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Solange Peters



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    ES09 - Biomarkers in Immunotherapy (ID 148)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 1
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      ES09.03 - Role of PD-L1 and Tumor Mutational Burden in NSCLC Immunotherapy (ID 3944)

      09:15 - 10:15  |  Presenting Author(s): Solange Peters

      • Abstract

      Abstract

      New cancer immunotherapy strategies have the potential to overcome tumor-mediated immune suppression. However, such therapies are not only associated with significant costs, but also potentially severe adverse side effects. Because only a minority of patients benefit from this strategy, it is of utmost importance to establish biomarkers to guide therapy decisions.

      For many tumor entities, assessment of programmed death ligand 1 (PD-L1) expression on tumor and/or immune cells by immunohistochemistry (IHC) is the approved companion diagnostic.

      As each PD-L1 IHC assay was independently developed for specific anti–programmed death 1 (PD-1)/PD-L1 therapy using a different PD-L1 diagnostic assays (primary antibody clone plus immunostaining platform/protocol), each assay potentially demonstrates distinct staining properties, which could prohibit the interchangeability of their clinical use. Several groups have demonstrated the comparability of the various PD-L1 IHC assays and their potential interchangeability in clinical adoption, starting with the IASLC Blueprint project 1 and 2.

      The results from the Blueprint phase 1 study demonstrated that three PD-L1 assays (22C3, 28-8, and SP263) showed comparable analytical performance for assessment of PD-L1 expression on TCs, whereas the SP-142 PD-L1 assay appeared to stain fewer TCs compared with the other assays. In contrast, all the assays stained tumor-infiltrating immune cells (ICs), but with poor concordance between assays. These data were confirmed in BP2 validation cohort.

      PD-L1 is currently mainly used to select patients for immunotherapy monotherapy frontline, in the scenario of a high expression on TC (>50%), initially based on KEYNOTE-024, and less commonly and in selected regions/countries, in case of PD-L1 positivity only, based on the more debated results of KEYNOTE-42 trial.

      As a basis for immunogenicity, it has been hypothesized that tumors with a high number of coding mutations are more likely to generate tumor-specific neoantigens that will be recognized by the immune system. Tumor mutational burden (TMB) has emerged as a novel biomarker to identify patients more likely to respond to immune checkpoint inhibitor therapy targeting the PD(L)-1 axis or cytotoxic T-lymphocyte associated protein 4 (CTLA-4). Recent data support a predictive potential of TMB for checkpoint inhibitor therapy in various cancer types.

      TMB can potentially identify — strictly independently from PD-L1 expression status — different patient cohorts likely to respond and, possibly in conjunction with PD-L1 status, help to predict non-responders and exceptional responders.

      Aided by recent progress in sequencing technologies, an increasing number of panel-based next-generation sequencing (NGS) assays and services to measure TMB is offered. Panel-based NGS fits very well into the clinical workflow of cancer tissue evaluation because (i) formalin-fixed and paraffin-embedded (FFPE) tissue samples can be used as input biomaterial, (ii) analysis of small biopsies is feasible as only small amounts of DNA are needed, (iii) there is no immediate need for analysis of paired normal tissue or blood samples as germline mutation filtering can be performed in silico, (iv) TMB measurement can be performed together with the analysis of druggable targets in a single assay and (v) the entire workflow including wet-lab analysis, bioinformatics pipeline and variant interpretation can be carried out within a few days. Thus, being the present-day mainstay of clinical mutation analysis in oncology, panel sequencing is expected to be the most widely adopted technology for clinical TMB measurement for the next years. Of major importance, such analysis is progressively moving to the analysis of circulating tumor DNA (ctDNA). ctDNA can be actively released into circulation or shed after tumor cells outgrow their blood supply, become hypoxic, and undergo apoptosis or necrosis. The goals of circulating tumor DNA monitoring are to capture genetic heterogeneity, identify targetable mutations, and monitor tumor evolution in real time. Studies in multiple tumor types have demonstrated high concordance for hotspot mutations between paired tissue and ctDNA biopsies. However, more recent TMB-oriented studies have stressed technical limitations for tissue vs blood comparisons, notably regarding variability in platforms, technologies, genetic alterations identification, sensitivity and thresholds used. Keeping in mind a strong need for harmonization, blood TMB profiled with ctDNA sequencing remains a promising non-invasive strategy for TMB, aiming at possibly more accurately predict immunotherapy benefit.

