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Glenwood Dillon Goss



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    IS02 - Industry Symposium Sponsored by AstraZeneca: Evolving the Role of Immunotherapy in Lung Cancer: ES-SCLC and Unresectable Stage III NSCLC (ID 278)

    • Event: WCLC 2020
    • Type: Industry Symposium
    • Track:
    • Presentations: 1
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      IS02.02 - Current Strategies for IO Therapy for Unresectable Stage III NSCLC (ID 4310)

      10:30 - 11:30  |  Presenting Author(s): Glenwood Dillon Goss

      • Abstract

      Abstract not provided

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    OA07 - Immuno-biology and Novel Immunotherapeutics from Bench to Bed (ID 228)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 1
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      OA07.08 - HUDSON: An Open-Label, Multi-Drug, Biomarker-Directed, Phase II Platform Study in Patients with NSCLC, who Progressed on Anti-PD(L)1 Therapy   (ID 3535)

      10:30 - 11:30  |  Author(s): Glenwood Dillon Goss

      • Abstract

      Introduction

      The HUDSON Platform trial (NCT03334617) is a multi-arm clinical trial for patients with non-small cell lung cancer (NSCLC) who had tumour progression on anti-PD(L)1 immunotherapy and received prior platinum-doublet chemotherapy. The study design allows efficacy, safety, and tolerability assessment of multiple tailored durvalumab based combinations. Novel treatment options for this population can be explored based on efficacy signals. Here we present initial results in Modules 1, 2, 3 and 5 and current status in Modules 6 and 7.

      Methods

      Patients are enrolled into cohorts defined according to a biomarker matched profile (Part A) or non-matched (Part B). Acquired resistance (ACQ) was defined as progression after >24 weeks of prior immunotherapy and primary resistance (PRI) defined as progression ≤24 weeks from onset of prior immunotherapy. Patients received durvalumab in combination with: olaparib (PARPi; Module 1), danvatirsen (STAT3i; Module 2), ceralasertib (ATRi; Module 3), oleclumab (anti-CD73 antibody; Module 5), trastuzumab deruxtecan (HER2 ADC; Module 6), and cediranib (VEGFRi; Module 7). A composite endpoint of overall response rate (ORR), progression-free survival (PFS; 6, 9 and 12 months) and overall survival (OS; 6, 9 and 12 months) was used to decide whether or not to expand the initial module size from 20 patients to 40. Safety, a secondary endpoint, was continuously monitored.

      Results

      Enrolment started in December 2017. As of 25th July 2020, 261 patients have been enrolled from 31 study sites in 6 countries. Enrolment into Modules 1, 2, and 5 is complete, ongoing in Modules 3, 6, and 7, and Module 4 was discontinued with one patient enrolled, when development of vistusertib was stopped. As of Q1 2020, efficacy (ORR), PFS and OS) results were available as per Table 1. Further efficacy updates for Modules 1, 2, 3 and 5 are scheduled in Q3 2020. The safety profile of combination therapy in each module was in line with the safety profile of the individual compounds.

      Table 1. Enrolment and efficacy outcomes to date per patient cohort

      Cohort

      Enrolment status

      Number
      enrolled

      6-month OS (%)

      6-month PFS (%)

      ORR
      (%)

      Median total

      treatment duration (months)

      Part A – Biomarker matched

      LKB1 (+olaparib)

      Complete

      21

      55.8

      10.7

      4.8

      1.84

      HRR (+olaparib)

      Complete

      21

      57.1

      21.8

      4.8

      3.68

      ATM (+ceralasertib)

      Ongoing

      18

      100

      61.2

      13.3

      4.14

      CD73 (+oleclumab)

      Complete

      23

      79.9

      8.3

      0

      2.79

      HER2 (+trastuzumab deruxtecan)

      Ongoing

      1

      Part B – Biomarker non-matched

      PARPi – ACQ
      (+olaparib)

      Complete

      23

      77.4

      26.1

      4.3

      4.70

      PARPi – PRI (+olaparib)

