Virtual Library
Start Your Search
Antonio Araujo
Moderator of
-
+
ES22 - Immunotherapy - Discovering New Areas (ID 25)
- Event: WCLC 2019
- Type: Educational Session
- Track: Immuno-oncology
- Presentations: 5
- Now Available
- Moderators:Manuel Cobo, Antonio Araujo
- Coordinates: 9/09/2019, 15:45 - 17:15, Vienna (2016)
-
+
ES22.01 - Immunotherapy in Resectable NSCLC (Now Available) (ID 3275)
15:45 - 17:15 | Presenting Author(s): Patrick M. Forde
- Abstract
- Presentation
Abstract
Immune checkpoint blockade with inhibitors of the PD-1/PD-L1 interaction have improved survival substantially for patients with advanced non-small cell lung cancer. Despite many clinical trials of different combination regimens, the benefit from perioperative platinum doublet chemotherapy in resectable lung cancer is modest with an approximate 5% improvement in 5 year survival over surgery alone.
This session will review the background of systemic therapy for resectable lung cancer and data reported to date with single agent PD-1 blockade, PD-(L)1-based immunotherapy combinations, and chemotherapy combined with anti-PD-1. Ongoing phase 3 clinical trials of neoadjuvant and adjuvant immunotherapy will be discussed and future directions both in novel science and clinical trials explored.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
ES22.02 - A Milestone in Locally Advanced NSCLC (Now Available) (ID 3276)
15:45 - 17:15 | Presenting Author(s): Solange Peters
- Abstract
- Presentation
Abstract
Stage III NSCLC encompasses locally advanced tumours with infiltration of locoregional nodes and central thoracic structures and accounts for about a third of newly diagnosed NSCLC[1]. It represents the most advanced stage of NSCLC in which treatment is delivered with curative intent, but eventually more than 60% of patients die from their disease.
Stage III NSCLC patients must strictly be discussed in a multidisciplinary tumor board, whereat the definition of resectability suffers from a certain heterogeneity across centers. Resectability is usually defined by the degree of invasion of lymph nodes, most often excluding multilevel or bulky N2 and N3 disease as well as invasion of the oesophagus, aorta and myocardium. Controversy exists on the role of surgery in stage III NSCLC since two large randomized trials investigated either induction chemoradiation therapy followed by resection versus radiotherapy[2], or induction chemotherapy followed by resection versus radiotherapy[3]. Both studies failed to demonstrate a difference in survival[2-5], however these treatment strategies are evidence-based and can be pursued in restectable NSCLC[6].
In the surgical scenario, randomised trials and meta-analyses have consistently shown that either adjuvant or neoadjuvant chemotherapy added to surgery results, with a better survival than surgery alone[7,8]. Adding preoperative radiotherapy to chemotherapy in patients with stage IIIA/N2 NSCLC did not improve the clinical outcome in a phase 3 randomised trial[9]. The role of adjuvant radiotherapy in stage IIIA/N2 after neoadjuvant chemotherapy followed by surgery has been evaluated in a unique randomized trial with awaited results (Lung ART, NCT00410683).
Early NSCLC stages offer a theoretical unique curative scenario for the development of immunotherapy startegies, with limited disease volumes, a relative immune system preservation as well as unique oportunities for the investigation and assessment of new biomarkers.
Perspectives, rational, hopes and ongoing attempts to combine immunotherapy in the surgical setting or alterenatively complementary to chemoradiation will be discussed, with a focus on locally advanced disease.
References
1. Detterbeck FC. The eighth edition TNM stage classification for lung cancer: What does it mean on main street? J Thorac Cardiovasc Surg 2018;155:356-9.
2. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-86.
3. van Meerbeeck JP, Kramer GW, Van Schil PE, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 2007;99:442-50.
4. O'Rourke N, Roque IFM, Farre Bernado N, Macbeth F. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2010:CD002140.
5. Auperin A, Le Pechoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010;28:2181-90.
6. Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:iv1-iv21.
