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Cristina Aguado



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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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      P1.01-56 - Increased ROS1 and RET Transcripts in Fusion-Negative NSCLC Patients (ID 2477)

      09:45 - 18:00  |  Author(s): Cristina Aguado

      • Abstract

      Background

      Fusion involving anaplastic lymphoma kinase (ALK), RET proto-oncogene (RET) or v-ros UR2 sarcoma virus oncogene homolog 1 (ROS1) occur in non-small cell lung cancers (NSCLC) and are important biomarkers for targeted therapies. However, little is known about the RNA expression levels of these genes regardless of fusions.

      Method

      We used a custom nCounter panel (NanoString Technologies) designed to detect several genetic alterations, including fusions and mRNA expression levels of ALK, ROS1 and RET in formalin-fixed paraffin embedded (FFPE) samples. RNA was purified from NSCLC tumor samples and analyzed with the custom panel. The counts corresponding to the 3’ probes were normalized using the geometrical mean of the housekeeping genes and then added to evaluate total mRNA expression levels. Cut-off values for overexpression were established as the average counts for each gene plus two times the standard deviation.

      Result

      A total of 400 stage III-IV NSCLC patients (p) from two different institutions were retrospectively analyzed. Overexpression of ALK was found in 55 p (13.8%). Of them, 48 (87%) were also positive for EML4-ALK fusions. One ALK-translocated patient with low levels of ALK mRNA expression did not respond to therapy. Fifteen p (3.8%) showed ROS1 overexpression. In contrast with ALK, only three of them (15%) had a concomitant ROS1 fusion. Among the remaining 12 patients overexpressing ROS1, four were ALK positive, five harbored mutations in EGFR and three were non-smoker females with no known drivers. Regarding RET, high expression levels were found in 14 p (3.5%) and only one of them showed a RET fusion (7%). Among the remaining 13 p, three presented neuroendocrine features and seven were smoker or ex-smoker without other known drivers.

      Conclusion

      Overexpression of ALK mRNA in NSCLC is associated with EML4-ALK translocations. In contrast, a significant number of fusion negative patients show high ROS1 or RET mRNA levels. Further research is warranted to determine the clinical relevance of this finding.

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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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      P2.04-22 - Programmed Death 1-mRNA Expression Predicts Benefit to Anti-PD1 Monotherapy in a Prospective Cohort of Advanced NSCLC (ID 1092)

      10:15 - 18:15  |  Author(s): Cristina Aguado

      • Abstract

      Background

      Immunotherapy (IO) targeting PD1 or PD-L1 represents a new treatment option for patients (pts) with advanced non-small cell lung cancer (NSCLC). Besides PD-L1 IHC, other predictive biomarkers are being explored as potential predictors of outcomes. Our group has recently described an association between PD1-mRNA expression and response to IO in a retrospective multi-tumor dataset (Annals Oncol 2018). We aimed to corroborate these results in a prospective cohort of advanced NSCLC.

      Method

      We prospectively evaluated the expression of 7 immune-related genes (CD4, CD8, PD1, PDL1, IFNG, GZMM andFOXP3) and 5 housekeeping genes in formalin-fixed paraffin-embedded tumor samples obtained before anti-PD1 therapy using the nCounter platform (Nanostring Technologies). The study cohort included consecutive pts with advanced NSCLC, ECOG/PS 0-1, no targetable oncogenes, treated in the first or second-line setting with anti-PD1 monotherapy from June 2017 to January 2019. Associations between the expression of PD1 mRNA (as a continuous variable and using a previously defined pre-specified cutpoint) and response (complete and partial response) were assessed using logistic regression analysis. Kaplan-Meier method was used for survival analysis. PD-L1 IHC tumor cell expression was assessed using the 22C3 clone. Pearson correlation between PD-L1 IHC and PD1 mRNA was explored.

      Result

      A total of 43 pts were included (men 79%; adenocarcinoma 53%; nivolumab 55%; pembrolizumab 45%; first-line 30%; second-line 70%). Response occurred in 23% of pts and was significantly associated with PD1 (p=0.029) and FOXP3 (p=0.035) expression. Using the pre-established PD1 cutoff (Annals Oncol 2018), 37% and 63% samples were PD1-high and PD1-low, respectively. PD1-high was significantly associated with increased overall response rate (ORR) (43% vs 11%, OR=6.22 [CI=1.31-29.44], p=0.021) and progression-free survival (HR 0.36 [CI= 0.14-0.90], p=0.028) but not with overall survival (p=0.117). PD-L1 IHC expression was available in 35 cases, of which 46% had high (>=50%) expression levels. A moderate concordance (0.49) was observed between PD-L1 IHC and PD1-mRNA. In this subset analysis, high PD-L1 IHC was significantly associated with response (50% vs 11%, OR=8.50 [CI= 1.45-49.53], p=0.043). Importantly, when combining predefined high/low-sets for both biomarkers (PD-L1 IHC/PD1-mRNA), response was significantly increased in PD-L1-high/PD1-high compared to PD-L1-low/PD1-low (ORR 58% vs 0%, p=0.019).

      Conclusion

      PD1-mRNA expression is associated with response to anti-PD1 monotherapy and can increase the predictive ability of PD-L1 IHC. Further validation of these findings in pivotal clinical trials evaluating IO in advanced NSCLC pts seems warranted.