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Steven H Lin



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    MA08 - Pawing the Way to Improve Outcomes in Stage III NSCLC (ID 127)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
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      MA08.01 - Analysis of PD-L1 Expression on Circulating Stromal and Tumor Cells in Lung Cancer Patients Treated with Chemoradiation Therapy and Atezolizumab (Now Available) (ID 2965)

      15:15 - 16:45  |  Presenting Author(s): Steven H Lin

      • Abstract
      • Presentation
      • Slides

      Background

      We have previously shown dynamic changes to PD-L1 expression during chemoradiotherapy (CRT) could be tracked by evaluating PD-L1 expression on circulating cells. How these changes relate to immunotherapy response is unknown. We prospectively monitored PD-L1 expression in 2 cell types found in circulation (Circulating tumor cells [CTCs] and Cancer Associated Macrophage-like Cells [CAMLs]) in locally advanced non-small cell lung cancer (LA-NSCLC) patients (pts) treated with atezolizumab and CRT.

      Method

      Samples were taken from a completed phase II DETERRED trial (NCT02525757) where atezolizumab was added for one year after completing CRT (N=10) or concurrently and after CRT (N=30). Samples from 39 pts from the study were available for analysis. Baseline blood sample (7.5 ml) were drawn prior to start of CRT (T0), and a second sample was drawn ~1 month after completing CRT (T1), and a 3rd sample was drawn ~2 months after completing CRT (T2). Blood was processed by CellSieve™ microfilters; stained for cytokeratin/PDL1/CD45 to identify CTCs and CAMLs. PD-L1 intensity was measured and grouped by 4 scores: 0-negative, 1-low, 2-medium, & 3-high. Tumor IHC for PD-L1 levels from core biopsies was done with Dako 22c3 and was compared to T0 samples. PD-L1 levels from tumor and in circulating cells were used to evaluate PFS and OS. Significance was assessed by log-rank testing.

      Result

      PD-L1 IHC was available for 85% of pts, and there was at least one cytokeratin positive cell (CTC or CAML) found in 100% of T0 samples. CTCs were found in 33% of T0, 24% of T1 & 43% T2. CAMLs were found in 92% of T0, 97% of T1, & 97% of T2 samples. No correlation was seen comparing tumor PD-L1 expression percentage and the T0 PD-L1 staining intensity on CTCs/CAMLs. Tumor PD-L1>1% was found in 58% and >50% in 24% of IHC samples, yet there was no correlation between tumor PD-L1 expression and PFS or OS. At T0, PD-L1 expression in CTCs/CAMLs was low (0-1) in 18 pts and high (2-3) in 15, but no relationship to PFS (HR=0.6, 95%CI 0.2-1.7, p=0.48) or OS (HR=1.7, 95%CI 0.5-6.4, p=0.66) was found. However, pts with high PD-L1 at T1 or T2, regardless of levels at T0, had a trend towards improved PFS (HR 2.5, 95%CI 0.7-8.6, p=0.13), and a significantly better OS (HR 14.2, 95%CI 2.4-81.8, p=0.003). Interestingly, of the 15 pts who had low PD-L1 at T0, 7 had induced PD-L1 expression at T1 or T2. All samples with induced PD-L1 expression had better PFS (HR 8.3, 95%CI 1.4-50.2, p=0.02) and OS (HR 8.7, 95%CI 1.2-64.0, p=0.03) compared to those who remained low.

      Conclusion

      While baseline tumor or circulating cellular PD-L1 expression was not correlated with clinical outcomes, sequential monitoring of high PD-L1 expression in CTCs/CAMLs after CRT appeared to be associated with better clinical outcomes in pts who received consolidation atezolizumab after CRT, particularly in pts who had induced expression at follow up during the consolidation phase. Dynamic tracking of PD-L1 may serve as a predictive biomarker for immunotherapy effectiveness in LA-NSCLC after CRT.

