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Ernest Nadal
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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Robert C. Doebele, J.C. Ho
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 316
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MA 07.03 - Incidence, Predictors and Prognostic Significance of Thromboembolic Events in Patients with Advanced Alk-Rearranged NSCLCs (ID 9532)
15:55 - 16:00 | Author(s): Ernest Nadal
- Abstract
- Presentation
Background:
The incidence of venous thromboembolic events all along the course of the disease in advanced-stage lung adenocarcinomas is approximately 15 %. It is plausible that the different molecular subtypes might influence on the risk of thrombosis. Based on our clinical observation, and supported by limited data from isolated small series, patients bearing ALK rearranged tumors could be at a particularly high-risk of thromboembolic disease.
Method:
We included consecutive patients diagnosed with advanced-stage ALK fusion positive non-small cell lung cancers (NSCLC) between January 2012 and December 2016. Clinical data were contributed by 29 Medical Centers from Spain and one large Academic Cancer Center from Portugal. Investigators at each institution retrospectively reviewed patients’ medical records. A thromboembolic event was defined as any venous or arterial thromboembolism, or both, at any site, documented by appropriate imaging studies, that occurred at the time or after advanced-stage cancer diagnosis.
Result:
A total of 241 ALK-rearranged NSCLCs were included in our study. Half of the patients were never smokers (52 %), and most had stage IV pulmonary adenocarcinomas (n=204, 85%). Baseline brain and liver metastasis were detected in 22 % and 25 % of the patients respectively. Seventy-three patients (30 %) developed thromboembolic disease. In 54 patients (74 %) thromboembolic complications occurred within the first 6 months from diagnosis. In the multivariate competing-risk regression analysis, the presence of baseline liver metastases (HR of 1.85, CI 95 % 1.09-3.15; p = 0.021) and baseline leukocyte counts > 11.0000 cells/mm3 (HR of 2.34, CI 95 % 1.43-3.82; p = 0.001) were independent predictors of thromboembolic disease. Remarkably, 50 % of the patients with either liver metastases or leukocytosis at diagnosis developed thromboembolic disease. Patients experiencing thromboembolic events had shorter median overall survival (OS) (20 months) than patients without thrombosis (36 months) (p = 0.035). In the multivariate Cox Model, thromboembolic disease remained associated with worse OS (HR of 1.70, CI 95 % 1.10-2.62; p = 0.016) when considered as a time-varying covariate. The presence of baseline thromboembolic disease (n = 24) was associated with a numerical non-significant increased risk of death (HR 1.67, CI 95 % 0.96-2.91; p = 0.068).
Conclusion:
Venous and/or arterial thromboembolic complications occur in a high proportion of patients with advanced-stage ALK fusion positive NSCLCs, particularly in the presence of baseline liver metastasis or leukocytosis. The development of thromboembolic disease is associated with a lower OS in these patients.
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-044 - Thyroid Disfunction in Advanced NSCLC Patients Treated with Nivolumab out of Clinical Trial: A Real-World Data Analysis (ID 10028)
09:30 - 09:30 | Author(s): Ernest Nadal
- Abstract
Background:
Immune-related adverse events occur in a subset of patients (pts) treated with immune checkpoint inhibitors blocking PD1/PD-L1 interaction. It has been reported that NSCLC pts treated with pembrolizumab who developed thyroid dysfunction (TD) had better clinical outcome. In this retrospective study, we examined the prognostic value of TD in advanced NSCLC pts treated with nivolumab.
Method:
Ninety-seven pts with advanced NSCLC treated with nivolumab in second and latter lines out of clinical trial at the Institut Català d’Oncologia (Barcelona, Spain) between November 2015 and March 2017 were included in this analysis. Thyroid tests were assessed at baseline and at the clinician’s discretion during treatment. TD was defined as abnormal levels of TSH value during nivolumab treatment. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method.
Result:
Of 97 pts, most patients received nivolumab in second line (73%). The median age was 63 years (38-82), most were men (76%), former or active smokers (87%), with adenocarcinoma (59%) or squamous cell carcinoma (31%), and had good performance status (88% ECOG PS 0-1). With a median follow-up of 8 months, 42 (43%) patients had died and 60 (62%) presented progressive disease. Sixteen pts (16.5%) developed TD that was G1 (9, 56%) or G2 (7, 44%). Two pts who developed G2 hyperthyroidism required steroid treatment and 5 pts who developed G2 hypothyroidism received substitutive hormone therapy. Median time until TD was 41 days (95% CI 37-45) and pts with TD received more cycles of nivolumab compared with euthyroid pts (11.5 versus 4, respectively). Pts with TD were more likely to achieve a tumor response compared to euthyroid pts (44% versus 14%, p=0.13). Median PFS and OS were significantly longer in pts who developed thyroid dysfunction compared with euthyroid pts. Median PFS was 3.7 months in euthyroid pts vs NR in pts with TD (p=0.001; odds ratio, 0.14; 95% CI 0.04-0.48) and median OS was 8.1 months vs NR, respectively (p=0.005; odds ratio, 0.15; 95% CI 0.03-0.69).
