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Joel W Neal



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    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)

      14:00 - 15:30  |  Author(s): Joel W Neal

      • Abstract
      • Presentation
      • Slides

      Background

      Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.

      Method

      620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.

      Result

      Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.

      Conclusion

      In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.

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    OA08 - Advanced Models and "Omics" for Therapeutic Development (ID 133)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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      OA08.03 - A Single-Cell Resolution Map of EMT and Drug Resistance States for Evaluating NSCLC Clinical Specimens (Now Available) (ID 2771)

      11:00 - 12:30  |  Author(s): Joel W Neal

      • Abstract
      • Presentation
      • Slides

      Background

      The role of epithelial-mesenchymal transition (EMT) in NSCLC is well reported and has been shown to prime cells for metastasis. EMT can be adopted or reversed (i.e. mesenchymal-epithelial transition, MET) by cells, revealing plasticity that can also lead to drug resistance. Although it is appreciated that EMT is not a binary process of two extremes but instead a spectrum of intermediate states of EMT phenotypes, these are poorly defined at the single-cell proteomic level in NSCLC clinical specimens. Our overall goal was to dynamically capture and characterize EMT-related drug resistance states in lung cancer cells to construct a single-cell resolution state map of clinical applicability.

      Method

      We used mass cytometry (CyTOF) time-course experimentation and novel computational tools to analyze TGFβ and drug treated NSCLC cell lines, as well as NSCLC clinical samples to identify clinically relevant drug resistant EMT and MET states and construct a single-cell resolution proteomic map of phenotypic states.

      Result

      Through TGFβ treatment and withdrawal we resolved previously unrealized EMT and MET states in NSCLC cell lines by analyzing the expression of up to 30 surface and intracellular markers. Using a novel computational tool (TRACER) we also provide evidence that EMT and MET trajectories differ and exert differential drug sensitivity profiles. We used the identified EMT and MET states to construct a NSCLC reference EMT-MET state map, on which we projected NSCLC clinical samples to characterize their phenotypic profile in terms of our in vitro EMT-MET analysis. Finally, we extended our mass cytometry time-course analysis to NSCLC cells that underwent various drug treatments (e.g. Erlotinib, Docetaxel) and subsequent withdrawal to augment our EMT-MET state map with drug resistance phenotypic traits. We found that NSCLC resistant cells displayed through time overlapping morphological and cell signaling features with EMT and MET and were able to rebound from short-term drug-induced effects. These data are currently being used to evaluate EMT-related drug resistant cell states detected in pleural effusions during and after the course of treatment in different NSCLC patient therapy time-points.

      Conclusion

      In summary, we provide a framework that can be extended to phenotypically characterize clinical samples with single-cell resolution in the context of in vitro studies showing differential EMT-MET traits related to drug sensitivity. This sets the foundation for developing tools towards evaluating - at a personalized level – disease status and response to treatment in NSCLC patients.

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    OA11 - Decomplexifying Molecular Targets, Immunotherapy and Treatment Settings in the Real World (ID 137)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Now Available
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      OA11.04 - Discussant - OA11.01, OA11.02, OA11.03 (Now Available) (ID 3769)

      14:00 - 15:30  |  Presenting Author(s): Joel W Neal

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-113 - Phase 1b Trial of Cabozantinib or Cabozantinib Plus Atezolizumab in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 1455)

      09:45 - 18:00  |  Author(s): Joel W Neal

      • Abstract

      Background

      Cabozantinib is an inhibitor of tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, RET, ROS1, and TAM family kinases (Tyro3, AXL, MER). Preclinical and clinical studies suggest that cabozantinib promotes an immune-permissive tumor environment, which may enhance response to immune checkpoint inhibitors (ICIs) such as the anti–PD-L1 mAb atezolizumab. Cabozantinib has demonstrated clinical activity in phase 1/2 studies of advanced NSCLC. Atezolizumab is approved for select patients with advanced NSCLC as monotherapy or as part of a combination regimen. Clinical studies in solid tumors, including NSCLC, indicate that the combination of a VEGF-targeting agent with an ICI may reverse ICI resistance.Here we present the study design of an ongoing phase 1b trial of cabozantinib alone or in combination with atezolizumab that includes cohorts with advanced non-squamous (nsq) NSCLC.

