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A. Chella
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MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA07.06 - Crizotinib in ROS1 Rearranged or MET Deregulated Non-Small-Cell Lung Cancer (NSCLC): Preliminary Results of the METROS Trial (ID 6003)
11:36 - 11:42 | Author(s): A. Chella
- Abstract
- Presentation
Background:
Crizotinib is an orally active inhibitor of receptor tyrosine kinases effective in NSCLC with ALK rearrangement. Recent data showed that this agent is dramatically effective in patients with ROS1 rearrangement and at least in some patients with MET deregulation, particularly individuals with exon 14 skipping mutations or with high levels of MET amplification.
Methods:
The METROS trial is a multicenter prospective phase II study designed to assess the efficacy and safety and tolerability of Crizotinib in pretreated metastatic NSCLC with MET amplification or MET exon 14 mutation or ROS1 rearrangement. The co-primary end-point was response rate to crizotinib in two cohorts of patients: cohort A) ROS1+: patients with ROS1 rearrangement; B) MET+: patients with MET amplification defined as ratio MET/CEP7 >2.2 on FISH testing or MET exon 14 skipping mutations. Eligible patients were treated with with crizotinib at the standard dose of 250 mg BID p.o.
Results:
At the time of the present analysis, preliminary data on the MET cohort are available. A total of 249 patients were screened and 18 resulted as MET+ (12 amplified and 6 mutated). Among them, 10 patients (9 amplified and 1 mutated) were included onto the study and received at least one dose of crizotinib, 6 patients were not eligibible beacause of not progressing to front line therapy, whereas 2 patients did not received crizotinib due to rapidly progressive disease. Characteristics of enrolled patients were: median age 68 years (range 39-77); male/female 8/2; ECOG PS 0/1/2: 6/3/1. In 8 cases crizotinib was offered as second-line therapy. All but one patients were current or past smokers. According to RECIST criteria, 2 partial responses and 4 stable disease were so far documented, with an overall disease control rate of 60%. Three patients are still on treatment. Therapy was generally well tolerated, with only 1 patient delaying therapy due to adverse events. Enrollment is still ongoing.
Conclusion:
Preliminary analysis of the METROS trial supports the potential efficacy of crizotinib in patients with MET deregulation, with a favorable toxicity profile. Updated results including median progression-free survival and survival were will be presented at the meeting.
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OA22 - Novel Trials and Biomarkers in Malignant Pleural Mesothelioma (ID 403)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:H. Pass, N. Van Zandwijk
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 3
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OA22.01 - STELLAR - Interim Results of a Phase 2 Trial of TTFields with Chemotherapy for First Line Treatment of Malignant Mesothelioma (ID 6034)
14:20 - 14:30 | Author(s): A. Chella
- Abstract
- Presentation
Background:
Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, based on low intensity alternating electric fields delivered non-invasively using a portable, home use, medical device. In-vitro, human mesothelioma cells were found to be highly susceptible to TTFields. TTFields have been shown to extend survival of patients with glioblastoma when added to standard of care chemotherapy.
Methods:
The trial will accrue a total of 80 patients with unresectable, previously untreated mesothelioma. Patients are treated with TTFields in combination with pemetrexed and cisplatin or carboplatin. Continuous TTFields at 150 kHz for a minimum of 18 hours/day are applied to the thorax together with standard dosing of chemotherapy. Inclusion criteria include ECOG 0-1, pathological evidence mesothelioma and at least one measurable lesion according to modified RECIST criteria. Patients are followed q3 weeks (CT scan q6 weeks) until disease progression. The primary endpoint is overall survival (OS) and secondary endpoints are response rate, progression free survival (PFS) and treatment-emergent toxicity. This prospective, single arm study assumes that historical control has an exponential survival distribution and a median survival of 12.1 Months (Vogelzang et al.). The sample size provides 80% power with a two sided alpha of 0.05 to detect a Hazard Ratio of 0.67 for OS, compared to the historical data.
