- Email: [email protected]
ED14.05 Immunotherapy of Small Cell Lung Cancer
January 2017
tumors could be potential candidates for surgery in a diagnostic or therapeutic intention g. In selected patients with IIIA N2 disease and complete histological regression of tumor tissue in the mediastinal lymph nodes after induction chemotherapy or chemoradiortherapy, surgery can improve local control and survival. Taking into account the TNM use in SCLC and the encouraging SEER results for patients submitted to surgery, a reconsideration of the role of surgery seems to be mandatory. Finally, to improve current management strategies for SCLC, surgeons should participate in the evaluation of SCLC patients together with oncologists and radiotherapists and common guidelines for indications and therapy concepts should be adopted. Interdisciplinary approaches should be employed in the context of controlled clinical trials. References: 1. Fox W, Scadding JG. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of the bronchus. Ten-year follow-up. Lancet 1973;2(7820):63-65 2. Lad T, Piantadosi S, Thomas P, et al. A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy. Chest 1994;106:320-323 3. Waddell TK, Shepherd FA. Should aggressive surgery ever be part of the management of small cell lung cancer? Thorac Surg Clin 2004;14:271-281 4. Eberhardt W, Stamatis G. Stuschke M, et al. Prognostically orientated multimodality treatment including surgery for selected patients of small-cell lung cancer patients stage Ib to IIIB: long-term results ofc a phase II trial. Br J Cancer 1999;81:1206-12 5. Shepherd FA, Crowley J, Van Houte P, Postmus PE, Carney D, Chansky K, Shaokh Z, Goldstraw P. International Association for the Study of Lung Cancer International Staging Committee and Participating Institutions. The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2007;2:1067-77 6. Valliéres E, Shepherd FA, Crowley J, Van Houte P, Postmus PE, Carney D, Chansky K, Shaokh Z, Goldstraw P. International Association for the Study of Lung Cancer International Staging Committee and Participating Institutions. The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathological staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2009;4:1049-59 7. Yu JB, Decker RH, Detterbeck FC, et al. Surveillance Epidemiology and End Results Evaluation on the Role of Surgery for Stage I Small Cell Lung Cancer.
Abstracts
S65
J Thorac Oncol 2010;5:215-9. 8. Weksler B, Nason KS, Shende M, et al. Surgical resection should be considered for stage I and II small cell carcinoma of the lung. Ann Thorac Surg 2012; 94:889e93. 9. Stamatis G. Neuroendocrine tumors of the lung: the role of surgery in small cell lung cancer Thorac Surg Clin. 2014 Aug; 24(3):313-26. Keywords: SCLC Surgery Results Prognosis
ED14.05 Immunotherapy of Small Cell Lung Cancer Nevin Murray Medical Oncology, British Columbia Cancer Agency, Vancouver/BC/Canada Immunotherapy of Small Cell Lung Cancer Nevin Murray MD, British Columbia Cancer Agency, Vancouver, Canada The general principles of cytotoxic chemotherapy for advanced SCLC and NSCLC have many similarities and have advanced minimally over the past two decades.1 The success of cancer genomics research in changing the care of patients with NSCLC with a driver mutation suitable for targeted treatment has been a powerful incentive to discover such molecular targets in SCLC. Although comparative genomic profiling shows some similarities between SCLC and NSCLC, for SCLC, the abnormalities identified to date are mainly tumor suppressor genes.2 These loss-of-function alterations do not provide the clear opportunity for rapid clinical translation offered by an activating mutation in a known receptor tyrosine kinase. A considerable number of targeted agents have already been tried in SCLC clinical trials without notable success.3 In contrast, there is a growing body of evidence for immunotherapy as a promising new treatment for both SCLC and NSCLC. Immunotherapy investigated for SCLC includes interferon, vaccines, antibody-drug conjugates and immune checkpoint inhibitors. Interferon and vaccines have been studied in phase II and III trials without sufficient activity to change practice. Although preliminary, the data emerging from trials of antibody-drug conjugates and immune checkpoint inhibitors has generated more excitement and are the focus for this abstract. Antibody-drug conjugates: The components of an antibody-drug conjugate include an antibody directed at a defined antigen on cancer cells, a linker, and a cytotoxic agent. This package represents an effective mechanism of targeted drug delivery potentially resulting in decreased toxicity and an improved therapeutic index. Rovalpituzumab teserine targets the Notch pathway with a monoclonal antibody portion directed against the cell
S66
