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N. Girard

Moderator of

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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: 8
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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): C. Basse, S. Thureau, S. Bota, E. Dansin, P.A. Thomas, E. Pichon, H. Léna, C. Massabeau, C. Clément-Duchêne, G. Massard, V. Westeel, F. Thillays, X. Quantin, Y. Oulkhouir, S. Danhier, D. Lerouge, L. Thiberville, B. Besse, N. Girard

      • Abstract
      • Presentation
      • Slides

      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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      OA18.02 - Evaluation of a Modified Dosing Regimen (2-Weeks on/1-Week off) of Sunitinib as Part of a Phase II Trial in Thymic Carcinoma (ID 6289)

      11:00 - 12:30  |  Author(s): A. Rajan, C. Kim, U. Guha, E. Szabo, A. Berman, L. Sciuto, A..J. Spittler, J.B. Trepel, S.M. Steinberg, P. Harris, R. Hassan, P.J. Loehrer, Sr.

      • Abstract
      • Presentation
      • Slides

      Background:
      Sunitinib is active in patients with recurrent thymic carcinoma (TC). We have previously reported an objective response rate of 26% and disease control rate (partial response and stable disease) of 91% in patients with TC when sunitinib is administered at a dose of 50 mg once daily for 4 weeks followed by 2 weeks off (4/2 dosing schedule). Grade 3 or 4 treatment-related adverse events (TEAEs) occurring in more than 10% of patients included fatigue, oral mucositis and lymphocytopenia (20% each), and hypertension (13%). Grade 3 decrease in left ventricular ejection fraction (LVEF) was observed in 8% of patients. Alternative dosing schedules have been evaluated in solid tumors to improve tolerability. As part of an ongoing phase II study (NCT01621568), we evaluated the clinical activity and tolerability of sunitinib in patients with TC using a 2-weeks-on/1-week-off (2/1) dosing regimen.

      Methods:
      Patients with progressive TC after at least one prior platinum-containing chemotherapy regimen, measurable disease, and adequate end organ function were enrolled and received sunitinib at a dose of 50 mg orally once daily using a 2/1 schedule until disease progression or development of intolerable adverse events. The primary objective was evaluation of response rate. Tumor assessments were performed every 6 weeks using RECIST version 1.1 and toxicity was assessed every 3 weeks using CTCAE version 4.0. Exploratory correlative studies including evaluation of immune cell subsets will be reported separately.

      Results:
      Between July 8, 2014 and January 14, 2016, 15 patients were enrolled. Median age was 62 years (range, 41-76), and 33% were male. A median of 4 (range, 1 – 33+) cycles of sunitinib was administered. Among 13 evaluable patients, there was 1 (8%) partial response, 11 (85%) stable disease and 1 (8%) progressive disease. After a median follow-up of 16 months, the median progression-free survival was 5 months and median overall survival was 16 months. Grade 3 or 4 TEAEs occurring in more than 10% of patients included lymphocytopenia (40%), neutropenia and leucopenia (20% each), thrombocytopenia and oral mucositis (13% each). Grade 3 decrease in LVEF was observed in 1 (7%) patient.

      Conclusion:
      Sunitinib, administered using a 2/1 dosing schedule, has clinical activity in patients with TC, and the frequency of clinically significant TEAEs (fatigue, mucositis, hypertension) is acceptable. Studies are ongoing to identify novel immunological biomarkers of activity.

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      OA18.03 - Safety and Clinical Activity of Avelumab (MSB0010718C; Anti-PD-L1) in Patients with Advanced Thymic Epithelial Tumors (TETs) (ID 6141)

      11:00 - 12:30  |  Author(s): A. Rajan, C.R. Heery, A.L. Mammen, S. Pittaluga, L.M. Lepone, R.N. Donahue, I. Grenga, J. Schlom, J.L. Gulley, R. Hassan

      • Abstract
      • Slides

      Background:
      Avelumab (MSB0010718C) is a fully human, IgG1 anti-PD-L1 antibody under clinical development. We report safety and clinical activity in patients with relapsed TETs enrolled in a phase I trial (NCT01772004).

      Methods:
      Patients previously treated with one or more standard therapies, no prior immune checkpoint inhibitors, and with no history of autoimmune disease were eligible. Treatment consisted of avelumab at doses of 10-20 mg/kg iv q2 weeks until disease progression or toxicity. Responses were assessed q6 weeks by RECIST 1.1. Correlative studies included evaluation of tumor cell PD-L1 expression and peripheral blood immune subset analysis.

