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B. Besse
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GR 03 - Extensive Small Cell with Excellent Response to 1st Line Rx (PCI, Chest and/or Oligomet RT) and Second Line and Treatment of Thymic Malignancies (ID 16)
- Event: WCLC 2015
- Type: Grand Rounds
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:B.E. Johnson, B. Kavanagh, P. Kosmidis, E. Ruffini
- Coordinates: 9/09/2015, 14:15 - 15:45, 102+104+106
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GR03.05 - Thymic Epithelial Tumors: New Hope on the Horizon with Novel Therapeutic Strategies (ID 1843)
14:15 - 15:45 | Author(s): B. Besse
- Abstract
- Presentation
Abstract:
Thymic Epithelial Tumors (TET) comprised of thymoma (T) and thymic carcinoma (TC) are rare cancers with an incidence of 1.7 and 1.3 per million per year in Europe[i] and the US[ii], respectively. Five-year overall survival (OS) varies significantly sitting at > 80% for T compared with ~40% for TC[iii],[iv]. Surgery remains the treatment of choice for operable TET, whereas chemotherapy is standard of care for metastatic or inoperable / recurrent disease. The response rate (RR) of TET to current chemotherapy agents differs by histological features: T responds better to first-line platinum based chemotherapy than TC (69% vs. 41%)[v]. No standard treatments are available for advanced TET after failure of first-line platinum-based chemotherapy, although single agents are generally used with modest benefit. For example pemetrexed, has been associated with a 17% partial response (PR) rate in T and 10% of PR in TC, with a median progression free survival (PFS) of 13.8 months and 6.5 months, respectively[vi]. Other drugs have recently been tested in second-line with promising results. In a phase II trial which recruited 14 T and 19 TC patients, amrubicin (a topoisomerase II inhibitor) was administered at 35 mg/m[2] IV days 1-3 on a 21-day cycle, producing an 18% RR (n=6, all PR: 29% in T and 11% in TC) without unexpected toxicity or cardiotoxicity[vii]. Another phase II trial investigated the combination of capecitabine plus gemcitabine in 30 pretreated TET patients (22 T and 8 TC). Overall RR was 40% (3 CR and 8 PR, with 3 PR in TC 3), PFS for T and TC was 11 months and 6 months, respectively and median OS was 16 months[viii]. In octreoscan positive patients with TET, somatostatin analogs with or without prednisone have also been shown to be effective as maintenance or as second-line treatment[ix][,[x]]. Given the poor survival of advanced TET, especially TC, there is a clear need for new treatment options. However, the molecular pathogenesis of TET is poorly understood at present. Profiled somatic genetic variations in 78 advanced-TET[xi] cases showed higher a incidence of somatic non-synonymous mutations in TC compared to T (62% vs. 13%; p<0.0001). TP53 was the most frequently mutated gene (overall in TET was 17% and especially in TC, 26%) and was associated with poorer OS (p<0.0001). Moreover, genes invovlved with histone modification (e.g. BAP1), chromatin remodelling, DNA methylation genes and c-KIT were also frequently mutated in advanced TCs. Although the presence of activating mutations is low in TET, the SPECTA-lung trial (NCT02214134) will allow analysis of more than 360 genes in patients with thoracic tumors, including T and TC. In this EORTC/ETOP umbrella study, eighteen European centres will allocate patients to different treatment arms based on the molecular characteristics of their disease, suggesting that basket trials allow the study of the genetics of less common malignancies[xii]. Despite data demonstrating EGFR and KIT overexpression in TET, EGFR and c-KIT mutations are rare, reported at 2%-10% and 9%, respectively[xiii]. This low percentage could explain the lack of RR observed in phase II studies evaluating Gefitinib, Erlotinib plus bevacizumab, and Glivec. In a recent retrospective analysis of 48 TC and thymic neuroendocrine tumors, the probability to finding c-KIT mutations was higher in CD117-positive thymic squamous cell carcinoma with poorly-differentiation and co-expression of CD5 and p63 in the absence of neuroendocrine markers (6 out of 23, 26%)[xiv], suggesting that a subgroup of TC might respond to c-KIT inhibitors. Recently SRC inhibitors (AZD0530) reported no RR in a phase II trial[xv]. Angiogenesis is another relevant pathway in TET. VEGF-A, -C, -D and VEGFR-1,-2,-3- are all overexpressed in high risk T and TC[xvi]. Sunitinib is an oral tyrosine kinase inhibitor (TKI) of VEGFR, KIT, and PDGFR. In a single arm phase 2 trial of sunitinib (50 mg/day for 4 weeks on, 2 weeks off) after at least one previous line of chemotherapy, a PR was reported in 26% of TC and 6% in T, with a mPFS of 7.2 months and 8.5 months, respectively. Main adverse events (AE) reported were lymphocytopenia, fatigue, and oral mucositis[xvii]. Although response was mainly limited to TC, sunitinib demonstrated an unprecedented activity for a targeted agent so far. Other antiangiogenic compounds that could be of value include Lucitanib, a selective TKI of FGFR1-3, VEGFR1-3, and PDGFR α/β. Efficacy data in 15 patients will be reported for this drug at the WCLC 2015. Insulin-like growth factor-1 receptor (IGF-1R) over-expression has been reported in 86% of TC and 43% of T[xviii], and carries poor prognosis. In a recent phase II trial of 49 patients with recurrent TET (37 T and 12 TC), single agent cixutumumab (a fully human IgG1 monoclonal antibody anti-IGF-1R, 20 mg/kg every 3 weeks), reported clinical activity only in T (14% PR, 28% SD, TTP 9 months and OS 27.5 months). No activity was recorded in the TC cohort (42% SD, TTP 1.7 months and OS 8.4 months). The most common toxicity in both groups was hypoglycemia (10%). Of note, 9 patients with T experienced autoimmune disorders[xix]. A phase II trial, Belinostat (PXD101, a pan-histone deacetylase inhibitor, 1g/m2 on days 1 through 5 in a 3-week schedule) among 41 patients (25 T and 16 TC) has reported only modest activity, with an 8% RR in T and no responses observed in TC. However, based on the duration of response and disease stabilization (median TTP and OS were 5.8 and 19.1 months, respectively), additional testing of belinostat in this disease may be warranted[xx]. Milciclib (PHA-848125AC) is an inhibitor of cyclin-dependent kinase2/cyclin A and SRC family members. Milciclib (150 mg/d 7 days on / 7 days off, 2-week cycles) has been evaluated in a phase II trial with 43 patients (26 TC and 9 B3-T). Out of 30 patients, 14 cases (46.7%) reached the primary end point and were PFS at 3 months, including PR. Five cases of SD lived longer than 1 year. The median PFS was 8.2 months and median OS has not been yet reached. The toxicity profile appeared favourable with nausea, asthenia and neutropenia (8.3%) reported as the most common severe AEs[xxi]. The mTOR inhibitor everolimus (10 mg/d) has been tested in a phase II trial in 50 patients with advanced or recurrent T (n=30) or TC (n=19) previously treated with cisplatin-containing chemotherapy. Preliminary data among the 43 evaluable patients showed a disease control rate (DCR) of 86% (1 CR, 10 PR, 32 SD) that was beyond the pre-specified endpoint of 40% DCR. The median PFS was 11.3 months (T not reached vs. 5.5 months in TC), and median OS was 18.6 months for TC and not reached for T. Few severe AEs were reported (asthenia, dyspnoea, neutropenia and hyperglycemia)[xxii]. Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has clinical activity in many tumors types. In a cohort of 139 TET, retrospective PDL-1 expression by IHC with the E1L3N antibody has been reported in 70% of TC and 23% of T, respectively. PDL-1 expression was not a significant prognostic factor in multivariable analysis[xxiii], although in other reported cohorts overexpression of PD-L1 was associated with worse prognosis [xxv, xxiv]. These results generally support immunotherapeutic strategies in TET (NCT02364076). At present, antiangiogenics, mTOR and CDK inhibitors, are the most promising drugs in TET treatment. Consensus on meaningful end-points, and knowledge of predictive biomarkers are challenges in this disease. [i] Siesling S, van der Zwan JM, Izarzugaza I et al. Rare thoracic cancers, including peritoneum mesothelioma. Eur J Cancer 2012; 48: 949-60. [ii] Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol 2010; 5 (10 Suppl 4): S260–S265. [iii] Mariano C, Ionescu DN, Cheung WY et al. Thymoma. A population-based study of the management and outcomes for the province of British Columbia. J Thorac Oncol 2013; 8: 109–117. [iv] de Jong WK, Blaauwgeers JLG, Schaapveld M et al. Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy. Eur J Cancer 2008; 44(1): 123–130. [v] Okuma Y, Saito M, Hosomi Y et al. Key components of chemotherapy for thymic malignancies: a systemic review and pooled analysis for anthracyclines-, carboplatin- or cisplatin-based chemotherapy. J Cancer Res Clin Oncol 2015; 141: 323-31 [vi] Liang Y, Padda SK, Riess JW et al. Pemetrexed in patients with thymic malignancies previously treated with chemotherapy. Lung Cancer 2015, 87: 34-8 [vii] Wakelee HA, Padda SK, Burns M et al. Phase II trial of single agent amrubicin in patients with previously treated advanced thymic malignancies. J Clin Oncol 2015; 33 (suppls; abstr 7580) [viii] Palmieri G, Buonerba C, Ottaviano M, et al. Capecitabine plus gemcitabine in thymic epithelial tumors: Final analysisof a phase II trial. Future oncology 2014; 10: 2141-7 [ix] Palmieri G, Ottaviano M, Nappi L et al. Somatostatin analogs as maintenance therapy in heavily pretreated thymic epithelial tumors. J Clin Oncol 2015; 33 (suppl; abstract 7581) [x] Ottaviano M, Damiano V, Nappi L et al. Effectiveness of somatotstain analogs plus prednisone in aggressive histotype and advanced stage of thymic epithelial tumors. J Clin Oncol 2015; 33 (suppl; abstract 7582) [xi] Wang Y, Thomas A, Lau Ch et al. Mutations of epigenetic regulatory genes are common in thymic carcinomas. Scientific Reports 2014; 4: 7336 [xii] Lopez-Chavez A, Thomas A, Rajan A et al. Molecular profiling and targeted therapy for advanced thoracic malignancies: A biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol 2015; 33: 1000-7 [xiii] Yoh K, Nishiwaki Y, Ishii G et al. Mutational status of EGFR and KIT in thymoma and thymic carcinoma. Lung Cancer 2008; 62: 31-20 [xiv] Schirosi L, Nannini N, nociloi D et al. Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors. Ann Oncol 2012; 23: 2409-14 [xv] Gubens MA, Burns M, Perkins SM et al. A phase II study of saracatinib (AZD0530), a SRC inhibitor, administered orally daily to patients with advanced thymic malignancies. Lung Cancer 2015; 89: 57-60 [xvi] Lattanzio R, La Sorda R, Facciolo F et al. Thymic epithelial tumors express vascular endothelial growth factors and their receptors as potential targets of antiangiogenic therapy: A tissue micro array-based multicenter study. Lung Cancer 2014; 85: 191-6 [xvii] Thomas A, Rajan A, Berman A et al. Sunitinib in patients with chemotherapy-refrtactory thymoma and thymic carcinoma: an open-label phase 2 trial Lancet Oncol 2015; 16: 177-86 [xviii] Girard N, Teruya-Feldstein J, Payabyab EC et al. Insulin-like growth factor-1 rceptor expression in thymic malignancies. J Thorac Oncol 2010; 5: 1439-46 [xix] Rajan A, Carter CA, Berman A et al. Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial. Lancet Oncol 2014; 15:191–200. [xx] Giaccone G, Rajan A, Berman A et al. Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors. J Clin Oncol 2011; 29: 2052-9 [xxi] Besse B, Garassino MA, Rajan A et al. A phase II study of milciclib (PHA-848125AC) in patients with thymic carcinoma. J Clin Oncol 2014; 32 (suppl; abstract 7526) [xxii] Zucali PA, Martino de Pas T, Palmieri G et al. Phase II study of everolimus in patients with thymoma and thymic carcinoma previously treated with cisplatin-based chemotherapy. J Clin Oncol 2014; 32 (suppl; abstract 7527) [xxiii] Katsuya Y, Fujita Y, Horinouchi H et al. Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma. Lung Cancer 2015; 88: 154-9 [xxiv] Programmed cell death 1 (PD-1) and its ligand (PD-L1) expression in thymic epithelial tumors (TETs): Impact on the treatment efficacy and alteration in expression after chemotherapy (C) J Clin Oncol 2015; 33 (suppl; abstr 7515) [xxv] Padda SK, Riess JW, Schwartz EJ et al. Diffuse high intensity PDL-1 staining in thymic epithelial tumors. J Thorac Oncol 2015; 10: 500-8
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MINI 07 - ChemoRT and Translational Science (ID 110)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:D. Raben, B. Kavanagh
- Coordinates: 9/07/2015, 16:45 - 18:15, 201+203
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MINI07.08 - Mutation Profile Prognostic Value in Stage III Non Small Cell Lung Cancer (NSCLC) Patients Treated with Chemo-Radiotherapy (CRT) (ID 2262)
16:45 - 18:15 | Author(s): B. Besse
- Abstract
- Presentation
Background:
Molecular profiling is a standard procedure in advanced non squamous NSCLC. Gene alteration in EGFR, BRAF or ALK gene can lead to prescription of targeted therapies and prolongs survival. The influence of molecular abnormalities on the survival of stage III NSCLC patients definitely treated by CRT is unknown.
