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Kai He



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    EP1.12 - Small Cell Lung Cancer/NET (ID 202)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.12-38 - Retrospective Analysis of Immunotherapy Utilization in Advanced Small Cell Carcinoma at an Academic Cancer Center (Now Available) (ID 2520)

      08:00 - 18:00  |  Author(s): Kai He

      • Abstract
      • Slides

      Background

      Small-cell carcinoma (SCC) is an aggressive neuroendocrine carcinoma which commonly originates in the lung (SCLC). In contrast to non-small cell lung cancer (NSCLC), immunotherapy (IO) utilization has been limited for SCLC. Nivolumab was approved as a single agent in 2018 for third-line therapy. In 2019, the IMpower133 trial led to approval of first-line chemo-IO (atezolizumab plus carboplatin and etoposide) for extensive-stage SCLC. Despite these approvals, there is limited data about experience utilizing IO in SCC outside of clinical trials, including patterns of care, survival, and incidence of brain metastases. We therefore conducted a retrospective review of IO utilization at an academic cancer center in the United States.

      Method

      Institutional pharmacy database was used to perform an unstructured data collection of medical record numbers based on SCC diagnosis and IO treatment codes between January 1, 2008 and October 1, 2018 at The Ohio State University Medical Center. Patient data was then abstracted from the electronic medical record. Variables included demographics, co-morbidities, stage, metastatic sites (including brain), treatment history (including chemotherapy, IO and radiation), and treatment response. Survival from the start of IO to death and median overall survival (OS) from diagnosis to death were calculated.

      Result

      Forty patients, 17 women and 23 men, were eligible for evaluation. The median age was 64 years (30-91 yo); 36 patients were current/former smokers. At diagnosis, most were extensive-stage (65%). Common metastatic sites at diagnosis included brain (20%), bone (35%) and liver (33%). Overall, 22 patients (55%) developed brain metastases over the course of disease. Median line of IO was 2nd line (range 2nd-5th line); nivolumab-ipilimumab was the most common regimen (43%), followed by nivolumab (38%), then pembrolizumab (20%). Patients received an average of 4 cycles of IO (range 1-35). Nine patients were treated on clinical trial. Median survival after IO was 4.2 months and median OS of 17.3 months. Median survival for patients with brain metastases was 2.2 months vs. 10.3 months without (P=.01). Most patients had no durable response to IO; however, responses were observed in 7 patients (1 CR, 6 PR) and 8 patients had stable disease.

      Table 1: Treatment Summary

      Treatment

      Patients – no.

      Chemotherapy – any line

      Carboplatin

      28

      Cisplatin

      15

      Etoposide

      40

      Topotecan

      19

      Irinotecan

      23

      Paclitaxel

      11

      Gemcitabine

      1

      Immunotherapy

      Nivolumab-ipilimumab

      17

      Nivolumab

      15

      Pembrolizumab

      9

      Radiation Therapy

      Radiation (non-CNS site)

      36

      Radiation (CNS)

      24

      Type of CNS radiation

      Prophylactic Cranial Irradiation

      8

      Whole brain radiation (therapeutic)

      16

      Gamma knife/stereotactic radiation

      6

      Conclusion

      This retrospective review describes our experience utilizing IO in advanced SCLC at our academic institution. Although treatment patterns are changing with first-line IO, this data reflects the variability of patient responses. Several patients had prolonged responses, indicating potential areas of further investigation. This data will also be used to evaluate IO activity in CNS disease.

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

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

      11:30 - 13:00  |  Author(s): Kai He

      • Abstract
      • Presentation
      • Slides

      Background

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

      Method

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

      Result

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

      table 1-page-001.jpeg

      Conclusion

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

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-71 - Bone Metastases and Skeletal-Related Events in Patients with Metastatic NSCLC Treated with ICIs: A Multi-Institutional Study (Now Available) (ID 2421)

      09:45 - 18:00  |  Author(s): Kai He

      • Abstract
      • Slides

      Background

      Skeletal-related events (SRE) occur frequently in patients (pts) with metastatic NSCLC (mNSCLC) and confer a poor prognosis. Data on SRE and the effects of bone modifying agents (BMA) in NSCLC pts treated with immune checkpoint inhibitors (ICI) are limited as is the effect of bone modifying agents (BMA) on development of SRE and overall survival (OS). Here we report the incidence, impact on survival, and risk factors for SRE in pts with mNSCLC treated with ICI in a multi-institutional cohort.

      Method

      We conducted a retrospective study of pts with mNSCLC treated with ICI at our institutions from 2014 to 2017. Overall survival (OS) was calculated from the date of ICI initiation to death from any cause or last follow-up. Cox regression model was used to study the association between OS and baseline bone metastases (BM). The associations between SRE and categorical outcomes were studied using chi-square/Fisher’s exact test. The study was approved by each institution’s ethics review board.

