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Jamie E. Chaft



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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): Jamie E. Chaft

      • 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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    OA13 - Ideal Approach to Lung Resection and Novel Perioperative Therapy (ID 146)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      OA13.07 - Neoadjuvant Atezolizumab in Resectable NSCLC Patients: Immunophenotyping Results from the Interim Analysis of the Multicenter Trial LCMC3 (Now Available) (ID 1755)

      11:30 - 13:00  |  Author(s): Jamie E. Chaft

      • Abstract
      • Presentation
      • Slides

      Background

      The immune mechanisms dictating response and resistance to PD-(L)1 blockade are not well understood in early stage non-small cell lung cancer (NSCLC). Understanding these mechanisms will be key to improve outcomes and identify the next generation of predictive biomarkers of response to these therapies. Here, we present updated immunophenotyping at time of interim analysis of LCMC3, a multicenter trial of neoadjuvant atezolizumab in resectable NSCLC (NCT02927301).

      Method

      Patients received 2 cycles of atezolizumab before resection. Tumor, LN biopsies and PB were obtained pre-atezolizumab and at surgery. Paired PB, screening and surgical LN were analyzed using IMMUNOME flow cytometry. Plasma-based cytokine arrays were performed on a subset of patients. Immunophenotypic analyses were correlated with treatment effect, major pathologic response (MPR, primary endpoint) and preoperative treatment-related adverse events (preop-TRAE).

      Result

      We report on 55 patients with paired PB samples (analyzed within 72h after collection) and completed surgery. We observed preop-TRAE in 32/55 patients (18 grade 1, 13 grade 2, 1 grade 3). CD1c+ and CD141+ myeloid cells (MC) were lower at baseline in patients developing preop-TRAEs, while monocytic M-MDSCs were higher in those patients. Senescent T cells decreased in patients with preop-TRAE and increased in patients with non-preop-TRAE. After treatment, the absolute cell counts of late activated CD4+and CD8+T cells decreased in patients achieving MPR. LN IMMUNOME data, cytokine data and 12-month follow-up (DFS, OS) will be reported.

      table 1-page-001.jpeg

      Conclusion

      Preliminary immunophenotyping data from the interim analysis showed significantly lower baseline immunosuppressive cell subsets in patients with preop-TRAE and decreased late activated CD4+and CD8+T cells from PB in patients with MPR.These results, together with additional LN IMMUNOME and cytokine analyses, may improve our understanding of immunophenotypic features associated with outcome, and changes induced by neoadjuvant atezolizumab in early stage NSCLC patients.

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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): Jamie E. Chaft

      • 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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      P2.04-88 - Surgical Outcomes of a Multicenter Phase II Trial of Neoadjuvant Atezolizumab in Resectable Stages IB-IIIB NSCLC: Update on LCMC3 Clinical Trial (ID 1817)

      10:15 - 18:15  |  Author(s): Jamie E. Chaft

      • Abstract
      • Slides

      Background

      The role of immune checkpoint inhibitors in resectable NSCLC remains undefined. We report the updated safety results of the first multicenter trial assessing neoadjuvant atezolizumab (a PD-L1 inhibitor) for resectable NSCLC.

      Method

      Eligible patients with clinical stage IB-IIIB resectable NSCLC received 2 cycles of neoadjuvant atezolizumab (1200 mg, days 1, 22) followed by surgical resection (day 40±10). Pre- and post-treatment PET/CT, pulmonary function tests (PFT), and bio-specimens were obtained. Adverse events (AE) were recorded according to CTCAEv.4.0. Preoperative treatment-related TRAE (preop-TRAE) and postoperative TRAE (postop-TRAE) defined as AE onset on, or after date of surgery, were analyzed.

