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J. Remon
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ORAL 06 - Next Generation Sequencing and Testing Implications (ID 90)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:G. De Lima Lopes, V. Miller
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 1a-1f
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ORAL06.05 - Molecular Tumor Board (MTB) in Non-Small Cell Lung Cancers (NSCLC) to Optimize Targeted Therapies: 4 Years' Experience at Gustave Roussy (ID 2563)
11:48 - 11:59 | Author(s): J. Remon
- Abstract
- Presentation
Background:
Molecular biology has changed the treatment of advanced NSCLC, leading to many small subgroups of patients (pts) eligible for targeted therapies, many of them being not approved. Since 2010 we created a monthly MTB dedicated to NSCLC pts with potential driving molecular abnormalitie(s). MTB includes expert physicians from the lung tumor board and phase I unit, radiation therapists, researchers, geneticists, pathologists and biologists. A medical report summarizes the findings and treatment recommendations for each pts. We report 4 years of activity of MTB at Gustave-Roussy.
Methods:
All consecutive files discussed in MTB for a NSCLC were reviewed. MTB included pts with at least one molecular alteration based on a 75 gene panel (NGS analysis and FISH for ALK, HER2, MET, FGFR1, ROS1 and RET). Tumor and pts characteristics were collected as well as treatments. Pts outcome was calculated from the MTB date. Kaplan-Meier methods, and Cox proportional hazards models were used for survival analysis, adjusting for sex, histology, smoking status, metastasis at diagnosis, number of line(s) before MTB.
Results:
502 files were discussed between 02/2010 and 09/2014. Median age was 60 yrs (25–88 yrs), 53% were male, 86% Caucasian, 26% never-smokers, and 93% had PS ≤1. Initial clinical stage was III-IV in 417 pts (84%) and 79%/10%/11% were adenocarcinomas/squamous cell carcinomas/others NSCLC. Median number of treatment-lines before MTB was 1 (0-10), 86% were previously treated by a platinum-based chemotherapy regimen, 17% in a therapeutic trial, and median time from diagnosis to MTB was 5 months. Biopsy for Molecular Analysis (MoA) mostly came from CT guided biopsies (62%), surgery (21%) or endoscopy (16%). Biopsy was repeated in 19% of pts to get enough material for MoA. The MoA results were ALK rearrangement in 11%, exon 18/19/20/21 EGFR mutation (mut) in 2/14/4/7% respectively, KRAS mut in 32%, PI3KCA mut in 3%, BRAF mut in 5%, HER2 mut (Exon 20) in 2%, HER2 amplification in 2%, FGFR1 amplification in 3%, MET amplification in 3% and other rare mutations in 27%. MTB recommended a targeted therapy in 344 pts (68%) either within clinical trials (57%), EMA approved therapy (23%), an off label drug (9%), or an expanded access program (11%). 162pts (47%) actually received the recommended therapy, 141 (41%) did not and 41 (12%) might receive it at the time of progression. Median follow-up was 24 months (1-24; follow-up censored after 24 months). Median OS was 13.1 months [95%CI: 8.8; 18.2] for non-oriented pts, and 14.3 months [11.5; 16.7] for oriented pts (p=0.39). We observed a significant difference between EGFR/ALK/ROS1 mutated/rearranged pts (median 23.8 months) vs. pts with KRAS (8.6 months) or others mutations (11.1 months) or non-oriented pts (13.1 m; p=0.0008, HR=0.56, 1.15 and 0.97 respectively compared to non-oriented).
Conclusion:
MTB is feasible in daily practice with treatment recommendations in a majority of NSCLC pts (68%), enrichment in clinical trials or expanded access programs, and limitation of off-label drugs use. Benefit on survival for all oriented pts has to be clarified based on the type of molecular abnormality. Update results will be presented at the meeting.
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-008 - Efficacy of Palliative Chemotherapy in Malignant Pleural Mesothelioma from Spanish BEMME Database. The Spanish Lung Cancer Group (SLCG) (ID 2356)
09:30 - 09:30 | Author(s): J. Remon
- Abstract
Background:
Palliative chemotherapy with cisplatin and antifolate (pemetrexed or raltitrexed) conferred a median overall survival of 12 months with a response rate of 24% to 43% in malignant pleural mesothelioma (MPM) patients. BEMME (Base Epidemiológica Mesotelioma Maligno en España) is an observational and retrospective study sponsored by the Spanish Lung Cancer Group that aimed to characterize the patient’s and tumor’s features as well as the treatment modalities outcomes of patients diagnosed with mesothelioma in Spain.