      Results:
      7 patients with thymoma and 1 with thymic carcinoma (TC) were treated with avelumab; 3 patients with thymoma (2 B3, 1 B2/B3) received avelumab 20 mg/kg; 4 patients with thymoma (1 B1, 3 B2) and 1 TC received 10 mg/kg. Two (29%) patients with thymoma had a confirmed partial response (PR;1 at 20 mg/kg, and 1 at 10 mg/kg), 2 (29%) had unconfirmed PRs, 2 (29%) stable disease (SD) and 1 (14%) progressive disease; the TC patient had SD. Most adverse events (AEs) were mild (grade 1 or 2). Grade 3 and 4 AEs were observed in 3 (38%) patients each, and included potential immune-related AEs (irAEs) in 5 cases. irAEs resolved completely with oral steroids in 3 patients, and incompletely in 1 patient. One patient required cyclosporine A for treatment of irAEs. All 4 responders experienced irAEs (myositis in 3 patients, all after 1 dose of avelumab, and enteritis in 1 patient). Pre- and post-treatment tumor biopsies were available for analysis of PD-L1 expression and intratumoral immune infiltrates from three patients treated at 20 mg/kg. In one case the post-treatment biopsy showed necrotic tissue with no viable tumor. In the other two cases diffuse, membranous PD-L1 staining of epithelial cells was seen in both pre- and post-treatment biopsies. The immune infiltrate consisted of immature T cells in pre-treatment tumor samples in both cases. The post-treatment biopsy showed continued presence of immature T cells in one case and a mature CD8+ T cell phenotype in the other case. Decreased CTLA4+ regulatory T cells and decreased ratio of granulocytic vs. monocytic myeloid-derived suppressor cells was seen post-treatment at the 20mg/kg dose.

      Conclusion:
      Avelumab is active in patients with recurrent thymoma. Strategies need to be developed to reduce the risk of development of irAEs in response to immune checkpoint inhibitor therapy in patients with thymoma.

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

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      OA18.04 - Discussant for OA18.01, OA18.02, OA18.03 (ID 7044)

      11:00 - 12:30  |  Author(s): A. Rimner

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA18.05 - FDG-PET in Thymic Epithelial Tumors: An Evaluation of Only Resected Tumors (ID 5635)

      11:00 - 12:30  |  Author(s): K. Nakagawa, S. Takahashi, Y. Ohde, H. Kurihara, T. Terauchi

      • Abstract
      • Presentation
      • Slides

      Background:
      [18]F-Fluorodeoxy glucose positron emission tomography (FDG- PET) is thought to be useful for predicting the histologic grade in thymic epithelial tumors (TETs). Although there have been many reports on the use of FDG-PET for evaluating TETs, no previous studies have included only resected cases. Therefore, we investigated the relationship between the degree of FDG-uptake in the tumor and either the WHO histologic subtype or the tumor stage in patients with resected TETs.

      Methods:
      We retrospectively reviewed FDG-PET findings in 112 patients with TETs (92 with thymomas and 20 with thymic carcinomas) resected at 2 institutes in Japan. The Spearman rank correlation coefficient was used to assess the association between the maximum standardized uptake value (SUV max) in the tumor and both the histologic subtype and tumor stage. The cut-off value of SUV max for differentiating thymoma from thymic carcinoma was calculated using a receiver operating characteristic (ROC) curve analysis.

      Results:
      The Table shows the relationship between SUV max in the tumor and the WHO histologic subtype. SUV max according to each tumor stage was 3.9 ± 1.7 (mean ± SD) in stage I (n = 89), 4.7 ± 1.7 in stage II (n = 3), 7.4 ± 5.3 in stage III (n =11), and 7.6 ± 3.9 in stage IV (n = 9). SUV max was strongly related to both the WHO histologic subtype and tumor stage (Spearman rank correlation coefficient = 0.485 and 0.432; p = 0.000 and 0.000, respectively). The optimal cut-off value of SUV max for differentiating thymoma from thymic carcinoma was 4.6, with a sensitivity of 80% and a specificity of 70%.