      Result

      Follow-up data to post-surgery visit were analyzed for 101 patients out of planned 180: mean age: 64.6 years; male: 47/101(46.5%); current smokers: 23/101(22.8%); non-squamous histology: 66/101(65.3%); and clinical stages IB(10.9%), IIA(15.8%), IIB(27.7%), IIIA(38.6%), and IIIB(6.9%). Two cycles of atezolizumab were not completed in 5/101(5.0%) patients due to grade 1 or 2 AEs. Surgery was not performed in 11/101(10.9%) patients: 5 demonstrated disease progression, and 6 for ‘other’ reasons. 6/101(5.9%) patients were deemed unresectable. Surgery was delayed (outside of 10-day window) in 10/90(11.1%) patients by an average of 11(1-39) days. Two of these delays were due to TRAEs (hypothyroidism and pneumonitis), 3 were patient-elected delays, 2 were surgeon-related, and 3 for ‘other’ reasons. Intraoperative vascular complications occurred in 2/90(2.2%) and extensive hilar fibrosis was noted in 20/90(22.2%) patients. Overall, there was insignificant mean change in the PFTs pre- vs. post-atezolizumab therapy. Only 3/101(3.0%) patients had treatment-related dyspnea, dyspnea on exertion, or pneumonitis.

      Table 1

      Treatment Related Adverse Events

      (TRAE)

      Preoperative TRAE

      (N = 101)

      Postoperative TRAE

      (N = 90)

      All AEs

      Any grade

      55 (54.5%)

      20 (22.2%)

      Grade 1

      29 (28.7%)

      7 (7.8%)

      Grade 2

      24 (23.8%)

      9 (10.0%)

      Grade 3

      2 (2.0%)

      4 (4.4%)

      Grade 4

      0

      0

      Grade 5

      0

      0

      Specific AEs

      Dyspnea

      1 (1.0%; grade 2)

      3 (3.3%; grade 1)

      Dyspnea on exertion

      1 (1.0%; grade 1)

      0

      Myalgia

      4 (4.0%; grade 1 or 2)

      0

      Hyperthyroidism

      3 (3.0%; grade 1 or 2)

      1 (1.1%; grade 1)

      Hypothyroidism

      0

      1 (1.1%; grade 2)

      Pneumonitis

      1 (1.0%; grade 3)

      3 (3.3%; grade 2 or 3)

      Transaminitis (AST or ALT)

      8 (7.9%; grade 1 or 2)

      3 (3.3%; grade 1 or 2)

      Post-atezolizumab Change in Pulmonary Function Tests

      PFT factor

      Mean change (95% Confidence Interval)

      FEV1 (N = 72)

      -0.6% (-2.6% to 1.3%)

      FVC (N = 72)

      0.0% (-1.8% to 1.8%)

      DCLO (N = 64)

      -1.2% (-4.1% to 1.7%)

      Conclusion

      Treatment with neoadjuvant atezolizumab in resectable stage IB-IIIB NSCLC was well tolerated, with minimal delay to surgery, and few treatment associated AEs. This trial continues to accrue and assess MPR, survival, and other long-term endpoints.

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    PL03 - Relevant Aspects of Lung Cancer Management (ID 90)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      PL03.02 - Bringing Immunotherapy into the Curative Setting: Emerging Data on Neoadjuvant Strategies (Now Available) (ID 3592)

      09:15 - 10:45  |  Presenting Author(s): Jamie E. Chaft

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immunotherapy with checkpoint inhibitors targeting PD-1 and PD-L1, as monotherapy or in combination with chemotherapy, have become standard of care in all patients with advanced lung cancer who do not have an actionable oncogene or contraindication.1, 2 Similarly patients with unresectable stage III non-small cell lung cancer who do not progress through concurrent chemoradiotherapy have improved progression free and overall survival with anti-PD-L1 consolidation therapy.3

      In early-stage disease, four randomized phase 3 studies are evaluating the role of adjuvant immunotherapy following standard of care chemotherapy. As is the nature of adjuvant investigation, these studies require years of clinical follow-up and will not mature until sufficient recurrence and/or death events occur.

