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Patrick M. Forde



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    ES22 - Immunotherapy - Discovering New Areas (ID 25)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      ES22.01 - Immunotherapy in Resectable NSCLC (Now Available) (ID 3275)

      15:45 - 17:15  |  Presenting Author(s): Patrick M. Forde

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immune checkpoint blockade with inhibitors of the PD-1/PD-L1 interaction have improved survival substantially for patients with advanced non-small cell lung cancer. Despite many clinical trials of different combination regimens, the benefit from perioperative platinum doublet chemotherapy in resectable lung cancer is modest with an approximate 5% improvement in 5 year survival over surgery alone.

      This session will review the background of systemic therapy for resectable lung cancer and data reported to date with single agent PD-1 blockade, PD-(L)1-based immunotherapy combinations, and chemotherapy combined with anti-PD-1. Ongoing phase 3 clinical trials of neoadjuvant and adjuvant immunotherapy will be discussed and future directions both in novel science and clinical trials explored.

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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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      MA11.10 - Peripheral T Cell Repertoire Evolution in Resectable NSCLC Treated with Neoadjuvant PD-1 Blockade (Now Available) (ID 1999)

      14:00 - 15:30  |  Author(s): Patrick M. Forde

      • Abstract
      • Presentation
      • Slides

      Background

      Neoadjuvant PD-1 blockade has emerged as a promising treatment for resectable NSCLC. The neoadjuvant setting provides a unique opportunity to examine temporal-spatial dynamics of the T cell repertoire in the peripheral and tumoral compartments in response to PD-1 blockade.

      Method

      T-cell receptor (TCR) repertoire dynamics and composition were assessed in matched tumor, normal lung, and longitudinal peripheral blood from 20 NSCLC patients treated with neoadjuvant nivolumab (NCT02259621) and were correlated with major pathologic response (MPR , ≤10% viable tumor in resected specimen) at the time of resection. Treatment-induced dynamics of activated T cell clonotypes were additionally evaluated using TCR sequencing (TCRseq) of flow-sorted PD-1+ T cell populations. To focus on the phenotype of on-treatment intratumoral T cell clones that were recruited from the periphery, combined single-cell RNAseq/TCRseq was performed on post-treatment tumors of 6 patients (3 MPR and 3 non-MPR).

      Result

      MPR was associated with a more clonal intratumoral TCR repertoire and greater clonotypic sharing between pre-treatment blood and post-treatment tumor bed relative to non-MPR. Peripheral repertoire remodeling in response to anti-PD-1 treatment correlated with increased tumor infiltration. Specifically, in patients with MPR, the post-treatment tumor bed was enriched with T cell clones that were peripherally expanded between 2-4 weeks after PD-1 blockade. Clonotypic tracking of the peripherally expanded clones revealed persistence of those clones in the periphery 1+ years following surgical resection and cessation of PD-1 blockade. Single-cell RNAseq/TCRseq analyses revealed distinct phenotypes of peripherally expanded TIL for patients with MPR, with upregulated gene programs associated with cytotoxicity and cytoprotective effects against oxidative stress. Long-term peripherally-persistent TILs had significant upregulation of genes including GZMK, DUSP2, NKG7, 4-1BB and down-regulation of CTLA-4, CXCL13 and PDCD1 as compared to short-lived clones.

      Conclusion

      Our findings support the notion that neoadjuvant checkpoint blockade expands anti-tumor T cell clones in the periphery that can accumulate in tumor bed, facilitate tumor regression, and promote clonotypic persistence in the periphery. Importantly, our data demonstrate the systemic effect of neoadjuvant PD-1 blockade and indicate that the periphery may be an underappreciated originating compartment of effective anti-tumor immunity.