Methods:
We reviewed all consecutive patients that received CRT or RT with a curative intent for stage III NSCLC in a single institution. Paraffin embedded tissue block were collected. DNA was extracted for gene mutation analysis by next generation sequencing and ALK, ROS1 and RET rearrangements were detected by FISH analysis. Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis, adjusting for performance status (0, ≥1), stage (IIIA, IIIB) and thoracic surgery (yes, no). Median follow-up was estimated by the Schemper method.
Results:
Between January2002 and June 2013, clinical data from 190 patients were collected. Median dose of RT was 66 Gy (46-70). Platinum-based chemotherapy was administrated concomitantly in 108 patients, as induction/consolidation treatment in 170 patients, and 15 patients did not receive any chemotherapy. Seventy-eight patients were evaluable for mutation profile, 20 (26%) were female, 47 (60%) were current smoker, 40 (51%) had adenocarcinoma and there were 47/31 stage IIIA/IIIB. Mutations were positive as follow: EGFR 12% (9/78), KRAS 15% (12/78), BRAF 5% (3/66), PI3KCA 2% (1/58), HER2 0% (0/65), NRAS 3% (1/32), CTNNB1 3% (1/32). FISH was positive for ALK in 5% (3/56) of the NSCLC. In 32 NSCLC for which the test was performed, there was no alteration in ROS1, RET, HRAS and AKT1. Median Follow-up was 3.1 years (minimum 0.9 year). EGFR mutated or ALK+ (EGFR/ALK) group (n=11) and other mutation group (n=17) had a poorer progression free survival (median 0.8[95%CI: 0.6 ; 0.9] year and 0.5 [0.4 ; 0.8] year ; multivariate hazard ratio (HR)= 1.8 [0.8 ; 3.8] and 2.8 [1.5 ; 5.1] respectively, p=0.004) compared to the wild group (n=50) (median 1 year [0.9;1.3]). There was no significant difference (p=0.23, multivariate Cox) in overall survival: median 2.4 years [1.3 ; NR] for EGFR/ALK group, 1.1 [0.6 ; 2.5] for other mutation group and 1.9 [1.5 ; 2.5] for wild type. In multivariate analysis, only the dose of radiotherapy was significantly associated with overall survival (HR=0.5 [0.3 ; 1.0], p=0.04 in contrast with performance status or stage.
Conclusion:
This study suggests that selected gene alterations could be associated with a poorer survival in stage III NSCLC patients treated by combined modality treatment or radiotherapy alone. Their prognostic and/or predictive value should be further evaluated in a larger population.
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MINI 10 - ALK and EGFR (ID 105)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:T. Yap, T. Li
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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MINI10.08 - Discussant for MINI10.05, MINI10.06, MINI10.07 (ID 3400)
16:45 - 18:15 | Author(s): B. Besse
- Abstract
- Presentation
Abstract not provided
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MINI 25 - Trials, Radiation and Other (ID 142)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 2
- Moderators:J.M. Clavero, R. Hassan
- Coordinates: 9/08/2015, 16:45 - 18:15, 702+704+706
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MINI25.07 - Clinical Activity of Lucitanib in Advanced Thymic Epithelial Tumours (ID 2153)
16:45 - 18:15 | Author(s): B. Besse
- Abstract
- Presentation
Background:
Thymic epithelial tumours are rare malignancies for which there is no standard treatment for patients with advanced disease progressing on or after chemotherapy. Despite the lack of identified targets in thymic malignancies, several studies demonstrated that VEGFR and KIT pathways are the most relevant targets for therapeutic intervention. Lucitanib is an oral, potent, selective inhibitor of the tyrosine kinase activity of FGFR1-3, VEGFR1-3, and PDGFR α/β, all key targets involved in pro-angiogenic and proliferative pathways leading to tumour progression. Therefore, lucitanib could be a potential therapeutic alternative for patients with recurrent or refractory disease.
Methods:
This first in human study is currently evaluating oral lucitanib as monotherapy in various solid tumours. The escalation phase used a 3+3 design in patients with advanced solid tumours to establish the recommended phase II dose. Safety and efficacy were further evaluated in patients whose tumours were determined to be FGF aberrant (FGFR1 and/or 11q amplification) or in patients with tumours known to be anti-angiogenesis-sensitive such as thymic epithelial tumours. In addition, different doses and administration schedules were investigated.
