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D. Jovanovic
Moderator of
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SC11 - ALK, ROS1 and Rare Mutations in NSCLC (ID 335)
- Event: WCLC 2016
- Type: Science Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 4
- Moderators:D. Kim, D. Jovanovic
- Coordinates: 12/05/2016, 16:00 - 17:30, Lehar 1-2
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SC11.01 - Optimal Application & Sequence of ALK Inhibition Therapy (ID 6641)
16:00 - 17:30 | Author(s): B. Solomon
- Abstract
- Presentation
Abstract not provided
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SC11.02 - Resistance to ALK Inhibitor Therapy (ID 6642)
16:00 - 17:30 | Author(s): S. Ou
- Abstract
- Presentation
Abstract not provided
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SC11.03 - ROS1 as a Therapeutic Target in Advanced NSCLC (ID 6643)
16:00 - 17:30 | Author(s): J. Wolf
- Abstract
- Presentation
Abstract:
In non-small cell lung cancer (NSCLC) chromosomal rearrangements involving the gene encoding for the receptor tyrosine kinase ROS1 have been first described in 2007 (1). These aberrations have been shown to trigger constitutive kinase activity and activation of downstream pathways like the MAPK pathway. ROS1 rearrangements can be found in about 2% of lung adenocarcinoma and are associated with female gender and never-smoking status (2). Different fusion partners have been described. In routine diagnostics ROS1 fusion genes can be reliably detected by fluorescence in situ hybridization (FISH; e.g. dual color break apart FISH), RT-PCR or next-generation sequencing (NGS). ROS1 fusions occur mutually exclusive of aberrations in EGFR, ALK and KRAS. However, using NGS, co-occuring mutations, preferentially in TP53, but also in other genes involved in oncogenic pathways, can be found in about 50% of these patients (3). ROS1 fusions also seem to be of prognostic relevance, since remarkable long survival times have been described in patients treated with chemotherapy only (3). The ALK/MET/ROS1 inhibitor crizotinib has been evaluated in a US-American cohort of 50 ROS1 positive patients with advanced, mostly pretreated lung adenocarcinoma and showed impressive activity (4). The overall response rate (ORR) was 72% (95% CI 58 to 84) with 3 complete responses. Median progression free survival (PFS) was 19.2 months (95% CI 14.4 to not reached). Treatment was well tolerated and the side effect profile resembled that observed in the treatment of ALK positive lung cancer with crizotinib. A similiar ORR of 80% was reported in a retrospectively analyzed European cohort (5). However, PFS was only 9.1 months in these patients. The EUCROSS trial, a collaborative study of the German Lung Cancer Group Cologne and the Spanish Lung Cancer Group, is a prospective European phase II trial which recruited 34 ROS1 positive patients between June 2014 and September 2015. ROS1 fusion genes were diagnosed using dual color break apart FISH and the results were confirmed by next-generation sequencing. With an ORR of 69% (95% CI, 49.1 to 84.3) similar efficacy has been reported (6). Based on its high activity and favorable toxicity profile, crizotinib is now approved for the treatment of ROS1-positive NSCLC by the FDA since March 2016 and by the EMA since August 2016. Treatment of ROS1-positive NSCLC with crizotinib thus has become standard first-line treatment in the leading international guidelines. Current challenges for the further development and improvement of targeted treatment of ROS1-positive patients are (I) implementation of ROS1 diagnostics in routine molecular diagnostics and (II) development of next-generation ROS1 inhibitors overcoming crizotinib resistance. The increasing number of actionable mutations in NSCLC including ROS1 requires implementation of molecular multiplex testing, since sequentially conducted single gene assays are no more feasible given the usually limited biopsy tissue specimens. However, conventional NGS technology is restricted to point mutations and does not cover copy number variations (CNV) and gene fusions. Thus, new NGS technologies have to be integrated in routine diagnostics like hybrid capture-based NGS, which does not require DNA amplification by PCR and thus allows to detect reliably CNV and gene fusions. While increasing knowledge of the molecular mechanisms underlying TKI resistance has led to the development of a series of highly potent next-generation inhibitors in ALK-positive NSCLC now, resistance of ROS1-positive patients to crizotinib is incompletely understood. In preclinical studies as well as in biopsy tissue, somatic mutations in the ROS1 kinase domain associated with acquired crizotinib resistance have been described (7). In functional studies these mutations were associated with different degrees of resistance. Alternatively, bypass activation of oncogenic signal transduction pathways has been described as mechanism underlying resistance. For instance, a cKIT activating mutation and EGFR pathway activation have been reported in single cases (8). In vitro, the multikinase inhibitors cabozantinib, foretinib and lorlatinib have been shown to overcome crizotinib reistance triggered by secondary mutations in ROS1. Response to cabozantinib has also been described in a ROS1-positive patient with a mutation confering resistance to crizotinib (10) and was also observed in a phase I trial of lorlatinib in the same clinical setting. In summary, ROS1 