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ES22 - Immunotherapy - Discovering New Areas (ID 25)
- Event: WCLC 2019
- Type: Educational Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
ES22.05 - Role in Thymic Epithelial Tumours (Now Available) (ID 3279)
15:45 - 17:15 | Presenting Author(s): Rina Hui
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.
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.
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OA04 - Immuno Combinations and the Role of TMB (ID 126)
- Event: WCLC 2019
- Type: Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
OA04.06 - Evaluation of TMB in KEYNOTE-189: Pembrolizumab Plus Chemotherapy vs Placebo Plus Chemotherapy for Nonsquamous NSCLC (Now Available) (ID 1936)
15:15 - 16:45 | Author(s): Rina Hui
First-line pembrolizumab plus chemotherapy with pemetrexed and platinum significantly improved OS (HR 0.49, P < .001), PFS (HR 0.52, P < .001) and ORR (47.6% vs 18.9%, P < .001) vs placebo plus chemotherapy with pemetrexed and platinum for metastatic nonsquamous NSCLC in the double-blind phase 3 KEYNOTE-189 study (NCT02578680); benefit was observed in all analyzed subgroups, including PD-L1 TPS <1%, 1-49%, and ≥50%. We explored the association of TMB with efficacy in KEYNOTE-189.Method
616 patients were randomized 2:1 to pembrolizumab plus chemotherapy or placebo plus chemotherapy. TMB was determined by whole-exome sequencing of tumor and matched normal DNA. Association of TMB (continuous log10 transformed) with outcomes in each arm was assessed using Cox proportional hazards models (OS, PFS) and logistic regression (ORR); statistical significance was determined at the 0.05 level without multiplicity adjustment. The clinical utility of TMB on outcomes was assessed using prespecified TMB cutpoints of 175 and 150 Mut/exome (~13 and ~10 Mut/Mb by FoundationOne CDx). Data cutoff was 21 Sep 2018.Result
293 (48.3%) treated patients had evaluable TMB data: 207 for pembrolizumab plus chemotherapy, 86 for placebo plus chemotherapy. Baseline characteristics and outcomes were generally similar in the TMB-evaluable and total populations. TMB as a continuous variable was not significantly associated with OS, PFS, or ORR for pembrolizumab plus chemotherapy (one-sided P = .174, .075 and .072, respectively) or placebo plus chemotherapy (two-sided P = .856, .055 and .434, respectively). Pembrolizumab plus chemotherapy improved OS, PFS, and ORR for TMB ≥175 and <175 (Table). Results were similar for TMB ≥150 and <150.Conclusion
TMB was not significantly associated with efficacy of pembrolizumab plus chemotherapy or placebo plus chemotherapy as first-line therapy for metastatic nonsquamous NSCLC. Pembrolizumab plus chemotherapy had a similar OS benefit in the TMB-high and low subgroups.
TMB ≥175 TMB <175
Pembrolizumab plus Chemotherapyn = 100
Placebo plus Chemotherapyn = 34
Pembrolizumab plus Chemotherapyn = 107
Placebo plus Chemotherapyn = 52
Median OS (95% CI), mo 23.5
HR (95% CI) 0.64 (0.38-1.07) 0.64 (0.42-0.97) Median PFS (95% CI), mo 9.2
HR (95% CI) 0.32 (0.21-0.51) 0.51 (0.35-0.74) ORR, % (95% CI) 50.0