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H. Carranza
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-050 - Acquired Resistance to EGFR Tyrosine Kinase Inhibitors (TKIs) in EGFR-Mutant Lung Adenocarcinoma among Hispanics (Rbiop-CLICaP) (ID 5955)
14:30 - 14:30 | Author(s): H. Carranza
- Abstract
Background:
Patients with epidermal growth factor receptor (EGFR)-mutant lung carcinoma eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). In 50% of these cases, a secondary EGFR mutation, T790M, underlies the acquired resistance. Other alterations include amplification of MET, PI3K mutations, changes in MAPK1, Her2, AXL and even transformation to small cell lung carcinoma (SCLC). We assessed histological, clinical characteristics and survival outcomes in Hispanic patients with EGFR mutation after disease progression.
Methods:
34 EGFR-mutant lung cancer patients with acquired resistance to EGFR TKIs were identified as part of a prospective registry (active between January 2011 and January 2015) in which post-progression tumor specimens were collected for molecular analysis using SNaPshot tumor genotyping assay to detect mutations in EGFR, KRAS, BRAF, PI3KCA, TP53, MET and Her2, and FISH for MET, ALK and EGFR. Samples also underwent immunohistochemistry analysis for E-cadherin, synaptophysin, CD56 and PDL1. Post-progression interventions, response and survival were assessed and compared to those with and without T790M.
Results:
Mean age was 59.4±13.9 years; 62% were female, 65% were never-smokers and 53% had a performance status ≥80%; main metastatic sites were lung (16/47%), bone (20/58%), brain (18/52%) and liver (13/38%). All patients received erlotinib as first- line treatment and documented mutations were: 60% DelE19 (Del746–750) and 40% L858R. Overall response rate (ORR) with first line TKI was 61.8% and progression free survival (PFS) was 16.8 months (range, 13.7–19.9 m). After progressing to TKI, all patients were re-biopsied, of whom 16 had the T790M mutation (47.1%); 5 had PI3K mutations (14.7), 5 had EGFR amplification (14.7%), 2 had a KRAS mutation (5.9%), 3 had MET amplification (8.8%), 2 had Her2 alterations (5.8%, deletions/insertions in e20), and one had SCLC transformation (2.9%). 79.4% received treatment after progression. ORR for post-TKI treatments was 47.1% (CR 2/PR 14) and median PFS was 8.3 months (CI95% 2.2–36.6). There were no differences in PFS according to gender (p=0.10) or type of acquired alteration (p=0.63). Median survival was 32.9 months (CI95% 30.4–35.3), and only the use of post-progression therapy affected OS in multivariate analysis (p=0.05).
Conclusion:
Hispanic patients with acquired resistance to EGFR TKIs continued to be sensitive to other treatments after progression. Proportion of T790M+ patients appears to be similar to previously reported results in Caucasians.
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P1.02-058 - EGFR Amplification and Sensitizing Mutations Correlates with Survival from Erlotinib in Lung Adenocarcinoma Patients (MutP-CLICAP) (ID 6335)
14:30 - 14:30 | Author(s): H. Carranza
- Abstract
Background:
Tumor heterogeneity, which causes different EGFR mutation abundance, is believed to be responsible for varied progression-free survival (PFS) in lung adenocarcinoma (ADC) patients receiving EGFR-TKI treatment. Frequent EGFR amplification and its common affection inEGFR mutant allele promote the hypothesis that EGFR mutant abundance might be determined by EGFR copy number variation and therefore examination of EGFR amplification status in EGFR mutant patients could predict the efficacy of EGFR-TKI treatment.
Methods:
72 lung ADC patients who harbored EGFR activating mutations and received erlotinib as first line treatment, were examined for EGFR amplification by FISH. EGFR mutational and copy number status were compared with response, overall-survival (OS), and progression-free-survival (PFS).
Results:
Median age was 62-yo (r, 20-87 years), 53 patients were females (73%), and 89% have common mutations. Twenty-two (30.6%) samples with EGFR activating mutations were identified with EGFR amplification. EGFR amplification was more frequent in patients with exon 19 deletion (p=0.05) and in those with better performance status (p=0.01). Patients with EGFR gene amplification had a significantly longer PFS than those without [(25.2 months, 95%CI 22.0-38.5) vs. (12.4 months, 95%CI 5.3-19.5); p=0.002] as well as better OS [(EGFR amplified 37.8 months, 95%CI 30.9-44.7) vs. (EGFR non-amplified 27.1 months, 95%CI 12.8-41.3); p=0.009]. EGFR amplification significantly influenced the response to erlotinib (p=0.0001).