Conclusion:
This real-world data analysis showed that treatment-related TD predicts favorable clinical outcome from nivolumab in advanced NSCLC pts. A comprehensive analysis of thyroid stimulating hormone (TSH) kinetics will be presented at the meeting.
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P2.08 - Locally Advanced Nsclc (ID 709)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.08-006 - Immunological Biomarkers Characterization in Locally Advanced Non-Small Cell Lung Cancer Treated with Concurrent Chemo-Radiotherapy (ID 9584)
09:30 - 09:30 | Presenting Author(s): Ernest Nadal
- Abstract
Background:
The immune microenvironment of locally advanced non-small cell lung cancer (NSCLC) has not been systematically studied. Our aim was to determine the prognostic value of immunological biomarkers expression in a cohort of patients (pts) in this clinical setting.
Method:
We retrospectively reviewed 46 bronchial biopsies from locally advanced NSCLC. Pts were treated between 2010 and 2014 with concurrent chemo-radiotherapy (cCRT) at the Catalan Institute of Oncology. The following immunological markers were assessed by immunohistochemistry: PD-L1, ≥5% membrane expression on tumor cells was considered positive (+); HLA-Class I expression was classified into 0,1+,2+ according to membrane intensity; CD8+ tumor infiltrating lymphocytes (CD8 TILs) classified into low ≤5% or high >5% intratumoral infiltration. Chi-square test for assessing correlation and survival analysis by Kaplan-Meier method were used.
Result:
From 46 pts: Median age was 65 (43-81); gender: male 94%, female 6%; ECOG≤1 96%; smoking status: current 67%, former 30%, never 3%; histology: squamous cell carcinoma (SCC) 63%, adenocarcinoma (ADC) 24%, NSCLC (NOS+large cell) 13%; cN0-1 30%, cN2 57%, cN3 13%. Platinum doublet CT: Cisplatin 57%, Carboplatin 43%. PD-L1 was positive in 38% of cases and was positively correlated with HLA-I expression (p= 0.015) and CD8-TILs (p= 0.008). No correlations between PD-L1/CD8 TILs status and G3-4 radio-induced toxicities (pneumonitis, esophagitis) were found. At a median follow-up of 48 months (m), 53% of pts had relapsed. According to immune phenotype, median overall survival (mOS) was 20m (PD-L1 +, CD8 high; n=10) vs 17 m (PDL1 negative, CD8 low; n=19) vs not reached (PD-L1 negative, CD8 high; n=5) (p=0.23). Considering CD8 TILs, mOS in high CD8 (n=15) was 35m vs 18 m in low CD8 (n=26) (p=0.22).
Conclusion:
PD-L1, HLA-I and TILs CD8 expression was positively correlated. The potential role of TILs CD8+ as a prognostic biomarker in this cohort of pts that comprised mostly SCC histology, is promising. These results should be investigated in a larger cohort.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-071 - Randomized Phase 1b/3 Study of Erlotinib + Ramucirumab in Untreated EGFR Mutation-Positive Stage IV NSCLC: Phase 1b Outcomes (ID 8468)
09:30 - 09:30 | Author(s): Ernest Nadal
- Abstract
Background:
Despite the likelihood of an initial response to an EGFR TKI, NSCLC patients with an activating EGFR mutation eventually develop disease progression. Anti-angiogenic agents in combination with an EGFR TKI may provide additional benefit in EGFR-mutant NSCLC, but additional studies are needed to confirm the benefit.
Method:
This ongoing phase 1b/3 study (NCT02411448; RELAY) enrolled patients with previously untreated stage IV NSCLC, ECOG PS 0-1, and an activating EGFR mutation (exon 19 deletion or exon 21 L858R substitution). In part A (phase 1b), patients received ramucirumab (anti-VEGFR2 antibody) 10 mg/kg intravenously on day 1 of a 14-day cycle and oral erlotinib at 150 mg/day. Treatment continued until disease progression or unacceptable toxicity. The primary objective of part A was to assess safety and tolerability, in terms of dose-limiting toxicities (DLTs) during the first two cycles of therapy, and to determine the recommended dose for Part B (phase 3). Data cutoff was 31-May-2017.