      In June 2020, the US Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mut/Mb] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

      This approval was based on efficacy data from 10 refractory solid tumor cohorts enrolled in a multicenter, non-randomized, open-label trial [KEYNOTE-158 (NCT02628067)].

      Altogether, 102 patients (13%) had TMB-H tumors, defined as TMB ≥10 mut/Mb. The objective response rate was 29% [95% confidence interval (CI): 21% to 39%]. Overall, about half the responses were of greater than 2 years with many ongoing, a durability of response rarely observed in heavily pretreated metastatic cancers with treatment modalities other than immunotherapy.

      TMB, in concert with PD-L1 expression, has been demonstrated to be a useful biomarker for immune checkpoint blockade selection across some cancer types. However, further prospective validation studies are still required. TMB determination by selected targeted panels has been correlated with WES. Calibration and harmonization will be required for optimal utility and alignment across all platforms currently used internationally. Key challenges will need to be addressed before broader use - or routine practice application - across different tumor types

      References

      1. Budczies, J., Quantifying potential confounders of panel-based tumor mutational burden (TMB) measurement. Lung Cancer 142, 114-119 (2020).

      2. Chan, T.A., Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol 30, 44-56 (2019).

      3. Hirsch, F.R., PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project. J Thorac Oncol 12, 208-222 (2017).

      4. Kazdal, D., Spatial and Temporal Heterogeneity of Panel-Based Tumor Mutational Burden in Pulmonary Adenocarcinoma: Separating Biology From Technical Artifacts. J Thorac Oncol 14, 1935-1947 (2019).

      5. Subbiah, V., nn Oncol 31, 1115-1118 (2020).

      6. Tsao, M.S., J Thorac Oncol 13, 1302-1311 (2018).

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    IS07 - Industry Symposium Sponsored by Roche: Expert Perspectives on the Management of Lung Cancer (ID 284)

    • Event: WCLC 2020
    • Type: Industry Symposium
    • Track:
    • Presentations: 2
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      IS07.01 - The Past, Present and Future of Biomarker-Driven Advanced NSCLC (ID 4339)

      16:45 - 17:45  |  Presenting Author(s): Solange Peters

      • Abstract

      Abstract not provided

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      IS07.02 - Future Directions for Cancer Immunotherapy: Resectable NSCLC and Novel Combinations in Lung Cancer (ID 4340)

      16:45 - 17:45  |  Presenting Author(s): Solange Peters

      • Abstract

      Abstract not provided

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    MA06 - Molecular Developments and Novel Treatments in Mesothelioma and Thymoma (ID 134)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
    • Presentations: 1
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      MA06.03 - Phosphorylated Ribosomal Protein S6, Correlation With Characteristics and Clinical Outcome in Patients With MPM: Results from ETOP Mesoscape (ID 2260)

      14:15 - 15:15  |  Author(s): Solange Peters

      • Abstract

      Introduction

      Malignant pleural mesothelioma (MPM) is an aggressive malignancy with increasing prevalence and poor prognosis. The European Thoracic Oncology Platform (ETOP) Mesoscape project was designed to address clinical, pathological, and molecular characteristics of MPM patients and their impact on outcome, along with having formalin-fixed paraffin embedded tumour tissue available for central analysis. In previous studies the phosphorylated ribosomal protein S6 (pS6), which is a downstream target of PI3K /mTORC1 signaling, was associated with clinical outcome, and low pS6 immunoreactivity was significantly correlated with longer progression free survival in other MPM patients. Correlating pS6 with the clinical as well as pathological information in Mesoscape allows researchers to improve the knowledge and facilitate decision-making in patients with MPM.