Results:
Of the 134 patients treated in the study, 3 had B-type Thymoma (T) and 12 had Thymic Carcinoma (TC). Among these patients, median age was 54 years [range 37-72], 7 were males and 8 females. Twelve patients (80%) were treated at 12.5mg on daily basis. The other 3 patients (T) received 5, 15 and 20mg respectively. Patients had received a median of 2 previous anti-cancer treatments [range: 0-6]. Median duration of treatment with lucitanib was 7 cycles [range 2-44]. All patients were evaluable for anti-tumour activity according to RECIST v1.1. Two patients had confirmed partial response (1T / 1TC) lasting at least 7 months (TC patient is still ongoing) and 10 patients had a stable disease with 6 of them lasting at least 6 months. To date, 4 patients are still ongoing and receiving benefit from lucitanib independently of the number of previous regimens. The most common adverse events related to lucitanib in this population (all grades, all doses) were hypertension (80%), hypothyroidism (53%), proteinuria (53%) and diarrhoea (40%). There was no major bleeding event reported. These findings were in line with the overall safety profile of lucitanib already described.
Conclusion:
The results of this tumour cohort analysis suggest that lucitanib has signs of clinical activity in patients with advanced thymic epithelial tumours, and should be further investigated in dedicated studies.
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MINI25.08 - Systemic Treatment in Advanced Thymic Epithelial Tumors. Insights From a Prospective Cohort of 888 Patients Enrolled in RYTHMIC (ID 1166)
16:45 - 18:15 | Author(s): B. Besse
- Abstract
Background:
RYTHMIC (Réseau tumeurs THYMiques et Cancer) is the French nationwide network for thymic malignancies. Starting 2012, all patients diagnosed with thymic tumor had to be enrolled, as recommended by the French National Cancer Institute, part of good clinical practice.
Methods:
RYTHMIC prospective database is hosted by the French Thoracic Cancer Intergroup (IFCT), and collects clinical, imaging, treatment, and follow-up data of patients discussed at the reference national multidisciplinary tumor board (MTB). Data cutoff was April 1[st], 2015 for this analysis.
Results:
1089 questions were raised at the MTB about the management of 888 patients with thymic epithelial tumor. Among assessable cases, Masaoka-Koga stage III-IV tumors accounted for 42% of cases; histology was thymoma in 82% of cases, and thymic carcinoma in 18% of cases. First-line treatment of locally advanced disease, and management (diagnosis and treatment) of recurrent disease led to raise 227 (21%), and 234 (21%) questions at the MTB, respectively, 312 (68%) of which were about the modalities of systemic treatment. Figure 2 shows the proposed regimens for primary (A) and exclusive (B) chemotherapy in treatment-naïve patients, and chemotherapy (C) and targeted agents (D) for recurrent tumors. Combination of cisplatin, adriamycin, and cyclophosphamide and carboplatine, paclitaxel were the most frequently proposed regimens as first- and second-line treatment, respectively. Figure 1 Figure 2
Conclusion:
RYTHMIC is an exhaustive registry of thymic malignancies, which provides unique insights in the management of advanced and recurrent tumors with systemic agents. Meanwhile, limited data have been made available in the literature so far, as clinical trials were conducted in small numbers of patients, and existing databases enrolled a majority of surgically resected, early-stage tumors. Through the use of targeted agents, RYTHMIC allows the rapid implementation of new results in clinical practice, while ensuring patients an equal access to therapeutic innovation. Supported by Institut National du Cancer
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.12 - A Phase II Trial of Pictilisib with Chemotherapy in First-Line Non-Squamous NSCLC (ID 1432)
18:30 - 20:00 | Author(s): B. Besse
- Abstract
- Presentation
Background:
In non-squamous non-small cell lung cancer (NSCLC), PI3-kinase (PI3K) pathway activation, including downregulation of phosphatase and tensin homolog (PTEN) expression, may promote cell survival and enhance chemotherapy resistance. Additionally, mutations in KRAS have been shown preclinically to confer resistance to PI3K inhibition. The pan-PI3K inhibitor pictilisib potentiates the activity of taxanes, platinum agents, and antivascular endothelial growth factor therapy in preclinical models of NSCLC. This phase II hypothesis-generating study (NCT01493843) evaluated the safety and efficacy of pictilisib in combination with carboplatin, paclitaxel, and bevacizumab in patients not treated for advanced or recurrent non-squamous NSCLC.
Methods:
Overall, 158 patients were randomized to receive carboplatin (area under the curve [AUC] = 6 mg/ml/min), paclitaxel (200 mg/m[2]), and bevacizumab (15 mg/kg) every 3 weeks (q3w) with 340 mg oral pictilisib (n=79) or placebo (n=79) daily in the first 2 weeks of each cycle for a total of 4 cycles. Bevacizumab q3w with daily pictilisib or placebo was continued until disease progression or unacceptable toxicity. Stratification factors included Eastern Cooperative Oncology Group performance status and smoking status. The primary endpoint was progression-free survival (PFS) in the intention-to-treat (ITT) population and in patients with PTEN null/low expression (assessed by immunohistochemistry). Overall survival (OS), objective response rate (ORR), and safety were secondary endpoints. Pre-planned exploratory analyses included efficacy in the KRAS-wildtype subgroup. Tumor assessment was based on RECIST v1.1. Safety analyses were performed on patients who received at least one dose of study drug.
Results:
Median PFS in the ITT population was 6.9 months in the pictilisib arm and 5.9 months in the placebo arm (HR 0.82; 90% CI 0.59–1.13), while median OS was 13.6 months (pictilisib arm) versus 16.1 months (placebo arm) (HR 1.12; 90% CI 0.79–1.59). In patients with PTEN null/low expression, median PFS was 5.9 months (pictilisib arm) and 5.7 months (placebo arm) (HR 0.74; 90% CI 0.41–1.32). In the KRAS-wildtype subgroup, median PFS was 9.7 months (pictilisib arm) versus 5.7 months (placebo arm) (HR 0.70; 90% CI 0.45–1.09); median OS was 14.5 months in both arms. ORR in the ITT population was 37% (pictilisib arm) versus 29% (placebo arm). In the pictilisib arm, common grade ≥3 adverse events (AEs) included neutropenia (23%), rash (20%), thrombocytopenia (8%), febrile neutropenia (5%), and hyperglycemia (5%). AEs led to higher rates of discontinuation in the pictilisib arm (26% versus 16% in the placebo arm), particularly during the first 4 cycles. However, the proportion of AE-related deaths was higher in the placebo arm (9 [12%] versus 5 [6%] in the pictilisib arm).
