al: CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov 4:415-22, 2014

      10. Jonna S, Feldman RA, Swensen J, et al: Detection of NRG1 Gene Fusions in Solid Tumors. Clin Cancer Res, 2019

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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
    • +

      PL02.10 - Discussant - PL02.08, PL02.09 (Now Available) (ID 3914)

      08:00 - 10:15  |  Presenting Author(s): Robert C. Doebele

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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