      Complete

      22

      59.1

      15.1

      0

      3.35

      STAT3i – ACQ

      (+danvatirsen)

      Complete

      22

      75.2

      38.5

      0

      3.15

      STAT3i – PRI (+danvatirsen)

      Complete

      23

      50.2

      5.1

      0

      1.91

      ATRi – ACQ (+ceralasertib)

      Complete

      24

      77.3

      37.0

      8.7

      6.44

      ATRi – PRI (+ceralasertib)

      Complete

      20

      74.8

      53.8

      11.1

      2.78

      CD73 Ab – ACQ
      (+oleclumab)

      Complete

      25

      64.4

      26.1

      0

      2.73

      CD73 Ab – PRI (+oleclumab)

      Complete

      9

      NC

      NC

      0

      1.53

      VEGFi – ACQ
      (+cediranib)

      Ongoing

      9

      NA

      Please note: OS, PFS and ORR are currently available for patients enrolled by January 2020. Number enrolled reflects the total enrolled by 25th July 2020.

      Conclusion

      Preliminary efficacy signals were observed with ATRi, which may be more pronounced in ATM selected patients. The subgroup of LKB1 selected patients appear to have the lowest 6-month OS and PFS of subgroups in Module 1 (durvalumab + olaparib). An update is scheduled for Q3 2020.

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    P03 - Early Stage/Localized Disease - Clinical Trials in Progress (ID 112)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P03.03 - MERMAID-1: A Phase III Study of Adjuvant Durvalumab plus Chemotherapy in Resected NSCLC Patients with MRD+ Post-Surgery (ID 3322)

      00:00 - 00:00  |  Author(s): Glenwood Dillon Goss

      • Abstract
      • Slides

      Introduction

      30% of non-small-cell lung cancer (NSCLC) patients present with surgically resectable disease at diagnosis. To reduce disease recurrence, adjuvant chemotherapy is standard of care (SoC) for patients with completely (R0) resected stage II/III NSCLC. However, 5-year disease-free survival (DFS) rates remain low (~40%), with a 5-year absolute benefit of only 5.4% derived from chemotherapy (Pignon et al. JCO 2008;26:3552-9). Determining who will benefit from adjuvant chemotherapy remains challenging. Identifying minimal residual disease (MRD) through detection of circulating tumour (ct) DNA post-surgery could predict early disease recurrence. Durvalumab is a selective, high‑affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. In the phase III PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression following radical platinum-based concurrent chemoradiotherapy, durvalumab improved progression-free survival (PFS) and overall survival (OS), demonstrating its efficacy in situations of residual disease. Further, initial data from POSEIDON showed durvalumab plus chemotherapy prolongs PFS versus chemotherapy in first line treatment of metastatic NSCLC. In the adjuvant setting (i.e. following complete tumour resection), this regimen could provide additional DFS benefit versus chemotherapy alone. MRD assessment could facilitate earlier, more selective adjuvant therapy for MRD+ patients, allowing for treatment intensification for this potentially biologically distinct disease, while minimising overtreatment of MRD– patients. MERMAID‑1 will investigate the efficacy and safety of adjuvant durvalumab + SoC chemotherapy versus placebo + SoC chemotherapy in patients with completely resected stage II/III NSCLC, to assess the benefits of adjuvant therapy in patients with MRD+ status.