Results:
To date, 42 patients have been enrolled in the trial with an average follow up time of 11.5 months. Median age is 67±9 (range 43-78), 79% are male and 48% smokers. 14% (6 patients) have metastatic disease and 33% (14 patients) have an ECOG score of 1. Median survival has not been reached at this time. The 12-month survival rate is 79.7% (95% CI 57.2-91.2) and median PFS is 7.3 months (95% CI 5.6-NA). No device-related serious adverse events (AEs) have been reported to date. Expected TTFields-related dermatitis was reported in 55% (23 patients). Only 2 patients had grade 3 dermatitis. The following severe (grade 3-4) systemic AEs were reported: hematological (26%), hepatobiliary (2%), respiratory (2%).
Conclusion:
These interim results of the ongoing STELLAR study demonstrated no safety concerns for the combination of TTFields to the thorax together with standard chemotherapy for previously untreated mesothelioma patients. The 12-month survival rate was significantly higher, and PFS longer, than that of historical controls reported by Vogelzang et al. Final analysis of the study will be performed after enrollment and follow up of all 80 patients in the study are completed.
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P1.06 - Poster Session with Presenters Present (ID 458)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.06-017 - Observational Study on Prolonged Disease Stabilization in Advanced NSCLC EGFR WT/Unknown Patients Treated with Erlotinib in Second Line (ID 4998)
14:30 - 14:30 | Author(s): A. Chella
- Abstract
Background:
In advanced NSCLC, erlotinib treatment was shown to improve survival independently of EGFR status and induce high rates of prolonged stable disease (SD). It has previously been reported that, after second-/third-line erlotinib, PFS and OS are long-lasting and similar between patients with SD ≥8 months and those attaining partial/complete response (PR/CR). The present study investigated the clinical value of SD in a real-world setting of advanced NSCLC.
Methods:
This Italian multicenter observational study enrolled patients with stage IIIB-IV NSCLC on second-line erlotinib and wild-type/unknown EGFR mutational status, with SD, CR or PR per RECIST v1.1 lasting for ≥4 weeks. Patients were observed from the beginning of erlotinib for approximately 8 months or until death. Primary end-points were the rate and duration of SD (i.e. time interval from erlotinib start to the last evidence of SD by RECIST) or CR+PR. Secondary end-points were OS and PFS (i.e. time interval from the erlotininb start to the first evidence of progression), estimated by the Kaplan-Meier method and calculated by response duration or disease stabilization. Adverse events occurring during the observation period were also recorded.
Results:
At the cut-off date of 30/04/16, 144/172 (83.7%) enrolled patients were evaluable for response (mean age 69.1 years, 61.8% males). At the start of erlotinib treatment, 85.4% were non-smokers, 89.6% had an ECOG-PS of 0-1, and 84.7% had stage IV NSCLC (83.3% adenocarcinoma and 11.8% squamous cell carcinoma). Following second-line erlotinib, 82.6% (119/144) of patients achieved SD and 17.4% (25/144) PR. Notably, SD was maintained for ≥8 months in 27% (39/144) of cases. At the end of the observation period, 12 (8.3%) patients had deceased, none with SD ≥8 months. Median OS had not been reached by the entire population. According to SD duration, median OS was 4.3 months if <2 months, 6.8 if between 2 and 5 months, and not reached if ≥5 months or if PR. Median PFS was 9.0 months in the entire population, 8.7 among patients with SD and 10.8 with PR. According to SD duration, PFS was 1.4 if <2 months, 4.4 months if between 2 and 5 months, 7.5 if between 5 and 8 months and 10.5 if ≥8 months. No unexpected toxicities were observed.
Conclusion:
In advanced NSCLC, second-line erlotinib yielded a high rate of SD, lasting ≥8 months in 27% of cases, with PFS similar to PR patients and low mortality rate.
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P3.02a - Poster Session with Presenters Present (ID 470)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02a-010 - Evaluation of Aberrant ALK Expression in Lung Cancer by RT-PCR and Comparison with FISH and Immunohistochemistry (ID 5490)
14:30 - 14:30 | Author(s): A. Chella
- Abstract
Background:
In advanced lung cancer patients the gold standard for detecting ALK gene rearrangements is fluorescence in situ hybridization (FISH), and ALK protein expression can be also evaluated by immunohistochemistry (IHC). A single analysis performed alone may not detect all the ALK-positive cases and some patients with discordant FISH and IHC respond to tyrosine kinase inhibitors (TKIs). In this study we evaluated ALK aberrant expression in lung cancer patients by a reverse-transcription (RT)-PCR, to investigate its clinical utility and its concordance with FISH and IHC.