      Methods

      A biobank with fully annotated tissue samples was established for ETOP Mesoscape, and Tissue Micro Arrays (TMAs) were constructed. Expression of phospho-S6 (p-S6, Ser240/244, Cell Signaling Technology, 1:50 dilution) was explored in the ETOP Mesoscape cohort. Immunohistochemical evaluation of the TMAs was conducted by two independent observers in a blinded manner. The staining intensity was semi-quantitatively scored 0 (negative), 1 (weak), 2 (moderate), or 3 (strong). Furthermore, the percentage of cells with any positivity was proportionally scored 0 (0%), 0.1 (1%–9%), 0.5 (10%–49%), or 1.0 (50% and more). An aggregate H-score was obtained by multiplication of intensity with percentage staining (final range: 0-3 per core). The final H-score was determined by averaging the H-scores of all the cores from the same patient. Patients’ classification as pS6-high/low, was based on median H-score.

      Results

      Up to 14 July 2020, the ETOP Mesoscape included pS6 IHC results on 269 of the 499 patients from 10 centers, diagnosed between 1999-2018. The remaining cases are currently undergoing pS6 scoring.

      Overall, patients in the Mesoscape database are primarily men (84%), of 0/1 ECOG Performance status (46/46%), with known previous exposure to asbestos (75%) and a median age of 64 years. The primary histology of included tumours is epithelioid (72%), followed by biphasic (22%) and sarcomatoid (6%). Clinical staging is available for 77%. The stage distribution (I/II/III/IV) is 14/29/42/15%.

      Calretinin and WT1 are detected in the vast majority of patients tested (Calretinin: 97%; WT1: 89%). Also, 90% (of those tested) are CK5/6 positive, 91% D2-40 positive and 97% Pan-CK positive. Palliative treatment has been administered in 41%.

      PS6-high patients (128 patients with H-score>1.375) are significantly associated with higher age, more T-stage of 3/4, and higher percentage of right localization compared to pS6-low patients (141 patients with H-score≤1.375). Overall survival (OS) is non-significantly different between pS6-low and pS6-high patients (medians: 21.4 months; 95%CI:[15.3-23.4] and 17.8 months; 95%CI:[15.1-20.7], respectively; log-rank p=0.61]. In the multivariate Cox model, pS6 is also non-significant (p=0.31), while gender, histology, and treatment strategy are the only significant survival predictors.

      Conclusion

      Based on preliminary data, high pS6 expression is associated with higher age and T-stage; effect in survival is non-significant. Updated and additional results on the expression and clinical significance of pS6 from the full ETOP Mesoscape cohort will be presented at the conference.

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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  |  Presenting Author(s): Solange Peters

      • 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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    P09 - Health Services Research/Health Economics - Real World Outcomes (ID 121)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Health Services Research/Health Economics
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P09.18 - COVID-19 Outcomes in Patients With Thoracic Malignancies According to Gender and Ethnicity (TERAVOLT) (ID 3702)

      00:00 - 00:00  |  Author(s): Solange Peters

      • Abstract
      • Slides

      Introduction

      Previously reported data on patients with thoracic malignancies who develop COVID-19 have suggested a higher mortality rate compared to the general population and to other cancer types, particularly in patients over 65 years of age or suffering from active or progressive disease. Preliminary data from other studies have suggested that gender and ethnicity may also impact patient outcomes.

      Methods

      TERAVOLT is a multi-center, international observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria include the presence of any thoracic cancer and a COVID-19 diagnosis confirmed in the laboratory with RT-PCR/serology, highly suspicious radiological and clinical findings, or suspected with symptoms and known contact with a positive person. The overarching goals of this consortium are to provide data for guidance to oncology professionals on managing patients with thoracic malignancies while understanding the risk factors for morbidity and mortality from this novel virus. Clinical outcomes including hospitalization, ICU admission, oxygen requirement and mortality were collected. The association between demographic/clinical characteristics and outcomes were measured with odds ratio with 95% confidence intervals using a logistic regression model.

      Results

      As of August 20, 2020, a total of 1,053 patients with COVID-19 and thoracic cancers from 19 countries and 130 centers have been identified, including 42% females and 84% White, 9.3% African American, 25% Hispanic. The median age of male patients was 69 compared to 66 years of age for females. While ECOG PS was similar between treatment groups, 77% of males were admitted to hospital with a mortality rate of 37% compared to 66% of females with a mortality rate of 28%. The median age of African American patients was 66 years of age compared to 68 and 69 years of age for white and Hispanic patients, respectively; 26% of African American and 25% White patients had an ECOG PS ≥2 compared to 19% of Hispanics. A similar percentage of patients were admitted to the hospital and ICU, while the mortality rate for Hispanics was 36% compared to 34% for whites and 26% for African Americans.

