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E. Pichon
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OA10 - EGFR Mutations (ID 382)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
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OA10.06 - Characteristics and Outcomes of Patients with Lung Cancer Harboring Multiple Molecular Alterations (Biomarker IFCT Study) (ID 5425)
11:00 - 12:30 | Author(s): E. Pichon
- Abstract
- Presentation
Background:
Carcinogenesis of non-small cell lung cancer (NSCLC) can be driven by oncogenic addiction that can be targeted by specific inhibitors. It is commonly accepted that these molecular alterations are mutually exclusive. Nevertheless, limited series suggest that concomitant molecular alteration can occur in lung cancer and little is known about their sensitivity to treatment. Based on a nationwide screening program conducted during one year, we aimed to analyze the largest molecular database to date for concomitant mutations in order to determine the prevalence of multiple genomic alterations in NSCLC and their impact on both prognosis and response to treatment.
Methods:
The database of Biomarker France IFCT study collecting the molecular profile of 17 664 NSCLC has been used. The prevalence of multiple alterations and of each association was calculated. Impact on prognosis (overall survival, OS), response to targeted or conventional treatments (progression free survival, PFS and objective response rate, ORR) were established and compared with the population of patients harboring single mutations and full wild-type.
Results:
We identified 162 (0.9%) patients with double genetic alterations and 3 with triple alterations. Multiple mutations involved preferentially KRAS (67.3%), PI3K (53.3%) and EGFR (42.4%). Patients with multiple alterations were male (56.4%) with a median age of 66.7 and essentially adenocarcinoma (83.6%). More never-smokers were observed in comparison with patient with singles alterations (34.7 vs. 25.8 %, p<0.001). OS was not significantly different between single and multiple alterations whatever the type of mutations. Patients with EGFR/KRAS and EGFR/PI3K mutated tumors had worse PFS after biomarker analysis than patients with EGFR single mutation (7.1 and 7.1 months vs. 14.9 months, p=0.02 and 0.002, respectively). Concomitant mutations in patients harboring ALK rearrangement had little impact on OS (17.7 months vs. 20.3 months, p=0.57) or PFS (10.3 months vs. 12.1 months, p=0.93). Patients harboring KRAS mutations with another alteration had similar OS (13.4 vs. 11.2 months, p=0.28), PFS (6.4 months vs. 7.2 months, p=0.78) and ORR to first-line chemotherapy (41.7% vs. 37.2%) to those only harboring KRAS mutations.
Conclusion:
With almost 1% of patients harboring multiple genomic alterations, the dogma of mutually exclusive mutations should be reconsidered. Double mutations do not significantly decrease OS but alter PFS under first line treatment for EGFR mutated patients. Therapies targeting the dominant oncogene remain generally active in this setting.
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OA18 - New Insights in the Treatment of Thymic Malignancies (ID 408)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 2
- Moderators:N. Girard, S.B. Watzka
- Coordinates: 12/07/2016, 11:00 - 12:30, Schubert 2
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OA18.01 - Postoperative Radiotherapy in Thymic Epithelial Tumors: Insights from the RYTHMIC Prospective Cohort (ID 4271)
11:00 - 12:30 | Author(s): E. Pichon
- Abstract
- Presentation
Background:
Thymic Epithelial Tumors (TET) are rare intrathoracic malignancies, for which surgery represents the mainstay of the treatment strategy. Current practice for postoperative mediastinal radiotherapy is highly variable, and there is paucity of prospective, multicentre evidence. RYTHMIC is the nationwide network for TET in France, established in 2012. Whether postoperative radiotherapy (PORT) should be delivered was the most frequent question raised at the RYTHMIC multi-disciplinary tumor board (MTB) over the past 3 years, accounting for 494 (35%) of a total of 1401 questions.
Methods:
All consecutive patients for whom postoperative adjuvant radiotherapy was discussed at the RYTHMIC MTB from 2012 to 2015 were identified from the RYTHMIC prospective database.