Methods:
ALK aberrant expression was retrospectively investigated on RNA from formalin-fixed paraffin-embedded tissue (FFPEt) of 24 advanced lung adenocarcinoma patients, previously evaluated by FISH and IHC. We used a one-step Scorpion RT-PCR that allowed in a single reaction either the mRNA reverse transcription and the cDNA amplification for ALK kinase-domain, normally not expressed, and a control gene, to assess RNA quality.
Results:
Results are reported in Table 1.Figure 1
Conclusion:
Despite the instability of mRNA from FFPEt, only 2 samples resulted inadequate for RT-PCR. RT-PCR was in disagreement with both FISH and IHC in one case, which is likely to be a RT-PCR false positive. RT-PCR did not detect ALK aberrant expression in a FISH positive case, which was negative also by IHC; unfortunately, this patient died after a cycle of pemetrexed therapy, before undergoing a second line TKI treatment. The presence of ALK rearrangements does not necessarily imply increased protein levels, because of the complex transcriptional and post-transcriptional regulations, so further analysis at RNA levels may clarify discrepancy between FISH and IHC allowing a better stratification of patients who could benefit from TKIs. Therefore, according to our results the RT-PCR evaluating ALK aberrant expression regardless of the fusion partners should be considered for introduction into routine ALK testing in lung cancer.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-027 - Detection of EGFR Mutations in Plasma of Lung Adenocarcinoma Patients Using Real-Time PCR and Mass Spectrometry (ID 5475)
14:30 - 14:30 | Author(s): A. Chella
- Abstract
Background:
Lung adenocarcinoma patients harbouring sensitizing EGFR mutations can benefit from treatment with tyrosine kinase inhibitors (TKI). Whenever tumour tissue is inadequate or unavailable, detection of EGFR mutations in circulating cell-free tumour (ct) DNA from plasma is crucial to predict and monitor response to therapy. In this study we compared EGFR status between tumour tissue and plasma, using real-time PCR. Moreover, we evaluated the adequacy of ctDNA for a multi-target mass spectrometry (MS) analysis.
Methods:
EGFR mutations were investigated in paired plasma and tumour tissues from a prospective series of 105 lung adenocarcinoma patients: 79 had no prior TKI treatment and 26 underwent re-biopsy for TKI-acquired resistance. Molecular analyses were performed on tissue by a routine MS test (evaluation of 307 hot-spots in 10 genes including EGFR) and on ctDNA by a validated Scorpion/LNA real-time PCR (evaluation of 30 EGFR mutations). In the 26 postTKI patients ctDNA analysis was performed also by MS.
Results:
1-Plasma versus tissue by real-time PCR: overall sensitivity, specificity and concordance were 64.8%, 95.4% and 82%. In preTKI patients, 17 harboured EGFR sensitizing mutations on tissue,10 detected also in plasma (sensitivity 58.8 %, specificity 100%, concordance 91%). All 26 postTKI patients preserved EGFR sensitizing mutations. Regarding the detection of EGFR T790M resistance mutation, sensitivity, specificity and concordance were 63.6%, 80% and 73%. Specifically, 11 patients were T790M-positive (42%): 7 on both specimens, 4 only on tissue and 3 only on ctDNA. 2-Plasma versus tissue by MS: sensitivity, specificity and concordance for T790M were 50%, 93.3% and 76%. Particularly, 6 patients had a T790M-positive ctDNA: 5 concordant and 1 discordant with tissue; 4 T790M-positive cases on tissue were undetected in plasma; 1 sample was not evaluable.
Conclusion:
The real-time PCR on ctDNA showed a sensitivity consistent with literature and a high specificity, mostly in preTKI group. Concordance rates, influenced by biological and methodological factors, were lower in postTKI group. Indeed, some T790M mutations were detected only on ctDNA, which is expected to effectively mirror tumour heterogeneity better than bioptic samples, thus giving a global view of tumour. Finally, we demonstrated the adequacy of ctDNA for MS, in terms of quantity and quality. The use of a multi-target analysis on ctDNA might improve tumour characterization and response monitoring, evaluating important oncogenes other than EGFR, like PIK3CA, KRAS and BRAF. However, further studies are needed to better explore MS applicability on ctDNA.