      Conclusion

      Similar to the general population, the mortality rate of males with thoracic cancer is higher than females. Regarding ethnicity, there is a difference in the median age of African American patients compared to Whites and Hispanics. Although the severity of COVID-19 disease, as defined by hospital admission, is similar between ethnic groups, the mortality rate in Hispanics is higher. We will present a multivariate analysis of these data according to gender and ethnicity, including the impact of cancer stage, prior cancer therapy, and COVID-19 therapy on outcomes.

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    P83 - Immunotherapy (Phase II/III Trials) - Immunotherapy Plus Targeted Therapy (ID 260)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immunotherapy (Phase II/III Trials)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P83.02 - Niraparib + Pembrolizumab (Pembro) Versus Placebo + Pembro 1L Maintenance Therapy in Advanced NSCLC: ZEAL-1L Phase III Study (ID 3405)

      00:00 - 00:00  |  Author(s): Solange Peters

      • Abstract
      • Slides

      Introduction

      The poly (ADP-ribose) polymerase (PARP) inhibitor niraparib exerts antitumor activity primarily by impairing the ability of cells to repair DNA damage via the homologous recombination repair pathway. Preclinical data suggests that niraparib may also activate the stimulator of interferon gene (STING) pathway, recruit T cells, and upregulate programmed cell death ligand-1 (PD-L1) in some cancers. Accordingly, the potential synergistic antitumor effect of niraparib and the programmed cell death 1 inhibitor pembro has been observed, along with a tolerable safety profile, in the Phase II TOPACIO/KEYNOTE-162 (NCT02657889) trial of patients with triple-negative breast cancer and platinum-resistant ovarian cancer (Vinayak et al. JAMA Oncol 2019). Early results of the Phase II JASPER (NCT03308942) trial in locally advanced and metastatic NSCLC suggest that this combination is active and well tolerated as first-line (1L) therapy. Maximizing treatment efficacy is important in this setting, as progression-free survival (PFS) is limited to <9 months with standard-of-care chemotherapy plus pembro, and patients with recurrent disease have few treatment options.

      The objective of the Phase III ZEAL-1L study is to compare the efficacy and safety of maintenance niraparib plus pembro versus placebo plus pembro, following 1L therapy, in patients with advanced/metastatic NSCLC without known driver mutations.

      Methods

      ZEAL-1L is a Phase III randomized, double-blind, global, multicenter trial of niraparib plus pembro versus placebo plus pembro in patients with Stage IIIB–IV NSCLC that has not progressed (stable disease [SD], with partial or complete response [PR or CR]) after 4–6 cycles of 1L induction platinum-based chemotherapy plus pembro. Patients with controlled, asymptomatic brain metastasis can participate. Approximately 650 participants will be recruited.

      The dual primary objectives of the study are to evaluate radiographic PFS as assessed by blinded independent central radiology review (BICR) per Response Evaluation in Solid Tumors (RECIST v1.1) criteria and overall survival for patients treated with niraparib plus pembro versus placebo plus pembro. Participants will be stratified by histology (squamous vs non-squamous), PD-L1 status (tumor cells [TC] <1% vs TC ≥1%), and best response to induction therapy (SD vs PR/CR). Niraparib crosses the blood–brain barrier in preclinical models; therefore, the key secondary objective is time to progression in the central nervous system as assessed by BICR using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Patient-reported outcomes, safety, and pharmacokinetic profiles will also be evaluated.

      Participants will be randomized (1:1) to niraparib (200 or 300 mg, orally, daily, depending on body weight) or placebo. Treatment will continue until disease progression, unacceptable toxicity or death, or for up to 3 years. All patients will continue on pembro (200 mg intravenously on Day 1 of each 21-day cycle) up to a maximum of 35 cycles from the beginning of induction therapy. Study (recruitment) start date: September 2020.

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