Conclusion:
This phase II trial of first-line pictilisib plus chemotherapy and bevacizumab in patients with non-squamous NSCLC showed a modest trend for improved PFS, with additional toxicity and no OS benefit. The safety profile was consistent with other pictilisib trials. PTEN null/low expression was not a predictive biomarker, although its prognostic value cannot be excluded. A trend for improved PFS, but not OS, was observed in the KRAS-wildtype subgroup, especially during the maintenance phase of treatment.
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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)
10:45 - 12:15 | Author(s): B. Besse
- 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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ORAL 33 - ALK (ID 145)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:S. Gadgeel
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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ORAL33.01 - Crizotinib Outcome and Post-Progression Management in ALK+ NSCLC: IFCT-1302 CLINALK (ID 1355)
16:45 - 18:15 | Author(s): B. Besse
- Abstract
- Presentation
Background:
Phase III trials have demonstrated the superiority of the ALK tyrosine kinase inhibitor (ALK-TKI) crizotinib compared to standard chemotherapy in advanced ALK positive non-small cell lung cancers (ALK+ NSCLC) in first line and second line setting. Objective response rate (ORR) with crizotinib ranged from 65 to 75% and median progression free survival (PFS) from 7.7 to 10.9 months. However a resistance to crizotinib always occurs. The French Cooperative Thoracic Intergroup (IFCT)-1302 CLINALK study aimed to describe clinical outcome and post-progression management in a large cohort of French patients with ALK+ NSCLC treated with crizotinib.
Methods:
IFCT-1302 CLINALK is a multicentric observational retrospective study. Patients with ALK+ NSCLC from centers of the IFCT network were included according to the main following criteria: advanced stage III or stage IV NSCLC, ALK immunochemistry (IHC) and/or ALK FISH positivity, crizotinib treatment in the setting of the French expanded access cohort program or as approved drug. Epidemiological and clinical data, crizotinib efficacy (objective response based on RECIST, PFS, overall survival (OS)), duration of treatment with crizotinib after disease progression and post progression outcome were collected on a case report form. The study inclusion period was from November 18 2011 to December 31 2013. The data cut-off was December 31 2014.
Results:
318 patients were included (median age 58.3, female 49.4%, caucasian 98.6%, non-smoker 55.1%, performance status 0/1 78.7%, adenocarcinoma 91.7%, stage III 14.5%, stage IV 85.5%, brain metastasis 35.9%). IHC was positive in 151/173 patients and FISH in 279/283 patients. Before crizotinib treatment, patients received platinum-based chemotherapy in 89% of cases and pemetrexed-based chemotherapy in 76.1%. Crizotinib was prescribed as first-line treatment in 17 patients (5.3%), second-line in 168 patients (52.8%), third-line in 58 patients (18.2%) and more than third-line in 75 patients (23.7%). Objective response was complete response in 1 patient (0.3%), partial response in 126 patients (40.0%), stable disease in 62 patients (19.7%) and progression in 58 patients (18.4%). ORR was 40.3 % (95%CI, 34.9-45.7). 262/318 patients presented progressive disease (82.4%) at time of analysis. Median PFS was 6.9 months (95%CI, 5.7-8.6). Median OS with crizotinib was 18.7 months (95%CI, 15.2-22.5). Median duration of treatment with crizotinib after disease progression was 56 days (29-203). Among 143 patients with subsequent treatments, crizotinib was rechallenged in 32 patients (22.4%). 58/143 patients (40.6%) were treated after crizotinib failure with another ALK-TKI, either alectinib (19/58, 32.8%) or ceritinib (40/58, 69.0%). The ALK-TKI sequence was crizotinib-alectinib in 18 patients, crizotinib-ceritinib in 39 patients and crizotinib-alectinib-ceritinib in 1 patient.
Conclusion:
This retrospective study of 318 patients with ALK+ NSCLC showed a remarkable efficacy of crizotinib, with a 18.7 months median OS, a 40.3% ORR and a 6.9 months median PFS. However, ORR and mPFS were lower than those reported in phase III trials, which may be due to less stringent selection criteria. Analysis of predictive factors of response and survival including post-progression strategies will be presented.
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ORAL33.07 - Clinical Activity and Safety of the ALK/ROS1 TK Inhibitor PF-06463922 in Advanced NSCLC (ID 295)
16:45 - 18:15 | Author(s): B. Besse
- Abstract
- Presentation
Background:
Overcoming acquired resistance in ALK+ and ROS1+ non-small-cell lung cancer (NSCLC) patients (pts) is key to optimizing therapy. PF-06463922 is a selective, brain-penetrant tyrosine kinase inhibitor (TKI) with demonstrated clinical activity against de novo fusions as well as resistance mutations, including ALK G1202R, that arise during treatment with other TKIs.
Methods:
In this ongoing phase I study, eligible pts had ALK+ or ROS1+ NSCLC, with or without brain metastases, and were treatment naïve or had disease progression after at least 1 prior TKIs. Pts with central nervous system (CNS) metastases, including untreated asymptomatic metastases, were eligible. Tumor tissue (archival sample or de novo biopsy) was required for enrollment. A modified continual reassessment method was used to estimate the maximum tolerated dose (MTD) and select a recommended phase II dose (RP2D). Once- (QD) or twice-daily (BID) dosing in 21-day cycles was explored. Secondary objectives included efficacy, safety, tolerability, pharmacokinetics (PK), effect on cognitive function, patient-reported outcomes, potential to induce/inhibit CYP3A4, biomarkers of drug response and resistance, and intracranial antitumor activity.