      Method

      This global, phase 1b, open-label trial (COSMIC-021) is evaluating the safety, tolerability, preliminary efficacy, and pharmacokinetics of cabozantinib alone or in combination with atezolizumab (NCT03170960). The study consists of a dose-escalation stage (completed) and an expansion stage. In the expansion stage, 18 cohorts are being enrolled at the recommended expansion dose of cabozantinib (40 mg po qd) + a standard dose of atezolizumab (1200 mg q3w IV), including 3 advanced NSCLC cohorts: (1) nsqNSCLC with prior ICI therapy, (2) nsqNSCLC without prior systemic anticancer therapy for metastatic disease, and (3) EGFR-mutant nsqNSCLC with prior EGFR-targeting therapy. Thirty patients are being enrolled per cohort, with potential for extended enrollment pending Study Oversight Committee review. Two exploratory single-agent cohorts (N=30) are being enrolled to receive a 60-mg dose of cabozantinib, including a cohort of patients with nsqNSCLC who received prior ICI therapy. Patients will continue treatment as long as they experience clinical benefit per investigator or until unacceptable toxicity. The primary endpoint of the expansion stage is the objective response rate for each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers and immune cell profiles with clinical outcome.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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      P1.01-127 - Antitumor Activity of the Oral EGFR/HER2 Inhibitor TAK-788 in NSCLC with EGFR Exon 20 Insertions (ID 1302)

      09:45 - 18:00  |  Author(s): Joel W Neal

      • Abstract
      • Slides

      Background

      We report results of a phase 1/2 open-label, multicenter study of TAK-788 (NCT02716116), an oral investigational EGFR/HER2 inhibitor.

      Method

      Patients with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for patients with EGFR exon 20 insertions who received TAK-788 160 mg QD. Safety is reported for all patients across all doses and at 160 mg. To improve gastrointestinal tolerability, food intake instructions in this ongoing study were amended to allow for administration with or without a low-fat meal based on emerging clinical pharmacokinetic data in a healthy volunteer study (data on file).

      Result

      As of 14 Sep 2018, 101 patients (median age, 61 y; female, 70%; ≥2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5–180 mg QD. RP2D was determined to be 160 mg QD. 28 patients with EGFR exon 20 insertions were treated with 160 mg QD during dose escalation or in expansion cohort 1 (3.6 months on treatment; 3.8 treatment cycles [medians]); 24 patients remain on treatment. At data cutoff, best response (RECIST v1.1) among 26 patients with ≥1 disease assessment was PR, n=14; SD, n=9; and PD, n=1 (objective response rate, 54%; 95% CI: 33.4%–73.4%); 2 patients were unevaluable. 7/14 objective responses (all PR) were confirmed (6 awaiting confirmation; 1 unconfirmed PR at 160 mg QD); median time to response in these 14 patients was 56 days. 23/26 patients (89%; 95% CI: 69.9%–97.6%) achieved disease control. 23/24 evaluable patients with EGFR exon 20 insertions treated at 160 mg QD had decreased target lesion measurements (median best percent change, -32.6% [-79.1%–3.8%]). Most common TEAEs (≥20%) in patients treated with 160 mg QD: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), stomatitis (22%); grade ≥3 TEAEs (≥5%): diarrhea (26%); hypokalemia, nausea, stomatitis (7% each). Among patients treated with 160 mg QD, median dose intensity was 93%, rate of dose reduction due to AEs was 21.7%, and rate of treatment discontinuation due to AEs was 10.9%. There was no clear trend that response to TAK-788 was enriched in any single EGFR exon 20 insertion variant.

      Conclusion

      In NSCLC patients with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and a safety profile consistent with other EGFR TKIs.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-32 - Rash and Efficacy in Anaplastic Lymphoma Kinase Positive (ALK+) Non-Small Cell Lung Cancer Patients Treated with Ensartinib (ID 2382)

      09:45 - 18:00  |  Author(s): Joel W Neal

      • Abstract
      • Slides

      Background

      Ensartinib is a potent ALK small molecule tyrosine kinase inhibitor (TKI). In a phase 1/2 study, ensartinib was generally well tolerated and demonstrated good clinical activity in pts with ALK+ non-small cell lung cancer (NSCLC). This post hoc analysis sought to determine the relationship between ensartinib-related rash and clinical benefit.

