Virtual Library

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    ES01 - Choosing Systemic Therapies After Chemoimmunotherapy in NSCLC (ID 147)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
    • Presentations: 3
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      ES01.01 - Non-Squamous (ID 3939)

      09:15 - 10:15  |  Presenting Author(s): Virote Sriuranpong

      • Abstract
      • Slides

      Abstract not provided

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      ES01.02 - Choosing Systemic Therapies After Chemoimmunotherapy – Squamous (ID 3940)

      09:15 - 10:15  |  Presenting Author(s): Claudio Marcelo Martin

      • Abstract
      • Slides

      Abstract

      Concurrent chemoimmunotherapy, chemotherapy followed by immunotherapy, and immunotherapy followed by platinum based chemotherapy are options for patients with squamous cell carcinoma. No randomized trials have been done in this scenario and currently all our information comes from trials done in the pre-immunotherapy era.

      Docetaxel, docetaxel plus ramucirumab, and afatinib are options in this setting.

      New target therapies are being explored as well as new immunotherapeutical approaches, like targeting IL B 1.

      Other options for squamous cell carcinoma after chemoimmunotherapy are clearly needed.

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      ES01.03 - Systemic Therapy after Chemo IO in Small Cell Lung Cancer (ID 3941)

      09:15 - 10:15  |  Presenting Author(s): Charu Aggarwal

      • Abstract
      • Slides

      Abstract not provided

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    ES02 - Pro-Con: Do We Need Biomarkers to Guide the Choice of Immunotherapy Treatment? (ID 157)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Immunotherapy (Phase II/III Trials)
    • Presentations: 4
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      ES02.01 - We Should Choose Treatment Based on PD-L1, TMB and Other Biomarkers (ID 3970)

      10:30 - 11:30  |  Presenting Author(s): Ticiana A Leal

      • Abstract
      • Slides

      Abstract not provided

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      ES02.02 - Immune Checkpoint Blockade for All NSCLC Regardless of PD-L1, TMB or Other Biomarkers (ID 3971)

      10:30 - 11:30  |  Presenting Author(s): Naiyer Rizvi

      • Abstract
      • Slides

      Abstract not provided

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      ES02.03 - We Should Use IO Alone as Maintenance (ID 3972)

      10:30 - 11:30  |  Presenting Author(s): Roy S. Herbst

      • Abstract
      • Slides

      Abstract not provided

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      ES02.04 - We Should Use Combination of IO and Chemotherapy as Maintenance (ID 3973)

      10:30 - 11:30  |  Presenting Author(s): Marina Chiara Garassino

      • Abstract
      • Slides

      Abstract not provided

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    ES03 - Understanding and Treating Oligometastatic Diseases (ID 161)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Locoregional and Oligometastatic Disease
    • Presentations: 6
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      ES03.01 - Chair (ID 3975)

      10:30 - 11:30  |  Presenting Author(s): Linda W Martin

      • Abstract

      Abstract not provided

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      ES03.02 - Chair (ID 3976)

      10:30 - 11:30  |  Presenting Author(s): Yasushi Nagata

      • Abstract

      Abstract not provided

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      ES03.03 - Characterization and Classification of Oligometastatic Disease (ID 3977)

      10:30 - 11:30  |  Presenting Author(s): Matthias Guckenberger

      • Abstract
      • Slides

      Abstract not provided

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      ES03.04 - Timing of Systemic Therapy in OMD (ID 3978)

      10:30 - 11:30  |  Presenting Author(s): Simon Ekman

      • Abstract
      • Slides

      Abstract

      The optimal treatment sequence of systemic therapy and local ablative therapy (LAT) in non-small cell lung cancer is still unclear. An individualized assessment of every patient is necessary to develop a radical-intent treatment plan and the use of multidisciplinary teams is encouraged. There are several factors to consider for systemic therapy in the OMD setting, including extension of primary tumor, presence or absence of targetable mutations, number and location of metastases, synchronous vs. metachronous OMD, patient-related factors and previous systemic treatments. This presentation will explain the scientific evidence that exists for different treatment strategies integrating systemic therapy and LAT, including for oncogenic-driven tumors, chemotherapy and immunotherapy.

      References:

      Guckenberger et al. Lancet Oncol 2020; 21: e18–28

      Dingemans et al. Journal of Thoracic Oncology Vol. 14 No. 12: 2109-2119

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      ES03.05 - Surgery as a Component of Local Consolidative Therapy (ID 3979)

      10:30 - 11:30  |  Presenting Author(s): Mara B Antonoff

      • Abstract
      • Slides

      Abstract

      Historically, treatment for non-small cell lung cancer (NSCLC) has been stage-dependent, with surgery typically considered the standard of care for stage I disease and a potential component of multi-modality care for stages II-III. By contrast, for stage IV disease, therapy aimed at prolongation of life has included systemic treatments, including chemotherapy, and, in recent years, targeted agents and immunotherapy. For metastatic disease, surgery has previously had a fairly limited role. However, oligometastatic disease may offer a potential opportunity for more aggressive local options. The distinct tumor biology and limited disease burden may be associated with improved outcomes.1

      The landmark oligometastatic trial published by Gomez in 20162 aimed to assess the effect of local consolidative therapy (LCT) on progression-free survival (PFS) of patients with 3 or fewer metastases who received standard first-line chemotherapy, and patients were randomized to LCT vs maintenance treatment. LCT improved PFS and time to development of new metastatic lesions. Moreover, comprehensive LCT (cLCT) was also shown to improve overall survival (OS).3 A subsequent review from our institution of 194 patients, including those both on and off the oligometastatic clinical trial, aimed to identify those patients who would derive greatest benefit from LCT.4 This study revealed that cLCT was associated with improved OS, with median survival of 29 months for cLCT compared to 23 months for those with subcomprehensive LCT or no LCT. Moreover, lower intrathoracic stage, non-squamous histology, and absence of bone metastases were all associated with improved OS after cLCT, theoretically identifying those patients most likely to benefit from aggressive local therapy—which can consist of surgery or radiation.

      In terms of surgery itself, we next aimed to evaluate the outcomes of operative pulmonary resection as LCT in oligometastatic disease,5 using radiotherapy as a benchmark comparator. Evaluating patients with 3 or fewer synchronous metastases and received LCT to all sites, we analyzed survival and progression. Surgery to the primary tumor was performed in 28% after a median of 3.7 months. 90-day post-treatment mortality after surgery was 0%, and, after a median follow-up of 57 months, median OS after surgery was greater than 55 months. Median OS for radiation in this group was 23 months. Thus, it was concluded that surgery should remain a component of LCT for operable oligometastatic NSCLC patients, and it should be considered in randomized trial for patients with metastatic disease.

      While surgery has demonstrated survival benefits in the oligometastatic population, the potential complexity of these procedures cannot be overstated. In our institutional experience, thoracotomies have been required in more than 4/5 of operations, and adhesions and hilar fibrosis have been common. Events such as need for proximal pulmonary arterial control and unplanned changes in extent of operation are not infrequent, and the majority of cases have been reported as more difficult than usual. Thus, proper patient selection for surgery is imperative, as is preparation for the types of resources potentially needed for these cases. Despite surgical complexity, ability to achieve negative margins and to safely manage the patients perioperatively has been reassuring.