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P3.02b-034 - Clinical Impact of Pretreatment EGFR T790M Mutation in Lung Adenocarcinoma Patients (ID 5463)
14:30 - 14:30 | Author(s): A. Chella
- Abstract
Background:
About a half of lung adenocarcinoma patients with an activating EGFR mutation undergoing tyrosine kinase inhibitor (TKI) therapy develop the EGFR T790M resistance mutation. Previous studies have reported that T790M positive clones are already present before the TKI treatment in the 0.32-80% of cases, depending on methodology and population. Whereas a statistical association between the presence of pretreatment T790M and the L858R activating mutation has been demonstrated, little is known about the influence of preexisting T790M clones on the clinical outcome. The aim of our study is to investigate whether pretreatment T790M affect the response to TKIs.
Methods:
We selected 18 patients who developed a T790M-related resistance to TKI therapy. Their sensitizing mutations were L858R or exon 19 deletion in 8 and 10 cases respectively. For all patients pre- and post-treatment tumor tissues were available to detect and quantify T790M mutant alleles with a highly sensitive digital PCR analysis (Raindance Technologies).
Results:
Pretreatment T790M was found in 5 out of 18 patients (28%), with a mutation frequency ranging from 0.03% and 0.14% (mean frequency 0.08%). The mean T790M allele frequency in posttreatment tumors was 12%. The presence of T790M before TKIs was not associated with a specific activating mutation (L858R or exon 19 deletion), nor with the disease stage and worse response to treatment, independently from the type of TKI drug.
Conclusion:
Our results confirm that T790M-positive clones can coexist with the activating mutation clones in lung adenocarcinoma even before TKI treatment. A previously reported analysis, performed with a methodology as much sensitive as ours by Watanabe et al., showed a pretreatment T790M mutation frequency raising the 80% in a series of lung adenocarcinoma patients harboring an EGFR activating mutation, with no regard to TKI treatment or resistance. In contrast, we found 28% of cases having T790M before treatment. This discrepancy can be due to the different criteria adopted for samples selection, since our cohort included only patients found positive for T790M after TKI therapy. In our series of cases, the presence of T790M before TKIs did not correlate with significant clinical parameters. In conclusion, in this preliminary study we did not identify a direct association between the presence of small amounts of pre-TKI T790M mutant alleles and patients’ clinical outcome. However, in order to better assess the impact of T790M in predicting the response to therapy, further studies on larger series of patients are needed.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-024 - Malignant Pleural Mesothelioma: Gene Expression Profiling of the Main Histological Subtypes (ID 5465)
14:30 - 14:30 | Author(s): A. Chella
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a low-incidence, aggressive, asbestos-related tumor, whose treatment options are currently limited. MPM is a heterogeneous tumor with three main histological subtypes: epithelioid (E), sarcomatoid (S) and biphasic (B). S- and B- MPMs are rarer and have a poorer prognosis than the E-subtype. In the present study we compared the expression profile of 117 genes with a crucial role in cancer between the E- and S/B- subtypes, in order to identify histology-specific molecular markers.
Methods:
Gene expression analysis was performed by Nanostring system directly on RNA from 38 formalin-fixed and paraffin-embedded tissues of MPM patients (25 E-subtype, 13 S/B-subtypes). After data normalization, differences of gene expression levels between the two groups were evaluated by a non-parametric Mann-Whitney U-test (p-value < 0.05).
Results:
39 genes were differentially expressed. In particular, 21 genes were statistically up-regulated and 18 down-regulated in E- compared to S/B-subtypes (Table 1). Figure 1
Conclusion:
The identification of gene expression profiles specific for each histological subtype could improve the clinical approach to MPM. In this study we found genes differentially expressed between E- and S/B-subtypes. In detail, up-regulated genes in E-MPM encode for proteins involved in epithelial cell differentiation and regulation of apoptosis, whereas down-regulated genes belong to pathways related to extracellular matrix, cell adhesion and angiogenesis. Moreover, some of the deregulated genes have been already described to influence the sensitivity to chemotherapy, such as ASS1, to play an important role in the mesenchymal transition, like MMP9, and others, among which ESR2, have been proposed as potential therapeutic targets. Our results reveal genes activated or inactivated in a histotype-dependent manner as new potential biomarkers for MPM, however, further studies are needed to better understand their clinical value.