Results:
285 patients were identified, 274 (52% men, 48% women) of whom fulfilled inclusion criteria. Average age at time of TET diagnostic was 60 years. TET histology was thymoma in 243 (89%) cases - including type A in 11% of cases, type AB in 28%, type B1 in 17%, type B2 in 29%, and type B3 in 14% -, and thymic carcinoma in 31 (11%) of cases. Complete resection was achieved in 81% of patients. Masaoka-Koga stage was stage I in 29% of cases, IIA in 21%, IIB in 21%, III in 18%, and IVA/B in 11%. Decision of the MTB was consistent with guidelines in 221 (92%) assessable cases. Clinical situations for which PORT was indicated in accordance with guidelines (84 cases) were thymoma/R1 resection (30 patients), thymoma/R0 resection/stage III (22 patients), thymoma/R0 resection/stage IIB/type B2/B3 histology (11 patients), thymic carcinoma/R1 resection (6 patients), thymic carcinoma/R0 resection (13 patients), thymoma/R0 resection/stage IIA/type B3 histology (2 patients). Inconsistencies between decision of the MTB and guidelines – 20 (8%) cases - consisted of abstention related to poor general condition (10 patients), carcinoid histology (2 patients), and discordance in staging (1 patient), and of delivery of radiotherapy related to peroperative tumor fragmentation (2 patients); for 5 patients who received PORT, a clear explanation for inconsistency with guidelines was not found, but those cases actually corresponded to those in a “grey zone” of guidelines. MTB decision for PORT was actually implemented for 99 (85%) of patients; most frequent reason for not delivering radiotherapy was prolonged delay since surgery.
Conclusion:
Our data provide with a unique insight into the decision-making process for PORT in thymic epithelial tumors, highlighting the need for a systematic discussion at an expert MTB, while stressing the value of current available guidelines.
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OA18.07 - Quality of Resection and Outcome in Stage III TETs: The French RYTHMIC Network Experience (ID 6173)
11:00 - 12:30 | Author(s): E. Pichon
- Abstract
- Presentation
Background:
Stage III TET represents a heterogeneous population and their optimal approach remains unclear; most of the available literature is composed of small series spanned over extended periods of time. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French nationwide network for TET with the objective of territorial coverage by regional expert centers and systematic discussion of patients management at national tumor board. We reviewed our experience in stage III thymic tumors in order to evaluate the value of tumor board recommendations and multidisciplinary approach.
Methods:
We conducted a retrospective analysis of patients (pts) with stage III TET discussed at the RYTHMIC tumor board from January 2012 to December 2015. Clinical, pathologic and surgical data were prospectively collected in a central database. Survival rates were based on Kaplan-Meier estimation. Cox proportional hazard models were used to evaluate prognostic factors for disease free survival (DFS) and overall survival (OS).
Results:
150 pts were included in the analysis. Median age was 64 years [18 – 91], 56% males, thymoma A-B2/ B3-thymic carcinoma in 52% and 47% respectively; 12% presented with autoimmune disorder (76% myasthenia). Local treatment was surgery in 134 pts (90%) followed by radiotherapy (RT) in 90 pts; 26 pts received preoperative chemotherapy (CT). Complete resection rate (R0) was 53%. Among 38 pts considered non-surgical candidates at diagnosis, 26 pts became resectable after induction CT with a R0 rate of 58%; 12 pts received CT-RT and/or CT as primary treatment. Recurrence rate was 38% (n=57), first sites were pleural (n=32) and lung (n=12). The 5-year OS and DFS were 88% and 32% respectively. Gender (HR: 0.2 [95%CI 0.04 - 0.97] p=0.04), histology (HR: 0.19 [95%CI 0.05 - 0.70] p=0.02) and surgery (HR: 0.4 [95%CI 0.01 - 0.20] p<0.001) as primary treatment modality were significant prognostic factors for OS in multivariate analysis. Histology (HR: 0.5 [95%CI 0.30 - 0.90] p=0.02) and adjuvant RT (HR: 0.4 [95%CI 0.20 – 1.00] p=0.05) were significantly associated with DFS. Completeness of resection was not associated with survival in our cohort.
Conclusion:
Surgery followed by radiotherapy improves outcome irrespectively of R0. Stage III TET not candidate to surgery should be reassessed for resection after induction chemotherapy.