      Given the success of surgery as a component of LCT, surgery has become an important part of ongoing clinical trials evaluating LCT after novel agents for metastatic NSCLC. The LONESTAR trial6 aims to evaluate the benefits of LCT after immunotherapy, in that patients receive 12 weeeks of ipilumimab and nivolumab, after which those individuals with non-progressive disease are randomized to LCT + continued immunotherapy vs continued immunotherapy alone. While radiation is required to at least one disease site, surgery to the primary site of disease is emphasized whenever possible. Similar to the LONESTAR trial, the NORTHSTAR trial is investigating the role of LCT after tyrosine-kinase inhibitor therapy for patients with EGFR-mutant metastatic NSCLC. Patients who have non-progressive disease after 6-12 weeks of osimertinib are randomized to LCT vs continued targeted therapy, again, offering surgery whenever feasible to the primary site of disease.7 More recently, the BRIGHTSTAR trial was initiated, evaluating the role of LCT after 8 weeks of brigatinib for patients with metastatic ALK-mutated NSCLC, with the primary endpoints of safety and feasibility and secondary endpoints of PFS, OS, and time to progression.8 A number of patients have already undergone surgery on each of these trials, with promising perioperative outcomes.

      Despite the potential for innovation and expanded surgical indications, consideration must be given to the safety and potential technical challenges in such cases. We must consider issues related to fibrosis, adhesions, and sclerotic lymph nodes, as well as our limitations in identifying those patients with residual disease vs complete response.

      Surgery as LCT for oligometastatic NSCLC represents an exciting frontier for thoracic surgery, as a potential opportunity to help patients with advanced disease. Implications for training and resource allocation remain ever pertinent, and surgery needs to be considered as a potential therapeutic component in novel clinical trials in even advanced disease.


      References:

      1. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995 Jan;13(1):8-10.

      2. Gomez DR et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016 Dec;17(12):1672-1682.

      3. Gomez DR et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol. 2019 Jun 20;37(18):1558-1565.

      4. Mitchell KG et al. Improved Overall Survival With Comprehensive Local Consolidative Therapy in Synchronous Oligometastatic Non-Small-Cell Lung Cancer. Clin Lung Cancer. 2020 Jan;21(1):37-46.e7.

      5. Mitchell KG et al. Pulmonary resection is associated with long-term survival and should remain a therapeutic option in oligometastatic lung cancer. J Thorac Cardiovasc Surg. 2020 Mar 25:S0022-5223(20)30633-4.

      6. Phase III Trial of (LCT) After Nivolumab and Ipilimumab, https://clinicaltrials.gov/ct2/show/NCT03391869

      7. Elamin YY et al. Randomized phase II trial of osimertinib with or without local consolidation therapy (LCT) for patients with EGFR-mutant metastatic NSCLC (NORTHSTAR). Annals of Oncology (2018)29 (suppl_8):viii493-viii547.

      8. Elamin Y et al. BRIGHTSTAR: A pilot trial of local consolidative therapy (LCT) with brigatinib in tyrosine kinase inhibitor (TKI)-naïve ALK-rearranged advanced NSCLC.Journal of Clinical Oncology 2020 38:15_suppl, 9624-9624

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      ES03.06 - Radiation as a Component of Treatment for Oligometastatic Disease (ID 3980)

      10:30 - 11:30  |  Presenting Author(s): Kevin Lee Min Chua

      • Abstract
      • Slides

      Abstract not provided

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    ES04 - Strategies to Increase Cure Rates in Stage III NSCLC: Optimising Checkpoint Inhibitors and Beyond (ID 181)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Locoregional and Oligometastatic Disease
    • Presentations: 3
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      ES04.01 - Navigating the Evaluation of Novel Systemic Agents in Stage III Disease (ID 4009)

      11:45 - 12:45  |  Presenting Author(s): Karen Kelly

      • Abstract
      • Slides

      Abstract

      Navigating the Evaluation of Novel Systemic Agents in Stage III Disease. Karen Kelly, MD University of California, Davis, Sacramento California. Stage III non-small cell lung cancer (NSCLC) is diagnosed in approximately 22% of lung cancer patients. For the majority of patients who are unresectable, the standard treatment is chemoradiotherapy followed by one year of consolidation durvalumab based upon the PACIFIC results that compared consolidation durvalumab to placebo (1). The recent 4-year efficacy data continued to show a significant overall survival and progression free survival benefit with durvalumab 49.6% versus 36.3% (HR=0.71 ;95% CI 0.57 – 0.88) and 35.4% versus 19.5% (HR=0.55; 95% CI 0.44-0.67), respectively (2). Durvalumab consolidation is the first major advancement in the treatment of Stage III disease in decades. However distant metastases remain the barrier to cure. Hence, continued evaluation of systemic agents is needed but how do we incorporate the evaluation of novel agents within this new regimen? There are multiple approaches: 1) the evaluation of dual immunotherapy regimens in the consolidation setting, 2) adding immunotherapy to the chemoradiotherapy backbone followed by consolidation immunotherapy, 3) the addition of neoadjuvant regimens, and 4) substituting immunotherapy for chemotherapy in combination with radiotherapy. Trials evaluating each of these approaches are underway. Similar strategies are being pursued with tyrosine kinase inhibitors (TKI) for patients with oncogenic driven stage III NSCLC. For patients with resectable stage III NSCLC, consistent and impressive antitumor activity has been demonstrated with neoadjuvant immunotherapy plus chemotherapy across several small phase II trials. For example, NADIM a multi-center phase II trial administered 3 cycles of paclitaxel, carboplatin and nivolumab prior to resection in 46 patients with N2 or T4N0/1 NSCLC (3). The study met its primary endpoint of progression free survival at 24 months with 77% of patient’s progression free at this time point. Major pathological response was seen in 82.6% of patients with 63.4% of patients achieving a complete pathological response. Neoadjuvant TKIs are also being evaluated in this setting but face unique challenges.
      An important component of drug development includes parallel development of predictive biomarkers. This is critical for achieving our goal of precision therapy for Stage III patients. In the PACIFIC study, an unplanned subset analysis revealed patients whose tumors did not express PD-L1 did not have a progression free or overall survival benefit compared to placebo (1). This information led the EMA to approve consolidation durvalumab in PD-L1 expressors while the FDA approval included all patients regardless of tumor PD-L1 expression level. Both tissue and blood based predictive biomarkers are under consideration.
      This presentation will review the multiple trial designs evaluating novel agents, show the current data utilizing these designs, discuss associated biomarkers and close with future directions.
      1. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 377: 1919-1931, 2017.
      2. Faivre-Finn C, Vicente D, Kurata T, et al. Durvlaumb after Chemoradiotherapy in Stage III NSCLC: 4-year survival update from the Phase 3 PACIFIC trial. ESMO 2020.
      3. Provencio M, Nadal E, Insa A, et al. Neoadjuvant Chemotherapy and Nivolumab in Resectable Non- Small-Cell Lung Cancer (NADIM): An Open-Label, Multicenter, Single-Arm, Phase II Trial. Lancet Oncol 2020; published online Sept. 24.