Conclusion:
EGFR amplification occurs in one third of patients with lung ADC harboring EGFR activating mutations, and could serve as an indicator for better response and survival from EGFR-TKI treatment.
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P2.03a - Poster Session with Presenters Present (ID 464)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03a-007 - Pem/CBP/Bev Followed by Pem/Bev in Hispanic Patients with NSCLC: Outcomes According to Combined Score of TS, ERCC1 and VEGF Expression (ID 6293)
14:30 - 14:30 | Author(s): H. Carranza
- Abstract
Background:
To evaluate the efficacy and safety of pemetrexed, carboplatin and bevacizumab (PCB) followed by maintenance pemetrexed and bevacizumab (PB) in chemotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer (NSCLC) through the influence of thymidylate synthase (TS), ERCC1 and VEGF mRNA expression on several outcomes. The primary endpoints were the overall response rate (ORR), progression-free survival (PFS) and overall survival (OS).
Methods:
Patients were administered pemetrexed (500 mg/m2), carboplatin (AUC, 5.0 mg/ml/min) and bevacizumab (7.5 mg/kg) intravenously every three weeks for up to four cycles. Maintenance pemetrexed and bevacizumab was administered until disease progression or unacceptable toxicity.
Results:
One hundred forty-four Hispanic patients with a median follow-up of 13.8 months and a median number of maintenance cycles of 6 (range, 1- 32) were assessed. The ORR among the patients was 66% (95% CI, 47% to 79%). The median progression-free and overall survival (OS) rates were 7.9 months (95% CI, 5.9-10.0 months) and 21.4 months (95% CI, 18.3 to 24.4 months), respectively. Median TS, ERCC1 and VEGF mRNA levels were 1.45 (range, 0.17–2.52), 0.58 (range, 0.44-1.20), and 2.72 (range, 1.84-3.21), respectively. OS was significantly higher in patients with the lowest TS mRNA levels [29.6 months (95%CI 26.2-32.9) compared with those with higher levels 9.3 months (95%CI 6.6-12.0); p=0.0001]. ERCC1 mRNA levels also influenced the OS [median for ERCC1 mRNA˂0.58 28.7 months (95%CI 26.3-31.2) vs. ERCC1 mRNA˃0.58 11.1 months (95%CI 9.6-12.7); p=0.0001] as well as VEGF mRNA levels [median OS for VEGF mRNA˂2.72 26.4 months (95%CI 22.8-30.0) vs. VEGF mRNA˃2.72 18.2 months (95%CI 8.4-27.9); p=0.009]. TS mRNA did not influence treatment response, however the ORR was significantly higher in patients with low levels of ERCC1 (p = 0.003) and elevated VEGF (p = 0.005). Multivariate analysis found that TS mRNA levels (p=0.0001), VEGF mRNA levels (p=0.007) and PS (p=0.014) were independent prognostic factors.
Conclusion:
Overall, PCB followed by maintenance pemetrexed and bevacizumab was in Hispanic patients with non-squamous NSCLC. This regimen was associated with prolonged OS, particularly in patients with low TS, ERCC1 and VEGF mRNA expression. These biomarkers alone or in combination may be useful to assess the prognosis of patients with NSCLC treated with CBP/Pem/Bev.
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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: 4
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-035 - Prognostic Role of hENT1 and RRM1 in Patients with Advanced Pleural Mesothelioma Treated with Second Line Gemcitabine Based Regimens (ID 6328)
14:30 - 14:30 | Author(s): H. Carranza
- Abstract
Background:
Nucleoside transporter proteins mediates the transport of nucleosides and nucleoside analog drugs across the plasma membrane. The human equilibrative nucleoside transporter 1 (hENT1) is a nucleoside transporter protein that mediates cellular entry of gemcitabine, cytarabine, and fludarabine. The hENT1 expression has been demonstrated to be related with prognosis and activity of gemcitabine-based therapy in breast, ampullary, lung, and pancreatic cancer. In the same way, RRM1 encodes the regulatory subunit of ribonucleotide reductase and is a molecular target of gemcitabine. Previous studies showed increased RRM1 expression on continuous exposure of cell lines to gemcitabine and suggested improved survival for patients with low RRM1 expression.