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P2.04 - Poster Session with Presenters Present (ID 466)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.04-003 - Chemotherapy in Advanced Thymic Epithelial Tumors: Insights from the RYTHMIC Prospective Cohort (ID 4275)
14:30 - 15:45 | Author(s): E. Pichon
- Abstract
Background:
Thymic Epithelial Tumors (TET) are rare intrathoracic malignancies, which may be aggressive and difficult to treat. In the advanced setting, chemotherapy may be delivered as a primary/induction therapy before subsequent surgery or definitive radiotherapy, and/or as exclusive treatment in patients for whom no focal treatment is feasible, and/or in the setting of recurrences. As no randomized trial and a limited number of prospective studies are available, there is paucity of prospective, multicentre evidence regarding response rates and survival of patients. RYTHMIC is the nationwide network for TET in France. The RYTHMIC prospective database is hosted by the French Intergroup (IFCT), and collects data for all patients diagnosed with TET, for whom management is discussed at a national multidisciplinary tumor board (MTB) based on consensual recommendations. Primary, exclusive chemotherapy, and chemotherapy for recurrence accounted for 149 (11%), 37 (3%), and 67 (5%) questions of a total of 1401 questions raised at the MTB between 2012 and 2015.
Methods:
All consecutive patients for whom chemotherapy and/or systemic treatment was discussed at the RYTHMIC MTB from 2012 to 2015 were identified from the RYTHMIC prospective database. Main endpoints were response rates and progression-free and overall survival.
Results:
At the time of analysis, data were available for 156 patients (80 thymic carcinomas, and 76 thymomas), for whom the management led to raise 283 questions at the MTB: 67 (24%) for primary chemotherapy, 35 (11%) for exclusive chemotherapy, and 181 (64%) for recurrences. For primary and exclusive chemotherapy, the most frequently administered regimen was CAP, producing response rates of 70% and 60%, respectively. A total of 104 patients received at least one line of chemotherapy for recurrence; 53 patients received second-line treatment, and 13 and 7 patients received third- and fourth line treatment. In the setting of first recurrence, carboplatine-paclitaxel combination was the most preferred regimen, administered to 54% of patients; overall response and disease control rates to systemic treatments for recurrences were 13% and 42% in thymic carcinomas, and 19% and 43% in thymomas (p=0.38 and p=0.92, respectively). Median recurrence-free survival after primary chemotherapy was 16.6 months; median progression-free survival after exclusive chemotherapy, and first-, second-, and third-line chemotherapy for recurrence were 6.0 months, and 7.6 months, 6.2 months, and 6.0 months.
Conclusion:
Our data provide with a unique insight in the efficacy of chemotherapy for advanced thymic epithelial tumors in a real-life setting; our results help the decision-making to better define the optimal therapeutic strategies.
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P2.04-006 - Updated Incidence of Thymic Epithelial Tumors (TET) in France and Clinical Presentation at Diagnosis (ID 5952)
14:30 - 15:45 | Author(s): E. Pichon
- Abstract
Background:
TETs are rare malignancies with an overall described incidence of 0.13 per 100.000 person-years. Given this, most of our knowledge is largely derived from small single-institution series. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French network for TET with the objective of territorial coverage by 14 regional expert centers, systematic discussion of patients at national tumor board and collection of nationwide data within a centralized database. We reviewed our activity in 2015 in order to describe the epidemiology and main characteristics at diagnosis of thymic malignancies in France.
Methods:
Through RYTHMIC, we prospectively collected all patients (pts) with new diagnosis of primary TET in France in 2015. Epidemiologic, clinical, pathologic and surgical data were prospectively collected within a centralized database. Histologic subtype was centrally reviewed according to the WHO classification and stage by modified Masaoka-Koga classification.
Results:
A total of 234 cases with new diagnosis of primary thymoma (T) or thymic carcinoma (TC) have been discussed at RYTHMIC between Jan to Dec 2015. Among them, 58% were males; median age was 62 years [range 27; 86] for males and 61 years for females [range 24; 84]; 20% of the pts presented an autoimmune disorder (AI); myasthenia gravis was the most common in 76% of them. History of previous malignancies was described in 15% of the pts, being melanoma, prostate and breast cancer the most frequently observed. Any potentially relevant environmental exposure was declared for most of the pts. Histology was characterized as follows: A / AB / B1 / B2 / B3 / TC / neuroendocrine tumors and rare variants in 7% / 23% / 13% / 24% / 9% / 16% / 8% respectively. Stage I-II / III-IV tumors were observed in 63% / 37% respectively. Mediastinal pleura, mediastinal nodes and lung were the most common metastatic sites. Significant correlations were found between histologic sub-type (T vs TC) and presence of AI (p=0.01) and stage (I-II vs III-IV, p=0.004); no significant correlations were seen with gender (p=0.27).