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      ES04.02 - Biology Guided Adaptive Radiation Therapy (BigART) and Personalized Immunotherapy in Unresectable Stage (ID 4010)

      11:45 - 12:45  |  Presenting Author(s): Feng-Ming (Spring) Kong

      • Abstract

      Abstract not provided

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      ES04.03 - Extending Durvalumab Maintenance to Special Populations (ID 4011)

      11:45 - 12:45  |  Presenting Author(s): Raffaele Califano

      • Abstract
      • Slides

      Abstract not provided

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    ES05 - Value in Lung Cancer, from Screening to Treatment (ID 203)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Health Services Research/Health Economics
    • Presentations: 7
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      ES05.01 - Chair (ID 4037)

      14:15 - 15:15  |  Presenting Author(s): Antonio Calles

      • Abstract

      Abstract not provided

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      ES05.02 - Chair (ID 4038)

      14:15 - 15:15  |  Presenting Author(s): Lucinda Morris

      • Abstract

      Abstract not provided

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      ES05.03 - Radiation Oncology: Value and Innovation (ID 4039)

      14:15 - 15:15  |  Presenting Author(s): Fumiko Ladd Chino

      • Abstract
      • Slides

      Abstract

      Radiation therapy continues to be an integral part of a multimodality treatment plan in the definitive, preoperative, postoperative, and palliative management of all stages of lung cancer. As radation techniques continue to evolve though innovative technological improvements, escalating costs related to advanced technologies must be balanced with potential benefits in terms of disease or symptom/toxicity control. "Value" in cancer care can be be difficult to strictly define and quantify but standardly involves assessment of quality vs costs. Frameworks for defining value within Radiation Oncology have been proposed to include elements from the quality of care delivery to both objective and subjective outcomes including survival and patient-reported outcomes. Advanced techniques within Radiation Oncology have been shown to be cost effective in many situations, but, as always, careful patient selection is key.

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      ES05.04 - Lung Cancer Screening in Lower Resource Settings (ID 4040)

      14:15 - 15:15  |  Presenting Author(s): Ricardo Santos

      • Abstract
      • Slides

      Abstract not provided

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      ES05.05 - Age, Gender and Ethnicity: Disparities in Lung Cancer (ID 4041)

      14:15 - 15:15  |  Presenting Author(s): Linda Coate

      • Abstract
      • Slides

      Abstract not provided

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      ES05.06 - Molecular Testing, Targeted Agents and Immunotherapy in Lung Cancer: Are They Worth the Cost? (ID 4042)

      14:15 - 15:15  |  Presenting Author(s): Gilberto Lopes

      • Abstract
      • Slides

      Abstract not provided

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      ES05.07 - Defining Value and Common Sense in Lung Cancer (ID 4043)

      14:15 - 15:15  |  Presenting Author(s): Bishal Gyawali

      • Abstract
      • Slides

      Abstract

      Sometimes, in the enthusiasm for new technologies and drugs, we tend to forget the basic philosophy of cancer care- to help patients live longer and better lives. Common sense in oncology is a revolution that attempts to bring the fundamental philosophy of helping patients live longer and better lives back to oncology care, education, and policy. In my talk, I will discuss some key domains of the “common sense in oncology” philosophy with relevant examples from lung cancer. I will discuss issues primarily related to the hijacking of evidence-based medicine (statistical significance versus clinical meaning, suboptimal control arms, subgroup analyses, non-inferiority designs, spins, and biases) in the context of lung cancer. I will also discuss the concepts of avoiding wisely, financial toxicity, and "cancer groundshot". These discussions will make the audience aware of the need to critically appraise the lung cancer literature, think in terms of prioritization of resources, and apply these concepts in clinical practice, education of trainees and policy planning related to lung cancer.

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    ES06 - Perioperative Therapy for Early Stage NSCLC (ID 221)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Early Stage/Localized Disease
    • Presentations: 4
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      ES06.01 - Neoadjuvant IO Monotherapy vs. Chemo-IO (ID 4046)

      14:15 - 15:15  |  Presenting Author(s): Mariano Provencio  |  Author(s): Virginia Calvo, Raquel Laza Briviesca, Alberto Cruz-Bermudez

      • Abstract
      • Slides

      Abstract

      Anti-PD1/PD-L1 (anti-PD(L)1) antibodies activity is based on the blockade of PD-1 protein in lymphocytes or PD-L1 in tumor cells, preventing lymphocytes inactivation and promoting tumor elimination. A great part of the knowledge of its mechanism is due to neoadjuvant immunotherapy studies. In the situation with the intact tumor, on one side, anti-PD(L)1 rejuvenates the tumor-specific cytotoxic T cells from the tumor microenvironment, causing them to activate, proliferate and mobilize to eliminate distant micrometastasis. Additionally, anti-PD(L)1 increases tumor antigen presentation by dendritic cells in the tumor-draining lymph nodes activating new tumor-specific T cells that then migrate to tumor sites. Both processes trigger a powerful systemic anti-tumor immune response and the generation of memory T-cells that may provide long-term protection. Conversely, the neoantigen repertoire is reduced when the primary tumor is resected, limiting this anti-tumor immune response in the adjuvant setting and representing a strong argument for the neoadjuvant approach. Moreover, several immunological pathways are disrupted by surgical stress. While essential for wound healing, surgical stress leads to the expansion of Tregs, MDSC, and M2 macrophages, resulting in an overall state of immunosuppression with PD-1/CTLA-4 increase and T-cell exhaustion. Immune checkpoint inhibitors in neoadjuvant settings might be advantageous in activating tumor-infiltrating T-cells prior to surgery, and avoiding PD-1 expression on immune cells in the postoperative period.

      Patients with NSCLC treated with neoadjuvant chemotherapy exhibited higher levels of PD-L1+ malignant cells and TILs than patients who underwent upfront tumor resection without neoadjuvant treatment. In patients who underwent neoadjuvant treatment, those with higher abundance of helper T cells and TAMs survived longer, suggesting that these cells may be important in chemotherapy response.

      The neoadjuvant treatment has theoretical advantages like assessment of response to chemotherapy in vivo and this, in turn, helps identify patients who will potentially benefit from this therapy; perhaps the better locoregional drug delivery because of intact vessels presurgery; better tolerability; early treatment of micrometastatic disease; downstaging with improved resectability and offers the possibility for the identification of surrogate clinical and biological markers that may correlate with response to therapy and a potential long-term outcome. However neoadjuvant therapy has potential disadvantages: delay in local therapy due to toxicity, risk progression in chemoresistant patients, and pre-operative complications.

      The prolonged duration of clinical trials for resectable stages I and III NSCLC, in which OS has been used as the primary endpoint, has resulted in slow progress and high expenses. There is a need for surrogate markers of efficacy outcome, aside from the traditional endpoints of OS or PFS, to accelerate the development of new therapies in early-stage NSCLC. Complete surgical resection, tumor downstaging, and complete and major pathologic responses after neoadjuvant chemotherapy have been associated with improved survival in resectable NSCLC.

      Multiple checkpoint inhibitors have been evaluated as neoadjuvant treatment, but their use in this setting remains investigational.

      Forde, et al. evaluated the feasibility of two doses of neoadjuvant PD-1 blockade in a recent pilot study in 21 patients with early-stage (I–IIIA) NSCLC (NCT02259621). Two preoperative doses of the anti-PD-1 inhibitor nivolumab (3mg/kg) were administered intravenously every two weeks, with surgery planned about 4 weeks after starting the neoadjuvant therapy. While only 10% of patients had objective responses on post-treatment CT-scans, MPR occurred in 45% of patients who went to surgery and 13% of patients had pathologic complete responses. Furthermore, MPR occurred in PD-L1-positive and PD-L1-negative tumors, and TMB was predictive of pathologic response to anti-PD-1 therapy.

