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Aurélie Swalduz



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    MA21 - Non EGFR/MET Targeted Therapies (ID 153)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA21.07 - Circulating Tumor DNA Analysis Depicts Potential Mechanisms of Resistance to BRAF-Targeted Therapies in BRAF+ Non-Small Cell Lung Cancer (Now Available) (ID 1365)

      14:30 - 16:00  |  Author(s): Aurélie Swalduz

      • Abstract
      • Presentation
      • Slides

      Background

      Oncogenic BRAF-V600 mutations are observed in 1-2% of non-small cell lung cancer (NSCLC). Targeted therapies including vemurafenib (V), dabrafenib (D) or combination of dabrafenib plus trametinib (D+T) are associated with favorable outcomes in these patients (pts). The mechanisms of resistance to BRAF-targeted therapies (BRAF-TT) in NSCLC are largely unknown.

      Method

      We performed genomic profiling of serial circulating-tumor DNA (ctDNA) in a cohort of 79 metastatic BRAF-mutant NSCLC pts (96% V600E, 4% non-V600). BRAFmutational status was ascertained based on local testing. Plasma samples were collected, from 2014-2018 in 27 Hospitals, from pts treated with V (n=34), D (n=2) or D+T (n=23). We collected 41 plasma samples at baseline to BRAF-TT, 40 at progressive disease (PD) and ~200 samples during treatment follow-up, concomitant to routine radiological evaluation. Inivata InVisionSeq™ assay was used to detect the presence of SNVs, indels and CNAs in 36-cancer related genes.

      Result

      At baseline, 72,5% of BRAF mutations (V600E and non-V600E) were detected in plasma. BRAF-V600E detection in plasma was associated with the presence of liver metastasis, versus BRAF-V600E-negative cases (22% vs. 7%, respectively). Co-occurring molecular alterations at baseline, besides BRAF-V600E, were observed in 18/26 (70%) cases: FGFR2 (1pt), PIK3CA (2pts), ERBB2 (1pt), CTNNB1 (2pts) and IDH1 (2pts). FGFR2, PIK3CA or CTNNB1 alterations were associated with PD as the best response to the subsequent BRAF-TT. TP53 and STK11 mutations were observed in 54% (14/26) and 8% (2/26) of pts, respectively. Complete clearance of BRAF-V600E in plasma at baseline was observed at the first CT-scan evaluation in 42% (3/7) and 82% (9/11) pts treated with V or D+T, respectively. These pts were in complete or partial response, suggesting that monitoring BRAF-V600E levels in plasma on treatment may be a clinically useful marker of tumor response. At PD, a consistent rebound in BRAF-V600E plasma levels was observed in 60% (24/40) pts. Resistance to V was associated with alterations in the MAPK pathway: 1pt (KRAS), 1pt (GNA11), 1pt (NRAS and GNAS) and 1pt (MAP2K1 and NFE2L2). Activating PI3KCA mutations were observed in 4 pts who progressed in <6 months on V treatment. ctDNA analyses at PD under D+T revealed that, similar to what we observed in patients who progressed on V, alterations in KRAS, NRAS, PIK3CA and CTNNB1 are associated with D+T resistance. Prediction of the impact of these alterations, at the protein level, was assessed using in silico structure modeling and will be presented.

      Conclusion

      ctDNA monitoring might be an informative tool for assessing disease response and resistance in NSCLC pts treated with BRAF-TT. MAPK reactivation remains an important resistance mechanism to BRAFi-monotherapy or to BRAFi and MEKi combination therapy.

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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
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-116 - Early Immune-Related Adverse Events Under PD-1/PD-L1 Inhibitors Predict Better Progression-Free Survival in NSCLC (ID 1932)

      09:45 - 18:00  |  Author(s): Aurélie Swalduz

      • Abstract

      Background

      Immune checkpoint blockers (ICB) targeting the PD-1/PD-L1 axis improve survival in patients with advanced non-small-cell lung cancer (NSCLC) without oncogenic addiction; however, they are also responsible for immune-related adverse events (irAE) sometimes leading to treatment discontinuation. Despite a clear association with response to ICB in melanoma, the predictive significance of a better outcome for irAE in NSCLC is unclear.

      Method

      We retrospectively collected clinical and basic biological data from 160 stage IV NSCLC patients who received nivolumab, pembrolizumab or atezolizumab as second-line single agent in two cancer centers in France between January 2015 and December 2017. All irAE were collected using the Common Terminology Criteria for Adverse Events v5.0 ; general symptoms (e.g. fatigue) and cancer-related symptoms were discarded. We used two different statistical approaches to evaluate whether early irAE (≤ 12 weeks) were correlated to a better progression-free survival: i- a 12-week landmark method, including a multivariate Cox proportional hazards model (with ECOG PS and PD-L1 as covariates), ii- a propensity score matching (PSM) method, using PD-L1 level as the matching variable, followed by a Cox proportional hazards model. Finally, we investigated whether grade and number of early irAE were associated with improved PFS.

      Result

      Most patients were male (n=107; 66.3%), smokers (n=146; 91.3%) and ECOG PS 0-1 (n=121; 75.7%) and received ICB as second (n=96; 60%), third line (n=38; 23.8%) or more (n=22; 13.8%). Nivolumab was the most used ICB (n=145; 90.6%). Within the first 12 weeks of treatment, 46 irAE occurred in 30 patients (18.8%), including 3 grade 3 irAE (1 pneumonitis, 1 myocarditis, 1 renal failure). Musculoskeletal (8.8%) and skin toxicity (5%) were the most frequent irAE. Clinical baseline characteristics were comparable between patients displaying early irAE (irAE+) and those who did not (irAE-), except for ECOG status (71.5% of PS 0-1 patients in irAE- group versus 93.3% in irAE+, p = 0.023) and PD-L1 level (PD-L1 ≥ 50% in 13.1% of patients in irAE- group versus 30.0% of patients in the irAE+ group, p = 0.016). The 12-week landmark analysis included 80 patients; 23/80 (28.8%) of them experienced at least 1 early irAE. PFS was improved in the irAE+ group in both univariate (HR = 0.24 [0.11-0.53], p < 0.001), and multivariate Cox models (HR = 0.33 [0.14-0.76] p = 0.009). After matching irAE+ and irAE- patients on PD-L1 level, early irAE were still associated with prolonged PFS (HR = 0.29 [0.15-0.57], p = 0.001). In the 12-week landmark population, grade ≥2 irAE were associated with even longer PFS (HR = 0.43 [0.26-0.71], p = 0.0009), and so were multiple co-occurring early irAE (HR = 0.30 [0.15-0.60], p = 0.0007).

      Conclusion

      Early occurrence of irAE before 12 weeks appears to be associated with prolonged response to ICBs, independently of PD-L1 baseline expression in advanced NSCLC.