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S. Zöchbauer-Müller
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ED14 - Small Cell Lung Cancer (ID 283)
- Event: WCLC 2016
- Type: Education Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 5
- Moderators:J.B. Sørensen, S. Zöchbauer-Müller
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall C2
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ED14.01 - Chemotherapy of Small Cell Lung Cancer (ID 6501)
14:30 - 15:45 | Author(s): P. Lara
- Abstract
- Presentation
Abstract:
Small cell lung cancer, which accounts for 10-15% of all lung cancers, is a biologically and clinically virulent malignancy that has a propensity to disseminate systemically and therefore is often initially diagnosed at an advanced incurable stage. Although typically associated with heavy tobacco use, there have been recent clinical observations of histologic evolution from adenocarcinoma to a SCLC phenotype, particularly in tumors harboring activating mutations in the epidermal growth factor receptor (EGFR) gene that had been treated with EGFR inhibitors. Due to its high proliferative rate, SCLC is known to be highly responsive – at least initially - to cytotoxic chemotherapy. Tumor response rates of 50-70% following platinum-based chemotherapy are usually expected. Intracranial metastases, a common feature of ES-SCLC, have been also shown to respond at a similar rate to cytotoxic therapy as that of metastases to other visceral organs. The standard frontline chemotherapy for ES-SCLC, unchanged for the past three decades, has been platinum (either cisplatin or carboplatin) plus etoposide. No other regimen has convincingly been demonstrated to be superior to platinum-etoposide in the frontline setting. Neither dose intensification approaches nor the incorporation of other cytotoxic agents into the platinum backbone have yielded any palpable or tangible survival benefits. In recent years, only prophylactic cranial irradiation and (in highly selected patients) consolidative thoracic irradiation have been shown to marginally improve survival outcomes. Furthermore, despite the high initial response rates to chemotherapy, drug resistance and subsequent tumor progression are universal events. Following failure of frontline platinum-based therapy, therapeutic options are limited and generally are of very modest clinical benefit. Current investigations into optimizing cytotoxic therapy include the development of novel cytotoxics (e.g., alisertib), sequential/combination strategies that involve novel “targeted” therapies and immunotherapeutics such as checkpoint inhibitors, or conjugating a cytotoxic payload onto a monoclonal antibody directed against an antigen expressed on SCLC, among others. A critical appraisal of the current status and future directions of cytotoxic therapy in ES-SCLC will be presented.
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ED14.02 - Thoracic Radiotherapy of SCLC (ID 6502)
14:30 - 15:45 | Author(s): B. Slotman
- Abstract
- Presentation
Abstract:
Limited stage Small cell lung cancer (SCLC) comprises 10-15% of all lung tumors and is associated with an aggressive clinical behavior. Two out of three patients presents with hematogenous metastases at diagnosis (extensive stage (ES)). For patients without hematogenous metastases (limited stage (LS)), chemoradiotherapy is the standard treatment. Although radiotherapy after chemotherapy has the theoretical benefit of treating smaller target volumes with less toxicity, concurrent chemoradiotherapy has shown to be superior. Moreover, earlier use of radiotherapy during chemotherapy leads to better results. The absolute benefit of early versus late radiotherapy was about 10% for patients who had received cisplatinum-based chemotherapy [1]. Turrisi et al. [2] demonstrated that twice daily radiotherapy starting with a first course of chemotherapy resulted in improved survival rates. Median survival was 23 months for patients who received twice-daily radiotherapy (45Gy/30fractions/3weeks) versus 19 months for once daily treated patients (45Gy/25fractions/5weeks). The corresponding 5 years survival rates were 26% and 16%. However, more Grade 3-4 oesophagitis was seen during twice-daily treatment (32% versus 16%). Only a minority of patients in the US and Europe receive twice daily radiotherapy. Recently the results of the CONVERT trial, in which once-daily radiotherapy (70Gy) was compared with twice daily radiotherapy (45 Gy) were presented [3]. Radiotherapy was initiated at the 2nd course of 4-6 cycles of cisplatin/etoposide. There was no statistically significant difference in overall survival between the two arms. Overall survival at 2 years was 56% for patients treated twice-daily versus 51% for patients treated once-daily (p= 0.15) [3]. There was also no significant difference in time to progression. There were no differences in a acute toxicity, except for Grade 3-4 neutropenia, which occurred more often in the twice-daily treatment arm (74% versus 65%). There were no differences in Grade 3-5 oesophagitis (19%) and pneumonitis (2%). The authors concluded that survival in both study arms was higher than reported previously and that radiation related toxicities were lower than expected, probably