      LCMC3 trial (NCT02927301) is a phase II single-arm study of neoadjuvant atezolizumab monotherapy in patients with resectable early-stage NSCLC. The initial safety analysis of the first 54 of 180 planned patients who received two cycles of atezolizumab (PD-L1 inhibitor) monotherapy every three weeks in patients with stages IB to selected IIIB (T3N2) resectable NSCLC prior to surgical resection. By RECIST, 6/82 patients had a partial response, 72 had stable disease and 4 had progressive disease. The MPR rate was 18% (95% CI: 11-28%) 15/82, 4 patients had CPR (5%).

      NEOSTAR study (NCT03158129) is a phase II study of induction checkpoint blockade for untreated patients with stage I-IIIA (single N2) NSCLC. The patients received three doses of nivolumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg q2w followed by surgery. Five of the 31 patients initially scheduled for surgery did not proceed to resection (one with hypoxemia grade 3, two with high surgical risk and two were no longer resectable). In the 26 resected patients, MPR rate was 28% with nivolumab and 31% with the combination. In ASCO 2019 updated data were presented, 39 of 44 underwent surgery, 89% resectability. The MPR rate was 24% overall, 17% with nivolumab, and 33% with the combination therapy. Secondary adverse events were 4%, including 2 bronchopleural fistulas and 8 air leaks.

      As for combined ICI and chemotherapy, there are also different studies.

      NADIM trial (NCT03081689) is a prospective, open-label, single-arm phase 2 trial, that evaluated the safety and efficacy of neoadjuvant chemotherapy paclitaxel + carboplatin plus nivolumab followed by adjuvant nivolumab in 46 patients with resectable stage IIIA (N2 or T4) NSCLC. The primary endpoint was progression‑free survival (PFS) at 24 months. Forty-one of 46 patients had undergone surgery and all tumors were resectable with R0 resection. At 24 months, progression-free survival was 77%. Intention to treat analysis shows 34 patients (83%) achieved MPR of which 26 (63%) had complete pathologic response (CPR). Downstaging was seen in 37 (90%) of cases. This is the first multi-center study to explore chemotherapy and immunotherapy in the neoadjuvant setting in stage IIIA.

      In Shu C trial (NCT02716038), from Columbia University, patients received neoadjuvant treatment with atezolizumab, nab-paclitaxel, and carboplatin. Results show that 17/30 patients (57%) achieved MPR of which 10 (33%) had CPR.

      Immunotherapy has revolutionized the treatment of advanced stages of lung cancer, becoming early stages of its next challenge.

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      ES06.02 - Radiation and IO for Operable Early Stage NSCLC (ID 4047)

      14:15 - 15:15  |  Presenting Author(s): Suresh Senan  |  Author(s): Famke Schneiders

      • Abstract
      • Slides

      Abstract

      The goal of surgery in patients presenting with an early-stage NSCLC is cure, but novel treatment strategies are necessary in order to improve current outcomes. In patients presenting with a large primary tumor (T3/4) with limited volume nodal metastases (N1 or single station N2 disease), induction therapies including chemo-radiotherapy have been used to both improve the likelihood of a complete surgical resection, and to treat occult metastatic disease. However, despite trimodality treatments, between 30-50 % of these patients develop distant disease relapse. In fit patients with stage I NSCLC, distant metastases manifest in approximately 30% after primary surgery and a nodal recurrence. New treatment strategies are currently being investigated, notably neoadjuvant immunotherapy either as monotherapy, in combination with chemotherapy, or as a dual combination of immune-agents (IO) such as anti-PD-(L)1 and anti-CTLA-4 (dual-IO). A less commonly explored strategy is the use of combined neoadjuvant radiotherapy plus immunotherapy, either with or without chemotherapy.

      In the presence of a pre-treatment tumor mass, the neoadjuvant administration of immune checkpoint inhibitors can achieve immune priming or boosting as dying tumor cells are engulfed by antigen presenting cells, which in turn can drive tumor-specific memory T-cell responses. Findings of preclinical and early clinical studies suggest that a broader and stronger T-cell response may be induced with this approach (Rudqvist NP, 2018, Formenti S, 2018 ). A relatively unknown aspect of immunoradiotherapy is the optimal dose of radiation required in patients. Murine studies have shown radiation-induced immune responses orchestrated by the cGAS-STING pathway, which is attenuated by the DNA exonuclease TREX1, induced by radiation doses above 12-18 Gy (Vanpouille-Box C, 2017). For optimization of future clinical trial design, clinical information about the immunological effects of dose, fractionation schedule and scheduling with immunotherapy is urgently required. Ionizing radiation induces DNA damage, which can trigger immunogenic tumor cell death leading to a pro-inflammatory immune response (Chen DS, 2013). As the stress responses accompanying surgical trauma disrupt several immunological pathways, leading to immune suppression (Krall JA, 2018 ), the immune activation induced by neoadjuvant treatment can potentially protect against microscopic disease. This can lead to a diminished risk of distant metastases or even local disease recurrence.

      Potential risks of the neoadjuvant approach in general are the possibility of tumor progression with delayed surgery, delays arising from toxicity of induction therapy and uncertainty of the prognostic significance of a major pathological response (MPR) as study end-point. In addition, the optimal radiation doses for use with IO in the neoadjuvant setting are unclear, as is the impact of irradiating tumor draining lymph nodes (TDLN). With the use of highly-precise image guided radiotherapy approaches, not only can organs at risk be spared, but also irradiation of draining lymph nodes, which could lead to improved T-cell mediated immunity (van de Ven R, 2017).

      The relevant issues in trial design will be elaborated upon using ongoing trials exploring the safety and feasibility of radiotherapy and IO in operable early-stage NSCLC, including NCT02904954; EudraCT-Number: 2019–003454-83; EudraCT-Number: 2016‐003819‐36. Translational research will be an essential component of such trials as this may provide signals identifying the most promising immune priming neoadjuvant strategies. For example, the INCREASE trial [2019–003454-83; Dickhoff C, 2020] will investigate (i) the presence and distribution pattern of tumor infiltrating lymphocytes (TIL’s) in the tumor microenvironment (TME) at baseline and after induction therapy; (ii) correlate post induction TIL’s with residual tumor cells/pCR; (iii) changes in immune suppressive subsets/mechanisms in the TME and TDLN between pre and post induction; and (iv) correlation of these changes to residual viable tumor cells.

      Advanced immunological methods like multiplex IHC, multiparameter flow cytometry, immuno-PET imaging (Niemeijer AN, 2018) and molecular techniques (e.g. RNA sequencing , tumor-educated blood platelets [TEPs]) can give insights in immunological responses upon different doses and schemes of ionizing radiation and can provide promising insights for future trial design. Translational endpoints related to the characterization and spatiotemporal visualization of immune cells within the TDLN and TME will reveal whether (chemo-)radiotherapy and IO can induce a more pro-inflammatory immune response (e.g. increase in effector- and memory T cell subsets and activation of antigen presenting myeloid cells) and a decline in immune suppressive subsets (e.g. regulatory T cells and myeloid derived suppressor cells). Furthermore, the role of tertiary lymphoid structures (TLS) (Sautès-Fridman C, 2019) on responses to multimodality therapy, and their correlation with oncological outcomes, is being explored.