surface available Notch ligand delta-like protein 3 (DLL3), which is over-expressed in SCLC tumor-initiating cells but not in normal tissue. Rudin et al.4 have reported a phase I study including 74 patients with previously treated SCLC. The confirmed response rate in 56 evaluable patients was 16%, but in 26 that showed high DLL3 expression, the response rate was 31%. Response rate was 13% in second-line and 25% in the third-line setting with some durable responses observed. A phase II trial for third-line treatment of patients with DLL3 expressing tumors has begun and if positive will be the first approved agent in this setting. Sacituzumab govitecan is another antibody-drug conjugate of a topoisomerase I inhibitor linked to an antibody to the Trop-2 epithelial antigen.5 In a phase I/II clinical trial enrolling 33 evaluable SCLC patients with a median of 2.5 previous chemotherapies, the response rate was 24% and the median overall survival was 8.1 months. Dose limiting neutropenia was 34% and grade 3+ diarrhea was seen in 9%. Immune checkpoint inhibitors: Since immune checkpoint blockade is more active in hyper-mutated tumors, SCLC should be a good candidate disease for this treatment because of a strong association with tobacco carcinogenesis and a high frequency of somatic mutations.2 The most advanced trial evidence is available for a cytotoxic T-cell antibody (CTLA4) and data for two programmed death (PD-1) immune checkpoint inhibitors is emerging. After a randomized phase II trial of ipilimumab and phased chemotherapy showed a modest improvement in progression-free survival as first-line treatment of advanced SCLC,6 a large phase III placebo controlled trial was performed in which 1,132 previously untreated patients were randomly assigned to receive either etoposide and platinum for four cycles alone or together with the CTLA-4 antibody ipilimumab.7 The trial was negative with similar response rates and no difference in the primary end point of overall survival (hazard ratio 0.94; 95% CI 0.81-1.09). Immune checkpoint blockade with PD-1 or dual CTLA-4 and PD-1 inhibition may be a more effective strategy. In a large phase I/II trial including 180 previously treated SCLC patients, Antonia et al.8 reported a response rate of 13% (7/80) with nivolumab 3 mg/kg and 31% (14/45) in a cohort of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg. The activity of nivolumab alone or combined with ipilimumab was seen regardless of PD-L1 expression and not related to platinum sensitivity or line of therapy. The responses were durable with one-year overall survival of 27% for nivolumab alone and 48% for the combination arm. These results have led to two phase III studies among patients with SCLC evaluating nivolumab, nivolumab/ipilimumab versus placebo in the maintenance
Journal of Thoracic Oncology
Vol. 12 No. 1S
setting after first-line therapy and nivolumab versus placebo in the second-line setting. As part of a phase IB multi-cohort study (KEYNOTE-028), pembrolizumab was evaluated among patients with relapsed SCLC with PD-L1 positive tumors.9 Of the 135 SCLC patients screened, 37 (27%) had PD-L1 positive tumors. The response rate was 29% in 24 evaluable patients. The median duration of response was 29 weeks and durable responses were observed. There is an ongoing phase II study of this agent as maintenance therapy after the completion of standard first-line therapy in extensive stage disease. A phase I trial is evaluating pembrolizumab with conconcurrent chemoradiation. Adverse events associated with checkpoint inhibitors is greater with CTLA-4 combined with the PD-1 antibody combination but were generally manageable. The proportion discontinuing therapy for toxicity was usually less than 10%. The literature contains anecdotes of autoimmune syndromes such as limbic encephalitis.8 Immune para-neoplastic syndromes are expected in a small proportion of patients with SCLC and an increase in their occurrence with immunotherapy requires close monitoring. However, this concern is currently insufficient to impede further trials with these promising agents. Conclusion: Over the past 20 years, almost all phase III trials of systemic therapy for SCLC have failed to improve outcome and advances have been restricted to improved application of radiotherapy. Like squamous carcinomas, the SCLC molecular battlefield is complex and bleak with little opportunity of even temporary respite by identification of mutually exclusive oncogenic drivers that can be treated for patient benefit. Ironically, this hyper-mutated genome and greater neo-antigen expression may enhance the probability of success with immunotherapy. One senses that the likelihood is high for approval of antibody-drug conjugates and immune checkpoint inhibitors for SCLC after the current roster of clinical trials are reported. References: 1. Murray N, Lam S. Contrasting Management of Small Cell Lung Cancer and Non-Small Cell Lung Cancer: Emerging Data for Low-Dose Computed Tomography Screening. J Thorac Oncol. 2016 Feb;11(2):139-41. 2. Pietanza MC, Ladanyi M. Bringing the genomic landscape of small-cell lung cancer into focus. Nat Genet. 2012 Oct;44(10):1074-5. 3. Murray N, Noonan K. Can we expect progress of targeted therapy of small cell lung cancer? In: Dingemans A, Reck M, Westeel V, editors. Lung cancer. Sheffield: European Respiratory Society; 2015. p. 234. 4. Rudin CM, Pietanza MC, Bauer TM, Spigel DR, Ready N, Morgensztern D, et al. Safety and efficacy of single-agent rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted
January 2017
antibody-drug conjugate (ADC) in recurrent or refractory small cell lung cancer (SCLC). ASCO Meeting Abstracts. 2016 June 21;34(18_suppl):LBA8505. 5. Starodub A, Camidge DR, Scheff RJ, Thomas SS, Guarino MJ, Masters GA, et al. Trop-2 as a therapeutic target for the antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132), in patients (pts) with previously treated metastatic small-cell lung cancer (mSCLC). ASCO Meeting Abstracts. 2016 May 31;34(15_suppl):8559. 6. Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensivedisease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013 Jan;24(1):75-83. 7. Reck M, Luft A, Szczesna A, Havel L, Kim SW, Akerley W, et al. Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol. 2016 Jul 25. 8. Antonia SJ, Lopez-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, 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 Jul;17(7):883-95. 9. Ott PA, Callahan MK, Odunsi K, Park AJ, Pan LS, Venhaus RR, et al. A phase I study to evaluate the safety and tolerability of MEDI4736, an anti- programmed cell death-ligand-1 (PD-L1) antibody, in combination with tremelimumab in patients with advanced solid tumors. ASCO Meeting Abstracts. 2015 May 18;33(15_suppl):TPS3099.
ED15.02 Chemotherapy and Targeted Therapies of Thymic Malignancies Nicolas Girard, Claire Merveilleux Du Vignaux Hospices Civils de Lyon, Lyon/France 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 tumors is a paradigm of multidisciplinary collaboration. The treatment strategy is primarily based on the resectability of the tumor. If complete resection is deemed not to be achievable upfront based on imaging studies, what is the case in
Abstracts
S67
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 standard in 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
tumors could be potential candidates for surgery in a diagnostic or therapeutic intention g. In selected patients with IIIA N2 disease and complete histological regression of tumor tissue in the mediastinal lymph nodes after induction chemotherapy or chemoradiortherapy, surgery can improve local control and survival. Taking into account the TNM use in SCLC and the encouraging SEER results for patients submitted to surgery, a reconsideration of the role of surgery seems to be mandatory. Finally, to improve current management strategies for SCLC, surgeons should participate in the evaluation of SCLC patients together with oncologists and radiotherapists and common guidelines for indications and therapy concepts should be adopted. Interdisciplinary approaches should be employed in the context of controlled clinical trials. References: 1. Fox W, Scadding JG. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of the bronchus. Ten-year follow-up. Lancet 1973;2(7820):63-65 2. Lad T, Piantadosi S, Thomas P, et al. A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy. Chest 1994;106:320-323 3. Waddell TK, Shepherd FA. Should aggressive surgery ever be part of the management of small cell lung cancer? Thorac Surg Clin 2004;14:271-281 4. Eberhardt W, Stamatis G. Stuschke M, et al. Prognostically orientated multimodality treatment including surgery for selected patients of small-cell lung cancer patients stage Ib to IIIB: long-term results ofc a phase II trial. Br J Cancer 1999;81:1206-12 5. Shepherd FA, Crowley J, Van Houte P, Postmus PE, Carney D, Chansky K, Shaokh Z, Goldstraw P. International Association for the Study of Lung Cancer International Staging Committee and Participating Institutions. The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2007;2:1067-77 6. Valliéres E, Shepherd FA, Crowley J, Van Houte P, Postmus PE, Carney D, Chansky K, Shaokh Z, Goldstraw P. International Association for the Study of Lung Cancer International Staging Committee and Participating Institutions. The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathological staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2009;4:1049-59 7. Yu JB, Decker RH, Detterbeck FC, et al. Surveillance Epidemiology and End Results Evaluation on the Role of Surgery for Stage I Small Cell Lung Cancer.