7. Group NM-aC. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 2014;383:1561-71.
8. Group NM-aC, Arriagada R, Auperin A, et al. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010;375:1267-77.
9. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet 2015;386:1049-56.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
ES22.03 - New Hope in SCLC? (Now Available) (ID 3277)
15:45 - 17:15 | Presenting Author(s): Leora Horn
- Abstract
- Presentation
Abstract
Lung cancer is the leading cause of cancer-related death worldwide. Small cell lung cancer (SCLC) accounts for approximately 15-20% of cases. This aggressive tumor is characterized by rapid growth, early development of disseminated disease and dramatic responses to first line chemotherapy. For decades, first line therapy has traditionally included four to six cycles of platinum-based chemotherapy. While up to 80% of patients respond to first-line chemotherapy, the majority eventually relapse with a median survival of 8 to 12 months for patients with extensive stage disease and 12 to 20 months for those with limited stage disease. Until recently, topotecan was the only FDA approved second line therapeutic option. The shortcomings of traditional chemotherapy, as well as the limited role of targeted therapy in SCLC, led to the investigation of novel mechanisms to target lung cancer and specifically the discovery of immune checkpoint inhibitors.
Immune checkpoint inhibitors work by blocking interactions between T cells and antigen presenting cells (APCs) or tumor cells. By inhibiting this interaction, the immune system is effectively upregulated and T-cells become activated against tumor cells. There are three major classes of checkpoint inhibitors. Ipilimumab and tremelimumab inhibit T-lymphocyte antigen-4 (CTLA-4); nivolumab and pembrolizumab target the programmed cell death-1 receptor (PD-1); and atezolizumab, durvalumab, and avelumab block PD-L1, the ligand of PD-1. Prior studies have shown lack of PD-L1 expression on tumor cells in patients with pulmonary and extra pulmonary SCLC. While PD-1 and PD-L1 are expressed in the tumor stroma of small cell carcinomas.[1] In addition PD-L1 has been shown to be prognostic in patients with SCLC.[2] The aggressive nature of SCLC is underscored by its high mutational burden, including loss of the tumor suppressor genes p53 in 75%–90% and retinoblastoma in almost 100% of tumors.[3] Higher tumor mutation burden has been associated with outcome in patients with select tumors treated with checkpoint inhibitor therapy, including non-small cell lung cancer. [4]
Recently singly agent nivolumab and combination nivolumab and ipilimumab were shown to have activity in the second and third line setting for patients with advanced SCLC with response rates of approximately 10% and 20% respectively. Combination nivolumab and ipilimumab appeared particularly promising in patients with tumors with high tumor mutation burden and in 2018 nivolumab received approval in the third line setting for patients with advanced SCLC. [5] However, disappointingly Chekckmate 331, a large phase III trial of patients who had progressed on first line platinum-based chemotherapy, found nivolumab was not superior to topotecan or amrubicin in the second line setting. Recently a combined analysis of patients treated on the Keynote 158[6] and 028 trial[7] with pembrolizumab in the second line setting demonstrated a response rate of approximately 20% in patients, with a greater benefit in patients with tumors that were PD-L1 positive.
In the first line setting, a single arm phase II trial demonstrated no benefit to maintenance pembrolizumab following induction chemotherapy in patients with advanced SCLC with a progression free survival of less than 2 months. [8] Earlier this year, a phase III trial (Checkmate 451) also found maintenance nivolumab with or without ipilimumab following induction chemotherapy in patients with advanced small cell lung cancer was not superior to placebo, suggesting this is not the optimal strategy in patients with advanced stage disease.
Importantly, he Impower 133 phase III trial demonstrated combination chemotherapy with carboplatin, etoposide and atezolizumab was superior to chemotherapy alone in patients with advanced SCLC with a significant improvement in progression free and overall survival leading to FDA approval and a new standard of care for patients with advanced disease. [9] Two large phase III trials Keynote 604 and Poseidon are comparing a similar strategy with pembrolizumab and durvalumab respectively, with data anticipated in the upcoming year.