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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
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.16-06 - Early Changes in Pulmonary Function Are Associated with Development of Pneumonitis in NSCLC Patients Receiving Immune Checkpoint Blockade (ID 526)

      09:45 - 18:00  |  Author(s): Patrick M. Forde

      • Abstract

      Background

      Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event of immune checkpoint inhibitors (ICI). Pulmonary function test (PFT) changes have been noted in patients receiving drugs such as bleomycin, and PFTs are routinely used to monitor for lung toxicity in such patients. We retrospectively analyzed PFTs in ICI-treated non-small cell lung cancer (NSCLC) patients to identify PFT changes associated with ICI use, and determine whether CIP modified this association.

      Method

      The study cohort included NSCLC patients who were treated with PD-(L)1 ICI as standard-of-care or part of a clinical trial at Johns Hopkins from 1/2007 - 7/2017 and had ≥1 PFT in the year preceding and/or following ICI initiation. The primary outcomes of interest were forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. Linear regression based on generalized estimating equations (GEE) was used to evaluate changes overall and by CIP status (CIP+: Patients who develop CIP, CIP-: Patients who do not develop CIP).

      Result

      A total of 58 patients (43 CIP-, 15 CIP+) were included. Median age was 66y and 96% of patients were current/former smokers. 52% had adenocarcinoma and 45% had squamous histology. 75% had stage III/IV disease at initial diagnosis. Patients received single agent PD-(L)1 ICI (77%), ipilimumab+nivolumab (ipi/nivo) (12%), and novel PD-(L)1 ICI (10%). Compared to CIP- patients, CIP+ patients were more likely to have squamous histology (67% vs. 34%) and receive ipi/nivo (27% vs 7%). In the overall study cohort, ICI initiation was associated with a 0.335L reduction in FEV1 (95% CI: -0.713, 0.042), 0.747L reduction in FVC (-1.21, -0.28), and 0.061 increase in FEV1/FVC (0.006, 0.116) consistent with restrictive lung physiology. Compared to CIP- patients, CIP+ patients had a 0.35L (-0.724, 0.013) lower FEV1 and 0.516L (-1.06, 0.02) lower FVC, while FEV1/FVC did not differ (-0.07, 0.07). The rate of change of FEV1/FVC over time was significantly higher among patients with vs without CIP (p<0.05).

      Conclusion

      Our data suggest that initiation of PD-(L)1 ICI is associated with progressively restrictive lung function changes on PFTs (increased FEV1/FVC) irrespective of CIP development. Furthermore, our results indicate that patients who eventually develop CIP may have an altered respiratory physiology prior to ICI initiation, with longitudinal changes in lung function that differ when compared to CIP- patients who receive checkpoint blockade. To further characterize PFT changes associated with CIP, a prospective study assessing serial PFTs in NSCLC patients receiving ICIs is underway.

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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): Patrick M. Forde

      • 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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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-24 - Transcriptional Profiling of Neoantigen Specific T Cells in Resectable NSCLC Treated with Neoadjuvant Anti-PD-1 (Now Available) (ID 2357)

      10:15 - 18:15  |  Author(s): Patrick M. Forde

      • Abstract
      • Slides

      Background

      Neoadjuvant nivolumab has a manageable safety profile and can be effective in patients with resectable non-small cell lung cancer (NSCLC). To characterize the immune response in these patients, we sought to evaluate the existence and dynamics of neoantigen specific tumor-infiltrating T cells and identify their molecular phenotype including co-inhibitory checkpoint expression.

      Method

      We evaluated peripheral blood and tumor infiltrating lymphocytes from seven patients treated with nivolumab. To identify neoantigen-specific T cell responses, we used MANAFEST (Mutation Associated Neoantigen Functional Expansion of Specific T cells), an assay we developed that links antigen specificity with unique CD8+ TCR Vβ CDR3 identities. We then carried out single cell TCRseq/RNAseq of tumor infiltrating T lymphocytes (TIL) to enumerate the genome wide digital gene expression and T cell clonotypic identity of each single cell (VDJ+DGE analysis), and particularly those with Vβ CDR3 regions identical to those identified as neoantigen-specific by MANAFEST.