      SUV max
      ~Histologic subtype~ No. of patients ~Mean ± SD~ Range
      A 12 ~3.5 ± 1.3~ ~1.3 – 6.3~
      AB 45 ~3.5 ± 1.3~ [1.2 – 6.9]
      B1 19 ~4.1 ± 0.9~ [2.5 – 6.5]
      B2 10 [4.2 ± 1.0] [2.7 – 5.9]
      B3 6 [4.8 ± 2.6] [2.4 – 8.6]
      Thymic carcinoma 20 [8.0 ± 4.7] [3.0 – 21.8]
      Total 112 [4.5 ± 2.8] [1.2 – 21.8]


      Conclusion:
      Our results suggest that FDG-PET is useful for differentiating thymoma from thymic carcinoma. Further studies will be needed to assess other potential clinical applications of FDG-PET for the evaluation of TETs.

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      OA18.06 - Treatment, Outcome and Prognostic Factors of Patients with Thymic Epithelial Tumors at First Recurrence (ID 5594)

      11:00 - 12:30  |  Author(s): G.L. Banna, A. Sheel, V. Sheel, A. Bille, T. Routledge, S. Fernando, A. Nair, R. Lal

      • Abstract
      • Presentation
      • Slides

      Background:
      The treatment of patients with recurrent thymic tumors remains uncertain due to limited data because of the rare nature of this disease. This retrospective analysis was conducted to investigate clinical characteristics, outcomes and possible prognostic factors of patients presenting with a first recurrence of thymic tumors.

      Methods:
      107 patients with thymic neoplasms registered as C37 by ICD10 coding at Guy’s Hospital during the 2007-2016 period with first recurrence following primary treatment were selected and retrospectively reviewed via descriptive analysis. Differences in survival were assessed using Kaplan-Meier analysis and uni & multivariate Cox proportional hazards regression analyses.

      Results:
      25 patients (14 male & 11 female) with a median age of 51 years (range 36-80 years) experienced a first recurrence of thymoma (20 patients – 80%) or thymic carcinoma (5 patients – 20%) with a median time from diagnosis of 36 months (range, 7-270). At diagnosis, modified Masaoka disease stage was IIA/IIB/IIIA/IIIB/IVA/IVB in 4/0/8/2/6/5 patients; 18 patients’ (72%) primary resection was R0/R1/R2 in 11/3/4 patients; 9 patients (36%) received radiotherapy; 19 received chemotherapy (76%); CAP (n=10) and platinum-etoposide (n=6) regimens. At first relapse, 19 patients (76%) had thoracic recurrence and 6 patients (24%) extrathoracic recurrence. Nine patients (26%) underwent redo surgery, 3 of which recieved chemotherapy prior to resection. Overall resection status was 2/5/1 (1 patient’s data is not yet assessable) R0/R1/R2. Chemotherapy was administered in 17 patients (68%) with a median cycle of 4 (range, 1-6): 16 patients received combination chemotherapy consisting of platinum etoposide (n=10) or cisplatin-anthracycline based (CAP/CAV/AC n=5). Dose reduction and withdrawal were reported in 3 (18%) and 7 (41%) patients, respectively. In 4 out of these 7 patients withdrawal was due to PD; disease control rate (=CR+PR+SD) was 67% (in 10 out of 15 assessable patients). Three patients (12%) received radiotherapy of which one was treated exclusively with radiotherapy. Time to progression since the first recurrence was 12 months (range 2-52 months); in 16 patients extrathoracic recurrence was seen in 4 patients (25%) and thoracic in 12 patients (75%). Eight recurring patients (50%) received further chemotherapy. With a median follow-up of 32.5 months, 19 patients (75%) are alive and 2 (8%) disease-free; median OS has not been reached, median PFS was 29.5 months (range, 26.3-33.2). Analysis of possible prognostic factors will be presented.

      Conclusion:
      Patients with first recurrence of thymic tumors may benefit from combination chemotherapy and surgery when feasible.