      Method

      Adverse events (AEs) were coded using MedDRA v15.0; severity was assessed by investigators using NCI CTCAE v4.03. Objective response rate (ORR) and median progression-free survival (mPFS) were explored in the efficacy-evaluable population, which included ALK+ pts receiving ensartinib 225 mg QD who had a postbaseline response assessment.

      Result

      As of Feb 07, 2019, 80 pts were dosed at the phase 3 dose of 225 mg QD and were efficacy evaluable (13 were ALK TKI naive, 37 had received prior crizotinib only, and 30 had received a prior second-generation ALK TKI). Rash was the most common AE observed in 69% of pts, mostly grade 1/2. The rashes started most frequently (33%) at day 7 or 8. The most common types of rash were general rash, rash maculopapular, and rash erythematous. Rash was primarily managed with topical corticosteroids, with some dose reductions, or no intervention at all and rarely led to discontinuation (2% [n=2]). The median duration of rash was 22 days. The ORR and mPFS were better in pts with rash vs those without (ORR, 53% vs 40%; mPFS, 8.6 vs 5.7 mo; P=.0044) (Table). A multivariate Cox proportional hazards model controlling for baseline factor (eg, age, sex, ECOG PS, and prior ALK TKI) revealed a correlation between rash and PFS (HR=0.556; P=.0755). Pts are still being accrued in this study.

      table 1_wclc.jpg

      Conclusion

      Ensartinib was associated with mild to moderate rash that was easily managed. Preliminary findings suggest that rash is potentially associated with better clinical benefit with ensartinib.

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    P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.16-02 - The Real-World Risk of Brain Metastases in Stage 3 Lung Cancer Patients in the Era of PET and MRI Staging (Now Available) (ID 833)

      09:45 - 18:00  |  Author(s): Joel W Neal

      • Abstract
      • Slides

      Background

      Brain metastases (BMs) are a common site of recurrence in Stage 3 NSCLC following definitive chemoradiation. In small-cell lung cancer, prophylactic cranial irradiation (PCI) was historically offered to improve overall survival (OS). Studies of PCI in NSCLC failed to show OS benefit; many were based on a 30% 2-year risk of CNS metastases, using data from the era prior to routine brain imaging at staging. An increasing preference for stereotactic radiosurgery(SRS) over WBRT for BMs may also affect outcomes. The purpose of this study was to review surveillance, incidence, and treatment patterns of BMs in patients with stage 3 NSCLC at our institution.

      Method

      In this IRB approved study, we retrospectively reviewed stage 3A/3B NSCLC patients treated at Stanford from 2008-2018. Of 279 patients, 163 received radiation with curative intent, and had complete data regarding pathology, staging, imaging, radiation and follow-up.

      Result

      Ninety-seven patients had adenocarcinoma, 54 squamous, and12 other histology (usually large-cell neuro-endocrine). Two patients received PCI; neither developed BMs. For all patients, median survival was 50 months (95%CI:30, 61). Patients with adenocarcinoma had significantly longer survival than squamous (53 v. 24 months, p=0.0119). 37 patients (22.7%) developed BMs, with 2-year cumulative incidence of 17.1% (95%CI:11.6%, 23.5%). Patients with adenocarcinoma had higher cumulative incidence of BM at 2 years, 21.9%, versus squamous 7.9%, and other histology 21.7%(p=0.0295). Of 37 BM patients, 18 presented with one BM, 8 with 2-3, and 11 had >3 BMs. Seventeen patients had asymptomatic BMs discovered at re-staging for systemic recurrence, 3 patients had asymptomatic BMs on surveillance MRI, 14 had BMs on MRI ordered for neurologic symptoms, 3 had symptoms and pre-scheduled surveillance MRI confirmed BM. Twenty-nine patients received SRS for first BM, 3 received WBRT, 5 had no treatment. Time from first BM to death was not different between adeno and squamous histology (21.0 v. 16.5 months, p=0.6050) or symptomatic v. asymptomatic BMs (18 v. 21 months, p=0.8273).

      Conclusion

      Patients with stage 3A/3B NSCLC treated at our institution have a lower 2-year incidence of BMs than historically reported, but higher than recently reported in the PACIFIC study (11.8%, 25-month median follow-up). Suspicion for BM should remain high in this population. Our experience suggests imaging at the time of systemic recurrence or neurologic symptoms may capture the majority of brain metastases. Routine surveillance MRI may capture more asymptomatic metastasis, though impact on overall survival remains unclear.

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