Conclusion:
The estimated incidence of TETS in France in 2015 is 0.35 per 100.000 persons, based in our activity. The inclusion in the RYTHMIC network is mandatory but is still based on physician’s request. Although we might underestimate the incidence, it seems to be higher compared to other countries’ registries. The high occurrence of previous cancer might underlie variations in environmental or genetic risk factors.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-024 - Tedopi vs Standard Treatment as 2nd or 3rd Line in HLA-A2 Positive Advanced NSCLC Patients in a Phase 3, Randomized Trial: ATALANTE-1 (ID 5329)
14:30 - 15:45 | Author(s): E. Pichon
- Abstract
Background:
HLA-A2 is expressed in 40 to 50% of NSCLC patients. TEDOPI is a combination of neoepitopes that generates cytotoxic T lymphocytes responses. It consists of nine HLA-A2 supertype binding epitopes covering five tumor-associated antigens overexpressed in advanced NSCLC and the universal helper pan-DR epitope. In a phase II trial (NCT00104780, Barve et al. JCO 2008), TEDOPI showed a promising median overall survival of 17.3 months with a manageable safety profile in pre-treated HLA-A2 positive patients with advanced NSCLC. ATALANTE-1 (NCT02654587) is a randomized, open-label, phase 3 study comparing the efficacy and safety of TEDOPI with standard treatment in HLA-A2 positive patients with advanced NSCLC, as second- or third-line therapy.
Methods:
Section not applicable
Results:
Trial design: Patients with advanced NSCLC without EGFR-sensitizing mutations or ALK rearrangements, with progressive disease to first-line platinum-based chemotherapy or second-line immune checkpoint inhibitors (IC) are eligible if they have HLA-A2 positivity and ECOG PS 0-1. Treated and asymptomatic brain metastases are allowed. Patients are randomized 1:1 to receive 1 ml TEDOPI subcutaneously Q3W for 6 cycles, then every two months for the reminder of the year and finally every three months or standard treatment with: 75 mg/m[2] docetaxel Q3W or 500 mg/m[2] pemetrexed Q3W (in non-squamous histology and pemetrexed-naïve patients). In both arms, treatment continues until progression, intolerable toxicity, consent withdrawal, or investigator decision. In TEDOPI arm, treatment may continue beyond initial radiographic disease progression in case of clinical benefit. Randomisation is stratified by histology (squamous vs. non-squamous), initial response to first-line chemotherapy (partial or complete response vs. stabilization or progression), and previous treatment with IC (yes vs. no). Tumor assessment is performed every 6 weeks and adverse events are collected throughout the study and for 60 days and 90 days thereafter and graded per NCI CTCAE v4.0. Archival biopsies samples are required for assessing PD-L1 status (IHC22C3 pharmDx from Dako). Primary endpoint is overall survival; and secondary are progression free survival based on RECIST 1.1 criteria, objective response rate, disease control rate, duration of response, and quality of life measured by QLQ-C30 and QLQ-LC13 global scores. This is a superiority study with a hazard ratio of 0.7391, two-sided alpha 5% and power 80%, after 356 events are observed over 500 patients. The first patient was enrolled on 25th January 2016. Enrolment is ongoing in Europe and the US. Clinical trial identification: NCT02654587 Legal entity responsible for the study & Funding: OSE Immunotherapeutics, France
Conclusion:
Section not applicable
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-032 - Interstitial Pneumonitis Associated with Immune Checkpoint Inhibitors Treatment in Cancer Patients (ID 5670)
14:30 - 15:45 | Author(s): E. Pichon
- Abstract
Background:
Immunotherapy is now a standard of care in melanoma, lung cancer and is spreading across other tumours. Immune checkpoint inhibitors (ICI) are generally well tolerated but can also generate immune-related adverse effects. Since the first trials, pneumonitis has been identified as a rare but potentially life-threatening event.
Methods:
We conducted a retrospective study over a period of 5 months in centers experienced in ICI use in clinical trials, access programs or following national approval. We report the main features of possibly related pneumonitis occurring in patients treated with ICI with a particular focus on clinical presentation, radiologic patterns (with a double reviewing by radiologists and pulmonologists), pathology and therapeutic strategies.