      Methods

      MERMAID-1 (NCT04385368) is a phase III, parallel-arm, placebo-controlled, double‑blind, multicentre study, conducted across 16 countries. Patients aged ≥18 years with histologically confirmed EGFR-/ALK- Wild-type, stage II/III NSCLC will enter the first screening period; a personalised MRD panel will be created. Before randomisation, and following assessment of MRD status post-surgery, patients will be further screened for full eligibility (no evidence of disease recurrence, WHO/ECOG performance status 0/1). Patients who have received prior adjuvant therapy or durvalumab, and those with mixed small cell and NSCLC histology or evidence of post-operative disease recurrence are ineligible. MRD status will be determined via ctDNA analysis of plasma samples, collected 3–4 weeks post-surgery, and based on personalised panels (comprised of ≤50 tumour-specific DNA variants) created by whole exome sequencing analysis of the patient’s resected tumour tissue. Approximately 332 patients will be randomised 1:1 (stratified by disease stage, MRD status, and PD-L1 expression) to durvalumab (1500 mg, intravenously) or placebo, plus concurrent SoC chemotherapy, once every three weeks (Q3W) for 12 weeks. Patients will continue with durvalumab monotherapy/placebo Q4W thereafter, until Week 48 or disease recurrence, whichever occurs first. Following a baseline radiological scan prior to randomisation, patients will be assessed Q12W until disease recurrence (per RECIST v1.1). The primary endpoint is DFS in the MRD+ analysis set (investigator-assessed). Secondary endpoints include DFS in the full analysis set (FAS; investigator-assessed); DFS in the MRD+ analysis set and FAS (blinded independent central review); OS in the MRD+ analysis set and FAS; and safety and tolerability, and patient-reported outcomes.

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    P16 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Novel Immunotherapeutics (Translational) (ID 155)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P16.07 - Immuno-Modulatory Effects of Ceralasertib in Combination with Durvalumab in NSCLC with Progression on Anti-PD(L)1 Treatment (HUDSON)  (ID 3491)

      00:00 - 00:00  |  Author(s): Glenwood Dillon Goss

      • Abstract
      • Slides

      Introduction

      The HUDSON platform trial (NCT03334617) is a multi-arm clinical trial for patients with non-small cell lung cancer (NSCLC) who had tumour progression on anti-PD(L)1 immunotherapy and received prior platinum-doublet chemotherapy. We report preliminary translational data, where available, from patients treated with ceralasertib (an ataxia telangiectasia and Rad3-related protein inhibitor, ATRi) and the PDL1 inhibitor durvalumab.

      Methods

      The study protocol included analyses of archival and fresh tumour biopsies, and longitudinal liquid biopsies. Patients were enrolled into biomarker matched (ATM-selected) or unmatched arms after the development of primary or acquired resistance to PD-(L)1 immunotherapy. Primary and acquired resistance were defined as progression before or after 6 months on anti-PD(L)1 therapy respectively. Biomarker status was determined using next generation sequencing (Foundation Medicine) for ATM mutation status or immunohistochemistry (IHC, Ventana) for ATM protein expression. Gene expression from whole blood samples (PAXgene®) was analysed using the PanCancer IO gene panel from Nanostring Technologies.

      Results

      Translational data are currently only available from a subset of patients. Clinical response data will be presented separately. Tumour and liquid biopsy samples were collected from patients treated with ceralasertib and durvalumab. Gene expression data were available from 8 ATM biomarker-positive and 17 biomarker-negative patients. Peripheral gene expression analyses in responding patients showed greater than two-fold higher granzyme levels at baseline, when compared with non-responders. The 19 patients with controlled disease on ceralasertib (partial response or stable disease by RECIST v1.1) and available gene expression data also showed a two-fold reduction in peripheral IL-8 gene expression in paired blood samples when compared with the six patients showing progressive disease with available gene expression data. Samples collected during a ceralasertib-only period prior to durvalumab treatment showed modified biomarkers of peripheral immunity including significant increases in antigen presentation gene signature and significant decreases in both exhausted T cell and NK cell signatures from bulk whole-blood RNA samples. Ceralasertib also decreased 4 macrophage gene expression signatures in on-treatment samples. Similar gene expression profiles were not observed from comparable samples on other HUDSON arms. No correlation between ATM biomarker status and RECIST response was observed. No significant correlations with ceralasertib response were observed between tumour mutation burden or PDL1 status by IHC.

      Conclusion

      Taken together, these data support a role of immune activation by ceralasertib as a feature of response to combination therapy with ceralasertib plus durvalumab in NSCLC following progression on anti-PD(L)1.

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