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Francesco Verderame



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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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      P1.01-59 - Expanding Access to Large-Scale Genomic Mutational Analyses for Patients with Advanced NSCLC in Italy (ID 2410)

      09:45 - 18:00  |  Author(s): Francesco Verderame

      • Abstract

      Background

      In NSCLC, large-scale mutational analysis facilitates access to targeted treatments but is still not routinely employed due to significant technological barriers. The Alleanza Contro il Cancro (ACC) network of Italian Cancer Centers developed an affordable targeted sequencing panel for the identification of multiple genetic alterations with potential clinical utility, and designed a prospective multicentric trial to recruit 1000 newly diagnosed advanced NSCLC patients, aiming to i) compare panel performance against a set of externally validated biomarkers, including alterations in standard-of-care (EGFR, ROS1 and ALK) and non-standard-of-care (KRAS, BRAF, MET) biomarkers; ii) identify alterations in a large dataset of driver and potentially actionable genes; iii) correlate genotypes to survival outcomes and toxicity; iv) carry out ancillary studies on additional biomarkers and/or on specific patient groups (e.g. mutational burden, cfDNA, extensive characterization of immunotherapy-treated patients); v) build a centralized data repository for mutation interpretation and clinical recommendation.

      Method

      Through systematic literature mining and ad-hoc developed bioinformatic pipelines we identified: i) a set of 164 potentially actionable genes in solid tumors; ii) additional 18 genes with predicted driver function in NSCLC; iii) 70 actionable fusion transcripts; iii) 141 SNPs associated with pharmacogenomics markers. We designed a custom enrichment panel (~800 kb target) and compared PCR- and hybridization-based enrichment on semiconductor or by-synthesis sequencing to be subsequently deployed in a large observational trial. Sequencing is decentralized, to allow rapid turnaround time, but raw and processed data are collected in a single informatic infrastructure for centralized quality control and continuous bioinformatic pipeline improvement.

      Result

      PCR/semiconductor sequencing was selected for deployment based on cost and feasibility (2-day, highly automated workflow). 182 patients have been enrolled to date (90% stage IV, 10% IIIB). Of 65 patients with treatment information available, 28 (43%) subsequently received immunotherapy and 13 (20%) targeted therapy. For 56 patients with complete sequencing data, EGFR and KRAS status was concordant in 9/10 and 38/41 cases; discordant cases are being validated with orthogonal methods. Clinically significant MET amplifications were called in 2/2 cases. Remaining target regions did not show pathogenic alterations. Multiple alterations in potentially actionable genes were identified.

      Conclusion

      Large-scale sequencing is reliable, feasible and sustainable across multiple hospitals and provides clinically relevant results. The increased availability of genomic information may result in enhanced access to tailored therapies. Data and sample integration in centralized, shared repositories will allow multiple ancillary studies.

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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
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      PL02.11 - Overall Survival with Durvalumab Plus Etoposide-Platinum in First-Line Extensive-Stage SCLC: Results from the CASPIAN Study (Now Available) (ID 2265)

      08:00 - 10:15  |  Author(s): Francesco Verderame

      • Abstract
      • Presentation
      • Slides

      Background

      Extensive-stage (ES)-SCLC is a recalcitrant disease associated with a median OS of ~10 months following etoposide-platinum (EP); new treatments that prolong survival are needed. CASPIAN (NCT03043872) is an open-label, phase 3 study of durvalumab (anti-PD-L1), ± tremelimumab (anti-CTLA-4), combined with EP as first-line treatment for patients with ES-SCLC. Here we report results for durvalumab + EP (D+EP) versus EP from a planned interim analysis.

      Method

      Patients with previously untreated ES-SCLC (ECOG PS 0/1) were randomised (1:1:1) to durvalumab 1500 mg + EP q3w; durvalumab 1500 mg + tremelimumab 75 mg + EP q3w; or EP q3w. Patients in immunotherapy arms received up to 4 cycles of EP followed by maintenance durvalumab until progression. Patients in the EP arm received up to 6 cycles of EP and prophylactic cranial irradiation (PCI), at the investigator’s discretion. Investigator’s choice of cisplatin or carboplatin was allowed across all arms and was a stratification factor at randomisation. The primary endpoint was OS. Data cutoff: 11 March 2019.

      Result

      268 patients were randomised to D+EP and 269 to EP. Baseline characteristics were well balanced between arms. In the EP arm, 56.8% of patients received 6 cycles of EP. At the interim analysis, D+EP significantly improved OS compared to EP with a HR of 0.73 (95% CI, 0.591-0.909; p=0.0047); mOS 13.0 versus 10.3 months, respectively. 33.9% of patients were alive at 18 months with D+EP versus 24.7% with EP. Secondary endpoints of PFS and ORR were also improved with D+EP compared to EP: PFS HR 0.78 (95% CI, 0.645-0.936); mPFS 5.1 versus 5.4 months; 12-month PFS rate 17.5% versus 4.7%; investigator-assessed ORR (RECIST v1.1; unconfirmed) 79.5% versus 70.3% (odds ratio, 1.64 [95% CI, 1.106-2.443]). The incidences of grade 3/4 AEs (61.5% versus 62.4%) and AEs leading to discontinuation (9.4% each) were similar between arms; the incidence of haematological toxicities was numerically higher in the EP arm. The durvalumab + tremelimumab + EP arm continues blinded to final analysis.

      Conclusion

      The addition of durvalumab to EP as first-line treatment for ES-SCLC significantly improved OS (27% reduction in risk of death) versus a robust control arm that permitted up to 6 cycles of EP and PCI. Of note, this chemo-immunotherapy regimen offers flexibility in platinum choice (carboplatin or cisplatin), reflecting current clinical practice for this challenging disease. No new safety signals were identified.

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