      References

      Rudqvist NP. Radiotherapy and CTLA-4 Blockade Shape the TCR Repertoire of Tumor-Infiltrating T Cells Cancer Immunol Res. 2018 6(2):139-150.

      Formenti S. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med. 2018 24(12):1845-1851.

      Vanpouille-Box C. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 2017 8:15618.

      Chen DS. Oncology meets immunology: the cancer-immunity cycle Immunity. 2013 39(1):1-10.

      Krall J.A. The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy. Sci Transl Med . 2018;10(436):eaan3464.

      van de Ven R. High PD-1 expression on regulatory and effector T-cells in lung cancer draining lymph nodes. ERJ Open Res. 2017;3(2):00110-2016.

      Dickhoff C. Ipilimumab plus nivolumab and chemoradiotherapy followed by surgery in patients with resectable and borderline resectable T3-4N0-1 non-small cell lung cancer: the INCREASE trial. BMC Cancer 2020;20(1):764.

      Niemeijer AN. Nat Commun. 2018;9(1):4664. doi: 10.1038/s41467-018-07131-y.

      Sautès-Fridman C. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer. 2019;19(6):307-325.

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      ES06.03 - Neoadjvuant and Adjuvant Targeted Therapies (ID 4048)

      14:15 - 15:15  |  Presenting Author(s): Wen-zhao Zhong

      • Abstract
      • Slides

      Abstract not provided

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      ES06.04 - MPR and pCR as Primary Endpoints in Neoadjuvant Trials (ID 4049)

      14:15 - 15:15  |  Presenting Author(s): Noriko Motoi

      • Abstract
      • Slides

      Abstract

      Recent progress of therapeutic options for lung cancer expands neoadjuvant setting for advanced-stage patients. Pathologic regression degree of the resected lung specimen after neoadjuvant therapy can predict the survival outcome (Yamane, Y. et al. JTO 2010, Cascone T, et al. Ann Thorac Surg. 2018). Pathological response to neoadjuvant therapy is highlighting as a surrogate endpoint for survival or recurrence.

      The assessment method for regression grade of resected lung specimen after neoadjuvant therapy was reported in 1997 (Junker K et al. J Cancer Res Clin Oncol. 1997). IASLC multidisciplinary group has recently proposed the comprehensive recommendation for pathologic assessment of lung cancer resection specimens following neoadjuvant therapy in 2020 (Travis WD et al. JTO 2020).

      Major pathologic response (MPR) has been proposed as a surrogate marker defined as a 10% residual viable tumor following neoadjuvant therapy (Hellmann M.D. et al. Lancet Oncol. 2014). In their proposal, the pathological surrogate should have optimum qualities (Table 1). MPR is defined as less than 10% residual viable tumor after neoadjuvant therapy. MPR can be observed more frequently than a pathological complete response (pCR), defined as no viable residual tumor. The 10% cutoff is determined based on the previous studies on the pathologic assessment of resected lung after neoadjuvant chemoradiotherapy (Junker K, et al. J Cancer Res Clin Oncol. 1997; Pataer A et al. JTO 2012).

      According to IASLC recommendation, the resected lung specimen should be cut in 5-10mm serial section, then sampled optimal section to evaluate the tumor bed. A tumor bed is defined as the area composed of 1) viable tumor tissue, 2) necrosis, and 3) stromal tissue. Stromal tissues include both fibrosis and inflammation, which can be observed in a non-neoadjuvant specimen and have variable histologic features. It is difficult, sometimes impossible, to judge necrosis and stromal tissue whether it was the therapeutic response or not.

      The semiquantitative approach is practically recommended. The percentage of three components should be estimated as 10% in increments unless 5% in a single count and the total should be 100%. The pathologic response degree is calculated as a residual viable tumor percentage in the tumor bed.

      Pathologic assessment must sample the optimal area by careful pathologists’ observation in collaboration with surgeons and radiologists. The sections should include enough sections to determine the tumor bed and the tumor periphery to define the borderline. Pretreatment CT images may help to determine the complexity in the resected specimen.

      Lastly, several issues are on assessing pathologic response degree: reproducibility, reliability, and feasibility. It has been mentioned that neoadjuvant therapy response pathological features were different between chemotherapy and immunotherapy (Cottrell TR et al. Annals of Oncology. 2018); the optimal cutoff value may differ in several settings, including histology (Qu Y et al. JTO 2019).

      References

      Yamane Y, et al. A Novel Histopathological Evaluation Method Predicting the Outcome of Non-small Cell Lung Cancer Treated by Neoadjuvant Therapy; The Prognostic Importance of the Area of Residual Tumor. J Thorac Oncol. 2010;5:49-55.

      Cascone T et al. Induction Cisplatin Docetaxel Followed by Surgery and Erlotinib in Non-Small Cell Lung Cancer. Ann Thorac Surg. 2018;105(2):418-24.

      Junker K, et al. Tumour regression in non-small-cell lung cancer following neoadjuvant therapy. Histological assessment. J Cancer Res Clin Oncol. 1997;123(9):469-77.

      Travis WD, et al. IASLC multidisciplinary recommendation for pathologic assessment of lung cancer resection specimens following neoadjuvant therapy. Journal of Thoracic Oncology. 2020.

      Hellmann MD, et al. Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint. Lancet Oncol. 2014;15(1):e42-50.

      Pataer A et al. Histopathologic response criteria predict survival of patients with resected lung cancer after neoadjuvant chemotherapy. J Thorac Oncol. 2012;7(5):825-32.

      Forde PM, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med. 2018;378(21):1976-86.

      Cottrell TR, et al. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Annals of Oncology. 2018;29(8):1853-60.

      Qu Y, et al. Pathologic Assessment After Neoadjuvant Chemotherapy for NSCLC: Importance and Implications of Distinguishing Adenocarcinoma from Squamous Cell Carcinoma. J Thorac Oncol. 2019;14(3):482-93.

      Table 1: Optimum qualities of a pathological surrogate for survival after neoadjuvant therapy (modified from Hellman MD, Lancet Oncol. 2014)

      Factors

      Requirement

      Valid

      Improvement in the surrogate outcome should correlate with improvement in overall survival, including in specific histologic and molecular subgroups.

      Reflective

      Surrogate outcome should reflect the biologic impact of treatment as well as the magnitude of the effect of the treatment on survival.

      Moderately frequent

      Surrogate outcome should be sufficiently frequent to permit statistically relevant assessments using reasonable sample sizes, but sufficiently infrequent enough that improvement is attainable.

      Defined

      Surrogate outcome should have an unequivocal definition.

      Feasible

      Surrogate outcome should be easily and feasibly assessable with universally acceptable methods.

      Reproducible

      Surrogate outcome should be reproducible with minimal inter-observer variability.