While progress has finally been made. Limited tissue specimens in patients with SCLC remain a challenge and many unanswered questions remain including the optimal patient population in which these agents will have benefit (PD-L1 positive or negative, tumor mutation high or low), the optimal duration of therapy, the appropriate combinations (can we improve upon chemotherapy with a different checkpoint inhibitor), and the safety of these agents long term, particularly in patients with comorbid disease.
References:
1. Schultheis, A.M., et al., PD-L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer, 2015. 51(3): p. 421-6.
2. Ishii, H., et al., Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer. J Thorac Oncol, 2015. 10(3): p. 426-30.
3. Byers, L.A. and C.M. Rudin, Small cell lung cancer: where do we go from here? Cancer, 2015. 121(5): p. 664-72.
4. Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science, 2015. 348(6230): p. 124-8.
5. Antonia, S.J., et al., Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol, 2016. 17(7): p. 883-895.
6. Chung, H.C., et al., Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol, 2019. 37(17): p. 1470-1478.
7. Ott, P.A., et al., Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study. J Clin Oncol, 2017. 35(34): p. 3823-3829.
8. Gadgeel, S.M., et al., Phase II Study of Maintenance Pembrolizumab in Patients with Extensive-Stage Small Cell Lung Cancer (SCLC). J Thorac Oncol, 2018. 13(9): p. 1393-1399.
9. Horn, L., et al., First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med, 2018. 379(23): p. 2220-2229.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
ES22.04 - Any Chance in Mesothelioma (Now Available) (ID 3278)
15:45 - 17:15 | Presenting Author(s): Giorgio Vittorio Scagliotti
- Abstract
- Presentation
Abstract
Section not applicable
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
ES22.05 - Role in Thymic Epithelial Tumours (Now Available) (ID 3279)
15:45 - 17:15 | Presenting Author(s): Rina Hui
- Abstract
- Presentation
Abstract
Although thymic epithelial tumours (TETs) are rare, they are the commonest primary tumours of the anterior mediastinum. TETs are heterogenous with histological classification into thymoma and thymic carcinoma. Subtypes of thymomas include A, AB, B1, B2 and B3 depending on the presence of spindle cells, the relative proportion of lymphocytes and abnormal epithelial cells. The commonest histological subtype of thymic carcinoma is squamous cell, others include sarcomatoid, adenocarcinoma, basaloid etc. The traditional Masaoka-Koga staging system is widely used to stage TETs (I: no breaching of capsule; II: invasion through capsule to involve surrounding fatty tissue; III: invasion into nearby organs; IV: pleural/pericardial spread or distant metastases), while TNM staging (T1a: with or without invasion into mediastinal fat; T1b: mediastinal pleura; T2: pericardium; T3/T4: nearby organs; N1: peri-thymic anterior mediastinal nodes; N2: deep thoracic or cervical nodes; M1a: separate pleural or pericardial nodules; M1b: distant metastases) has been introduced more recently. The prognosis of TETs depends on both histology and disease extent. Thymomas are usually more indolent with 10- year overall survival rate of >80% for stage I and II, but thymic carcinoma confers poorer prognosis with 5-year survival of around 50% for stage III and 25% for stage IVa.
The treatment of choice for early stage disease is surgical resection with curative intent. Concurrent chemoradiation can be considered for unresectable locally advanced TETs. 10-15% of resected TETs recur and radical radiation may be appropriate for local recurrence. In unresectable stage III and IV disease with spread to pleural and pericardial cavities or beyond, standard first-line systemic treatment is platinum-based chemotherapy, usually with cisplatin, doxorubicin and cyclophosphamide. Although TETs are reported to be chemo-sensitive with a response rate (ORR) of 50% for thymomas and around 20% for thymic carcinoma, they ultimately will progress and research into second-line treatments besides chemotherapy is important. Targeted therapies including sunitinib and everolimus with disease control rate (DCR) of >80% in previously treated TETs have been reported.