Results:
25 ALK+ pts (20 with CNS metastases, 23 previously treated with at least 1 ALK TKIs) and 5 ROS1+ pts (3 with CNS metastases, 3 previously treated with crizotinib) have been enrolled across 7 QD dose levels and 2 BID dose levels. Of 21 patients evaluable for intracranial response, 16 had stable disease or confirmed complete/partial response. The most common treatment-related adverse events (AEs) were hypercholesterolemia, peripheral neuropathy, and peripheral edema, occurring in 47%, 27% and 23% of pts, respectively. Peripheral neuropathy was reversible following treatment delay or dose reduction. The most common grade 3 and higher treatment-related AE was hypercholesterolemia, occurring in 10% of pts, which was well managed with statins. One DLT was reported for a pt at 200 mg QD, who received less than 16 of the 21 planned doses of study drug due to grade 2 CNS effects. To date, 20 pts remain on treatment. Preliminary PK analyses suggest that exposure increased linearly from 10 to 75 mg QD, with a terminal half-life of 20-28 hrs. At doses beyond 75 mg QD, the increase in exposure appeared to be non-proportional. PF-06463922 is considered a moderate inducer of CYP3A4.
Conclusion:
PF-06463922 is a potent ALK/ROS1 TKI that has demonstrated clinical activity in ALK+ and ROS1+ NSCLC pts, most of whom had CNS metastases and had received at least 1 prior TKI. The RP2D has not yet been established.
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ORAL 36 - Translational Science/Radiation (ID 151)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:E. Vokes, B. Kavanagh
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 2c-3c
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ORAL36.02 - Efficacy of Chemo-Radiotherapy (CRT) in Stage III Non-Small Cell Lung Cancer (NSCLC) and PD-L1 Expression (ID 2432)
16:45 - 18:15 | Author(s): B. Besse
- Abstract
- Presentation
Background:
Inhibition of the PD1/PD-L1 axis has been successfully developed in advanced NSCLC, and its role in locally advanced NSCLC is under investigation. The prognostic and predictive values of PD-L1 expression is still debated in advanced NSCLC and unknown in stage III NSCLC patients definitely treated by CRT
Methods:
We reviewed all consecutive patients that received CRT or RT with a curative intentfor stage III NSCLC in a single institution. Paraffin embedded tissue block were collected, immunohistochemistry was performed on a Ventana Benchmarck Ultra platform using the E1L3N clone (Cell Signaling Technologies). All tumors were centrally reviewed and tumor cells were scored accordingly (Herbst et al., Nature 2014).Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis, adjusting for performance status (0, ≥1), stage (IIIA, IIIB) and thoracic surgery (yes, no). Median follow-up was estimated by the Schemper method
Results:
Between January 2002 and June 2013, clinical data from 190 patients were collected. Median dose of RT was 66 Gy (46-70). Chemotherapy, mostly based on doublets with platin salt was administrated concomitantly in 108 patients, as induction/consolidation treatment in 170 patients, and 15 patients did not receive any chemotherapy. Fifty NSCLC were evaluable for PD-L1 expression, 22 (44%) being positive. Fourteen (28%) were female, 24 (48%) were current-smoker, 17 (34%) had adenocarcinoma and there were 23/27 stage IIIA/IIIB. Evaluable and unevaluable populations for PD-L1 were not different. There were no clinical or pathological factors related to PD-L1 positivity. Median follow-up was 7.6 years (minimum: 0.7 year). Median OS was 1.1year(95% confidence interval (CI) 0.6-1.5) in PD-L1 positive (pos) and 2.0 years (95% CI 1.5-3.8) in PD-L1 negative (neg) (p=0.01), HR=2.3 (95% CI 1.2-4.5, p=0.01). Median PFS was 0.7 year (95% CI 0.6-0.8) in PD-L1pos and 1.0 year (95% CI 0.8-1.5) in PD-L1neg (p=0.04), HR=2.1 (95% CI1.1-4.0, p=0.03). There was no difference in terms of acute toxicity according to PD-L1 status (positive or negative):25 had oesophagitis (grade≥2) and 16 had pneumonitis (p=0.57 and p=0.23 respectively).
Conclusion:
PD-L1 positivity was associated to a poorer survival in stage III NSCLC patients treated by definitive chemo-radiotherapy. Its prognostic and/or predictive value should be further evaluated in this population.
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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: 2
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-025 - Tumor Control of Advanced Pulmonary Neuroendocrine Tumors (Carcinoids) with Somatostatin Analogs: Experience at Gustave Roussy (ID 2758)
09:30 - 17:00 | Author(s): B. Besse
- Abstract
Background:
Pulmonary carcinoids are rare neuroendocrine tumors (puNETs) of the lung with no standard therapeutic option. Antitumor control benefit of somatostatin analogs (SSAs) has been demonstrated in gastroeneropancreatic (GEP)-NETs, but only a few data have been published in puNETs.
Methods:
Data from advanced puNETs patients treated with SSAs in monotherapy between 1986 and 2014 at Gustave Roussy were retrospectively collected. Demographical, clinical and tumor-related features were recorded. Patients had a tumor evaluation by CT-scan and/or MRI every 3 months. Progression-free survival (PFS) and Overall survival (OS) were estimated using Kaplan-Meier. Response rate and toxicity were assessed according to RECIST (v1.0 until 2008 and v1.1 since 2009) and NCI.CTC v4.03 criteria respectively.
Results:
Sixty-one metastatic patients with a median follow-up of 5.8 yrs (0.4-13.0 yrs) were included, with a median age of 55 yrs (13-84 yrs), 55.7% were male, 29% current or former smokers, and 95% had PS ≤1. At diagnosis, 20 patients were classified as typical carcinoids (TCs) and 41 as atypical carcinoids (ACs) according to 2004 WHO classification. Before SSAs initiation, 49 patients (80%) showed uptake at somatostatin receptor scintigraphy (SRS) (grade ≥2) and 29 (52%) showed hormone-related symptoms. The majority of patients (75.4%) presented at least two metastatic sites, liver being the most frequent one (80.3%). Forty-six (75%) patients received SSAs as first-line therapy: 32 patients (70%) for disease progression and 14 patients (30%) for symptomatic carcinoid syndrome. The median duration of SSAs was 13.7 months (3.0-155.1). Overall, median PFS (mPFS) and OS (mOS) were 17.4 [95% CI=8.7-26.0] and 58.4 months [44.2-102.7], respectively. Best response was stable disease (SD) for 43 patients (70.5%) and progression disease (PD) for 14 patients (23%). All PD were ACs. The number of events and deaths was 46 (75%) and 29 (48%), respectively. mPFS was 24.8 months [10.1-36.3] for the TCs and 12.8 months [6.2-26.0] for the ACs patients (p=0.32). mPFS was significantly longer in functional puNETs with a mPFS of 28.7 months [13.2-55.6] vs. 8.7 months [5.8-21.2] in non-functional tumors (p=0.01). The most common adverse event was grade 1 diarrhea in 43% of patients. Only one grade 3 (abdominal pain) was reported with a consequent withdrawal of treatment.