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    ES07 - Pleural Effusion in a Cancer Patient (ID 235)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Diagnostics and Interventional Pulmonology
    • Presentations: 4
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      ES07.01 - Radiological Evaluation of Pleural Effusion in a Cancer Patient (ID 4075)

      15:30 - 16:30  |  Presenting Author(s): Yeun-Chung Chang

      • Abstract
      • Slides

      Abstract

      Pleural effusion (PE) is not infrequently seen in cancer patients. Malignant pleural effusion (MPE) is an exudative effusion with malignant cells. MPE is a common symptom and accompanying manifestation of metastatic disease. It affects up to 15% of all patients with cancer and is the most common in lung, breast cancer, and gastrointestinal tract adenocarcinoma or ovarian, gynecological malignancies and malignant mesothelioma. Once PE is identified in a cancer patient, the most important issue is to clarify the nature of pleural effusion which is benign or malignant. The most common radiographic evaluation of cancer patients is chest radiograph. Radiographical detection of small PE is difficult on chest PA view unless significant amount to obscured the lateral costophrenic angles. Computed tomography (CT) is commonly used for clinical staging which may reveal the presence of pleural effusion, thickening, nodularity or mass(es). The presence of pleural nodularity or masses in a cancer patient is frequently due to pleural metastasis or tumor seeding. Pleural effusion in patients with lung cancer may raise high suspicion of malignant pleural effusion (M1a) unless there is associated pneumonia or heart failure which may be the etiology of pleural effusion. Clinical workup of the persistent PE in a cancer patient should be carried out even nonvisualization of pleural nodularity or tumor seeding. Microscopic evidence or analysis of the cell block from PE is important to diagnose the etiology of pleural effusion. In this refreshed lecture, we are going to show typical MPE and suggested algorithm if PE is found in a cancer patient.

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      ES07.02 - Role of Pleural Fluid Molecular Markers and PD-L1 Testing (ID 4076)

      15:30 - 16:30  |  Presenting Author(s): Zoltan Lohinai

      • Abstract
      • Slides

      Abstract

      Patients with pleural metastases or lymphatic metastases in 50-60% develop pleural effusions (PE). Conventional cytology is negative (CNPE) in up to 40% of malignant PEs. The cells in PE are in a different microenvironment, affecting biology and biomarkers' expression considering the impact of tumor-host cell interactions. Obtaining PE, an early diagnostic step provides important biomarkers; when other tissue samples might not be available. PE represents tumor heterogeneity; tumor cells in pleural effusions might represent more lesions than biopsies. There are studies involving genomic, transcriptomic, proteomic, and metabolomics. Circulating cell-free DNA from PF supernatants may provide relevant information to clinicians that might complement or replace invasive diagnostic procedures.

      Cytology negative and positive PE is useful in early decision-making and when no additional time is available for later diagnostics steps due to disease aggressiveness. Biomarkers show high specificity, and the low sensitivity limits the diagnostic value that might increase with the PE amount available.

      Molecular testing on PE specimens is becoming a feasible alternative to tissue biopsy for phenotyping malignant PEs in lung cancer patients. PE might be suitable for assessing PD-L1 expression in malignant cells, and we compare the results of those reported for histological specimens.

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      ES07.03 - Malignant Pleural Effusion: Patient Presentation and Diagnostic Pathway (ID 4077)

      15:30 - 16:30  |  Presenting Author(s): Laura McNaughton

      • Abstract
      • Slides

      Abstract not provided

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      ES07.04 - Chemical Pleurodesis, Indwelling Pleural Catheter or Both for Malignant Pleural Effusion (ID 4078)

      15:30 - 16:30  |  Presenting Author(s): Pyng Lee

      • Abstract
      • Slides

      Abstract not provided

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    ES08 - The Solitary Pulmonary Nodule (ID 243)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Diagnostics and Interventional Pulmonology
    • Presentations: 6
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      ES08.01 - Chair (ID 4104)

      16:45 - 17:45  |  Presenting Author(s): Haja Mohideen Salahudeen Mohamed

      • Abstract

      Abstract not provided

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      ES08.02 - Chair (ID 4105)

      16:45 - 17:45  |  Presenting Author(s): Martin Johnston Phillips

      • Abstract

      Abstract not provided

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      ES08.03 - Evidence Based Evaluation of the Indeterminant Pulmonary Nodule (ID 4106)

      16:45 - 17:45  |  Presenting Author(s): Annette McWilliams

      • Abstract
      • Slides

      Abstract not provided

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      ES08.04 - Biomarkers in the Evaluation of Pulmonary Nodule (ID 4107)

      16:45 - 17:45  |  Presenting Author(s): James R Jett

      • Abstract
      • Slides

      Abstract

      Lung cancer mortality in the United States has decreased by 29% since 1991. Screening with LDCT and identification of the cancers among the indeterminate pulmonary nodules (IPNs) offers the best chance for improving lung cancer mortality even further.

      Low dose CT (LDCT) screening for high risk individuals has been available since 2013 but the adoption rate has been low. Less than one in 20 eligible adults received LDCT screening in the USA and the screening was not aligned with the lung cancer burden, which was higher in the Southern states (1).

      It has been estimated that 1.57 million IPNs are identified yearly in the USA on non-screening CT scans. The National Lung Cancer Screening Trial (NLST) also reported a positive screening rate of 24% of which approximately 95% were due to IPNs (2).There are multiple guidelines published for management of IPNs. In general, they recommend assessing the risk of malignancy based on clinical estimate or a risk calculator. Based on this estimate, each patient is placed into a low, intermediate, or high risk probability of cancer (pCA). For the ACCP these are <5%, 5-65%, >65%; for the BTS they are <10%, 10-70%, >70%. A PET scan is recommended for the intermediate risk groups (3,4). In a clinical practice review study in the US, PET scans were performed on only 37% of IPNs of 8-20 mm. Surgical resection of IPNs was similar at 17-21% in all three risk categories. Surgery for benign disease was performed in 35% (27 of 77) of individuals and there was a large percentage of biopsies for benign disease (5). This underscored the need for additional tools to assist physicians in the evaluation of IPNs.

      A IPN biomarker should improve the accuracy of the pCA to guide early evaluation or observation and improve clinical outcomes. There have been recent extensive reviews of biomarkers (6,7). My comments will be limited to three biomarkers that, in my estimation, are available and should be considered for clinical use at this time. While biomarkers could be from blood, urine, sputum, or breath, the most extensive evaluations have been performed on blood, specifically proteins, microRNA and autoantibodies.

      The three biomarkers are for risk assessment of IPNs (8-30 mm) are from CLIA approved laboratories in the US. First is the integrated classifier XL2 which is a proteomic analysis of 2 proteins, LG3BP and C163A, combined with 5 clinical factors. It is used to identify “likely benign” nodules. In the prospective PANOPTIC study, the analysis was performed on 178 patients with a pCA of 50% or less (16% had lung cancer) (8). The XL2 test classified 66 participants as “likely benign” and only one of these were subsequently proven to be lung cancer. The sensitivity of the test was 97% and the NPV was 98% and outperformed clinical risk stratification models and PET. If the test had been used to make clinical decisions, it would have resulted in 40% fewer biopsies of benign IPNs.

      The second test, CDT is a panel of 7 autoantibodies against tumor associated antigens (p53, CAGE, GBU 4-5, MAGE A4, NY-ESO-1, HuD and SOX-2). In clinical validation studies of all histological types and stages of lung cancer the panel performance was 40% sensitivity with a specificity of 93%. A real world clinical study 296 IPN patients had a 25% prevalence of lung cancer. A positive blood test represented a greater than two fold increased relative risk of lung cancer as compared to a negative test. When a “both positive rule” of combining calculated risk pCA (Mayo/Swensen nodule calculator) with a positive CDT it resulted in a specificity of >92% and a PPV of >70% (9). The CDT test has a high specificity and PPV and is best used to identify “likely malignant” IPNs. A positive CDT will frequently move the calculated pCA into the high risk category (>65%) where diagnostic evaluation should not be delayed. The majority of these high risk nodules will prove to be lung cancer.