Methods:
We measured hENT1 and RRM1 messenger RNA (mRNA) levels by quantitative real-time reverse transcription-polymerase chain reaction in tumor samples from 29 patients with advanced pleural mesothelioma (APM) treated in second line with gemcitabine based chemotherapy correlating these data with clinical parameters and disease outcomes (overall response rate-ORR, progression free survival-PFS and overall survival-OS).
Results:
The median age was 60-yo (r, 33-70 years), 15 patients were males (51%), 34% of cases undergone debulking surgery and the median follow-up was 13.4 months (95%CI 6.4-34). All patients were treated with Pem based chemotherapy in first line achieving a PFS of 8.1 months (95%CI 3.7-12.6), while PFS with second-line Gem based chemotherapy was 6.3 months (95%CI 3.6-8.8). 62% and 34.5% of patients had low levels of mRNA for hENT1 and RRM1, respectively. On univariate survival analysis, the hENT1 expression was associated with OS (p=0.001) and PFS (p=0.022). Specifically, those patients with overexpression of hENT1 showed a shorter OS p=0.021) and a shorter PFS (p=0.033). In contrast, mRNA expression of RRM1 did not influence the OS (p = 0.44) but it modifies positively the PFS (p=0.034). Multivariate analysis found that combined hENT1 (p=0.001) and RMM1 (p=0.012) predict survival in patients with APM treated with Gem based regimens.
Conclusion:
hENT1 mRNA expression carries prognostic information in patients with APM and combined with RRM1 holds promise as a predictive biomarkers in gemcitabine treated patients.
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P3.03-045 - Treatment of Malignant Pleural Mesothelioma beyond First-Line among Hispanics (MeSO-CLICaP) (ID 6271)
14:30 - 14:30 | Author(s): H. Carranza
- Abstract
Background:
Platinum/Pemetrexed chemotherapy is standard of care in first-line (FL) treatment of malignant pleural mesothelioma (MPM). Different second and third lines regimens are also considered, but the optimal treatment has not yet been defined.
Methods:
The aim of this study was to evaluate clinical outcomes of second (SL) and third line (TL) therapies in a series of MPMs included in a retrospective multinational database (MeSO-CLICaP). Clinical records of MPM-patients who received treatment beyond FL from 2008 to 2016 were reviewed. Study endpoints were response, overall-survival (OS), and progression-free-survival (PFS) for SL and TL, stratified for patient characteristics, FL-outcomes, and type of regimen. Out of 124 patients, 79 received SL/TL and had sufficient clinical data.
Results:
Of the 124 patients included in the MeSO-CLICaP registry, 79 (64%) received some treatment after first line. Median age was 59 years (range 33-81), 42 (53%) were men, 74% were current or former smokers and 77% had a baseline ECOG 0-1. After FL, 57 patients (76%) achieved disease-control (PR 24/32% and SD 33/44%) and 18 had a time-to-progression ≥8 months. Median PFS and OS to SL were 6.2 (95%CI 4.9-7.4) and 16.1 (95%CI 14.5-17.6) months, respectively. According to a multivariate analysis, disease control after SL-therapy was significantly related to pemetrexed-based treatment (OR 2.46; p=0.017) and FL-TTP≥12 months (OR 3.50; p=0.006). Improved PFS to SL was related to younger age (<65 years, HR: 0.60; p=0.045), ECOG 0-1 (HR 0.72; p=0.02), and FL-TTP≥12 months (HR 0.48; p<0.001). OS was significantly related to ECOG 0-1 (HR 0.43; p=0.011) and to FL-TTP≥12 months (HR 0.66; p=0.05). Fifty-two patients (42%) receive a TL achieving a disease control rate of 62% with a PFS of 5.9 months (95%CI 5.0-6.8).
Conclusion:
SL-chemotherapy appears to be active in Hispanic MPM-patients, particularly in younger patients with good PS and prolonged disease control with FL chemotherapy. Considering the important limitations of this study, due to retrospective nature and the possible selection bias, prospective clinical trials are warranted to clarify these issues.
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P3.03-048 - Profiling Response to Chemotherapy in Malignant Pleural Mesothelioma among Hispanics (MeSO-CLICaP) (ID 6319)
14:30 - 14:30 | Author(s): H. Carranza
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a rare malignant disease, and the understanding of molecular pathogenesis has lagged behind other malignancies.