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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): M.V. Bluthgen, E. Dansin, D. Ou, H. Léna, J. Mazieres, E. Pichon, F. Thillays, G. Massard, X. Quantin, Y. Oulkhouir, T. Nguyen, L. Thiberville, C. Clément-Duchêne, C. Lindsay, P. Missy, T. Molina, N. Girard, B. Besse, P.A. Thomas

      • Abstract
      • Presentation
      • Slides

      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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      OA18.08 - Discussant for OA18.05, OA18.06, OA18.07 (ID 7103)

      11:00 - 12:30  |  Author(s): E. Ruffini

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    ED15 - Thymic Malignancies: Update on Treatment (ID 285)

    • Event: WCLC 2016
    • Type: Education Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      ED15.02 - Chemotherapy and Targeted Therapies of Thymic Malignancies (ID 6507)

      14:30 - 15:50  |  Author(s): N. Girard

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Thymic malignancies represent a heterogeneous group of rare thoracic cancers. The histopathological classification distinguishes thymomas from thymic carcinomas. Thymomas are further subdivided into different types (so-called A, AB, B1, B2, and B3) based upon the atypia of tumor cells, the relative proportion of the associated non-tumoral lymphocytic component, and resemblance to the normal thymic architecture. Thymic carcinomas are similar to their extra-thymic counterpart, the most frequent subtype being squamous cell carcinoma. The management of thymic epithelial tumours is a paradigm of multidisciplinary collaboration. The treatment strategy is primarily based on the resectability of the tumour. If complete resection is deemed not to be achievable upfront based on imaging studies, what is the case in Masaoka-Koga stage III/IVA tumors (classified as stage IIIA/IIIB/IVA in the 2015 IASLC-ITMIG TNM proposed system), after a biopsy is performed, primary/induction chemotherapy is administered, part of curative-intent sequential strategy integrating subsequent surgery or radiotherapy. Cases not eligible for local treatment receive definitive chemotherapy. Primary/induction chemotherapy is then standardin non-resectable advanced thymic epithelial tumors. Cisplatin-based combination regimens should be administered; combinations of cisplatin, adriamycin, and cyclophosphamide, and cisplatin and etoposide are the most usually used. Primary chemoradiotherapy with platin and etoposide is an option, especially for thymic carcinomas. Usually 2-4 cycles are administered before imaging is performed to reassess resectability of the tumor. Surgery should be offered to patients for whom complete resection is thought to be ultimately achievable; extended resection may be required. Hyperthermic intrapleural chemotherapy, as well as extra-pleural pneumonectomy may be discussed in case of stage IVA tumor. Postoperative radiotherapy is usually delivered. When the patient is not deemed to be a surgical candidate - either because R0 resection is not thought to be achievable, or because of poor performance status or co-existent medical condition, definitive radiotherapy is recommended part of a sequential chemoradiotherapy strategy. Combination with chemotherapy (including cisplatin, etoposide chemotherapy and a total dose of radiation of 60 Gy) may be considered as well. Chemotherapy should be offered as the single modality treatment in advanced, non-resectable, non-irradiable or metastatic (stage IVB) thymic epithelial tumor to improve tumor-related symptoms the aim is to improve tumor-related symptoms through obtention of tumor response, while prolonged survival is uncertain. Cisplatin-based combination regimen should be administered. No randomized studies have been conducted, and it is unclear which regimens are best; multi-agent combination regimens and anthracycline-based regimens appear to have improved response rates compared to others, especially the etoposide, ifosfamide and cisplatin combination. Combinations of cisplatin, adriamycin, and cyclophosphamide is preferred. Combination of carboplatin and paclitaxel is an option for thymic carcinoma. Surgery or radiotherapy is possible in rare and selected cases with unknown survival benefit. Recurrences of thymic epithelial tumors should be managed according to the same strategy as newly diagnosed tumors. Complete resection of recurrent lesions represents a major predictor of favorable outcome, and surgery is then recommended in case of resectable lesion. In non-resectable recurrences, several consecutive lines of chemotherapy may be administered when the patient presents with tumor progression. The re-administration of a previously effective regimen has to be considered, especially in case of previous response, late occurring recurrence, and for anthracyclins, a patient in a good medical condition and not having received cumulative doses precluding the safe delivery of at least 3 additional cycles. Preferred regimens for second-line treatment include carboplatin plus paclitaxel, and platin plus etoposide; capecitabine plus gemcitabine is an option. These regimens were evaluated in dedicated phase II trials. Options for subsequent lines include pemetrexed, oral etoposide. In patients with octreoscan-positive thymoma, not eligible to receive additional chemotherapy, octreotide alone or with prednisone may represent a valuable option. The use of targeted agents may be done in an off-label setting in advanced thymic malignancies. While KIT is overexpressed in 80% of thymic carcinomas, KIT gene mutations are found only in 9% of cases, consisting of mutations observed in other malignancies (V560del, L576P) or mutations unique to thymic carcinomas (H697Y, D820E). Responses and possibly prolonged survival was reported with the use KIT inhibitors - imatinib, sunitinib, or sorafenib - , mostly in single-case observations. Non-pretreated reported KIT mutants are not uniformly sensitive to imatinib, based on the clinical and/or the preclinical evidence in thymic carcinoma and/or other KIT-mutant malignancies. KIT sequencing (exons 9-17) is an option for refractory thymic carcinomas in the setting of possible access to off-label use of such inhibitors. KIT inhibitors also potently inhibiting other kinases, including Vascular Endothelial Growth Factor Receptors and Platelet-Derived Growth Factor Receptors activated in thymic malignancies. A phase II trial recently demonstrated the efficacy of sunitinib in terms of response and disease control rate in thymic epithelial tumors, including thymic carcinomas (ORR 26%; DCR: 91%) and, to a lesser extent, thymomas (ORR:6%; DCR:81%). Sunitinib may then represent an option as second-line treatment for thymic carcinomas, independantly from KIT status. There is no clinical data reporting on antitumor efficacy of other antiangiogenic drugs. mTOR is emerging as a potential target in thymic epithelial tumors, following tumor responses observed in phase I trials. Everolimus (10 mg daily) was evaluated in thymic epithelial tumors in a recently reported phase II trial reporting on a 22% response rate, as well as a 93% disease control rate. Everolimus may then represent an option for refractory tumors. Several trials assessing the efficacy of PD-1 checkpoint inhibitors are currently ongoing. A phase II study of pembrolizumab, a fully humanized IgG4 Ab that targets the PD-1 receptor, was recently reported; the study has accrued 30 patients. Four serious autoimmune disorders developed. Out of 30 patients evaluable for response so far the response rate is 24%. The off-label use of checkpoint inhibitors is currently not recommended. Overall, a dramatic improvement in our knowledge of the management of thymic tumors has occurred in the last few years. This improvement has primarily resulted from an increased interest in these rare tumors at some dedicated centers, and from the development of international efforts that succeed in putting together large-volume, top-quality centers all over the world, for databases, translational research, and clinical trials.

