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Nathan Pennell



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    MA03 - Clinomics and Genomics (ID 119)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 2
    • Now Available
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      MA03.01 - The Impact of Early Steroids on Clinical Outcomes in Patients with Advanced NSCLC Treated with Immune Checkpoint Inhibitors- A Cancerlinq Cohort (Now Available) (ID 2807)

      10:30 - 12:00  |  Presenting Author(s): Nathan Pennell

      • Abstract
      • Presentation
      • Slides

      Background

      Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm for patients with NSCLC, however only a fraction of patients have objective responses to these agents. Identifying clinical factors that influence efficacy of ICIs is crucial for optimal patient selection for treatment. Since ICIs produce anti-tumor responses by reinvigorating cytotoxic effector T cells, one can surmise that patients who receive steroids within a short interval of initiating ICIs will have less robust anti-tumor responses. Clinical trials usually exclude patients receiving steroids for this reason. In clinical practice, patients with NSCLC often receive corticosteroids for various indications such as brain metastases, appetite stimulation, autoimmune disorders, or COPD. By analyzing data obtained from a large real world cohort of patients with NSCLC, we aim to study the impact of early steroids (within 30 days) on clinical outcomes in patients with advanced NSCLC treated with ICIs.

      Method

      Using the Cancerlinq Discovery Database which consists of data aggregated from the electronic medical records of oncology practices, 11,143 patients with advanced NSCLC treated with ICIs were identified. Of these, 1581 patients were prescribed or administered ≥ 10 mg of prednisone or equivalent corticosteroid dose within the first 30 days of initiating ICIs. To account for prognostic heterogeneity within the population, we created matched cohorts of patients that exhibited similar prognostic clinical characteristics such as age (using 65 years as a cutoff) and gender. Association between time on treatment with ICIs and early steroid use was evaluated using the Student’s t-test. Overall survival (OS) was estimated using the Kaplan-Meier method and analyzed using the Cox proportional-hazards model.

      Result

      The cohort consisted of a predominantly white population (53.4%), with a median age of 76 years and a slight male predominance (54.9%). The median time on ICI treatment was 3.8 months. Patients who received steroids within the first 30 days had a shorter time on treatment- median of 3.36 months vs 3.86 months for those without steroid use (p= 0.023). Early steroid use was also associated with significantly worse overall survival [HR 1.16, 95% CI (1.05, 1.28) p<0.002].

      Figure: Kaplan-Meier survival analyses of patients with NSCLC treated with ICIs according to early steroid use

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      Conclusion

      The use of ≥ 10 mg of prednisone equivalent corticosteroid dose within 30 days of initiating ICIs was associated with shorter time on treatment and worse overall survival in this large real world cohort of NSCLC patients. It is prudent that clinicians judiciously prescribe corticosteroids upon initiation of ICIs.

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      MA03.04 - Discussant - MA03.01, MA03.02, MA03.03 (Now Available) (ID 3723)

      10:30 - 12:00  |  Presenting Author(s): Nathan Pennell

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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): Nathan Pennell

      • 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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    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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      P2.04-16 - Novel CT Based Radiomic Features are Prognostic and Predictive of Benefit of Chemoimmunotherapy in Advanced Non-Squamous NSCLC (ID 2769)

      10:15 - 18:15  |  Author(s): Nathan Pennell

      • Abstract

      Background

      Carboplatin, pemetrexed and pembrolizumab (C/P/P) is currently approved for patients with advanced non-squamous carcinoma of the lung (NS-NSCLC) based on superior survival outcomes noted in KEYNOTE-189. Since clinical benefit was observed across all PD-L1 expression categories, there are currently no robust predictive biomarkers that can identify subsets of patients likely to derive benefit from this regimen. We sought to evaluate whether radiomic features extracted from within and outside the nodule on pre-therapy CT scans could predict response to C/P/P.

      Method

      We retrospectively identified 52 patients with stage IV NS-NSCLC who received C/P/P. Of these, 6 were excluded because of non-evaluable thoracic lesions. Lung tumors were contoured on 3D SLICER software by an expert reader. Textural and shape radiomic features were extracted from intra/peritumoral regions using MATLAB® 2018b platform (Mathworks, Natick, MA). The primary endpoint of our study was RECIST response and secondary end point was overall survival (OS). A linear discriminant analysis classifier (LDA) was used to predict response across 100 iterations of threefold cross validation in the dataset. Performance of classifier on response was measured by area under receiver operating characteristic curve (AUC). To build the multivariate radiomic signature for OS, least absolute shrinkage and selection operator (LASSO) Cox regression model was used and a risk score was computed according to a linear combination of selected features. Patients were divided into high-risk or low-risk groups based on median risk score.

      Result

      The top five radiomic features (intra/peritumoral textural patterns) predictive of response to C/P/P were identified by mRMR feature selection method. LDA classifier using these features could discriminate responders from non-responders with an AUC of 0.77 ± 0.05.

      The radiomic risk score was calculated using a linear combination of top six selected features from LASSO with corresponding coefficients. In a multivariate Cox proportional hazards model using a combination of clinicopathologic and radiomic features, the radiomics signature was found to be significantly associated with OS (averaged on 100 iteration of CV) (HR 10.42; 95% CI: 4.18-26; P = 4.92e-07). Kaplan-Meier survival analyses according to the radiomics signature risk-score showed significantly worse survival in the high risk category.

      Conclusion

      Textural features within and outside the nodule on pre-treatment CT images of patients with NS-NSCLC treated with C/P/P were predictive of responses and OS. Additional validation of these quantitative image-based biomarkers in independent cohorts is warranted.

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      Figure: Kaplan-Meier survival analyses of patients (N = 46) with NS-NSCLC treated with C/P/P using the radiomics signature risk-score.

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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
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      PL02.08 - Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers (Now Available) (ID 964)

      08:00 - 10:15  |  Author(s): Nathan Pennell

      • Abstract
      • Presentation
      • Slides

      Background

      No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.

      Method

      This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.

      Result

      As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.

      Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.

      The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.

      Conclusion

      LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.

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