      The third biomarker is the bronchial genomic classifier (10). The test is performed on a epithelial cells by brushing a main bronchus. It has been shown to improve the diagnostic performance of bronchoscopy in suspected lung cancer patients. In 101 individuals with an intermediate risk of cancer the bronchoscopy was negative in 83% (41% were subsequently proven to have lung cancer). With a negative bronchoscopy and adding a negative genomic classifier provided an NPV of 91% and a PPV of 40%. Given the high NPV, the investigators opined that the test can be used in those with an intermediate risk of cancer to limit further invasive testing.

      It should be noted that there are some especially promising biomarker blood tests in development and yet to be tested specifically in an IPN population. Cancer personalized profiling by deep sequencing (CAPP-Seq) analyzes ctDNA to facilitate screening but levels are very low in early stage lung cancer (Chabon et al Nature 2020). The Cancer-SEEK test combines circulation proteins with ctDNA and tests for 8 common cancer types including lung cancer. The sensitivity for Stage I lung cancer is about 40% in one small study (Cohen JD et al Science 2018). A targeted methylation analysis of ctDNA was tested against 12 cancer types including lung cancer (Liu MC et al Ann Oncol 2020). The sensitivity in Stage I lung cancer was <25%.

      In summary, biomarker research has progressed so that blood biomarkers are available for clinical use.

      References:

      Fedewa SA et al JNCI published online November 12, 2020

      The National Lung Screening team: NEJM 2011; 365:395-409

      Gould MK et al Chest 2013; 143: e93S-e120S

      Callister M et al Thorax 2015; 70; ii1-ii54

      Tanner NT et al Chest 2015:148:1405

      Seijo LM et al J Thorac Oncol 2019; 14:343-357

      Kammer MN et al J Thorac Dis2020;12:3317-3330

      Silvestri GA et al Chest 2018; 154:491-500

      Massion PP et al J Thorac Oncol 2017; 12:578-584

      Silvestri GA et al NEJM 2015; 373:243-251

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      ES08.05 - Targeting the SPN (ID 4108)

      16:45 - 17:45  |  Presenting Author(s): Kwun Fong

      • Abstract

      Abstract not provided

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      ES08.06 - Bronchoscopic Treatment of SPN: Opportunities and Challenges (ID 4109)

      16:45 - 17:45  |  Presenting Author(s): David Feller-Kopman

      • Abstract
      • Slides

      Abstract not provided

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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: 7
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      ES09.01 - Chair (ID 3942)

      09:15 - 10:15  |  Presenting Author(s): Katerina Politi

      • Abstract

      Abstract not provided

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      ES09.02 - Chair (ID 3943)

      09:15 - 10:15  |  Presenting Author(s): Melina Elpi Marmarelis

      • Abstract

      Abstract not provided

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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
      • Slides

      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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      ES09.04 - Individual Genomic Alterations as Predictive Factors for NSCLC Immunotherapy (ID 3945)

      09:15 - 10:15  |  Presenting Author(s): Ferdinandos Skoulidis

      • Abstract
      • Slides

      Abstract not provided

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      ES09.05 - Blood-based Biomarkers for Immunotherapy: Applications and Limitations (ID 3946)

      09:15 - 10:15  |  Presenting Author(s): Lizza Hendriks

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      • Slides

      Abstract

      Biomarkers are needed in the treatment of lung cancer patients with immune checkpoint inhibitors (ICI), as the majority of patients will not benefit from ICI, or will even be harmed (pseudoprogression, immune related toxicity). This presentation will focus on NSCLC.

      Currently, for those without a targetable oncogenic driver, only programmed-death ligand1 (PD-L1) expression on tumor cells is used for treatment selection in the ESMO guideline on metastatic NSCLC. However, PD-L1 is not a perfect biomarker, as only 32% of patients with NSCLC with high PD-L1 expression (≥50%), treated with first line monotherapy pembrolizumab are alive after five years. Importantly, PD-L1 expression levels are heterogeneous across sites of disease. Furthermore, biopsies are difficult to obtain during treatment with ICI, and easier to use biomarkers are needed both for treatment selection and monitoring.

      Examples of blood-based biomarkers are circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), blood tumor mutational burden (bTMB), cytokines, soluble PD-L1, lymphocyte counts, CRP, LDH, albumin. Drawbacks of most of these biomarkers are that analyses are not standardized and that different platforms are used. Furthermore, several analyses are expensive to perform. Importantly, to interpret the results of biomarker studies, a distinction should be made between predictive and prognostic markers.

      PD-L1 can be determined on CTCs. Small studies showed that there is no correlation between PD-L1 expression level on CTCs and on tumor cells on tissue. In contrast to PD-L1 expression on tissue, patients with NSCLC, treated with ICI, and baseline PD-L1+ CTCs, have a poorer progression free survival (PFS) compared with those without PD-L1+ CTCs. For soluble PD-L1, similar results have been found in small studies.

      bTMB has been extensively investigated. For monotherapy anti-PD-L1, patients with a high bTMB (corrected for ctDNA concentration) have a superior PFS on ICI compared with those with a low bTMB (atezolizumab OAK and POPLAR data). In contrast, bTMB is not associated with increased benefit for patients treated with chemotherapy-ICI, as was shown for example in the KEYNOTE189. Results for ICI-ICI combinations are conflicting. For example, in an exploratory analysis of the MYSTIC study, patients with a bTMB of ≥20 mut/Mb had the best outcome with the combination of durvalumab and tremelimumab, while there was no benefit for those with a bTMB of < 20 mut/Mb. However, the NEPTUNE trial, specifically evaluating durvalumab-tremelimumab in those with a high bTMB was reported to be negative. Of note, in the b-F1RST trial, those without detectable ctDNA had the best outcome. It could be that this is a patient population with a lower disease burden and low shedding of ctDNA.

      Specific ctDNA biomarkers are for example KEAP1, STK11 and ARID1A. in the MYSTIC trial, KEAP1 and STK11 seemed only prognostic, as patients with a KEAP1 or STK11 mutation had worse survival compared with the wild-type patients regardless of the treatment.

      ARID1A is a negative prognostic marker, but ARID1A deficiency seems to promote antitumor immunity, increases TMB and modulates the tumor microenvironment (increase in tumor infiltrating lymphocytes). In an exploratory analysis in the MYSTIC trial, ARID1A mutations were indeed associated with improved survival in those treated with durvalumab-tremelimumab, but not durvalumab monotherapy, compared with chemotherapy.

      ctDNA dynamics can also be used to select patients with the highest chance of long-term benefit, as patients with a reduction of ctDNA during ICI treatment had the best PFS on ICI. ctDNA dynamics can probably also be used to select patients for adjuvant ICI, and combination scores of ctDNA, its dynamics, PD-L1, TMB and CD8+ Tcells are in development. For example, in stage III NSCLC patients treated with chemoradiotherapy, patients with ctDNA clearance after chemoradiotherapy, survival was good regardless of adjuvant ICI. Of note, all studies are small and validation is needed.

      Standard of care lab values and its dynamics during ICI can probably also be used to select patients that will, or will not, benefit from ICI. Examples are derived NLR (neutro/[leuko-neutor]) and its change during ICI treatment, or the LIPI score (dNLR and LDH combined). Of note, although large, all studies are retrospective and prospective validation is needed.