related to the use of modern radiotherapy techniques. The results of the study support the use of either twice daily or once daily as standard of care for patients with limited stage disease and in good performance score. In RTOG0538 study, which also compares 70 Gy once-daily and 45 Gy twice-daily radiotherapy, radiotherapy commences with the first or second course of chemotherapy. The results of this study are eagerly awaited [4]. Extensive stage In the EORTC study on prophylactic cranial irradiation (PCI) for ES-SCLC, it was noted that the vast majority of patients still had intrathoracic disease after completion of chemotherapy. After on the positive effects of PCI which not only reduced the risk of symptomatic brain metastases (40 versus 15%) but also improved overall survival (1 year: 27 versus 13% (P= 0,003)) [5], the next logical step was to investigate the use of thoracic radiotherapy in ES-SCLC as well. Evidence for a possible role of thoracic radiotherapy (TRT) in ES-SCLC also comes from the results of a trial published by Jeremic et al. in 1999 [6] in which patients with ES-SCLC and good prognosis with a complete response outside the thorax were randomized between TRT plus PCI during chemotherapy versus chemotherapy and PCI only. Overall survival was 17 months for the patients who received thoracic radiotherapy versus 11 months for those who did not. In the CREST trial, patients with ES-SCLC and any response after 4-6 cycles of platinum based chemotherapy were randomized between PCI plus TRT (30Gy/10 fractions) or PCI only. Overall survival at one year, the primary endpoint of the study, was not statistically significant between the groups (p=0.066) but with longer follow up the survival curves diverged and at 2 years, survival was 13% in patients who received TRT versus 3% in the controls (p=0,004). There was also significant difference in progression free survival. In an additional analysis of patients with and without residual intrathoracic disease, which was one of the stratification factors of the study, it was demonstrated that there was no significant benefit of TRT in patients with a CR in the thorax. However, in patients with residual intrathoracic disease after chemotherapy, TRT led to a significant improvement in overall survival [7]. In patients who received thoracic radiotherapy the risk of intrathoracic recurrence was reduced from 80% to 44%. In patients who received thoracic radiotherapy the most recurrences occurred outside the brain and the thorax and at a later stage. The next logical step after demonstration of a beneficial effect of PCI and TRT would be the use of higher doses for TRT and possibly also treatment of extrathoracic metastatic sites. This topic was addressed in the NRG-RTOG0937 study and was presented at ASTRO 2015 [8]. patients with ES-SCLC and a CR or PR after chemotherapy and 1-4 metastatic lesions were randomized between PCI or PCI plus TRT plus radiotherapy of metastatic sites. The study which accrued very slowly was closed early due to observed toxicities. The study did not show a survival difference between the two groups, but included only 86 patients over a five years period and had imbalance groups with worse prognostic factors in the experimental arm. There were many, partly unrelated, Grade 4-5 toxicities in the experimental arm. To define which patients are most likely to benefit from a more aggressive approach we have performed an additional analysis for patients from the top accruing centers from the CREST trial. An evaluation of 260 patients showed significantly better outcome in patients with 0 to 2 metastases versus and without liver metastases [10]. These patients are believed to be best candidates for future studies. References 1. Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 2004. 22, 4837-45. 2. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999 340, 265-71. 3. Faivre-Finn C, Snee M, Ashcroft L. CONVERT: An international randomised trial of concurrent chemo-radiotherapy (cCTRT) comparing twice-daily (BD) and once-daily (OD) radiotherapy schedules in patients with limited stage small cell lung cancer (LS-SCLC) and good performance status (PS). ASCO Meeting abstracts J Clin Oncol 2016, 8504. 4. Slotman BJ, Senan S; Radiotherapy in small-cell lung cancer: Lessons learned and future directions. Int J Radiat Oncol Biol Phys 2011, 79, 998-1003. 5. Slotman BJ, Faivre-Finn C, Kramer G. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007, 357, 664-72. 6. Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined- modality treatment of patients with extensive disease small-cell lung cancer; A randomized study. J Clin Oncol 1999,17, 2092-9. 7. Slotman BJ, van Tinteren H, Praag JO, et al., Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 2015, 385, 239-44. 8. Slotman BJ, van Tinteren H. Which patients with extensive stage small-cell lung cancer should and should not receive thoracic radiotherapy? Transl Lung Cancer Res. 2015, 4, 292-4. 9. Gore EM, Hu C, Sun A, et al. NRG Oncology/RTOG 0937: Randomized phase II study comparing prophylactic cranial irradiation (PCI) alone to PCI and consolidative extra-cranial irradiation for extensive disease small cell lung cancer (ED-SCLC). Proc ASTRO, Int J Radiat Oncol Biol Phys 2016, 94, 5.
