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Shun Lu



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    FP12 - Tumor Biology and Systems Biology - Basic and Translational Science (ID 188)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP12.05 - Molecular Landscape of Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Chinese Advanced Non-Small Cell Lung Cancer (ID 3529)

      00:00 - 00:00  |  Author(s): Shun Lu

      • Abstract

      Introduction

      Immune checkpoint inhibitors (ICIs) have improved the prognosis of non-small cell lung cancer (NSCLC) patients. However, about 80% of patients do not respond at all ("primary resistance"), whereas others initially respond to immunotherapy, later relapse and develop therapy resistance ("acquired resistance"). Absence of PD-L1 expression is well regarded as a biomarker of primary resistance to ICIs, and tumor mutation burden (TMB), microsatellite instability (MSI), HLA genotype and tumor neoantigen burden (TNB) have also been reported in recent studies to be related to the resistance of immunotherapy. This research is to explore the molecular landscape of primary and acquired resistance in Chinese advanced NSCLC treated with anti-PD-L1/PD-1 antibodies based on results of whole exome sequencing (WES) and targeted sequencing (TS) containing comprehensive immune molecular markers.

      Methods

      WES (~39Mb CDS of over 18,000 genes) or TS (~1.6Mb CDS of 654 genes) were conducted on 50 samples from 45 patients received anti-PD-L1/PD-1 antibodies, including 18 baseline pretreatment and 32 resistant tumor samples (Figure 1A). The primary endpoints include objective response rate (ORR) and progression-free survival (PFS), and statistics was analyzed using Fisher’s exact test and Kaplan-Meier analysis.

      Results

      About 31% of patients (N=14) responded to anti-PD-L1/PD-1 antibodies in Chinese advanced NSCLC (Figure 1A, 1B), and 40% (N=18) had stable disease. TNB was a stronger prognosis predictor of ICIs than TMB in pretreatment samples (N=18, Figure 1C, 1D). Patients with high TNB had a significantly better objective response (P=0.007) and longer PFS (P=0.003) (Figure 1C). HLA supertype B27 (HR=0.350, P=0.021) and HLA B*15:02 (HR=0.330, P=0.018) were individually associated with a poor prognosis in total 45 patients received ICIs (Figure 1E, 1F). These results indicate that low TMB or presence of HLA B27 and HLA B*15:02 were associated with primary resistance to ICIs. For acquired resistance to ICIs, known mutations were found when disease progressed on ICIs (3/25), including B2M p.W80*, B2M p.L15Ffs*41 and JAK1 p.L235I (Figure 1G). One patient had PFS of 11.2 months with acquired B2M mutation p.L15Ffs*41 detected only in post-progression sample (Figure 1H).

      figure1_update20200827.png

      Conclusion

      In Chinese advanced NSCLC, low TNB and presence of HLA B*15:02 and supertype B27 are biomarkers of primary resistance to ICIs, implying TNB and HLA genotypes can help screen patients with greater clinical benefit from immunotherapy in addition to PD-L1. Known mutations of acquired resistance to ICIs are found in few samples, other molecular mechanisms need to be explored to understand acquired resistance to ICIs.

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    JICC01 - Joint IASLC-CAALC-CSCO Session: The Truth and Myth of Oral Anti-VEGFR Inhibitors for Advance NSCLC (ID 276)

    • Event: WCLC 2020
    • Type: Workshop
    • Track: N.A.
    • Presentations: 1
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      JICC01.12 - Molecular Landscape of Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Chinese Advanced Non-Small Cell Lung Cancer (ID 4276)