      Last, T-cell receptor clonality analysis and the dynamics during ICI treatment are promising to select patients for ICI, but studies so far have been very small.

      In conclusion, blood-based biomarkers are needed, to overcome the problems of tissue biopsies. Standard lab values are interesting but need prospective validation. ctDNA analysis is the most advanced, and seems especially useful for monitoring during ICI. CTC, soluble PD-L1 and Tcell receptor clonality analysis are interesting and promising but more research is needed, as is a balance between costs and usefullness.

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      ES09.06 - Immune Contexture and Immunotherapy Response in NSCLC (ID 3947)

      09:15 - 10:15  |  Presenting Author(s): Kurt Alex Schalper

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      Abstract not provided

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      ES09.07 - Immunotherapy Biomarkers in NSCLC: Looking into the Future (ID 3948)

      09:15 - 10:15  |  Presenting Author(s): Vamsidhar Velcheti

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      Abstract not provided

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    ES10 - Advances in Lung Cancer Screening Through Imaging and Data Analytics (ID 149)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Screening and Early Detection
    • Presentations: 5
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      ES10.01 - Chair (ID 3949)

      09:15 - 10:15  |  Presenting Author(s): Charlene J Liew

      • Abstract

      Abstract not provided

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      ES10.02 - Chair (ID 3950)

      09:15 - 10:15  |  Presenting Author(s): Yeol Kim

      • Abstract

      Abstract not provided

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      ES10.03 - AI-Enabled Lung Cancer Predictive Analytics - The Future of Lung Cancer Screening? (ID 3951)

      09:15 - 10:15  |  Presenting Author(s): Zaiyi Liu

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      Abstract not provided

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      ES10.05 - Size Isn't Everything - Other High-Risk CT Imaging Features (ID 3953)

      09:15 - 10:15  |  Presenting Author(s): Heber MacMahon

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      Abstract not provided

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      ES10.06 - Putting It Together: Current Best Practices in the Evaluation and Follow-Up of the Indeterminate Pulmonary Nodule (ID 3954)

      09:15 - 10:15  |  Presenting Author(s): David Raymond Baldwin

      • Abstract
      • Slides

      Abstract

      In a sense, all pulmonary nodules are indeterminate until there has been a definitive diagnosis or long-term follow-up. Which nodules are included in the “indeterminate” category is determined by the definition applied, and this can differ between established guidelines. For the purposes of this talk, which relates specifically to the context of LDCT screening for lung cancer, the recommendations from five key guidelines on the management of pulmonary nodules have been reviewed1 - 5. A further key guideline, the Fleischner Society 2017 update refers only to nodules detected incidentally, rather than in a screening setting so is not included in the comparisons6.

      Most comparisons of recommendations concentrate on the approach to nodules according to size categories because this is one of the major determinants of the probability that a nodule is both malignant and harmful. This is a useful approach but can produce some complicated tables. This talk approaches the subject from a slightly different and patient-centred angle. For participants in screening, it is important to think of the impact of management strategies and there are 3 key outcomes after either a prevalence or incident screen: return to the screening programme for the next scheduled screen; have additional low dose CT(s) before the next screen is due; and be referred to the hospital for further clinical work-up. The chance of harming the participant, both physically and psychologically, increases as we progress through these categories. It is thus important to avoid both additional LDCT and clinical work-up, unless beneficial. Guidelines aim to do this by managing the vast majority of nodules with minimal chance of harm whilst promptly investigating those nodules likely to be both malignant and harmful. It is important to appreciate that nodules that are malignant are not always harmful because they may be very slow growing and treating them may cause more harm. This can be the case for sub-solid nodules.

      Comparisons are made for four situations: baseline (prevalence) detection, new nodules (incidence screen), subsolid nodules and growing nodules. The table shows an example of a comparison for baseline detection. The Lung RADS 1.1 and NCCN guidelines essentially make the same recommendations. Guidelines generally agree on the threshold for returning to the screening programme but specify an annual screen (1 year interval) except for the British Thoracic Society (BTS), where the interval can be longer. Guidelines differ somewhat on the management of the nodules that require a shorter interval. It can be seen that there is the potential for a stage shift from T1a (≤10mm) for some of the recommendations although caveats are added such as the option for PET-CT or very short interval CT for larger nodules. Another potentially important difference is the use of semi-automated volumetry, which is the preferred method to measure nodules and their growth in both the BTS guideline and the European Position Statement (EUPS). Both of these documents make a case for the better accuracy of volumetry as compared with manual diameter measurements. This also has implications for some of the other recommendations for growing nodules where management is recommended on the basis of volume doubling time (VDT). For example, both BTS and the EUPS recommend work-up on the basis of specific VDTs, with less invasive options for participants who have nodules with a VDT of 400-600 days. I-ELCAP defines growth sufficient to prompt work-up as a VDT of 180 days, in contrast to BTS and EUPS where it is 400 days.

      BTS is the only guideline that firmly recommends the use of multivariable models in the management of people with nodules. The Brock / PanCan model is recommended at baseline to assist in deciding who should undergo PET-CT. This avoids this high-radiation dose scan in people who have low risk nodules. The Herder model is then used to classify nodules further. The use of PET-CT is generally recommended in the further assessment of nodules and the cut-off size is broadly >8-10mm diameter, reflecting the limitations of PET in nodules smaller than this.

      Guidelines are cautious with the management of sub-solid nodules, reflecting their often indolent nature and therefore the potential to harm participants by over-zealous treatment. The is particularly the case for pure ground glass / non-solid nodules; most guidelines only recommend an invasive approach if there is a solid component.

      Much progress has been made on the management of pulmonary nodules, and this is reflected in the much lower frequency of complications and invasive approaches in participants who do not have cancer. It will be important that screening centres adhere to guidelines to ensure participants experience the maximum benefit with least harm.

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      1. Callister ME, Baldwin DR, Akram AR, Barnard S, Cane P, Draffan J, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax. 2015;70 Suppl 2:ii1-ii54

      2. Matthijs Oudkerk AD, Rozemarijn Vliegenthart, Thomas Henzler, Helmut Prosch, Claus P Heussel, Gorka Bastarrika, Nicola Sverzellati,, Mario Mascalchi SD, David R Baldwin, Matthew E Callister, Nikolaus Becker, Marjolein A Heuvelmans, Witold Rzyman,, Maurizio V Infante UP, Jesper H Pedersen, Eugenio Paci, Stephen W Duffy, Harry de Koning, John K Field. European position statement on lung cancer screening. Lancet Oncology. 2017;18(12): e754–e66.

      3. American College Radiology. Lung RADS v 1.1 2019 [Available from: https://www.acr.org/-/media/ACR/Files/RADS/Lung-RADS/LungRADSAssessmentCategoriesv1-1.pdf?la=en.

      4. National Comprehensive Cancer Network. NCCN Lung Cancer Screening Version 1 2021 [Available from: https://www.nccn.org/professionals/physician_gls/pdf/lung_screening.pdf.

      5. International Early Lung Cancer Action Program Investigators Group. Protocol Documents 2016 [Available from: https://www.ielcap.org/sites/default/files/I-ELCAP-protocol-summary.pdf.

      6. MacMahon H, Naidich DP, Goo JM, Lee KS, Leung ANC, Mayo JR, et al. Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017. Radiology. 2017;284(1):228-43.

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