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Glenwood D. Goss



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    GR02 - Improving Patients Quality of Life During Treatment of Metastatic Disease (ID 30)

    • Event: WCLC 2019
    • Type: Grand Rounds Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      GR02.02 - What is the Best Management of Targeted Therapy Toxicity? (Now Available) (ID 3305)

      15:15 - 16:45  |  Presenting Author(s): Glenwood D. Goss

      • Abstract
      • Presentation
      • Slides

      Abstract

      GR02.02 - What Is the Best Management of Targeted Therapy Toxicity?

      15:35 - 15:55 | Presenting Author(s): Glenwood D. Goss

      Over the past decade, the discovery of oncogenic driver mutations in NSCLC and the subsequent advent of targeted therapies against these genomic alterations have significantly altered the management of adenocarcinoma of the lung for a significant proportion of patients. While most oncogenic driver mutations are rare, some exist in up to 50% of specific demographic groups, and together, oncogene-driven disease represents the majority of adenocarcinoma cases (1). Targeted therapies permit directed anti-neoplastic efficacy, with less systemic adverse events than chemotherapy. However, these agents are not without their own unique toxicities that must be managed for optimal drug compliance and therapeutic benefit. This talk will focus on the management of toxicities resulting from the targeting of aberrant pathways and common driver mutations in adenocarcinoma of the lung.

      We define targeted agents as pharmaceutical interventions directed specifically at one or more of the actionable genomic alterations that result in oncogenic phenotypes (proteins, signalling, etc.). Given the breadth of agents to be tested in this indication, the primary focus of the talk will be on approved (versus experimental) and commonly used agents, including small molecules and antibodies, but not antibody-drug conjugates. Genomic alterations to be addressed include at minimum the ERBB family of genes, KRAS, ALK, ROS-1, PI3K, VEGF and BRAF.

      For each agent directed against one of these aforementioned alterations, we will approach management of toxicity by contrasting the normal function of the pathway with adverse events associated with inhibition of this pathway. The management of the most frequent and serious adverse events of the pathway blockade will be the focus of the presentation.

      In conclusion, targeted therapies have had a profound impact on progression-free survival in a significant proportion of patients with metastatic adenocarcinoma of the lung, however they can be associated with a unique set of significant toxicities. The appropriate management of these toxicities may often determine whether a patient derives benefit or not from a targeted therapy, as toxicities can impact dose, frequency of delivery and compliance. Moving forward, increasing the specificity of targeted genomic alteration blockade is required to limit unwanted effects on wild-type proteins. The future of targeted therapy mandates that we devise newer agents with minimal toxicity.

      1. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014 Jul 31;511(7511):543–50.

      2. Kowanetz M. Vascular Endothelial Growth Factor Signaling Pathways: Therapeutic Perspective. Clin Cancer Res. 2006 Sep 1;12(17):5018–22.

      f1_sml.pngf2_sml.jpg

      Image 1: known (red) and putative (blue) driver mutations in adenocarcinoma of the lung, TGCA sample (1)

      Image 2: VEGF signaling in cancer and targets of inhibition.(2)

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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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      MA11.04 - Platinum Doublet + Durvalumab +/- Tremelimumab in Patients with Advanced NSCLC: A CCTG Phase IB Study - IND.226 (Now Available) (ID 927)

      14:00 - 15:30  |  Author(s): Glenwood D. Goss

      • Abstract
      • Presentation
      • Slides

      Background

      Studies of single agent immune checkpoint inhibitors with platinum-based chemotherapy in non-small cell lung cancer (NSCLC) have demonstrated survival benefit over chemotherapy alone. The primary objective of this multi-centre study was to evaluate the safety and tolerability of durvalumab (Du), a PD-L1 inhibitor, +/- tremelimumab (Tr), a CTLA-4 inhibitor, with one of four standard platinum-doublet regimens (pemetrexed (pem), gemcitabine, etoposide (each with cisplatin or carboplatin) or nab-paclitaxel (with carboplatin)), in order to establish a recommended phase II dose (R2PD) for each combination. This abstract updates the results in the NSCLC cohort in this study.

