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Sinead Cuffe



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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.01 - KEYNOTE-024 3-Year Survival Update: Pembrolizumab vs Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer (ID 1465)

      11:30 - 13:00  |  Author(s): Sinead Cuffe

      • Abstract
      • Slides

      Background

      In the phase 3 KEYNOTE-024 trial (NCT02142738), first-line pembrolizumab significantly improved PFS (hazard ratio [HR] 0.50, P<0.001) and OS (HR 0.60, P=0.005) vs platinum-based chemotherapy in patients with advanced NSCLC, PD-L1 tumor proportion score (TPS) ≥50%, and no targetable EGFR/ALK alterations (median follow-up, 11.2 months). We present data with 3-years minimum follow-up.

      Method

      Patients were randomized to pembrolizumab 200 mg Q3W for 2 years or platinum doublet (investigator’s choice) for 4‒6 cycles plus optional maintenance (nonsquamous), with stratification by ECOG PS (0/1), tumor histology (squamous/nonsquamous), and region (East Asia/non‒East Asia). Patients in the chemotherapy arm could cross over to pembrolizumab upon disease progression if they met eligibility criteria. The primary endpoint was PFS; OS was a key secondary endpoint. Response per investigator by RECIST version 1.1 is reported.

      Result

      305 patients were randomized (pembrolizumab, n=154; chemotherapy, n=151). At data cutoff (February 15, 2019), median (range) follow-up was 44.4 (39.6‒52.9) months. 210 patients had died (pembrolizumab, n=97; chemotherapy, n=113). 98 (64.9%) patients crossed over from chemotherapy to anti‒PD-(L)1 therapy during/outside of the study. Median (95% CI) OS in the pembrolizumab arm was 26.3 (18.3‒40.4) months vs 14.2 (9.8‒18.3) months in the chemotherapy arm (HR, 0.65; 95% CI, 0.50‒0.86). 36-month OS rate was 43.7% in the pembrolizumab arm vs 24.9% in the chemotherapy arm. Despite longer mean treatment duration in the pembrolizumab arm (11.1 vs 4.4 months), grade 3‒5 treatment-related adverse events (AEs) were less frequent with pembrolizumab vs chemotherapy: 31.2% vs 53.3%. 38 patients in the pembrolizumab arm completed 2 years (35 cycles) of therapy. Among these, 34 were alive, 31 (81.6%) had an objective response (including 3 with complete response), and median duration of response was not reached (range, 4.2‒46.7+ months). OS rate 12 months after completing pembrolizumab treatment (ie, ~36 months after initiating treatment) was 97.4% (95% CI, 82.8‒99.6). Among the 38 patients who completed 2 years, 5 (13.2%) had treatment-related grade 3-4 AEs; no fatal treatment-related AEs occurred. 10 patients who completed 2 years (1 completed 34 cycles) and subsequently progressed received second-course pembrolizumab; 7 had an objective response, 8 remain alive.

      Conclusion

      With >3 years’ follow-up, first-line pembrolizumab monotherapy continued to provide durable long-term OS benefit vs chemotherapy despite a majority of patients assigned to chemotherapy crossing over to pembrolizumab. Pembrolizumab was associated with less toxicity than chemotherapy. Patients who completed 35 cycles of pembrolizumab had durable clinical benefit and most were alive at data cutoff.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-19 - Co-Targeting PIM Kinase to Overcome MET Amplified Resistance to EGFR TKIs in NSCLC (ID 500)

      10:15 - 18:15  |  Author(s): Sinead Cuffe

      • Abstract

      Background

      Currently there are five EGFR tyrosine kinase inhibitors (TKIs) (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) available for treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However for virtually all patients, resistance is inevitable, and disease progression occurs within 1 to 2 years of starting a TKI. Efforts to overcome resistance define the landscape of TKI research resulting in the development of second-generation and now third-generation agents and combination regimens. Third-generation agents, such as osimertinib, show improved response rates and extended median overall survival (OS), with potential to overcome previously untreatable resistance mechanisms. However acquired resistance mutations and activation of bypass RTK signalling mechanisms such as MET can mediate primary and secondary resistance to all EGFR TKIs. MET amplification has been observed after prolonged exposure of HCC827 cell lines to third-generation EGFR-TKIs (osimertinib or CNX-2006). We have pinpointed a novel strategic downstream target that plays a key role in MET regulation, cancer progression, drug resistance and immune evasion namely PIM kinase (PIM). The PIM family of serine/threonine kinases constitute three major isoforms namely PIM-1, 2 and 3 and have been shown to synergise with c-Myc. We have shown that all three PIM isoforms are highly expressed in NSCLC cell lines and patient tumors and hypothesise that co-targeting PIM kinase and EGFR may provide a more durable response to treatment and overcome MET amplified EGFR TKI resistance.