      07:00 - 09:00  |  Author(s): Shun Lu

      • Abstract

      Introduction
      Immune checkpoint inhibitors (ICIs) have improved the prognosis of non-small cell lung cancer (NSCLC) patients. However, about 80% of patients do not respond at all ("primary resistance"), whereas others initially respond to immunotherapy, later relapse and develop therapy resistance ("acquired resistance"). Absence of PD-L1 expression is well regarded as a biomarker of primary resistance to ICIs, and tumor mutation burden (TMB), microsatellite instability (MSI), HLA genotype and tumor neoantigen burden (TNB) have also been reported in recent studies to be related to the resistance of immunotherapy. This research is to explore the molecular landscape of primary and acquired resistance in Chinese advanced NSCLC treated with anti-PD-L1/PD-1 antibodies based on results of whole exome sequencing (WES) and targeted sequencing (TS) containing comprehensive immune molecular markers. Methods
      WES (~39Mb CDS of over 18,000 genes) or TS (~1.6Mb CDS of 654 genes) were conducted on 50 samples from 45 patients received anti-PD-L1/PD-1 antibodies, including 18 baseline pretreatment and 32 resistant tumor samples (Figure 1A). The primary endpoints include objective response rate (ORR) and progression-free survival (PFS), and statistics was analyzed using Fisher’s exact test and Kaplan-Meier analysis. Results
      About 31% of patients (N=14) responded to anti-PD-L1/PD-1 antibodies in Chinese advanced NSCLC (Figure 1A, 1B), and 40% (N=18) had stable disease. TNB was a stronger prognosis predictor of ICIs than TMB in pretreatment samples (N=18, Figure 1C, 1D). Patients with high TNB had a significantly better objective response (P=0.007) and longer PFS (P=0.003) (Figure 1C). HLA supertype B27 (HR=0.350, P=0.021) and HLA B*15:02 (HR=0.330, P=0.018) were individually associated with a poor prognosis in total 45 patients received ICIs (Figure 1E, 1F). These results indicate that low TMB or presence of HLA B27 and HLA B*15:02 were associated with primary resistance to ICIs. For acquired resistance to ICIs, known mutations were found when disease progressed on ICIs (3/25), including B2M p.W80*, B2M p.L15Ffs*41 and JAK1 p.L235I (Figure 1G). One patient had PFS of 11.2 months with acquired B2M mutation p.L15Ffs*41 detected only in post-progression sample (Figure 1H).

      Conclusion
      In Chinese advanced NSCLC, low TNB and presence of HLA B*15:02 and supertype B27 are biomarkers of primary resistance to ICIs, implying TNB and HLA genotypes can help screen patients with greater clinical benefit from immunotherapy in addition to PD-L1. Known mutations of acquired resistance to ICIs are found in few samples, other molecular mechanisms need to be explored to understand acquired resistance to ICIs.

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    OA06 - Updates on EGFR Targeted Perioperative Therapy and Precision Adjuvant Chemotherapy (ID 118)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Early Stage/Localized Disease
    • Presentations: 2
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      OA06.03 - Patient-Reported Outcomes from ADAURA: Osimertinib as Adjuvant Therapy in Patients with Resected EGFR Mutated (EGFRm) NSCLC (ID 3505)

      16:45 - 17:45  |  Author(s): Shun Lu

      • Abstract

      The abstract for this presentation is currently under embargo or has not been submitted.

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      OA06.04 - Postoperative Chemotherapy Use and Outcomes from ADAURA: Osimertinib as Adjuvant Therapy for Resected EGFR Mutated NSCLC (ID 3464)

      16:45 - 17:45  |  Author(s): Shun Lu

      • Abstract

      The abstract for this presentation is currently under embargo or has not been submitted.

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    P35 - Pathology - Genomics (ID 105)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P35.23 - Integrated Analysis of Genomic and Immunological Features in Lung Adenocarcinoma with Micropapillary Component (ID 3514)

      00:00 - 00:00  |  Author(s): Shun Lu

      • Abstract

      Introduction

      Micropapillary adenocarcinoma is one of the most aggressive histologic subtypes of lung adenocarcinoma (LADC), and even a minor proportion of micropapillary component (MPC) within the LADC could contribute to poor prognosis. Comprehensive analysis of genetic and immunological features of LADC with different percentages of MPC would help better understand cancer biology of this LADC subtype and direct future treatments.

      Methods

      We performed next-generation sequencing (NGS) for a discovery cohort of 43 LADC patients whose tumors were microdissected to separate MPC and non-MPC lesions and a reference cohort of 113 LADC patients. MPC-enriched genetic alterations using the discovery cohort were then confirmed using a validation cohort of 183 LADC patients. Immunological staining was conducted for MPC-containing samples from the discovery cohort.

      Results

      Tumors with a higher percentage of MPC tended to harbor more tumor mutation burdens (TMBs) and chromosome instability (CIN). Some rare genetic events may serve as genetic landscape driving micropapillary tumor progression. Alterations in transcription termination factor 1 (TTF1), brain-specific angiogenesis inhibitor 3 (BAI3), mammalian target of rapamycin (MTOR), and cyclin-dependent kinase inhibitor 2A (CDKN2A) were cross-validated to be enriched in MPC-contained LADC. Tumors with a higher percentage of MPC were associated with a higher percentage of CD4+, CD8+, and PD-L1+ staining.