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ED14.03 - Update on Prophylactic Cranial Irradiation in SCLC (ID 6503)
14:30 - 15:45 | Author(s): T. Seto
- Abstract
- Presentation
Abstract:
Background: A previous study has shown that prophylactic cranial irradiation (PCI) reduced the risk of brain metastases (BM) and prolonged the overall survival (OS) of patients (pts) with extended disease small cell lung cancer (ED-SCLC). However Japanese trial to reconfirm these results was stopped at first interim analysis (n=163 pts) because of futurity. According to this study protocol, final follow up was done. Materials and methods: From March 2009 pts with ED-SCLC who had any response to first-line chemotherapy (platinum agent plus irinotecan or etoposide) were randomized to either PCI (25Gy/10 fractions) or observation (Obs) alone. The patients were required to prove the absence of BM by MRI prior to enrollment. The primary endpoint was OS and a planned sample size of 330 was determined to detect the hazard ratio (HR) of 0.75 at a significance level of 0.05 and a power of 80%. Secondary endpoints included time to BM (evaluated every 3 months by imaging), progression-free survival (PFS), and adverse effects (AEs) and mini mental status examination (MMSE). Results: In Apr 2014, follow up analysis was conducted for the survival data of 224 all enrolled pts. One hundred fourth-five deaths were observed. The median OS was 11.6 and 14.1 months for PCI (n=112) and Obs (n=111), respectively (HR=1.28, 95%CI= 0.95-1.72; stratified log-rank test, P=0.107). PCI significantly reduced the risk of BM as compared to Obs (33.6% vs 59.7% at 12 months; Gray’s test, P<0.001), whereas PFS was comparable between the two arms (median, 2.3 vs. 2.4 months; HR=0.98, 95%CI=0.75-1.28). No significant difference in AEs greater than Grade 2 was observed between the two arms. At the MMSE there was no statistical difference between two arms, however in pts age 70 and older pts in PCI tended to be worse over time. Conclusion: PCI after response to chemotherapy could not show the OS impact in pts with ED-SCLC even in this follow up data.
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ED14.04 - Is There a Role for Surgery in SCLC? (ID 6504)
14:30 - 15:45 | Author(s): G. Stamatis
- Abstract
- Presentation
Abstract:
The role of surgical treatment in the management of patients with small-cell lung cancer (SCLC) remains controversial. Although in the past, two randomized studies have failed to show any survival benefit by adding surgery to chemotherapy, different retrospective and prospective reports including the recently published studies using the database of Cancer Institute Surveillance Epidemiology and End Results (SEER), showed, that surgery offers a reasonable overall survival in a subset of patients with SCLC stage I and II disease. Two important recommendations have been introduced regarding the histology of SCLC as a high grade aggressive neuroendocrine tumor and the use of TNM classification in staging of SCLC and in clinical trials. Patient’s selection is important including extensive radiologic staging and biopsy of the mediastinal nodes. The use of PET scanning is likely to improve the accuracy of staging. Surgery can be performed with a curative intent in patients with SCLC and stage I or II disease or significant nodal response after chemotherapy. Weksler has used the SEER database and analyzed the outcomes of 3566 patients with SCLC stage I and II from 1988 to 2007. The surgical treatment was performed in 895 patients (25.1%); the median survival was 34 months in the surgical group versus 16 months in the nonsurgical group. In a similar report by Yu and colleagues, 21 the 5-year overall survival was 21.1%, but it was 50.3% for those patients who received a resection (45.7% after pneumonectomy and 33.7% after sublobar one). This analysis confirmed the acceptable survival rates in a subset of patients with stage I SCLC. By primary surgery or after induction chemotherapy complete tumor resection and systematic mediastinal lymphadenectomy should be undertaken. Adjuvant chemotherapy is recommended also for stage I patients; prophylactic cranial irradiation prolongs survival in those patients who achieve a complete or partial response to initial treatment. Until now, the standard systemic treatment of patients with LD-SCLC remains the combination of platinum and etoposide. The following groups of patients could potentially benefit from surgical resection: a. Patients with small lesion unexpectedly identified as SCLC at the time of thoracotomy. Complete resection and systematic lymph node dissection should be undertaken. Chemotherapy is recommended postoperatively and PCI should be considered. b. For stage I and II disease after chemotherapy and tumor response, surgery can improve local control and increase cure rates and long term survival. Complete resection and mediastinal lymph node resection should be performed. If possible, rather than pneumonectomy sleeve lobectomy should be preferred. c. In patients with mixed histology initial treatment should be chemotherapy to control the small cell component and after that surgery to control the non-small cell part of the tumor. d. For patients with initial failure to chemotherapy or patients with localized late relapse after treatment for pure small cell tumors salvage operations may be considered on individual basis. e. In patients with second primary small cell or non-small cell lung cancer who achieved cure from primary SCLC, surgery should be considered in the course of an multidisciplinary approach f. Patients with synchronous ispilateral or bilateral small and non small cell 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. 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 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 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 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 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 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 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. J Thorac Oncol 2010; 5:215–9. 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; 94:889–93. 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.