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    ISS02 - Industry Supported Symposium: ALK and ROS1 in NSCLC: Optimising the Continuum of Care - Pfizer Oncology (ID 436)

    • Event: WCLC 2016
    • Type: Industry Supported Symposium
    • Track:
    • Presentations: 3
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      ISS02.03 - ALK+ NSCLC: How Can We Maximise Clinical Outcome Today? (ID 7033)

      13:45 - 15:15  |  Author(s): N. Girard

      • Abstract

      Abstract not provided

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      ISS02.05 - Panel Discussion (ID 7032)

      13:45 - 15:15  |  Author(s): N. Girard

      • Abstract

      Abstract not provided

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      ISS02.07 - Panel Discussion (ID 7035)

      13:45 - 15:15  |  Author(s): N. Girard

      • Abstract

      Abstract not provided

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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
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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): N. Girard

      • Abstract
      • Presentation
      • Slides

      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): N. Girard

      • Abstract
      • Presentation
      • Slides

      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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    P1.06 - Poster Session with Presenters Present (ID 458)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P1.06-005 - An International Cohort of Patients with Small Cell Lung Cancer after a Non-Small Cell Lung Carcinoma Oncogene or Non-Oncogene Addicted (ID 4531)

      14:30 - 15:45  |  Author(s): N. Girard

      • Abstract
      • Slides

      Background:
      Phenotypic transformation from Non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a resistance mechanism in tyrosine kinase inhibitors (TKIs) treated EGFR mutant tumors. SCLC is also however less frequently diagnosed in patients without EGFR mutations treated with chemotherapy. These transformations are rare and little is known about the clinical and therapeutic characteristics of these patients. In this study we describe and compare the characteristics of SCLC arising from mutant or non mutant NSCLC.

      Methods:
      We performed a multicentric retrospective collection (27 centers in France and Italy) of cases. Between 2005 and 2015, patients with stage III or IV NSCLC with a secondary transformation to SCLC with histological proof were included.