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    P1.17 - Treatment of Early Stage/Localized Disease (ID 188)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.17-39 - Preoperative Prediction of Incomplete Resection in Non-Small Cell Lung Cancer: An Externally Validated Clinical Nomogram (Now Available) (ID 1722)

      09:45 - 18:00  |  Author(s): Steven H Lin

      • Abstract
      • Slides

      Background

      Patients who are surgically treated for stage I-III non-small cell lung cancer have a worse prognosis after incomplete (R1-R2) resection. Predictive factors for completeness of resection have not satisfactorily been established. Our study aimed to develop, and internally and externally validate a prediction model to estimate the risk of incomplete resection, based on preoperative patient-, tumor-, and treatment-related factors.

      Method

      From a Dutch national database (NKR) all consecutive NSCLC patients diagnosed from 2011 to 2014 who had surgery without neoadjuvant therapy were selected. Fifteen possible predictors were analyzed. Multivariable logistic regression analysis with stepwise backward elimination was used to create a prediction model. Discriminatory ability and calibration of the model was determined after internal validation. External validation was applied in an American dataset from the NCDB, whereupon the model was adjusted. The prediction model was presented as a nomogram.

      Result

      In the development set of 7,124 patients an incomplete resection was reached in 496 patients (7.0%). Remaining predictors were gender, histology, cT-stage, cN-stage, extent of surgical resection, time interval from diagnosis to surgery, open versus thoracoscopic procedure, and the interaction between procedure and cN-stage. After internal validation, the corrected c-statistic of the resulting nomogram was 0.73. Application of the nomogram to the external dataset of 85,235 patients with R1-R2 resections in 2,485 patients (2.9%) resulted in a c-statistic of 0.70. Calibration revealed good overall fit of the nomogram in both cohorts.

      nomogram.jpg

      Conclusion

      An internationally validated nomogram is presented providing the ability to predict the individual risk of an incomplete resection in patients with stage I-III NSCLC planned for surgery. In case of a relevant probability of incomplete resection, alternative treatment strategies could be considered, such as a larger extent of surgery, neoadjuvant or definitive chemoradiotherapy. In contrast, with a small predicted probability of incomplete resection, the use of surgery is further supported.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-93 - Detection of Giant Cancer-Associated Macrophage-Like Cells After Concurrent Chemoimmunoradiation Is Associated with Poor Survival in NSCLC (ID 2350)

      10:15 - 18:15  |  Author(s): Steven H Lin

      • Abstract
      • Slides

      Background

      Circulating cancer-associated macrophage-like cells (CAMLs) are a recently described stromal cell found in the peripheral blood of cancer patients that have been shown to be associated with disease progression. The presence of giant CAMLs (≥50 µm) was previously reported to be predictive of disease progression in multiple tumor types. In this phase II DETERRED trial of patients with unresectable locally advanced non-small cell lung cancer (NSCLC) treated with atezolizumab (atezo) combined with concurrent chemoradiation, we explored the utility of CAMLs in predicting progression based on blood samples collected throughout treatment and follow up.

      Method

      Patients were enrolled between February 2016 and April 2018. Patients were treated with carboplatin/paclitaxel (CP) and conventionally fractionated radiation therapy (60 – 66 Gy) with atezo, followed by CP-atezo, followed by maintenance atezo. Median follow up after the completion of concurrent chemoimmunoradiation (cCIRT) was 13.5 months. CAMLs were collected by obtaining peripheral blood from patients at baseline at the beginning, during, at the end, at first follow up, and final follow up after cCIRT. Blood was filtered using CellSieveTM filtration and CAMLs quantified. CAML size ≤49 µm or ≥50 µm was quantified with the observer blinded to clinical information. Relapse free survival (RFS), distant metastasis free survival (DMFS), progression free survival (PFS), and overall survival (OS) were analyzed at each time point.