Conclusion:
In the real-world setting, SSAs are safe and potentially effective for the antitumor control of puNETs. Our results suggest that patients with typical carcinoids and functional puNETs seem to benefit most from SSAs therapy.
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P1.08-035 - Pan-European Survey on Thymic Malignancies: A Collaboration of the EORTC Lung Cancer Group (LCG) with the RYTHMIC Network (ID 690)
09:30 - 17:00 | Author(s): B. Besse
- Abstract
Background:
Thymic malignancies are rare tumors with an incidence of over 0.15 cases per 100.000 persons/year. Because of the indolent course and sporadic occurrence, the management of this disease has been mainly based on single-institution retrospective, observational studies. Clinical trials have been run in the recent years but no uniformly accepted guidelines are available so far. For advanced disease at diagnosis or with relapse/ progression treatment options are limited in first line and there is no standard treatment for second line treatment. The EORTC Lung Cancer Group (LCG) and French RYTHMIC network developed a survey with the aim of assessing the current treatment strategies and respective outcomes, thus providing an overview on the management of these tumors in advanced stage.
Methods:
We conducted a 25-item survey disseminated as dedicated mailing in the EORTC LCG and RYTHMIC network. Descriptive statistical analysis was applied to assess and present the preliminary replies.
Results:
At the time of the analysis, a total of 45 physicians from 11 countries participated in the study, the majority of participants were EORTC members (60.8%) and 11.1% were both EORTC and RYTHMIC members. About half of the institutions have a dedicate team for thymic malignancies (46.7%) but almost all of them have in place multidisciplinary meeting to discuss new diagnosed patients (91.1%).Diagnosis is made on surgical sample in 53.4% of the cases flowed by core needle biopsy (33.6%) and open biopsy (13%). For both thymoma and thymic carcinoma, the preferred choice for induction chemotherapy is CAP (cisplatin, doxorubicin and cyclophosphamide) (42.2% and 31.1% respectively) followed by cisplatin and etoposide (13.3% and 13.3% respectively). Also for first line chemotherapy, for both thymoma and thymic carcinoma, the preferred choice is CAP (35.6% and 28.9% respectively). For first line treatment the reported Overall Response Rate (ORR) is about 40% for thymoma and 31% for thymic carcinoma, the median Progression Free Survival (PFS) is 8 months for thymoma and 3 months for thymic carcinoma and the reported median Overall Survival (OS) is 28 months for thymoma and 18 months for thymic carcinoma. For both thymoma and thymic carcinoma, the preferred first choice for second line chemotherapy is carboplatin and paclitaxel (35.6% and 31.1% respectively) and the prefered second choice is cisplatin and etoposide (13.3 and 17.8% respectively). For second line treatment the reported ORR is about 36% for thymoma and 23% for thymic carcinoma, the median reported PFS is 8 months for thymoma and 4 months for thymic carcinoma; the median OS is 15 months for thymoma and 9 months for thymic carcinoma. No testing for c-kit or EGFR mutations is routinely performed.
Conclusion:
The survey provides a large, multi-institutional overview of the clinical practice in the management of thymic tumors in Europe, and provides relevant and updated background for the development of future collaborative trials. The survey is still ongoing and final results will be presented at the conference.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-090 - A Phase 2, Single Arm Study of Lucitanib in Patients with Advanced/Metastatic Lung Cancer and FGF, VEGF, or PDGF-Related Genetic Changes (ID 2878)
09:30 - 17:00 | Author(s): B. Besse
- Abstract
Background:
Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of Fibroblast Growth Factor Receptors 1-3 (FGFR1-3), Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR1-3) and Platelet-Derived Growth Factor Receptors A/B (PDGFRA/B). Clinical activity was observed in a phase 1/2 study of lucitanib monotherapy in cancer patients with tumor amplification of FGF-related genes or in tumors with predicted sensitivity to VEGF inhibitors. Genomic evidence of FGF, VEGF or PDGF axis aberrancy is seen in up to 15% of patients with lung cancer, which provides a strong rationale to assess lucitanib in this setting.
Methods:
The current study evaluates daily oral lucitanib monotherapy in 40 patients with amplification or activating mutations in FGF, VEGF or PDGF-related genes. This is an international, multicenter, open-label, single-arm study. The primary endpoint is objective response rate (ORR; RECIST 1.1) with secondary endpoints of response duration, clinical benefit rate, progression-free survival, and safety. Exploratory objectives include volumetric assessment of tumor growth kinetics, serial circulating tumor DNA measurement, and identification of additional biomarkers of lucitanib activity. Key inclusion criteria include: patients with advanced/metastatic non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) or large cell lung cancer and tumor tissue evidence of relevant genomic aberrancies. Patients must have measurable disease and at least one previous treatment for advanced disease. Key exclusion criteria include: carcinoid histology, symptomatic CNS metastases, anti-cancer treatment for lung cancer within 28 days or 5 half-lives before first dose of lucitanib. This study is enrolling patients in the United States and Europe at centers skilled in the identification of patients with relatively uncommon genetic tumor alterations.