      Method

      Quantification & localisation of MET, c-MYC, PIM kinases and downstream substrates were examined by Western blot analysis and high content analysis (HCA) in EGFR TKI sensitive (HCC827P) and resistant (HCC827ER) cell lines and selected resistant clones (HCC827ER clone 3, HCC827ER clone 10). Efficacy of pan-PIM inhibitor (AZD1208) & novel PI3K/mTOR/PIM inhibitor (IBL-302) alone and in combination with erlotinib were quantified using the CellTiter-Blue, cell viability assay, in all cell lines. Effect of PIM inhibitors on intracellular signalling was quantified by PathScan® Intracellular Signaling Arrays.

      Result

      Activation of PIM-1, PIM-3 and c-MYC expression was demonstrated in MET amplified EGFR TKI resistant cells (HCC827ER) and (HCC827ER clone 3) compared to EGFR TKI sensitive cells (HCC827P). Erlotinib resistant clone that had undergone EMT (HCC827ER clone 10) had reduced expression of PIM-1, PIM-3 and c-MYC compared to MET amplified cells (HCC827ER clone 3). HCC827P and HCC827ER cells were both sensitive to AZD1208 (IC50 47.1μM versus 48.2μM). HCC827ER cells and HCC827ER clone3 cells were more sensitive than HCC827P cells to IBL-302 in a dose-response cell viability assay (IC50 0.277μM vs 0.253μM vs 0.351μM). IBL-302 inhibited downstream intracellular signalling at significantly lower concentrations than AZD1208 (250nM versus 2μM respectively).

      Conclusion

      We show here for the first time that PIM kinase is activated in MET amplified EGFR TKI resistant cells. Erlotinib resistant HCC827ER cells are sensitive to pan-PIM inhibitor AZD1208 and the novel triple targeted therapy IBL-302. These data demonstrate that PIM kinase is a pivotal mechanism involved in EGFR TKI resistance and is an ideal target for dual inhibition strategies.

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-16 - Assessment of PD-L1 and CD8 Expression in Lung Cancer Using RNA in Situ Hybridisation (ID 2693)

      10:15 - 18:15  |  Author(s): Sinead Cuffe

      • Abstract

      Background

      PD-L1 is routinely assessed using immunohistochemistry (IHC) as a companion-diagnostic test. However, patients may be missing out on therapy as issues exist in determining PD-L1 positivity. This is partly due to the use of different antibodies, staining platforms and positivity cut-offs. The use of RNA in-situ hybridisation (RISH) for the detection of PD-L1 levels may be a way to address this; particularly as PD-L1 mRNA expression levels are associated with better overall survival in NSCLC. It is well established that PD-L1 expression is associated with increased numbers of Tumour Infiltrating Lymphocytes (TILs) including those which are CD8+. Therefore, it may also be worthwhile to combine PD-L1 testing with additional marker testing such as CD8. The aim of this study is to investigate the expression of PD-L1 and CD8 by RISH in a cohort of NSCLC samples and correlate with clinical outcome.

      Method

      RISH protocols (RNAScope® 2.5 HD assay, Advanced Cell Diagnostics, Inc.) were initially optimised on a well annotated cell line TMA (low, moderate and high expression) and compared with standard IHC (DAKO - clone 22C3). Following successful optimisation of the technique, a test cohort of 35 full-face FFPE NSCLC samples were examined for PD-L1 expression by both RISH and IHC. All slides were scored independently by a pathologist. RISH slides were scored as per ACD guidelines (0-4; based on number of positive dots per cell and number of dot clusters). IHC was scored using the standard tumour proportion score system. Image analysis (IA) was subsequently performed by Visiopharm®. Currently, a further cohort of 200 FFPE samples is being assessed, in addition to 50 FFPE samples from patients who received an anti-PD-1 therapy. Optimisation is on-going for dual CD8/PD-L1 RISH staining.

      Result

      In the initial 35 samples, PD-L1 was detected in 20% of cases by IHC (≥50% positivity) with mRNA expression identified in 14% of cases by RISH (≥2). In contrast with other recently published studies, issues were identified between IHC and RISH. There were 3 cases which scored positive by IHC, which were negative by RISH. Additionally, 1 case was positive by RISH but negative by IHC. The comparison between both assays produced a ‘moderate agreement’ as assessed using Cohen’s kappa coefficient (ĸ=0.528, p=0.002). IA undertaken on both assays could not be statistically compared using Cohen’s kappa coefficient due to the use of a composite scoring matrix to quantify RISH mRNA signals. However, IHC stained sections scored by IA showed similarity to IHC scored by a pathologist. Further optimisation is required on the RISH IA scoring algorithm. A comparison of PD-L1 IHC with RISH, combined with dual CD8/PD-L1 staining in a larger cohort of clinical samples is on-going, which will further determine the clinical utility of this technique.

      Conclusion

      Data from our test cohort of samples have shown that PD-L1 detection by RISH is feasible and compares well to IHC. Preliminary data would also suggest that IA may be better than a pathologist alone, particularly in borderline cases. RISH may be a suitable method for improved detection of PD-L1 in NSCLC.