      Conclusion

      We identified multiple novel MPC-enriched genetic changes that could help understand the nature of this aggressive cancer subtype. MPC-predominant tumors tended to have higher levels of TMBs, T cell infiltration, and immunosuppression than low MPC tumors, making it a potential candidate for immunotherapy.

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    P42 - Screening and Early Detection - Risk Modelling and Artificial Intelligence (ID 177)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Screening and Early Detection
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P42.03 - A Dynamic Deep Learning Approach to Predict Clinical Outcomes of Patients with Advanced Non-Small Cell Lung Cancer under Nivolumab Monotherapy (ID 1910)

      00:00 - 00:00  |  Presenting Author(s): Shun Lu

      • Abstract

      Introduction

      Selecting patients with advanced non-small cell lung cancer (NSCLC) who will likely have survival benefit from immune checkpoint therapy seems not easy. In the study, we developed and evaluated a dynamic machine deep learning approach to predict clinical outcomes of advanced NSCLC patients treated with nivolumab monotherapy.

      Methods

      99 patients treated with nivolumab were included in this retrospective study. 107 radiomic features were extracted from CT imaging for each patient. A deep learning model incorporating radiomic features, laboratory examination data (e.g.blood cell counts and lactate dehydrogenase levels) 90 days prior to the time of efficacy assessment, and baseline clinical information (e. g.TNM,PS score) was developed to robustly differentiate nivolumab responders (R) from non-responders (NR) in a training set of 60 patients. Prediction performance was then tested in a validation set of 39 patients. A simple temporal attention (SimTA) model was designed to process asynchronous imaging time-series and laboratory data (Figure 1).figure 1. deep learning model with simta module.jpg

      Results

      The deep leaning-based predicting model achieves significantly predictive performance (area under the curve [AUC] is 0.79 [95% CI:0.63-0.94], p=0.00). This model stratified the patients into high- and low-risk NR groups according to a default threshold. Patients in low-risk group were associated with improved PFS (7.00 ±1.03 [95% CI: 4.98-9.02] months vs. 1.30±0.17 [95% CI: 0.97-1.63] months; Log-rank p=0.00 ) and OS (28.00 ±0.46 [95% CI: 27.10-28.90] months vs. 5.70 ±1.80 [95% CI: 2.17-9.23] months; Log-rank p=0.00) compared with high-risk group (Figure 2). Finally, an exploratory analysis of 11 patients with stable disease (after first efficacy assessment by RECIST 1.1) in the validation set showed that low-risk patients had superior OS than high-risk patients (28.6±11.98 [95% CI: 5.13-52.07] months vs. 8.80 months, Log-rank p=0.00).

      figure 2. deep learning prediction of pfs and os by risk stratification in the validation set.jpg

      Conclusion

      With easily available radiographic, laboratory and clinical information, SimTA-based dynamic deep learning provides a promising method of predicting treatment response and long-term survival in patients with advanced NSCLC under nivolumab monotherapy.

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    P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 2
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P76.66 - Real-World, First-Line Osimertinib Treatment in Epidermal Growth Factor Receptor Mutation-Positive (EGFRm) Advanced NSCLC (ID 3329)

      00:00 - 00:00  |  Author(s): Shun Lu

      • Abstract

      Introduction

      Real-world evidence studies provide vital insight into treatment practices and outcomes beyond the clinical trial setting, reflecting the reality of healthcare systems. Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations, and has demonstrated efficacy in EGFRm advanced non-small cell lung cancer (NSCLC), including central nervous system metastases. While osimertinib has demonstrated superior progression-free survival (PFS) and overall survival (OS) compared with first-generation EGFR-TKIs (erlotinib and gefitinib) as a first-line treatment in clinical trials, there remains a need to evaluate real-world disease characteristics and clinical outcomes of patients treated with first-line osimertinib monotherapy. This study aims to assess the long-term survival and treatment pathways after first-line osimertinib in patients with locally advanced/metastatic EGFRm NSCLC in a real-world setting.