positivity characterizes a subgroup of patients with a major benefit from treatment with crizotinib. Consequently, crizotinib has become the current standard of care for these patients. ROS1 status thus should be available before decision on first-line treatment. Acquired resitance to crizotinib may be caused by mutations in the ROS1 kinase domain or by activation of bypass pathways. The multikinase inhibitor cabozantinib and the next-generation ALK/ROS1 inhibitor lorlatinib have shown promising efficacy in early clinical evaluation. (1) Rikova K et al. Global survey of phosphotyrosine sgnaling identifies oncogenic kinases in lung cancer. Cell 2007, 14; 131(6):1190-203. (2) Bergethon K et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012, 30(8):863-70. (3) Scheffler M et al. ROS1 rearrangements in lung adenocarcinoma: prgnostic impact, therapeutic options and genetic variability. Oncotarget 2015, 6(12):10577-84. (4) Shaw A et al. Crizotinib in ROS1-rearranged non-small cell lung cancer. NEJM 2014, 371(21): 1963-71. (5) Mazieres J et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J Clin Oncol 2015, 33(8):867-76. (6) Michels e al. EUCROSS: a prospective European phase II trial to evaluate efficacy and safety of crizotinib in advanced adenocarcinoma of the lung harboring ROS1 translocations. WCLC 2016 (oral presentation). (7) Awas MM et al. Acquired resistance to crizotinib from a mutation in CD74-ROS1. NEJM 2013, 368(25):2395-401. (8) Dzadziuszko R et al. Activating KIT mutation induces crizotinib resistance in ROS1-positive lung cancer. J Thorac Oncol 2016, 11(8):1273-81. (9) Davies KD et al. Resistance to ROS1 inhibition mediated by EGFR pathway activation in non-small cell lung cancer. PLoS One 2013, 13 (8):e82236. (10) Drilon et al. A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer. Clin Cancer Res 2016, 22 (10):2351-8.
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SC11.04 - Rare Mutations in Lung Cancer (ID 6644)
16:00 - 17:30 | Author(s): O. Gautschi
- Abstract
- Presentation
Abstract:
"Lung adenocarcinoma" is a genetically heterogenous disease entity, characterized by a wide spectrum of different mutations. Some of these mutations lead to constitutive activation of receptor tyrosine kinases, which can be inhibited by small molecules (tyrosine kinase inhibitors, TKIs). EGFR mutations (2004) and ALK rearrangement (2007) were among the first actionable driver mutations identified in lung adenocarcinomas. Today, several drugs are approved for the treatment of advanced lung adenocarcinomas with EGFR mutations or ALK/ROS1 rearrangement. Combined, these molecular subgroups make up at least 20% of all lung adenocarcinomas or more, depending on the poplulation. Further actionable driver mutations include the genes BRAF, HER2, MET, and RET. These genes are less frequently mutated than EGFR/ALK, nevertheless, rare drivers are clinically relevant because of the availability of targeted therapies approved for other indications in oncology (ALK-lung, HER2-breast, RET-thyroid, and BRAF-melanoma). The discussant will summarize current knowledge about rare driver mutations, with a strong clinical focus. HER2 insertion 20, present in about 1% of lung adenocarcinomas, was initially proposed by Cappuzzo et al as a potential indication for trastuzumab-based therapy [1]. Prospective trials with HER2 targeting drugs are currently ongoing. BRAF V600E, present in about 3% of lung adenocarcinomas, was associated with high activity of combined therapy with dabrafenib and trametinib in a prospective phase II trial by Planchard et al [2]. Crizotinib, recently approved by the FDA for the treatment of ROS1-NSCLC, is also active in tumors harboring MET exon 14 mutations as demonstrated by Drilon et al [3]. Cabozantinib and vandetanib are active in tumors with RET rearrangement as shown by three recent phase II trials [4-6]. Entrectinib showed preliminary activity in tumors harboring TRK rearrangement in an early basket Trial [7]. These results will be discussed in detail, together with the results of international registries (EUHER2, EURAF, EUROS1 and GLORY [8]). Moreover, current treatment recommendations for patients with advanced lung adenocarcinomas and rare driver mutations will be summarized. References 1. Cappuzzo et al. N Engl J Med. 2006;354(24):2619-21. 2. Planchard et al. Lancet Oncol. 2016;17(7):984-93. 3. Drilon et al. J Clin Oncol 34, 2016 (suppl; abstr 108) 4. Drilon et al. Cancer Discov. 2013;3(6):630-5. 5. Seto et al. J Clin Oncol 2016;34(suppl; abstr 9012) 6. Lee et al. J Clin Oncol 2016;34(suppl; abstr 9013) 7. Drilon et al. AACR 2016 (abstract CT007) 8. Gautschi et al. WCLC 2016 (abstract 4325)
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Author of
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P1.05 - Poster Session with Presenters Present (ID 457)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.05-010 - Aberrant Promoter Methylation of ESR1 and CDH13 Gene Are an Independent Prognostic Marker in Surgically Resected Non-Small Cell Lung Cancer (ID 3840)
14:30 - 15:45 | Author(s): D. Jovanovic
- Abstract
Background:
Aberrant promoter hypermethylation of tumor suppressor genes are promising markers for lung cancer diagnosis and prognosis. The purpose of this study was to determine the correlation between the aberrant promoter methylation of multiple genes and 5-year survival rate in patients with nonsmall cell lung carcinoma (NSCLC) after a surgical resection.