Methods:
Clinical records of patients with malignant pleural mesothelioma were retrospectively reviewed to collect epidemiological and survival data into an electronic and anonymous database. Thirty-five Spanish hospitals participated in the project and 538 MPM patients were included in the BEMME database. Here we present a descriptive analysis of MPM patients (stage III and IV) treated with palliative chemotherapy.
Results:
From January 2008 to December 2013, 297 of 538 patients (p) (55%) with MPM were treated with palliative chemotherapy. Most patients were males (79%), aged between 60-70y (40%), and 60% had a performance status 1 at diagnosis. No exposure to asbestos was reported in 54% of patients. Epithelioid was the most frequent histological subtype (66%), followed by sarcomatoide (12%), biphasic (9%) and not specified (14%). In stage IV, the most frequent metastatic site was lung (35%). Among patients who received chemotherapy, 55% were treated with palliative intent and reached a disease control rate (CR+PR+SD) of 62%. Platinum plus pemetrexed was the most common schedule used as a palliative treatment, without differences in ORR according to platinum-based agent used (Cisplatin: 36% vs. Carboplatin: 32%). A total of 61 of the 297p (21%) received maintenance treatment with an ORR of 10% and stable disease in 50% of p. The median overall survival (OS) for all patients was 12.6 months (95% CI 10.8 – 14.3). There were statistically significant differences in OS according histological subtype. The median OS for epithelioid was significantly longer (15 months, 95% CI 13.8-18) as compared with non-epithelioid (7 months 95% CI 4.3-9, p<0.001). There were no statistically significant differences in OS according to gender, asbestos exposure or type of platinum chemotherapy (Cisplatin 15.2 months 95% CI: 13.7-18.75; vs. Carboplatin 18 months 95% 12-25.3, p=0.32).
Conclusion:
In Spain, OS of MPM patients treated with platinum palliative chemotherapy exceeded the median OS reported in phase III trials.
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P2.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 225)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.08-030 - Sunitinib in Patients with Advanced Thymoma and Thymic Carcinoma. Retrospective Analysis from RYTHMIC Database (ID 1160)
09:30 - 09:30 | Author(s): J. Remon
- Abstract
Background:
Sunitinib is a potent oral tyrosine kinase inhibitor of VEGFR, KIT and PDGFR. In a single arm phase 2 study of sunitinib after at least one previous line of chemotherapy, a 26% of partial response rate (PR) was reported in thymic carcinoma (TC) and 6% in thymoma (T), with a median progression free survival (mPFS) of 7.2 months and 8.5 months, respectively. We investigated if off-labelled prescription of sunitinib in this population induced the same efficacy signal.
Methods:
We investigated the database of the French thymic malignancies network. We reviewed advanced T and TC patients (p) who were treated with sunitinib in order to evaluate patient’s outcome.
Results:
From October 2011 to January 2015, 28 patients of 7 institutions were identified (20 TC and 8 T). 32% of patients were females and median age was 49.7 y. Fifteen patients (54%) received sunitinib in ≥ 4[th] line of treatment. Two patients received sunitinib in 1[st] line treatment (1 T and 1 TC). The 37.5 mg was the initial dose of sunitinib in 16p. In the whole population, the PR rate was 21% (of 20p with TC, 4 (20%) had a PR; and of 8p with T, 2 (25%) had partial responses). Of note, PR to sunitinib was independent of treatment line (1p at 1[st] lines, 1p at 3[rd] line, 2 p at 4[th] line and 2p at ≥ 5[th] line). 3 TC p were c-KIT positive, without a clear relationship with response rate (1 PR, 2 PD). The mPFS in whole population was 103 days. For TC the mPFS was 87 days and 139 days for T. Sunitinib adverse events were manageable and tolerable. 8p stopped sunitinib due to toxicity. The median overall survival (OS) in the whole population was 175 days, with prolonged OS in T vs. TC (403 days vs. 166 days)
Conclusion:
Sunitinib is an active treatment in thymic epithelial malignancies irrespective of histological subtype, even in a heavy pre-treated population, and treatment line, supporting antiangiogenic therapies as an alternative treatment option for these patients.
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PLEN 03 - Science Drives Lung Cancer Advances (ID 52)
- Event: WCLC 2015
- Type: Plenary
- Track: Plenary
- Presentations: 1
- Moderators:T. Mitsudomi, T. Mok
- Coordinates: 9/09/2015, 08:15 - 09:45, Plenary Hall (Bellco Theatre)
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PLEN03.04 - Personalized Medicine (ID 2046)
09:10 - 09:30 | Author(s): J. Remon
- Abstract
- Presentation
Abstract:
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.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
