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J. Soria

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    PLEN 03 - Science Drives Lung Cancer Advances (ID 52)

    • Event: WCLC 2015
    • Type: Plenary
    • Track: Plenary
    • Presentations: 1
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      PLEN03.04 - Personalized Medicine (ID 2046)

      08:15 - 09:45  |  Author(s): J. Soria

      • Abstract
      • Presentation
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      Platinum-based doublet chemotherapy is the standard first-line treatment for non-selected patients with advanced non-small cell lung cancer (NSCLC) who have a good performance status . However, some tumors are highly dependent on the function of specific oncogenes for proliferation and survival. This “oncogenic addiction” has leaded the development of targeted anticancer therapies and their ad hoc biomarkers as predictors of their efficacy. This fact has changed the diagnostic and treatment approach in NSCLC . Moreover, this ‘‘personalized medicine’’ approach, in which tumors might potentially benefit from a biology-guided treatment, has an impact in patients’ outcome . Personalized medicine is also feasible in other malignancies such as metastatic breast cancer, even for patients with rare genomic alterations (SAFIR01 trial) , and in other refractory malignancies (SHIVA trial) , reinforcing that the establishment of a comprehensive tumour molecular profile is feasible and compatible with clinical practice. Unlike “basket trials”, where researchers test the effect of a single drug on a single mutation in a variety of cancer types, “umbrella” trials are designed to test the impact of personalized medicine with different drugs on different mutations in a single type of cancer on the basis of a centralized molecular portrait . The phase II BATTLE (Biomarker-integrated Approaches of Targeted Therapy for lung Cancer) trial was the first prospective, biopsy-mandated, biomarker-based study, that adaptively randomised 255 pre-treated NSCLC patients to erlotinib, sorafenib, erlotinib plus bexarotene, or vandetanib, based on molecular biomarker analysed in fresh core needle biopsy specimens. Overall results included a 46% 8-week disease control rate (primary endpoint). This trial established the feasibility of “real-time” biopsies and personalized treatment in lung cancer. BATTLE-2 (NCT01248247), a phase II, randomised, multi-arm study in advanced pre-treated EGFR wild type and ALK non-rearranged NSCLC patients is currently ongoing. The SPECTA-lung (NCT02214134), included within the SPECTA-platform, is a program aiming at Screening Patients with thoracic tumors (lung cancer, malignant pleural mesothelioma, thymoma or thymic carcinoma at any stage) to identify the molecular characteristics of their disease for Efficient Clinical Trial Access. Second-generation trials encompass within the trial design to access to targeted therapies and usually incorporate a randomization process. SAFIR02-Lung (NCT02117167) is an open-label, multicentric randomised, phase II trial. Advanced no EGFR-activating mutation or ALK translocation NSCLC patients are biopsied during the two initial platinum-based chemotherapy cycles. A comparative genomic hybridisation (CGH) array and a next-generation sequencing are performed and analysed during the two subsequent cycles as a therapeutic decision tool. Only patients with a molecular alteration are randomized to maintenance targeted drug arm (AZD8931, Vandetanib, Selemutinib, AZD5363, AZD4547, AZD2014); or standard maintenance treatment (pemetrexed or erlotinib) after completion of four cycles of chemotherapy to test an improvement in progression free survival (PFS). Lung-MAP (NCT02154490) trial is a phase II/III multidrug, multi-sub-study, and biomarker-driven clinical trial in advanced second-line squamous lung cancer patients. Patients are randomized to standard second-line treatment (docetaxel / erlotinib) or five experimental drugs (four targeted therapies according NGS results and an anti-PDL1 immunotherapy based on immunochemistry results). The primary end-point of the trial is PFS. Approximately 500 and 1000 patients will be screened per year for over 200 cancer-related genes for genomic alterations. ALChEMIST trial (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials) is designed to assess whether adjuvant therapy with erlotinib (ALCHEMIST-erlotinib, NCT02193282) or crizotinib (ALCHEMIST-crizotinib, NCT02201992) for 2 years will improve survival over placebo for patients with completely resected stage IB-IIIA EGFR-mutant or ALK-rearranged NSCLC tumors following standard post-operative therapy. ALCHEMIST-screening trial (NCT02194738) will screen about 6,000 to 8,000 participants over 5 to 6 years, with 400 patients enrolled per arm. The RTOG1306 is a phase II trial in EGFR-mutant or ALK-rearranged unresectable stage IIIA (pN2) or IIIB (pN3) NSCLC patients. The aim of the study is to asses whether induction therapy with erlotinib or crizotinib for 12 weeks prior to chemo-radiotherapy improves PFS compared to those treated with standard care therapy alone. Molecular screening is also tested across prospective trials in different malignancies. The MOSCATO trial (NCT01566019) includes metastatic solid tumors and the primary objective is to use high throughput molecular analysis (CGH Array and sequencing) to guide treatment of patients with targeted therapeutics in order to improve the PFS compared to the previous treatment line. IMPACT trial (Initiative for Molecular Profiling in Advanced Cancer Therapy Trial, NCT00851032), is an umbrella protocol in 5,000 patients with advanced malignancies. The goal is to correlate the molecular profile with response to phase I therapies. The NCI-MATCH trial (Molecular Analysis for Therapy CHoice) trial is an umbrella protocol for multiple single-arm, phase II trials. Biopsies from as many as 3,000 patients will be screened by next-generation DNA sequencing to identify 100 actionable mutations, with 1000 participants being enrolled (25% of whom will have rare cancers). Co-primary end-points are overall response rate and PFS rate at 6 months. Finally, for advanced and refractory cancer patients who do not have recognised genetic abnormalities WINTHER trial (NCT01856296) aims at selecting rational therapeutics based on the analysis of matched tumors and normal biopsies according to micro arrays and gene expression profiling results. The main objective is to compare the PFS of the current treatment versus the previously prescribed treatment. Models of personalized medicine implementation (no organized compared with organized framework) , optimal technology for molecular profile , and the optimal patients’ selection are some of challenges to be overcome in personalized medicine. Moreover, the actual model of personalized medicine does not take in account secondary events, which will be involved in cancer resistance. A major challenge in molecular medicine will be to target these secondary events early enough, in order to avoid treatment resistance . Intratumoral heterogeneity plays a critical role in tumor evolution. However, molecular characterization of the tumor is provided from a single biopsy and at single time point. Multiregional evaluations to determine geographical heterogeneity, and molecular characterization of different samples collected over space and time to ascertain clonal evolution are not routinely carried out . The prospective TRACERx trial (TRAcking non-small cell lung Cancer Evolution through therapy [Rx], NCT01888601) in NSCLC patients, aims to define the evolutionary trajectories of lung cancer in both space and time through multi-region and longitudinal tumor sampling and genetic analysis by following cancer from diagnosis to relapse. The study aims to recruit 842 patients . Incorporating an analysis of the tumor immune contexture is also a key challenge and need for the design of new precision medicine trials . In the near future most patients with metastatic tumors will receive targeted therapies or immune modualtors delineated by tumor genotyping and analysis of immune contexture and all of these trials will help to validate current biomarkers facilitating rapid access to innovative therapies.

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