Methods:
A series of 53 formalin-fixed, paraffin-embedded tissue samples with clinical annotations were retrospectively tested for BAP1 and PI3K mutations and for mRNA expression of TS and EGFR. Immunohistochemistry staining for CD26 (dipeptidyl-peptidase IV, DPP-IV) and Fibulin3 (Fib3) proteins were also performed. Outcomes like progression free survival (PFS), overall survival (OS) and response rate (ORR) were recorded and evaluated according to biomarkers. Cox model was applied to determine variables associated with survival.
Results:
Median age was 58 years (range 36-76), 27 (51%) were men, 89% were current or former smokers, and six patients had previous contact with asbestos. 77% had a baseline ECOG 0-1 and almost all patients (n=52/98%) received cisplatin or carboplatin plus pemetrexed (Pem) as first line; 58% of them were treated with Pem as maintenance for a mean of 4.7 +/-2.8 cycles. 53.5% and 41.5% of patients were positive for CD26 and fibulin-3, while 49% and 43.4% had low levels of EGFR and TS mRNA, respectively. The majority of epithelioid and biphasic types expressed CD26 (p=0.008), Fibulin3 (0.013) and had lower levels of TS mRNA (p=0.008). Mutations in PI3K (c.1173A> G, c.32G> C and c.32G> T) were found in 5 patients and only one patient had a mutation in BAP1 (c.241T> G). First line PFS were significantly longer in CD26+ (p=0.0001), in those with low EGFR mRNA expression (p=0.001), in patients with positive Fib3 (p=0.006) and lower TS mRNA expression (p=0.0001). OS were significantly higher in patients with CD26+ (p=0.0001), EGFR- (p=0.001), Fib3 + (p=0.0002) and low TS mRNA expression level (p=0.0001). Multivariate analysis found that CD26+ (p=0.012), Fib3 (p=0.020) and TS mRNA levels (p=0.05) were independent prognostic factors.
Conclusion:
CD26, Fib3 and TS were prognostic factors significantly associated with improved survival in patients with advanced MPM.
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P3.03-060 - Characteristics and Long Term Outcomes of Advanced Pleural Mesothelioma in Latin America (MeSO-CLICaP) (ID 6265)
14:30 - 14:30 | Author(s): H. Carranza
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is an aggressive tumor, usually associated with a poor prognosis. MPM is a heterogeneous disease often associated with different clinical courses. Palliative platinum-based chemotherapy may help to improve symptoms and prolong life.
Methods:
The MeSO-CLICaP registry identified 124 patients with advanced MPM from 5 Latin American countries diagnosed and treated between January 2008 and March 2016. Data collected included age, gender, asbestos exposure, presenting signs/symptoms, performance status, histology, stage, treatment modalities including chemotherapy, and date of death or last follow-up. Outcomes like progression free survival (PFS), overall survival (OS) and response rate (ORR) were recorded. Cox model was applied to determine variables associated with survival.
Results:
median age was 59.5 years (range 33-84), 72 (58%) were men, 69% were current or former smokers and 37 patients (30%) had previous exposure to asbestos. Ninety-six patients (77%) had a baseline ECOG 0-1, 102 (82%) were epithelioid tumors, 47 (38%) and 77 (62%) cases had stage III or IV MPM. Only 20% (n=25) underwent pleurectomy, 28% (n=35) received radiotherapy and 123 patients received platinum-based chemotherapy in first line (plus Pem 68/54% and Gem 55/44%). ORR to first line chemotherapy was 48% (CR 3.2%/PR 43%), PFS was 10.5 months (95%CI 8.2-12.8) and 47 patients had Pem maintenance (mean number of cycles 4.4+/-3). Median OS was 25.3 months (95%CI 22.3-28.3) and according to a univariate analysis, stage (p=0.03), histology (p=0.005), and Pem manteinance (p=0.014) were associated with better OS. Multivariate analysis found that stage (p=0.002), histology (p=0.021), smoking history (p=0.001) and Pem manteinance (p=0.002) were independent prognostic factors.
Conclusion:
Our study identifies factors associated with a clinical benefit from chemotherapy among Hispanic patients with advanced MPM, and emphasizes the impact of histology and clinical benefit of chemotherapy on outcomes.