Methods:
Primary tumor samples (n=65) and corresponding nonmalignant lung tissues (n=65) were obtained from NSCLC patients who underwent curative surgery. The methylation status of seven genes (SOX1, RASSF1A, HOXA9, CDH13, MGMT, ESR1 i DAPK) was quantified using bisulfite pyrosequencing. Cox proportional hazards models were used to analyze the associations between gene methylation status and overall patient survival.
Results:
In the Cox proportional hazards model, ESR1 methylation in tumor tissue was associated with significantly poorer survival, with hazard ratio of 1.09 (95% confidence interval 1.02-1.16, p=0.01). This effect was independent of TNM stage, which was also a predictor of survival. We also found that aberrant methylation in CDH13 gene in tumor tissue was associated with inferior survival in surgically resected NSCLC pateints. In contrast, there were no significant survival differences noted between the methylation-positive and methylation-negative tumors for the other genes tested.
Conclusion:
Our study shows that aberrant promoter methylation of ESR1 and CDH13 genes may be associated with inferior survival, showing promise as a useful prognostic biomarker in patients with NSCLC.
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P2.02 - Poster Session with Presenters Present (ID 462)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.02-011 - Management of Non-Small-Cell Lung Cancer (NSCLC) Stage III Patients in Central European Countries (ID 4608)
14:30 - 15:45 | Author(s): D. Jovanovic
- Abstract
Background:
The aim of the study is to determine the actual standard management of patients with stage III NSCLC in Central European centres/countries. The project is a multicentre, prospective, non-interventional registry.
Methods:
After ethical committee approval and signed informed consent, the data about diagnostic and therapeutic procedures of consecutive patients diagnosed with stage III NSCLC (UICC7) were collected in web-based registry organised by the IBA MUNI, Brno, Czech Republic.
Results:
With cut-off 30 June 2016, 509 patients from 7 countries/16 centres were enrolled, median number of patients per centre being 23 (range 6-99). There were 163 (32%) women and 37 (7%) never smokers. Performance status distribution was as follows: ECOG 0, 1, 2 and 3 in 29%, 56%, 12% and 3%, respectively. Squamous cancer was found in 52%, adenocarcinoma in 39%, not otherwise specified in 5% and others in 4% of cases. Genetic mutations were examined in 119 (23%) patients, predominantly EGFR in 111 subjects with 10 (8%) positive findings, while the ALK mutation in 64 patients with no positive finding. Regular staging procedures were X-Ray scan (97%), chest CT (96%) and bronchoscopy (89%). Staging was completed by abdominal CT in 66% of patients, abdominal US in 29%, PET/CT in 22%, bone scan in 17% and brain CT or MRI in 13%, respectively. Stage IIIA was found in 59% and stage IIIB in 41% of patients. N2/N3 nodes were diagnosed in 60%/22% of patients. Pathological mediastinal lymph-node positivity was confirmed in 109 (21%) patients (6% EBUS, 0.2% VATS, 1% mediastinoscopy, 1% transbronchial biopsy and 13% surgery). Median time from diagnosis to first treatment was 23 days (range 0–321). Treatment procedures were: surgery 138 (27%), chest radiotherapy 246 (48%) and chemotherapy 409 (80%) of subjects, respectively. Chemotherapy as only modality was given in 136 (27%) of patients. Surgery was combined with radiation in 6 cases, with chemotherapy in 79 (16%) cases and with both chemotherapy and radiotherapy in 37 (7%) patients. Chemotherapy plus radiotherapy was given in 159 (31%) patients including concurrent chemoradiotherapy in 67 (13%) cases. At the time of cut-off, 64% patients were alive, median survival time was not reached, and the 1-year estimated survival rate was 71%.
Conclusion:
The most prevalent histology was squamous cancer. Histopathological examination of mediastinal lymph-nodes was done in 21% of patients, mostly during surgery. Majority of patients (55%) were treated with combination therapy. Palliative chemotherapy only was given in 27% of patients. Survival data are not mature.