      Method

      Patients (pts), regardless of tumour PD-L1 status, were enrolled into one of six dose levels (Table 1). Dose escalation was according to a Rolling Six type design. Concurrent enrollment of cohorts was allowed. ind 226 abstract wclc methods.png

      Result

      Seventy-three pts (median age=63 (range 34-80); 52% female; 77% non-squamous) were enrolled. The majority of drug-related adverse events (AEs) were grade 1 or 2. Most AEs were related to chemotherapy; other AEs were chemotherapy or immune-related (renal, hepatic, skin and pulmonary toxicity). AEs that were considered related to Du or Tr (immune related AEs (irAEs)) were mainly grade 1 or 2. The most common irAEs were fatigue (64%), rash/itch (42%), diarrhea/colitis (34%), anorexia (22%), thyroid dysfunction (19%), and nausea/vomiting (21/12%). The most common grade 3 or 4 irAEs were diarrhea/colitis (11%), fatigue (10%), and rash (5%). No treatment related grade 5 toxicities were reported. Twenty pts (27%) discontinued treatment due to an AE. Twelve pts (16%) discontinued treatment for toxicity related to D+/-T. Objective response rate (ORR) was 50.7% (95% CI = 38.7-62.6%). Median progression free survival (mPFS) was 6.5 months (95% CI = 5.5-9.4). Median overall survival (mOS) was 19.8 months (95% CI = 14.8-not yet reached). ORR was similar for all levels of PD-L1 staining including PD-L1 negative patients. ORR for pts with EGFR mutations (N=5) was similar to the ORR of wild type pts. Exploratory analyses suggest mPFS and mOS were longer in patients who experienced irAEs.

      Conclusion

      In this PD-L1 unselected patient population, Du and Tr can be safely combined with full doses of platinum-doublet chemotherapy. The ORR, mPFS and mOS are similar to results reported from other immunotherapy + chemotherapy combination trials. A randomized trial, CCTG BR.34, is evaluating the incremental benefit of adding platinum doublet to Du+Tr.

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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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      P2.01-07 - Open-Label, Biomarker-Directed Platform Study in NSCLC Patients Who Progressed on an Anti-PD-(L)1-Containing Therapy (HUDSON) (ID 643)

      10:15 - 18:15  |  Author(s): Glenwood D. Goss

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitor (ICI)-containing regimens have significantly improved survival outcomes in first- and second-line non-small cell lung cancer (NSCLC). However, few patients have-durable responses to anti-programmed cell death‑1/programmed cell death-ligand 1 (anti-PD-[L]1)-containing therapy (primary resistance) or other patients progress during anti-PD-(L)1-containing therapy (acquired resistance). HUDSON addresses the urgent need to identify new treatments and understand ICI resistance for patients who progressed after receiving anti-PD-(L)1-containing therapy.

      Method

      HUDSON is a multi-centre, international, multi-arm, platform study (NCT03334617), which will 1) evaluate therapies to reverse ICI resistance and 2) define mechanisms of ICI resistance in patients with NSCLC who have progressed following standard-of-care platinum- and ICI-based therapies. HUDSON consists of biomarker matched and non-matched groups (Figure). Allocation is guided by tumour molecular profile, using a pre-specified algorithm. Pre-existing local next generation sequence (NGS) data enables rapid patient allocation to biomarker-matched groups. Central molecular profiling comprises NGS and immunohistochemistry data. New groups will be added as new translational hypotheses emerge. Translational research will employ serial peripheral blood samples (including ctDNA) and tumour biopsies.

      Figure. Study design and biomarker prevalence

      wclc 2019 abstract figure.jpg

      Result

      Enrolment is ongoing; as of 01 April 2019, patients have been dosed in each of the drug combinations currently open for recruitment. Analyses of tissue and blood samples collected for exploratory research are ongoing, including genomic, transcriptomic and chemistry biomarkers such as tumour mutation burden, human leukocyte antigen status, T-cell receptor repertoire, and peripheral immune activation signatures.

      Conclusion

      Specific differences between patients on individual HUDSON arms that inform anti-PD(L)1 resistance mechanisms, plus learnings from the implementation of this innovative and complex platform study will be presented.

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