Cancer treatment landscape has been rapidly evolving in recent years due to the successful development of PD1 blockade in many cancer types including melanoma, non-small cell lung cancer, bladder cancer, renal cell cancer, head and neck cancer, etc. The function of thymus during childhood in the production, differentiation and maturation of immunocompetent T cells together with the observation of high level of PD-L1 expression in normal thymus and TETs suggest a possible role of immunotherapy in TETs. Of 40 eligible patients with chemotherapy refractory thymic carcinoma in a phase 2 study, pembrolizumab provided an ORR of 22.5%, DCR of 75%, median progression-free survival (PFS) of 4.2 months, and median overall survival (OS) of 24.9 months with 1-year OS rate of 71%. Exploratory analysis in this study suggested an association of high-level PD-L1 with longer PFS and OS. A similar phase 2 study of pembrolizumab after at least 1 line of chemotherapy in Korea included 7 patients with thymoma and 26 patients with thymic carcinoma achieving an ORR of 27% with DCR of 100% in thymoma and ORR of 19% with DCR of 73% in thymic carcinoma. A phase 1 study with avelumab showed confirmed ORR of 29% with DCR of 86% in 7 thymoma patients and stable disease in the 1 thymic carcinoma patient.
As thymus is involved in positive and negative T cell selection process for self-major histocompatibility complex molecules, thereby inducing self-tolerance avoiding auto-immunity, one third of thymoma is associated with autoimmune diseases, the commonest being myasthenia gravis. Other associated autoimmune conditions include systemic lupus erythematosus, pure red cell aplasia, syndrome of inappropriate anti-diuretic hormone secretion, bullous dermatoses autoimmune blistering diseases, polymyositis, dermatomyositis, pernicious anaemia, haemolytic anaemia, scleroderma, Sjogren’s syndrome, rheumatoid arthritis, ulcerative colitis, Takayasu syndrome, Grave’s disease etc. However, autoimmune disorders are much less likely to occur in thymic carcinoma. It is not surprising that a significant incidence of immune-related adverse events (irAE) is evident with immune-checkpoint inhibitors in the treatment of TETs with higher frequency of irAE in thymoma than in thymic carcinoma. 71% of patients with thymoma and 15% of patients with thymic carcinoma treated with pembrolizumab in the Korean study experienced grade 3-4 irAE including 12% hepatitis, 9% myocarditis, 6% myasthenia gravis, 3% thyroiditis, colitis, nephritis and myoclonus. The other phase 2 pembrolizumab study in patients with thymic carcinoma also reported similar incidence of 15% severe irAE with 5% myocarditis. IrAE was observed in 63% of patients in the phase 1 avelumab study with 38% myositis and 13% enteritis. PD-L1 status did not predict irAE.
In conclusion, the main issue of PD1 blockade in TETs is common irAEs with higher frequency in thymomas. Therefore, immunotherapy is still not standard of care, needing further research to identify possible biomarkers to spare patients with less likelihood to benefit taking the risk of serious irAEs. There may be a role of immunotherapy in advanced TETs with aggressive pathology after failing chemotherapy, but thorough discussion with patients about the potential irAEs is warranted.
References:
Girard N, Ruffini E, Marx A, et al. Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26:v40-v55.
Miyamoto K and Acoba J. Thymomas and thymic carcinomas: a review on pathology, presentation, staging, treatment, and novel systemic therapies. EMJ Respir. 2017;5:100-107.
Detterbeck F, Stratton K, Giroux D, et al. The IASLC/ITMIG thymic epithelial tumors staging project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM classification of malignant tumors. J Thorac Oncol. 2014;9:S65-S72.
Shelly S, Agmon-Levin N, Altman A, et al. Thymoma and autoimmunity. Cell Mol Immunol. 2011;8:199-202.
Giaccone G, Kim C, Thompson J, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol. 2018;19;347-355.
Cho J, Kim K, Ku B, et al. Pembrolizumab for patients with refractory or relapsed thymic epithelial tumor: an open-label phase II trial. J Clin Oncol. 2018;36:1-8.
Rajan A, Heery C, Mammen A, et al. Safety and clinical activity of avelumab in patients with advanced TETs. J Thorac Oncol. 2017;12:1S:OA18.03.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