      Methods

      This global, observational cohort study includes adult patients (≥18 years of age) diagnosed with advanced EGFRm NSCLC (stage IIIB–IV) or early stage disease (I–IIIA) that subsequently recurs or progresses, receiving first-line osimertinib monotherapy (initiating treatment between April 2018 and June 2021; initiation date range dependent on study country). Electronic health record (EHR) data from country-specific registries and hospital data provide de-identified information to characterise the patient population and understand treatment patterns and survival outcomes. These analyses will be conducted on each data source/geography separately and will not be pooled. Participating countries include USA (from the nationwide Flatiron Health de-identified EHR-derived database), Japan (chart review/EHRs), Germany (CRISP registry) and China (China Precision Medicine Lung Cancer Registry); data from other countries may be added later subject to availability of data and reimbursement status. Patient data will be extracted annually until June 2023, or until a median follow up of approximately 38 months is achieved; the cohort exit date will be defined as the earliest instance of either: the last day of available follow-up, date of death, or end of study period, whichever occurs first. The primary outcome measures are real-world OS and PFS (rwOS, rwPFS), treatment sequencing, and treatment dose and duration; second-line treatments after first-line osimertinib are included as part of the sequencing outcome. Baseline data will be assessed retrospectively from first date of NSCLC presentation until initiation of first-line osimertinib (index date). Patient characteristics at baseline and the incidence of brain metastases since baseline will be described using descriptive statistics; rwOS and rwPFS will be estimated using Kaplan-Meier methods, and the association between baseline characteristics and survival/progression outcomes will be examined using Cox proportional hazards models.

      Conclusion

      The characterisation of patients who receive first-line osimertinib monotherapy in the real world will provide further information on treatment patterns beyond the clinical trial setting, and describe the long-term survival and treatment pathways after first-line osimertinib.

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      P76.93 - The Efficacy of Second-Line Osimertinib  Plus Bevacizumab in Chinese Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 3770)

      00:00 - 00:00  |  Presenting Author(s): Shun Lu

      • Abstract

      Introduction

      Osimertinib has become the standard treatment for advanced non-small cell lung cancer patients with T790M mutation, who are resistant to EGFR tyrosine kinase inhibitors (EGFR TKIs). Moreover, Osimertinib has proven superior efficacy and safety over 1st-generation EGFR-TKIs in front-line setting, However, there is still insufficient evidence for the effect of Osimertinib combined with antiangiogenic therapy . Here, we reported the efficacy of Osimertinib plus Bevacizumab as second line treatment in advanced NSCLC patients in the real world setting.

      Methods

      We retrospectively reviewed the medical records of EGFRm NSCLC patients who had received the first line first generation EGFR-TKIand the T790M mutation was performed again when the disease progressed from April 1st2017 to July 30th2020 in Shanghai Chest Hospital. We mainly analyzed the baseline characteristics and ORRPFS of patients receiving second-line Osimertinib monotherapy or Osimertinib plus Bevacizumab.

      Results

      A total of 281 patients received second-line Osimertinib (monotherapy or in combination with Bevacizumab ). Among them, 212 patients received Osimertinib as the second-line drug, 33 patients received Bevacizumab combined with Osimertinib,. Most of 221 patients had T790M mutation (95.5%). Further analysis of 33 patients receiving Bevacizumab combined with Osimertinib showed that among the second-line Bev+OSI patients, CR + PR was 18.2% , and patients who achieve a response of stable disease (SD) was 66.7% at the first evaluation. The median PFS of second-line patients receiving Bev+OSI was 420 days. We compared the PFS of Bev+OSI and OSI monotherapy with propensity score in a ratio of 1:1,the PFS of the two groups was 420 days v.s. 336 days (P < 0.05).

      Conclusion

      Our analysis suggests that for patientswith T790M-positive advanced non–small-cell lung cancer who progressed following first-line EGFR-TKI therapy Bevacizumab combined with Osimertinib may further improve the PFS. Further research are needed to verify the results.

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    P79 - Immunotherapy (Phase II/III Trials) - Immunotherapy Plus Chemotherapy (ID 256)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immunotherapy (Phase II/III Trials)
    • Presentations: 2
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P79.03 - A Phase 3 Study of the PD-1 Inhibitor Retifanlimab (INCMGA00012) Plus Platinum-Based Chemotherapy in 1L mNSCLC: POD1UM-304 (ID 3305)

      00:00 - 00:00  |  Presenting Author(s): Shun Lu

      • Abstract

      Introduction

      Checkpoint inhibitors have significantly improved outcomes in patients with metastatic non-small cell lung cancer (mNSCLC), and are approved as first-line (1L) treatment as monotherapy as well as in combination with platinum-based chemotherapy. Retifanlimab is a an investigational humanized monoclonal anti–programmed death-1 (PD-1) antibody; in the POD1UM-101 phase 1 study (NCT03059823), retifanlimab demonstrated clinical activity and safety profile similar to other currently approved anti PD-1 antibodies in patients with advanced stage NSCLC. POD1UM-304 (NCT04205812) is a randomized, double-blind, phase 3 global study designed to investigate the efficacy and safety of retifanlimab plus platinum-based chemotherapy for 1L treatment of metastatic NSCLC.