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ED14.05 - Immunotherapy of Small Cell Lung Cancer (ID 6505)
14:30 - 15:45 | Author(s): N. Murray
- Abstract
- Presentation
Abstract:
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 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 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 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 extensive-disease-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.
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MTE09 - Biomarkers for Targeted Therapies and Immune Checkpoint Inhibitors in Advanced NSCLC (Ticketed Session) (ID 303)
- Event: WCLC 2016
- Type: Meet the Expert Session (Ticketed Session)
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 07:30 - 08:30, Stolz 1
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MTE09.02 - Biomarkers for Targeted Therapies and Immune Checkpoint Inhibitors in Advanced NSCLC (ID 6555)
07:30 - 08:30 | Author(s): S. Zöchbauer-Müller
- Abstract
- Presentation
Abstract:
Targeted therapies or immune checkpoint inhibitors may be the adequate treatment in some patients with advanced non-small cell lung cancer (NSCLC). So far, certain biomarkers are known which may predict tumor response to these drugs. Of major importance is the detection of activating epidermal growth factor receptor (EGFR) mutations. They occur more frequently in the asian compared to the caucasian population and are usually found within exon 18-20 of the EGFR gene. Most of them are either a deletion at exon 19 or the L858R point mutation at exon 21. Activating EGFR mutations are predominantly detected in female patients with adenocarcinoma histology and never (or low) smoking history. The efficacy of first (erlotinib, gefitinib) and second (afatinib) generation EGFR tyrosine kinase inhibitors (TKI) in patients with advanced NSCLC and an activating EGFR mutation was demonstrated in several clinical studies. However, at some time during treatment with a first- or second generation TKI usually resistance to these drugs occurs which is mediated by the EGFR T790M mutation in about 50%. Recent trials demonstrated that third generation EGFR TKIs like osimertinib and olmutinib may be effective in T790M mutation positive patients with an overall objective tumor response rate of about 60%. Another molecular aberration which is of importance for treatment decision in patients with advanced NSCLC is the rearrangement of the anaplastic lymphoma kinase (ALK) gene. It was demonstrated that patients with an ALK rearrangment do benefit from therapy with the ALK inhibitor crizotinib. Second generation ALK inbibitors (e.g. alectinib, brigatinib, ceritinib) can overcome resistance which may be mediated by secondary ALK mutations. Moreover, third generation ALK inhibitors (e.g. lorlatinib) were developed and are currently being tested. Similar to patients with an ALK rearrangement also patients with a ROS1 rearrangement may benefit from treatment with crizotinib. The relevance of other molecular characteristics like KRAS or BRAF mutations, c-met amplification and HER2 abnormalities as potential biomarkers for targeted therapies is currently under investigation. Programmed death 1 (PD-1) immune checkpoint inhibitor antibodies like nivolumab or pembrolizumab are used in the clinical routine, however, only about 20% of patients do benefit from this treatment. To use resources as effective as possible, a biomarker to predict tumor response to these type of drugs would be enormous helpful in order to save costs. So far, the impact of expression of the PD ligand 1 (PD-L1) regarding clinical benefit to PD1 and PD-L1 inhibitor therapy was, besides efficacy of these drugs in comparison to chemotherapy, investigated in several randomized clinical trials. While in the CheckMate 017 study the overall survival of squamous cell carcinoma patients treated with nivolumab was independent from PD-L1 expression on tumor cells, in the CheckMate 057 study there seems to be some association between the PD-L1 expression level and the overall survival of adenocarcinoma patients treated with nivolumab. In the KEYNOTE-010 trial especially patients (both squamous cell and adenocarcinoma histology) with high (≥ 50% score) PD-L1 expression on tumor cells did benefit from treatment with pembrolizumab. PD-L1 expression on tumor cells as well as on tumor infiltrating immune cells were investigated in patients