      Result

      Neoantigen-specific TCRs were detected in peripheral blood in all 3 patients with major pathologic response (MPR) and in 3 of 4 patients without MPR. Several of these clonotypes were found in the resected tumor and underwent peripheral expansions upon PD-1 blockade. In one notable patient, MD043-011, MANAFEST detected a T cell clonotype specific for a CARM1 R208W mutation, despite this patient having no evidence of pathologic response. This neoantigen-specific clonotype represented 3.4% of TIL. Two years later, this patient recurred with a solitary brain metastasis. Single cell analyses of TIL in the primary lung lesion and brain metastasis revealed the same neoantigen-specific T cell clonotype was detected in the metastatic lesion. Strikingly, this clonotype exhibited a differential expression profile in the primary and recurrent lesion, with the clonotype in the primary tumor having an enrichment and upregulation of heat shock proteins indicating molecular stress and the clone in the metastatic lesion having an upregulation of checkpoint molecules, including CTLA4, TIM3, and LAG3. T cell cloning and validation experiments, as well as identification of transcriptional programs associated with MPR, are ongoing.

      Conclusion

      The coupling of MANAFEST with single cell VDJ+ DGE analysis enabled us to characterize antigen specific clonotypes after differential expansion using the TCR as a molecular barcode. The presence of alternate co-inhibitory immune checkpoints on neoantigen-specific TIL from non-responding tumors suggests a potential driver of resistance to anti-PD-1 in early stage NSCLC. Ultimately, this integrative approach may provide key insights in predicting and understanding clinical response to neoadjuvant PD-1 blockade in NSCLC.

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      P2.04-28 - NeoCOAST: Neoadjuvant Durvalumab Alone or with Novel Agents for Resectable, Early-Stage (I–IIIA) Non‑Small Cell Lung Cancer (ID 56)

      10:15 - 18:15  |  Author(s): Patrick M. Forde

      • Abstract
      • Slides

      Background

      Resectable, early‑stage non‑small cell lung cancer (NSCLC) is a potentially curable disease.The current standard of care is surgery with or without adjuvant or neoadjuvant platinum‑based doublet chemotherapy. However, over half of patients eventually relapse after surgery and die from NSCLC. Clinical studies have shown that neoadjuvant programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) checkpoint inhibitors may yield clinically meaningful pathological responses in patients with resectable NSCLC.1–3 The NeoCOAST trial is a multidrug platform study to assess the PD-L1 checkpoint inhibitor durvalumab alone or in combination with novel agents, with the goal of identifying new treatment strategies to improve clinical outcomes of patients with resectable, early-stage NSCLC.

      Method

      NeoCOAST (NCT03794544) is a phase 2, open-label, randomized trial that will initially evaluate the clinical activity and safety of neoadjuvant durvalumab alone or in combination with the novel agents oleclumab (MEDI9447), monalizumab (IPH2201) and danvatirsen (AZD9150), in patients with resectable, stage I (>2 cm) to IIIA NSCLC. New treatment arms evaluating other durvalumab combinations may be added based on emerging preclinical and clinical data. The primary endpoint is major pathological response rate in the resected tumor specimen after treatment with neoadjuvant durvalumab alone or in combination with novel agents. Secondary objectives include feasibility of tumor resection surgery within 14 days of the end of the 4-week treatment period, safety, pathological complete response rate, pharmacokinetics and immunogenicity. Correlative translational analyses include tumor genomics, changes in the tumor microenvironment, and T cell populations. NeoCOAST is open for accrual with an estimated total target enrollment of up to 40 patients per treatment arm.

      References

      1Forde PM, et al. N Engl J Med. 2018;378:1976–86.

      2Rusch V, et al. MA04.09. Presented at IASLC 19th World Conference on Lung Cancer, 23–26 September 2018, Toronto, Canada.

      3Cascone T, et al. LBA49. Presented at European Society of Medical Oncology Congress, 19–23 October 2018, Munich, Germany 2018.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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