      Result

      We evaluated 40 patients with unresectable locally advanced NSCLC and obtained a total of 375 samples. CAMLs were identified in 80.5% of samples, averaging 2.5 CAMLs per 7.5 mL sample. Patients with giant CAMLs (≥50 µm) compared to those with smaller CAMLs (≤49 µm) exhibited no difference in RFS, PFS, DMFS, or OS at baseline, during, or immediately after completion of cCIRT. Patients with detectable giant CAMLs at the first follow up (median time 29 days from completion of cCIRT) demonstrated significantly worse RFS (HR=11.79, 95% CI 4.27-32.56, p=0.0021), DMFS (HR=6.48, 95% CI 2.15-19.54, p=0.0009), and PFS (HR=12.47, 95% CI 4.66-33.37, p=0.0014) while OS trended towards statistical significance (HR=5.39 95% CI 1.33-21.81, p=0.071). Long term evaluation of patients with CAML ≥50 µm at first follow up (N=16) revealed 3 patients who converted to CAML<49 µm at last follow up. Patients who converted did not experience any relapses, while all 13 patients who continued to have CAML ≥50 µm experienced progression or death.

      Conclusion

      Giant CAMLs at first follow up after completion of concurrent chemoimmunoradiation is predictive of disease progression and death. This may represent an immediate surrogate marker for poor response at the completion of definitive therapy. Long term follow up with maintenance immunotherapy indicates that a subset of patients convert from giant CAMLs to smaller CAMLs, with better outcomes than those that do not, suggesting that these patients may have derived benefit from maintenance immunotherapy. Continued prospective validation of CAMLs as a peripheral blood-based biomarker is needed to validate these findings.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-31 - Immune Phenotypic Biomarkers in Locally Advanced Non-Small Cell Lung Cancer Treated with Definitive Chemoradiation and Atezolizumab (ID 2597)

      10:15 - 18:15  |  Presenting Author(s): Steven H Lin

      • Abstract

      Background

      Consolidation durvalumab is the current standard of care for locally advanced non-small cell lung cancer (LA-NSCLC) after chemoradiation (CRT). However, predictive and prognostic biomarkers of response to immunotherapy are still poorly characterized. In particular, minimally-invasive blood-based biomarkers that can be sequentially assessed during therapy may prove useful in understanding the characteristics of response and optimal sequencing of therapy. We report serial blood immune-phenotyping of patients undergoing concurrent chemoradiation therapy (CRT) with PD-L1 blockade with atezolizumab.

      Method

      Between February 2016 and October 2018, 40 LA-NSCLC patients were evaluated in conjunction with the single-institution DETERRED trial. The first 10 patients were treated with carboplatin/paclitaxel chemotherapy and atezolizumab for two cycles followed by maintenance atezolizumab for 1 year after completing CRT, followed by 30 patients treated with atezolizumab concurrent with CRT followed by chemotherapy/atezolizumab and maintenance atezolizumab. In all, 38 patients were evaluable. Peripheral blood was drawn at the beginning (baseline), midway through CRT (2-4 weeks), and at the end of CRT, with periodic follow up samples for up to two and a half years. Immune phenotyping was performed by flow cytometry on fresh, whole blood within 24 hours of phlebotomy. Cox regression was preformed to assess biomarker correlations with survival.

      Result

      At the second blood sample midway through CRT, patients who eventually progressed had a larger increase from baseline in the percentage of peripheral blood CD4 T helper cells expressing PD-1 (p = 0.042) and this change was associated with both progression-free (PFS, p = 0.039) and overall survival (OS, p = 0.042). Progressors had a mean increase of 2.5 percentage points while non-progressors had a mean drop of 1.9. At the first post-CRT follow-up, an increase in the percentage of CD8 cytotoxic T lymphocytes expressing PD-1 was negatively associated with survival (PFS p = 0.0015, OS p = 0.023) as well as the percentage of granulocytic myeloid suppressor cells (PFS p = 0.0089, OS p = 0.034). These comparisons were not significant when corrected for multiple testing. However, the change in CD4 PD1 after 2-4 weeks of CRT was an independent prognostic indicator of PFS in multivariate cox regression analysis including age, stage, and histology (p = 0.02, hazard ratio 1.2, 95% CI 1.03 to 1.4).

      Conclusion

      Increases in peripheral blood lymphocytes expressing PD1 and myeloid suppressor cells may be prognostic for locally advanced patients treated with CRT and immune checkpoint blockade but additional studies are needed to verify these markers in immunotherapy resistance.