      Results:
      Forty seven cases of SCLC transformation were collected, 34 in EGFR mutant and 13 in non. Most of the patients (n=37, 82%) were stage IV, (n=27, 57%) female and (n=26, 76%) had an exon 19 mutation. The last treatment before transformation was a TKI in 23 (68%) cases in the mutant group and in 3 (23%) patients (erlotinib) in the non-mutant. Median time to SCLC transformation was 17 [IQR, 11-29] months in the mutant group and 26 [IQR 23-36] months in the other (p=0.03). Molecular analyses were not performed in the non mutant group, 25 (74%) had molecular analyses in the EGFR mutant. A driver mutation was identified in 22/25 (88%) patients: in most of the cases the same as the initial, 1 case of ALK fusion and 1 of PI3K mutation. Thirty patients (88%) received at least one line of treatment after transformation in the mutant group, in all cases a platinum-etoposide (P-E) chemotherapy. Median survival from initial diagnosis in the EGFR mutant group was significantly worse 28 [17-41] months vs 49 [36-118] months in the non EGFR mutant group (p=0.01). After transformation, the same tendency was observed with a median survival of 8 [3-12] months for the EGFR mutated patients vs 13 [6-15] months for the non EGFR mutated patients (p=0.06).

      Conclusion:
      SCLC that occurs in EGFR mutant treated by TKIs is more aggressive than classic SCLC, and differs on epidemiological characteristics. These transformed SCLC are not fully explained and we need to define the molecular characteristics of this cohort, before and after transformation and if funded the whole genome sequencing of the tumors to understand this TKIs mechanism of resistant.

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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: 3
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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): N. Girard

      • Abstract
      • Slides

      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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      P2.04-005 - WHO Classification and IASLC/ITMIG Staging Proposal in Thymic Tumors: Real-Life Assessment (ID 4273)

      14:30 - 15:45  |  Author(s): N. Girard

      • Abstract
      • Slides

      Background:
      Thymic epithelial tumors (TETs) are rare intrathoracic malignancies which are categorized histologically according to the World Health Organization (WHO) classification, recently updated in 2015 based on a consensus statement of ITMIG (Marx et al. J Thorac Oncol 2014;9:596), and for which the standard Masaoka-Koga staging system is intended to be replaced by a TNM staging system based on an IASLC/ITMIG proposal (Detterbeck et al. J Thorac Oncol 2014;9:S65). Our objectives were 1/ to analyze the feasibility of assessing ITMIG consensus major and minor morphological and immunohistochemical (IHC) criteria in a routine practice setting, and their diagnostic performance for TETs histologic subtyping, and 2/ to assess the feasibility and the relevance of the proposed IASLC/ITMIG TNM staging system with regards to the Masaoka-Koga staging system.

      Methods:
      This is a monocenter study conducted at the Lyon University Hospital, one of the largest centers for TETs in France. Overall, 188 consecutive TETs diagnosed in 181 patients since 2000 at our center were analyzed. Systematic pathological review of cases was conducted.

      Results:
      There were 168 (89%) thymomas, including 9 (5%) type A, 67 (36%) type AB, 19 (10%) type B1, 46 (24%) type B2, and 27 (14%) type B3, and 20 (11%) thymic carcinomas (TC). After exclusion of necrotic and non-suitable specimens, 178 tumors were reviewed for ITMIG consensus major and minor criteria. Major criteria were identified in 100% of type A, AB, B1 and B2 thymomas. With regard to minor criteria, rosettes, glandular formations, subcapsular cysts, and pericytomatous vascular pattern were typical for type A thymomas, and were not identified in other subtypes. Perivascular spaces were more frequent in type B thymomas (48% of cases) than AB thymomas (7% of cases). For type B3 thymomas, pink appearance at low magnification, lobular growth, lack of intercellular bridges and lack of expression of CD117 were presents in all cases. Masaoka-Koga staging was assessable for 156 patients: there were 42 (27%) stage I, 55 (35%) stage IIa, 28 (18%) stage IIb, 22 (14%) stage III, 4 (3%) stage IVa, and 5 (3%) stage IVb tumors. After restaging according to the IASLC/ITMIG TNM classification, there were 127 (81%) stage I, 3 (2%) stage II, 17 (11%) stage IIIa, no stage IIIb, 5 (3%) stage IVa, and 4 (2%) stage IVb.

      Conclusion:
      Our results indicate the feasibility of the ITMIG consensus statement on the WHO histological classification, and highlights the switch in staging when applying the IASLC/ITMIG TNM classification proposal.

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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): N. Girard

      • Abstract
      • Slides

      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
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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): N. Girard

      • 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: 1
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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): N. Girard

      • Abstract
      • Slides

      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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