treated with the PD-L1 inhibitor atezolizumab in the POPLAR study. The overall survival benefit from atezolizumab increased with increasing PD-L1 expression on tumor cells, tumor infiltrating immune cells or both. Overall, currently the impact of PD-L1 expression and the use of certain cut-off levels to predict response to PD-1 and PD-L1 inhibitors is still under discussion. Different findings may, at least partly, be explainded by the use of variables regarding tissue fixation and storage as well as by different antibodies for detection of PD-L1. Alternative biomarker approaches are currently being investigated. In particular, the mutational load as well as the number of predicted neoantigens may be of importance. An association between a higher nonsynonymous mutation burden in tumors and an improved objective reponse, durable clinical benefit as well as progression-free survival in patients treated with pembrolizumab was reported and, in addition, the efficacy was associated with the molecular smoking signature, higher neoantigen burden and DNA repair pathway mutations. Overall, additional studies are necessary to definitely define the impact of PD-L1 expression as biomarker for PD-1 and PD-L1 inhibitors as well as to investigate the value of alternative biomarkers. In conclusion, strong biomarkers are able to predict response to certain therapies. Thus, ineffective treatment strategies may be prevented and resources including costs may be saved. So far, a few biomarkers are known which are very well established in the clinical routine and are important for treatment decisions in NSCLC patients. Regarding immunotherapy, it seems that the expression of PD-L1 may has some impact to predict response to PD-1 and PD-L1 inhibitors, however, its role needs to be completely clarified. Several candidate biomarkers exist, however, their impact needs to be futher investigated.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-101 - EGFR T790M Resistance Mutation in NSCLC: Real-Life Data of Austrian Patients Treated with Osimertinib (ID 4225)
14:30 - 15:45 | Author(s): S. Zöchbauer-Müller
- Abstract
Background:
Somatic mutations in the epidermal growth factor receptor (EGFR) are detected in approximately 13% of the Austrian non-small cell lung cancer (NSCLC) patients. The EGFR T790M resistance mutation located on Exon 20 is the most common mechanism of drug resistance to EGFR tyrosine kinase inhibitors (TKI) in these patients. The mutation can be detected by re-biopsy as well liquid biopsy. Osimertinib (AZD9291), a 3[rd] generation EGFR-TKI, showed a highly clinical activity in these patients. We report about our experience with Osimertinib in EGFR-mutated NSCLC patients, who became resistant to first or second generation TKI`s due to EGFR T790M mutation.
Methods:
From April 2015 to June 2016 we administered osimertinib 80 mg daily to 82 patients who had disease progression after previous treatment with an EFGR TKI. The T790M mutation status was assessed by re-biopsy and/or liquid biopsy. For liquid biopsies, blood samples were collected in EDTA-containing vacutainer tubes and processed within 2 hours after collection. Cell-free plasma DNA was extracted by using the QIAamp circulating nucleic acid kit (Qiagen) according to the manufacturer’s instructions. Mutation status was assessed with QX-100™ Droplet Digital™ PCR System (Bio-Rad).
Results:
The T790M mutation status was assessed in 48 patients by liquid biopsy only and in 13 patients by re-biopsy of the tumor. In 21 patients the T790M mutation was detected by both methods. 70 (85%) patients showed a clear clinical and radiographic response. Out of these, 70 patients, 14 (17%) patients reached a complete remission, 56 (68%) patients showed partial response and in 5 (6%) patients, a stable disease after treatment with osimertinib was observed. Five patients had symptomatic brain metastasis initaly without any further option of local treatment, and showed a clear a clear clinical benefit and a partial remission radiographically. Osimertinib was well tolerated. No clinically relevant significant side effects were reported.
Conclusion:
Osimertinib was highly active in our patients, while showing good safety profile. Therefore, re-biopsy or liquid biopsy should be performed in clinical routine to detect the T790M mutation. With the above described method, liquid biopsy could replace re-biopsy in clinical practice in the future.