      Neoadjuvant therapy has many advantages to the patient and for the sake of science. As a therapy, preop treatment is better tolerated and can be monitored for efficacy by imaging and pathologic regression. In terms of research, the early pathologic response endpoint may accelerate trial readouts. Investigation into pathologic response as a surrogate for survival in lung cancer is ongoing.4

      The true excitement about neoadjuvant investigation with immunotherapy and/or chemo-immuno combinations, is the theoretical therapeutic superiority of this approach over an adjuvant approach. This is hypothesized to be due to the tumor with its associated mutation specific neoantigens in situ during exposure to the PD-1 treatment, enabling a more robust tumor specific immune response. In pre-clinical mouse models, PD-1 monotherapy is more effective when administered neoadjuvantly versus adjuvantly.5

      The first experience with neoadjuvant PD-1 therapy in NSCLC was a small pilot study performed for safety and feasibility of this approach. No unexpected safety signals were noted and unanticipated pathologic regression observed.6 Two additional series with neoadjuvant immunotherapy have been presented, the Lung Cancer Mutation Consortiums experience with PD-L1 monotherapy and the MD Anderson study of PD-1 +/- CTLA-4 therapy. Both studies confirmed this approach is both safe and induces pathologic regression (at times pathologic complete response) in some patients.7, 8 Correlative studies to try to identify predictors of response and resistance are ongoing. PD-L1 expression is not as clearly predictive in this patient population as in advanced disease.

      Shortly after PD-1 monotherapy was demonstrated to be safe and have some anti-cancer efficacy, many other monotherapy and combination studies launched. Two combination studies rapidly accrued. The combination of carboplatin, a taxane, and a PD-1/L1 agent have been demonstrated by two groups to induce major pathologic regression in the majority of patients.9, 10 In the Spanish Lung Cancer Group study, complete pathologic response was seen in more than 50% of resected patients.10

      These studies have spurred a tremendous interest in the best neoadjuvant therapy. There are 4 international phase 3 studies enrolling patients to receiving neoadjuvant chemotherapy with or without immunotherapy (NCT03800134, NCT03456063, NCT03425643, NCT02998528). Many of these studies have pre-specified pathologic response co-primary endpoints that will be evaluable well before classic clinical endpoints. These studies will help substantiate the role of immunotherapy in the preoperative setting and pathologic response as a possible surrogate endpoint.

      As the international adjuvant immunotherapy efforts wrap up, the research community should commit to enrolling patients on neoadjuvant studies. This is our best chance to improve cure rates in early stage lung cancer – to identify effective therapy for those cancers of a clinical stage to justify induction therapy and adjuvant therapy for those incidentally upstaged at the time of surgery. Within these therapeutic studies are essential biomarker efforts. These efforts are poised to be successful and position the research community to extend investigation into the earliest stages of non-small cell lung cancer, looking to improve cure rates for all stages of disease.

      1. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:2078-2092.

      2. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med 2018;379:2040-2051.

      3. Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med 2018;379:2342-2350.

      4. Blumenthal GM, Bunn PA, Jr., Chaft JE, et al. Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer. J Thorac Oncol 2018;13:1818-1831.

      5. Liu J, Blake SJ, Yong MC, et al. Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease. Cancer discovery 2016;6:1382-1399.

      6. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med 2018.

      7. Kwiatkowski DJ. Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3). J Clin Oncol 2019;37:abstr 8503.

      8. Cascone T. Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): Clinical and correlative results from the NEOSTAR study. J Clin Oncol 2019;37:abstr 8504.

      9. Shu CA. Neoadjuvant atezolizumab + chemotherapy in resectable non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2018;36:8532-8532.

      10. Provencio M. NEO-adjuvant chemo-immunotherapy for the treatment of STAGE IIIA resectable non-small-cell lung cancer (NSCLC): A phase II multicenter exploratory study—Final data of patients who underwent surgical assessment. J Clin Oncol 2019;37:abstr 8509.

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