Result:
Fourteen patients were enrolled and treated in part A. Two patients discontinued prior to completion of cycle 2, due to non-DLT adverse events of grade 2 interstitial pneumonia and grade 1 hemoptysis and were therefore not eligible for DLT assessment. Of the 12 DLT-evaluable patients (Japan, n=6; US/Europe, n=6), median age was 72 years (range 51-83), 83% were female, and 75% had ECOG PS of 1. Median duration of therapy was 64.3 weeks (interquartile range [IQR] 19.5-89.0) with ramucirumab and 68 weeks (IQR 44-95) with erlotinib. Treatment-emergent adverse events (TEAEs) occurred in all patients, most commonly rash (100%), diarrhea (92%), paronychia (67%), hypertension (58%), and dry skin (58%). Ten (83%) patients experienced grade 3 TEAEs (hypertension [n=4], rash [n=3], diarrhea [n=2], neutropenia, conjunctivitis, elevation of alanine aminotransferase [DLT; resolved within 4 days], and elevation of aspartate aminotransferase). No serious or grade 4-5 adverse events occurred. Median PFS was 17.1 months (95% CI 8.8-NR; 50% censored) and the PFS survival rate at 21-months was 46.9%. Five patients remain on study treatment.
Conclusion:
Ramucirumab plus erlotinib demonstrated encouraging clinical activity with no unexpected toxicities in Part A. Randomization into Part B began in January-2016, maintaining the dose of ramucirumab at 10 mg/kg Q2W with oral erlotinib at 150 mg/day.
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P3.08 - Locally Advanced Nsclc (ID 724)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.08-006a - Predictive Value of Geriatric Assessment and Screening Tools in Elderly Patients with Stage III NSCLC for Concurrent Chemoradiation (ID 9856)
09:30 - 09:30 | Presenting Author(s): Ernest Nadal
- Abstract
Background:
Concurrent chemoradiotherapy (cCRT) has proven to increase survival in patients with inoperable, locally advanced non-small-cell lung cancer (ILA_NSCLC), however there is no consensus on the treatment of elderly population. Our aim was to determine the prognostic value and ability to predict toxicity of the comprehensive geriatric assessment (CGA) in this clinical setting.
Method:
Elderly patients (≥ 75 years) with LA-NSCLC underwent CGA (assessing comorbidity, polypharmacy, functional status, geriatric syndromes, mood, cognition and nutritional status), the Vulnerable Elders Survey (VES-13) screening tool and the Cancer and Aging Research Group (CARG) toxicity predictive tool. Patients were classified according to the CGA into fit and medium-fit who were deemed candidates for cCRT (platinum-based chemotherapy concurrent with thoracic radiation therapy) and unfit patients that were assigned to best supportive care.
Result:
85 elderly patients with LA-NSCLC were included. Based on CGA, 37%, 48% and 15% were classified in fit, medium-fit and unfit respectively, and 56% were considered vulnerable according VES-13 (≥ 3). Out of 72 fit and medium-fit patients initially considered candidates for cCRT, only 54 patients (75%) were actually treated. The reasons for not administering cCRTwere: non-suitable for radiotherapy (tumor extension or poor respiratory function) (n=8), specific contraindication to chemotherapy (n=8), and patient’s decision (n=2). According to CARG-risk, fit and medium-fit patients candidates to receive cCRT were classified as high 10%, medium 52% and low 38%. Forty-two (78%) patients completed the scheduled treatment without differences between both CGA groups. The major reasons for not completing cCRT were: toxicity (10%), cancer recurrence (4%), patient decision (4%) or aggravation of comorbidities (4%). Fit and medium-fit patients receiving cCRT (63.5%) had mOS of 21.1 m (95% CI 16.2 – 26.0). VES-13 ≥ 3 was associated with shorter mOS (16.33 vs. 24.3 m; p=0.027). The most common grade 3-4 adverse events were neutropenia (20%), febrile neutropenia (7.5%), asthenia/fatigue (11%), respiratory infection (13%) and radiation pneumonitis (13%). There were not differences between GGA groups related to grade 3-4 toxicity. Medium risk patients defined by CARG had a trend towards higher risk of developing grade 3-4 toxicity (p= 0.086).Vulnerable patients defined by VES-13 had significantly higher risk of grade 3-4 toxicity (OR=3.99, 95% CI 1.28-12.37, p=0.017).
Conclusion:
CGA is useful in selecting elderly patients with LA-NSCLC that might benefit from adapted cCRT. VES-13 showed independent prognostic value and, unlike CARG score, it was significantly associated with higher risk of G3-4 toxicity in this clinical setting.