      Methods

      Previously untreated adults ≥18 years of age, with histologically or cytologically confirmed metastatic squamous or nonsquamous NSCLC, and documented absence of driver mutations or gene arrangements for EGFR, ALK, BRAF, or ROS1 (nonsquamous tumor histology) are eligible. Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors v1.1, an ECOG performance status ≤1, adequate organ function, and be able to provide tumor tissue during screening or have a fresh tumor biopsy after diagnosis of metastatic disease. Neoadjuvant or adjuvant therapy that did not include PD-1/programmed death-ligand 1 (PD-L1)–directed agents is permitted if completed ≥12 months before diagnosis of metastatic disease.

      Approximately 530 participants will be randomized 2:1 to retifanlimab 375 mg plus platinum-based chemotherapy or placebo plus platinum-based chemotherapy every 3 weeks (Q3W; figure). Participants in the placebo arm will have the option to crossover to retifanlimab monotherapy following disease progression.

      Primary study objectives include overall survival and progression-free survival in participants treated with retifanlimab plus chemotherapy versus placebo plus chemotherapy. Secondary objectives include objective response rate, duration of response, and safety and tolerability in the two treatment arms, as well as the pharmacokinetics of retifanlimab 375 mg Q3W when administered in combination with chemotherapy.

      ic240-20b pod1um 304_iaslc 2020 abstract_figure_jh02.png

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      P79.08 - Sintilimab ± IBI305 Plus Chemotherapy for Patients With EGFR-Mutant Non-Squamous NSCLC Failed to EGFR-TKI Treatment (ID 1304)

      00:00 - 00:00  |  Presenting Author(s): Shun Lu

      • Abstract

      Introduction

      The standard treatment for advanced non-squamous non-small cell lung cancer (nsqNSCLC) patients with EGFR-mutation is osimertinib or other recommended tyrosine kinase inhibitors (TKIs). For those who failed to TKI treatment, the choice of systemic treatment is limited, including platinum-based chemotherapy, and new therapy regimens are needed to improve the efficacy. T-cell mediated cancer cell killing of anti-PD-1 antibody may be enhanced through reversal of vascular endothelial growth factor (VEGF)-mediated immunosuppression. Sintilimab is a humanized, monoclonal antibody that blocks the interaction between PD-1 and its ligands. IBI305 is a biosimilar candidate for bevacizumab which is a monoclonal antibody against VEGF. ORIENT-31 study is a randomized, double-blind, multi-center, phase 3 study to compare the efficacy and safety of sintilimab with or without IBI305 plus pemetrexed and cisplatin versus placebo plus pemetrexed and cisplatin. (NCT03802240).

      Methods

      Patients, who have failed to epidermal growth factor receptor (EGFR)-TKI treatment, with histologically/cytologically confirmed Stage IIIB-IV nsqNSCLC with EGFR mutations will be enrolled in this two-stage study. The total planned sample size is 600, with 480 patients in the common enrollment stage and 120 patients in the extension enrollment stage. In the common enrollment stage, 480 patients will be enrolled and randomized (1:1:1) into Group A (sintilimab + IBI305 + pemetrexed + cisplatin), Group B (sintilimab + placebo 2 + pemetrexed + cisplatin) and Group C (placebo 1 + placebo 2 + pemetrexed + cisplatin). In the extension enrollment stage, 120 patients will be enrolled and randomized (1:1) into Group A and Group B. Stratification factors include gender (male or female) and brain metastasis (with or without). Sintilimab 200 mg with or without IBI305 15 mg/kg will be administrated every 3 weeks (Q3W) until disease progression, unacceptable toxicity or voluntary patient withdrawal for up to 24 months. The pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 will be administrated Q3W for up to 4 cycles. The primary efficacy endpoint is progression-free survival per RECIST V 1.1 by Independent Radiographic Review Committee. The secondary efficacy endpoints include overall survival, objective response rate, disease control rate, time to response and duration of response per RECIST V1.1. By March 9, 2020, 112 patients have been enrolled in this study.