Abstracts
S65
J Thorac Oncol 2010;5:215-9. 8. Weksler B, Nason KS, Shende M, et al. Surgical resection should be considered for stage I and II small cell carcinoma of the lung. Ann Thorac Surg 2012; 94:889e93. 9. Stamatis G. Neuroendocrine tumors of the lung: the role of surgery in small cell lung cancer Thorac Surg Clin. 2014 Aug; 24(3):313-26. Keywords: SCLC Surgery Results Prognosis
ED14.05 Immunotherapy of Small Cell Lung Cancer Nevin Murray Medical Oncology, British Columbia Cancer Agency, Vancouver/BC/Canada Immunotherapy of Small Cell Lung Cancer Nevin Murray MD, British Columbia Cancer Agency, Vancouver, Canada The general principles of cytotoxic chemotherapy for advanced SCLC and NSCLC have many similarities and have advanced minimally over the past two decades.1 The success of cancer genomics research in changing the care of patients with NSCLC with a driver mutation suitable for targeted treatment has been a powerful incentive to discover such molecular targets in SCLC. Although comparative genomic profiling shows some similarities between SCLC and NSCLC, for SCLC, the abnormalities identified to date are mainly tumor suppressor genes.2 These loss-of-function alterations do not provide the clear opportunity for rapid clinical translation offered by an activating mutation in a known receptor tyrosine kinase. A considerable number of targeted agents have already been tried in SCLC clinical trials without notable success.3 In contrast, there is a growing body of evidence for immunotherapy as a promising new treatment for both SCLC and NSCLC. Immunotherapy investigated for SCLC includes interferon, vaccines, antibody-drug conjugates and immune checkpoint inhibitors. Interferon and vaccines have been studied in phase II and III trials without sufficient activity to change practice. Although preliminary, the data emerging from trials of antibody-drug conjugates and immune checkpoint inhibitors has generated more excitement and are the focus for this abstract. Antibody-drug conjugates: The components of an antibody-drug conjugate include an antibody directed at a defined antigen on cancer cells, a linker, and a cytotoxic agent. This package represents an effective mechanism of targeted drug delivery potentially resulting in decreased toxicity and an improved therapeutic index. Rovalpituzumab teserine targets the Notch pathway with a monoclonal antibody portion directed against the cell
S66
surface available Notch ligand delta-like protein 3 (DLL3), which is over-expressed in SCLC tumor-initiating cells but not in normal tissue. Rudin et al.4 have reported a phase I study including 74 patients with previously treated SCLC. The confirmed response rate in 56 evaluable patients was 16%, but in 26 that showed high DLL3 expression, the response rate was 31%. Response rate was 13% in second-line and 25% in the third-line setting with some durable responses observed. A phase II trial for third-line treatment of patients with DLL3 expressing tumors has begun and if positive will be the first approved agent in this setting. Sacituzumab govitecan is another antibody-drug conjugate of a topoisomerase I inhibitor linked to an antibody to the Trop-2 epithelial antigen.5 In a phase I/II clinical trial enrolling 33 evaluable SCLC patients with a median of 2.5 previous chemotherapies, the response rate was 24% and the median overall survival was 8.1 months. Dose limiting neutropenia was 34% and grade 3+ diarrhea was seen in 9%. Immune checkpoint inhibitors: Since immune checkpoint blockade is more active in hyper-mutated tumors, SCLC should be a good candidate disease for this treatment because of a strong association with tobacco carcinogenesis and a high frequency of somatic mutations.2 The most advanced trial evidence is available for a cytotoxic T-cell antibody (CTLA4) and data for two programmed death (PD-1) immune checkpoint inhibitors is emerging. After a randomized phase II trial of ipilimumab and phased chemotherapy showed a modest improvement in progression-free survival as first-line treatment of advanced SCLC,6 a large phase III placebo controlled trial was performed in which 1,132 previously untreated patients were randomly assigned to receive either etoposide and platinum for four cycles alone or together with the CTLA-4 antibody ipilimumab.7 The trial was negative with similar response rates and no difference in the primary end point of overall survival (hazard ratio 0.94; 95% CI 0.81-1.09). Immune checkpoint blockade with PD-1 or dual CTLA-4 and PD-1 inhibition may be a more effective strategy. In a large phase I/II trial including 180 previously treated SCLC patients, Antonia et al.8 reported a response rate of 13% (7/80) with nivolumab 3 mg/kg and 31% (14/45) in a cohort of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg. The activity of nivolumab alone or combined with ipilimumab was seen regardless of PD-L1 expression and not related to platinum sensitivity or line of therapy. The responses were durable with one-year overall survival of 27% for nivolumab alone and 48% for the combination arm. These results have led to two phase III studies among patients with SCLC evaluating nivolumab, nivolumab/ipilimumab versus placebo in the maintenance