Results:
We identified 71 patients with possibly related pneumonitis including 54 NSCLC and 13 melanoma. They mainly received PD1 inhibitors. Pneumonitis usually occurred in male, former or current smokers with a median age of 59 years. We observed grade 2/3 (n= 45, 65.2%) and grade 5 (n= 6, 8.7%) pneumonitis. The median duration time between the introduction of immunotherapy and the pneumonitis was 2.2 months [0.1-27.4]. Ground glass opacitiy on lung CT-scan were the most predominant lesion 80.9% (n=55), followed by consolidations 44.1% (n=30), reticulations 36.7% (n=25) and bronchiectasis in 20.6% (n=14). When performed, bronchoalveolar lavage (BAL) showed a T-lymphocytic alveolitis and transbronchial biopsy an inflammatory and lymphocytic infiltration. Pneumonitis treatment was steroids (86.6%) and/or antibiotics (67.6%). Immunotherapy was stopped after the pneumonitis for 65 cases (92.9%) and reintroduced for 12 (9.4%) cases. Twenty-four patients (34.3%) were dead at the last follow-up and 46 patients (65.7%) were still alive. Among the living patients, the pneumonitis outcome was a total recovery in 12 patients, improvement in 22 patients, stability in 10 patients, worsening evolution in 1 patient (1 unknown). Causality of immunotherapy was evaluated by investigators as “possible” for 34 patients (49.3%), “probable” for 17 (24.6%), “certain” for 15 (21.7%) other causes for 3 (4.3%) and 2 unknowns. Median overall survival from the onset of pneumonitis was 6 months.
Conclusion:
This serie, the largest to date, of immune-related pneumonitis demonstrates that it occurs usually during the first months and displays specific radiologic features. As there is no clearly identified risk factor, oncologists should be able to detect, diagnose (with CT-scan and bronchoscopy) and treat this adverse event. An early management is usually associated with a favourable outcome and requires a close collaboration between pulmonologists, radiologists and oncologists.
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P3.02c-040 - Checkmate 384: A Phase 3B/4 Dose-Frequency Optimization Trial of Nivolumab in Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) (ID 4780)
14:30 - 15:45 | Author(s): E. Pichon
- Abstract
Background:
Nivolumab, an anti-programmed death-1 antibody, is approved for previously treated metastatic NSCLC, advanced melanoma, advanced renal cell carcinoma (RCC), and relapsed/progressive classical Hodgkin lymphoma. In two phase 3 trials (CheckMate 017 and 057), nivolumab 3 mg/kg every 2 weeks (Q2W) demonstrated superior survival and favorable safety versus docetaxel in previously treated patients with metastatic NSCLC. Clinically meaningful efficacy and a manageable safety profile have been observed in studies in melanoma (CheckMate 037, 066, and 067), RCC (CheckMate 025), and Hodgkin lymphoma (CheckMate 205 and 039). On this basis, the currently approved nivolumab dose is 3 mg/kg Q2W. Decreasing the frequency of nivolumab administration may enhance convenience and compliance while maintaining efficacy and safety in patients who receive long-term nivolumab therapy. CheckMate 384 is a phase 3B/4 trial that will evaluate the efficacy and safety of nivolumab administered at two dosing frequencies in patients with advanced/metastatic NSCLC following ~4 months’ administration of nivolumab 3 mg/kg or 240 mg Q2W.
Methods:
Adult patients with advanced/metastatic squamous or nonsquamous NSCLC and ECOG performance status 0–2 are eligible; disease can be newly diagnosed or recurrent/progressive following multimodal therapy. Patients with untreated, symptomatic brain metastases are ineligible. Patients must have tolerated and completed ~4 months (16 ± 2 weeks) of treatment with nivolumab (3 mg/kg or 240 mg) IV Q2W and achieved a complete or partial response or stable disease. After this pre-study period, patients will be randomized 1:1 to receive IV nivolumab on one of two fixed-dose regimens: 240 mg Q2W or 480 mg Q4W. Randomization will be stratified by histology and response to pre-study nivolumab treatment at randomization (complete/partial response vs stable disease). The table shows primary/secondary endpoints; the objective is to establish that nivolumab 480 mg Q4W is not inferior to 240 mg Q2W. Planned enrollment is 620 patients.Primary Endpoints Secondary Endpoints Progression-free survival rate at 6 months after randomization Progression-free survival rate at 1 year after randomization by tumor histology and by response before randomization Progression-free survival rate at 1 year after randomization Progression-free survival rate at 2 years after randomization Overall survival rate (annually, up to 5 years after randomization) Safety and tolerability, as assessed by incidence and severity of adverse events
Results:
Not applicable
Conclusion:
Not applicable