      Result
      Table 1. Multivariate survival analysis.
      Parameter Level Hazard Ratio 95% HR Confidence Limits P-value
      BM at baseline Absent Ref <0.0001
      Present 1.847 1.414-2.413
      ECOG 0 Ref 0.0006
      1 1.494 1.017-2.196
      2 1.506 0.969-2.341
      3 3.788 1.442-9.949
      Histology Adenocarcinoma Ref 0.969
      Squamous 1.057 0.786-1.420
      Lines of Therapy 1 Ref 0.0007
      2 1.580 1.123-2.223
      >=3 2.064 1.417-3.005

      We identified a cohort of 330 pts: 259 (72%) treated in second line or beyond; 211 (64%) received nivolumab; median age 63.4; median OS 10.4 mo (95% CI: 8.6, 12.5). In our cohort, 124 (38%) pts had BM at time of ICI, and 43 (13%) developed SRE after ICI (median 2.8 months; 19 pathologic fractures, 1 cord compression, 26 palliative radiation, 8 surgery). Patients with BM at ICI had shorter OS after controlling for ECOG, histology, and line of therapy (Table 1; Hazard Ratio 1.847; 95% CI 1.414 - 2.413; p <0.0001) compared to pts without baseline BM. Development of SRE was associated with presence of BM at baseline but not age, histology, or mutation status (EGFR, KRAS, and TP53). The use of BMA was not associated with OS or decreased risk of SRE. The development of new or progression of existing BM (22% of pts) during ICI was associated with a worse prognosis (mOS 7.1 vs 11.6 mo, p=0.017).

      Conclusion

      Bone metastases and SRE are a significant cause of morbidity in pts with mNSCLC treated with ICI. The presence of BM at baseline was associated with a worse prognosis after controlling for multiple clinical characteristics. In our cohort, the use of BMA was not associated with decreased risk of developing SRE, osseous progression, or survival.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-15 - Smoking Status Is Not a Replacement Biomarker for Tumor Mutation Burden in Non-Small Lung Cancer (ID 454)

      09:45 - 18:00  |  Presenting Author(s): Kai He

      • Abstract
      • Slides

      Background

      Recent clinical studies suggest tumor mutation burden (TMB) as a promising therapeutic biomarker of anti-tumor immune checkpoint blockade (ICB). Given the causal link between cancer-causing mutations and tobacco smoking, patients with a significant smoking history may respond better to ICB. However, it is not clear if smoking history is an adequate surrogate biomarker for TMB. Here, we sought assess the clinical utility of smoking history in predicting tumor mutation burden.

      Method

      Publicly available smoking history and DNA somatic alteration data from NSCLC were downloaded from The Cancer Genome Atlas and a large dataset of lung adenocarcinoma tumors published by Imielinski, et al (Cell, 2012) Tumor mutation burden was calculated as the sum of all somatic mutations divided by the exome sequencing coverage. Smoking history was analyzed both as categorical (ever, never, former) and semi-continous variables (pack years). Hypermutancy was defined as greater than or equal to 10 mutations per megabase.

      Result

      A total of 395 LUAD and 419 LUSC patients were included in this analysis. Smokers had significantly higher tumor mutation burdens than non-smokers; however, in both LUAD and LUSC, there were smokers with low TMB and non-smokers with high TMB. Smoking pack year history (SPY) was weakly positively correlated (Spearman ρ = 0.20, p = 2.5x10-4) in LUAD but uncorrelated (Spearman ρ = -0.026, p = 0.61) in LUSC. Non-smokers and patients without a recorded SPY were excluded from the SPY analysis. We calculated AUCs for predicting hypermutancy in tumors, using variable thresholds of SPY. In LUAD and LUSC, SPY had an AUC of 0.38 and 0.47 in predicting TMB, showing that SPY was not better than random prediction. We also sought to predict TMB from smoking as a binary variable. In LUSC, 8/18 (44%) non-smokers and 253/447 (57%) smokers were hypermutant. In LUAD, 9/61 (15%) non-smokers and 219/391 (56%) smokers were hypermutant. Additionally, we repeated this analysis on matched smoking history and TMB from an independent cohort of 162 LUAD tumors published by Imielinski, et al. Similarly, we found that 1/27 (4%) of nonsmokers and 66/135 (49%) of smokers were hypermutant. In this cohort, the AUC in predicting TMB with SPY was 0·21.

      Conclusion

      In this study, we investigated the relationship between tobacco smoking and TMB. While the average lung cancer patient with a history of tobacco smoking has a higher TMB than the average never-smoker, there is not a clear relationship between the extent of exposure in pack years and TMB. In general, smoking is not an informative biomarker for TMB, however, non-smokers who develop LUAD are unlikely to have high TMB. This study highlights the value of next generation sequencing for TMB in predicting therapeutic response to ICB.

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