Journal of Thoracic Oncology
Vol. 12 No. 1S
setting after first-line therapy and nivolumab versus placebo in the second-line setting. As part of a phase IB multi-cohort study (KEYNOTE-028), pembrolizumab was evaluated among patients with relapsed SCLC with PD-L1 positive tumors.9 Of the 135 SCLC patients screened, 37 (27%) had PD-L1 positive tumors. The response rate was 29% in 24 evaluable patients. The median duration of response was 29 weeks and durable responses were observed. There is an ongoing phase II study of this agent as maintenance therapy after the completion of standard first-line therapy in extensive stage disease. A phase I trial is evaluating pembrolizumab with conconcurrent chemoradiation. Adverse events associated with checkpoint inhibitors is greater with CTLA-4 combined with the PD-1 antibody combination but were generally manageable. The proportion discontinuing therapy for toxicity was usually less than 10%. The literature contains anecdotes of autoimmune syndromes such as limbic encephalitis.8 Immune para-neoplastic syndromes are expected in a small proportion of patients with SCLC and an increase in their occurrence with immunotherapy requires close monitoring. However, this concern is currently insufficient to impede further trials with these promising agents. Conclusion: Over the past 20 years, almost all phase III trials of systemic therapy for SCLC have failed to improve outcome and advances have been restricted to improved application of radiotherapy. Like squamous carcinomas, the SCLC molecular battlefield is complex and bleak with little opportunity of even temporary respite by identification of mutually exclusive oncogenic drivers that can be treated for patient benefit. Ironically, this hyper-mutated genome and greater neo-antigen expression may enhance the probability of success with immunotherapy. One senses that the likelihood is high for approval of antibody-drug conjugates and immune checkpoint inhibitors for SCLC after the current roster of clinical trials are reported. References: 1. Murray N, Lam S. Contrasting Management of Small Cell Lung Cancer and Non-Small Cell Lung Cancer: Emerging Data for Low-Dose Computed Tomography Screening. J Thorac Oncol. 2016 Feb;11(2):139-41. 2. Pietanza MC, Ladanyi M. Bringing the genomic landscape of small-cell lung cancer into focus. Nat Genet. 2012 Oct;44(10):1074-5. 3. Murray N, Noonan K. Can we expect progress of targeted therapy of small cell lung cancer? In: Dingemans A, Reck M, Westeel V, editors. Lung cancer. Sheffield: European Respiratory Society; 2015. p. 234. 4. Rudin CM, Pietanza MC, Bauer TM, Spigel DR, Ready N, Morgensztern D, et al. Safety and efficacy of single-agent rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted
January 2017
antibody-drug conjugate (ADC) in recurrent or refractory small cell lung cancer (SCLC). ASCO Meeting Abstracts. 2016 June 21;34(18_suppl):LBA8505. 5. Starodub A, Camidge DR, Scheff RJ, Thomas SS, Guarino MJ, Masters GA, et al. Trop-2 as a therapeutic target for the antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132), in patients (pts) with previously treated metastatic small-cell lung cancer (mSCLC). ASCO Meeting Abstracts. 2016 May 31;34(15_suppl):8559. 6. Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensivedisease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013 Jan;24(1):75-83. 7. Reck M, Luft A, Szczesna A, Havel L, Kim SW, Akerley W, et al. Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol. 2016 Jul 25. 8. Antonia SJ, Lopez-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, 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 Jul;17(7):883-95. 9. Ott PA, Callahan MK, Odunsi K, Park AJ, Pan LS, Venhaus RR, et al. A phase I study to evaluate the safety and tolerability of MEDI4736, an anti- programmed cell death-ligand-1 (PD-L1) antibody, in combination with tremelimumab in patients with advanced solid tumors. ASCO Meeting Abstracts. 2015 May 18;33(15_suppl):TPS3099.
ED15.02 Chemotherapy and Targeted Therapies of Thymic Malignancies Nicolas Girard, Claire Merveilleux Du Vignaux Hospices Civils de Lyon, Lyon/France 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 tumors is a paradigm of multidisciplinary collaboration. The treatment strategy is primarily based on the resectability of the tumor. If complete resection is deemed not to be achievable upfront based on imaging studies, what is the case in
Abstracts
S67
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 standard in 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