Results:
not applicable
Conclusion:
not applicable
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-093 - Assessment of Clinical Applications of Circulating Tumor DNA in Lung Cancer Using an Enhanced TAm-Seq Platform (ID 2270)
09:30 - 17:00 | Author(s): B. Besse
- Abstract
Background:
Novel biomarkers are required to assess tumor burden and response in lung cancer as conventional biopsies are invasive, costly and only provide a snapshot of the mutational profile at a given time and location. A promising biomarker is the detection of genomic material released from tumors into the blood plasma of patients, known as circulating tumor DNA (ctDNA). ctDNA has been detected in plasma for a wide range of solid tumors and can be distinguished from other (germline) cell-free DNA by the presence of tumor-specific DNA alterations or known hotspot mutations. However, the potential of ctDNA as a biomarker in lung cancer has not yet been fully realized due to technical challenges associated with its detection and analysis, including the short fragment sizes (140-170 bp), small number of amplifiable copies and low/variable allele fractions of ctDNA. To further develop applications of ctDNA in lung cancer, we have developed a process to analyse ctDNA and utilise it in a range of clinical studies.
Methods:
We have developed an enhanced platform for tagged-amplicon deep sequencing (TAm-Seq). Using a combination of improved library preparation and bespoke data analysis methods, this platform can be used to sequence established cancer hotspots and the entire coding regions of selected genes, while preserving high levels of specificity and sensitivity.
Results:
Using this approach, we have developed an assay that analyzes ~20 kb of the genome (including regions of interest in more than 30 genes) with sensitivity down to a few mutant copies. Performance of this assay has been demonstrated using spike-in experiments, dilution series and clinical sample cohorts from lung cancer patients.
Conclusion:
Our proof of concept studies show the potential of ctDNA to be used to assess tumor mutation status, monitor tumor dynamics, assess response to treatment and identify mutations associated with acquired drug resistance and disease progression. This non-invasive approach - a “liquid biopsy” - offers a revolution in how cancer can be detected, monitored and treated. Further studies in lung cancer are being developed and will be presented.
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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 - 17:00 | Author(s): B. Besse
- 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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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-042 - Evaluation of Texture Analysis Parameters in EGFR Mutated or ALK-Positive Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 1394)
09:30 - 17:00 | Author(s): B. Besse
- Abstract
Background:
The quantitative assessment of heterogeneity in tumor images through Texture Analysis is an emerging tool that can potentially provide a non-invasive prognostic biomarker. We investigated if Texture Analysis parameters derived from contrast-enhanced CT (CTTA) were associated with EGFR/ALK status and have a prognostic value in NSCLC patients treated with tyrosine-kinase inhibitors.
Methods:
The CT images of patients with EGFR mutated or ALK rearranged advanced NSCLC treated with tyrosine-kinase inhibitors were retrospectively reviewed. CTTA using the filtration-histogram method was applied to the region of interest (ROI) in the primary tumor of the enhanced-CT by two independent operators to examine the inter-individual reproducibility. A wilcoxon test was used to correlate CTTA with EGFR / ALK status and a Cox model to evaluate the prognostic value of CTTA for overall survival. A p-value cutoff of 0.01 was used to adjust for multiple testing.
Results:
CTTA parameters were evaluated in CT scan from 68 patients recruited in 2 centers between 2008 and 2013, of them, 80.9% (n=55) were EGFR mutated and 19.1 % (n=13) ALK+ NSCLC, 48.5% received treatment with gefitinib (n=33), 33.8% with erlotinib (n=23) and 17.7% with crizotinib (n=12). The CTTA measures were highly reproducible between the 2 operators as indicated by Bland-Altman plots and correlation values. The skewness of the distribution was significantly different between EGFR mutated and ALK+ tumors for coarse texture with spatial filter value 3.3 (p= 0.002), filter value 2.8 (p=0.001) and medium texture with spatial filter value 2.2 (p=0.004). The median follow-up time was 35 months; 39 deaths occurred. The A unit increase in skewness in coarse texture (2.8 spatial filter) was significantly associated with better survival with an univariate cox analysis (HR: 0.36 [0.2-0.69] p=0.002). A multivariate analysis adjusted by prognostic factors (PS, lymphocyte count, hepatic and adrenal metastasis) indicate a similar trend for better survival (HR: 0.40 [0.2-0.8] p=0.01).
Conclusion:
CTTA parameters were reproducible between the 2 operators. The skewness was significantly different between EGFR mutated and ALK rearranged advanced NSCLC and may have a prognostic value.
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P3.04-053 - SPECTAlung: Screening Patients with Thoracic Tumors for Efficient Clinical Trial Access (ID 1386)
09:30 - 17:00 | Author(s): B. Besse
- Abstract
Background:
The identification of molecular alteration and its targeting has completely changed the treatment and prognosis of lung cancer. However, designing and implementing clinical trials in small subsets of patients with a particular molecular alteration is challenging because of lack of uniform screening program. Across Europe, screening for molecular alterations is center or country dependent and, generally limited to a small subset of genes. SPECTAlung is the first European standardized, quality-assured molecular screening program of the European Organization for the Research and Treatment of Cancer (EORTC) in collaboration with the European Thoracic Oncology Platform (ETOP) to facilitate clinical trial access for patients with thoracic tumors. It is expected to test 500 to 1000 patients each year with the overall goal of offering patients clinical trials with targeted agents.
Methods:
Patients sign the informed consent for their tumor tissue to be collected, centralized and processed according to defined international quality control standards at Gustave Roussy Biobank (Villejuif, France). Next Generation Sequencing (NGS) is performed at Sanger Institute (Cambridge, UK) where a panel of about 360 genes is analyzed for mutation, rearrangements and gene copy number. Eligible patients will be those having a pathological diagnosis of any thoracic tumor (lung cancer, malignant pleural mesothelioma and thymic malignancies) at any stage of disease, availability of tumor tissue, age at least 18 years, PS 0-2, life expectancy > 3 months, no active malignancy in the 5 years before study entry and absence of any exclusion criteria that may prevent inclusion into clinical trials. A molecular report will be released to the investigator highlighting identified molecular alterations and also the trials for which the patients might be eligible. The study has been submitted to ethical committees of 15 selected highly specialized and qualified thoracic centres in 12 countries in Europe. EORTC and ETOP will promote the implementation of clinical trials in molecularly selected groups of patients at the SPECTAlung centers. SPECTAlung offers innovative and attractive models of collaboration with commercial and research organizations, by improving patient access to novel therapeutic clinical trial and support the development of personalized medicine. Clinical trial registry number NCT02214134.
Results:
Not applicable
Conclusion:
Not applicable
