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Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017 Study type # pts drugs Completed Chemotherapy Completed Surgery Completed Radiotherapy Outcome (mOS) SAKK 17/04 Lancet Onc 2015;16;1651 Neo-adj 151 Cis/pem 145 125 23/27 in 2nd stage 7.6-9.4 Frederico BMC Cancer 2013;13;22 Krug JCO 2009;27;3007 Weder JCO 2004;22;3451 Van Schil ERJ 2010;36;1362 Neo-adj 54 Cis/pem 96% 83% 41% 15.5 Neo-adj 77 Cis/pem 83% 74% 52% 16.8 Neo-adj 20 Cis/gem 90% 80% n.a. 23 Neo-adjuvant 59 Cis/pem 93% 79% 65% 18.4 Richards JCO 2006;24;1561 intracavitary 61 Cispl 50- 225 n.a. 72% n.a. 9.0 Tilleman JTCS 2009;138;405 intracavitary 121 Cispl 225 n.a 79% n.a. 12.8 Keywords: surgery; mesothelioma; chemotherapy ED13: TREATMENT OF MALIGNANT PLEURAL MESOTHELIOMA WEDNESDAY, DECEMBER 7, 2016 - 11:00-12:30 ED13.05 SYSTEMIC THERAPY OF INOPERABLE MALIGNANT PLEURAL MESOTHELIOMA Arnaud Scherpereel Pulmonary and Thoracic Oncology, Hospital of the University (CHRU) of Lille, Lille/ France To date, the treatment of malignant pleural mesothelioma (MPM), a rare and aggressive tumor usually induced by previous asbestos exposure, relies mostly on chemotherapy and best supportive care (BSC). But medical treatment has been so far quite deceptive with median overall survival (mOS) about one year at its best for the last 13 years with recommended first line chemotherapy by cisplatin (or carboplatin) and pemetrexed in patients fitted for it. The optimal duration of first line chemotherapy is unknown but a maximum of 6 cycles is recommended. There was no evidence supporting maintenance treatment by pemetrexed or other drug. Pathogenesis of MPM includes overexpression of growth factors, many genetic and epigenetic alterations and/or mutations of malignant cells responsible for cell proliferation and resistance to apoptosis, pleural inflammation and local immunosuppression induced by the tumor and favoring its growth. These elements provide the rationale for many targeted therapies and immunotherapy. But so far, very few drugs exhibited sufficient value to deserve further trials. Thus, first trials assessing anti-angiogenic drugs in MPM did not support their use in this cancer despite the key role of VEGF. A phase III testing thalidomide as maintenance treatment after cisplatin/ pemetrexed (Cis/Pem) was negative, as well as phase II trial of bevacizumab (anti-VEGF antibodies) combined with first line cisplatin/gemcitabine. But other phase II trials evaluating bevacizumab with Cis or Carbo/Pem were promising with progression-free survival (PFS) of 6.9 months. Therefore, a phase III randomized (1:1) « MAPS » trial recruited 448 unresectable MPM patients to test Cis/Pem with (arm B) or without (arm A) bevacizumab. Arm B non-progressive patients received bevacizumab maintenance until progression or toxicity. Median overall survival (mOS) was significantly longer in the B arm: 18.8 [95%CI: 15.9-22.6] vs. 16.1 months [14.0-17.9] in the A arm, (adj.HR= 0.76, p=0.012). Thus, bevacizumab addition to Cis/Pem provided a significantly longer survival in MPM patients with acceptable toxicity, making this triplet a new treatment paradigm for this cancer. Moreover, there was no detrimental effect of bevacizumab on quality of life (QoL) despite its higher specific but manageable toxicity. There was no significant difference between arms for the percentages of drug delivery or of second line treatment to explain why adding bevacizumab to Cis/Pem significantly increased mOS, even if MAPS standard arm patients had a longer OS than patients from historical series or previous trials. Based on the same rationale than the MAPS trial, nintedanib, a drug targeting VEGF, FGF and PDGF receptors, is currently tested versus placebo in MPM patients treated by first line Cis/ Pem chemotherapy in a large phase II/III randomized trial. Early I or II trials assessing drugs targeting mesothelin, a mesothelial cell surface molecule overexpressed in (mostly epithelioïd) MPM, showed promising results in combination with first-line Cis/Pem, justifying further, randomised and larger studies. Thus, very interesting trials are ongoing with anti-mesothelin monoclonal antibodies (mAbs) alone (amatuximab, a chimeric IgG1 antibody), or planned with immunotoxins (mAbs combined with anti-tubulin (anetumab ravsantine) or Listeria toxins (CRS-207) versus placebo combined with Cis/ Pem too. For non-epithelioïd MPM patients, another hope might come from the dependence to arginin exhibited by argininosuccinate synthetase -1 (ASS- 1) tumors such as mesothelioma, and the good results of Pegylated Arginine Deiminase (ADI-PEG 20) alone or in combination with Cis/Pem, assessed in the phase I « TRAP » trial recently presented by Szlosarek and al. A phase II/ III trial (Polaris), comparing first line Cis/Pem with ADI-PEG 20 or placebo, will start in 2017 for biphasic (mixed) or sarcomatoïd MPM only because they exhibit ASS-1 defect twice more frequently than epithelioïd subtype. Finally, other innovative drugs also candidates for first line treatment in combination with Cis/Pem, after preliminary positive clinical trials, include gene therapy, cell therapy using chimeric antigen receptors (CARs) or dendritic cells (DC), or oncovirotherapy, and will be assessed as first line treatment in MPM very soon or later. For example, the European “DENIM” phase III trial will test DC based immunotherapy with allogenic tumor cell lysate as maintenance treatment after Cis/Pem chemotherapy in MPM patients. But, as in lung cancers, immune checkpoint inhibitors (ICI) seem to represent presently the most exciting tool for MPM patients. In fact, even if a recent, large phase II trial (n=564; “Determine”) with anti-CTLA-4 mAb (tremelimumab) versus placebo in 2 nd /3rd line treatment did not meet its first endpoint (mOS) (21), early data of a phase Ib basket trial with anti-PD-1 mAb (pembrolizumab) showed promising response rate (RR) of 28% and DCR of 76% in PD-L1 positive MPM (22). Other trials with checkpoint inhibitors are ongoing with anti-PD-1 alone (nivolumab, pembrolizumab), or a combination of anti-PD-1 (nivolumab) or anti-PD-L1 (durvalumab) and anti-CTLA-4 (tremelimumab or ipilimumab) as first or 2 nd /3rd lines treatment. Interestingly, new clinical trials are already underway to assess value of ICI, such as nivolumab + ipilimumab combo, versus Cis/Pem as first line treatment. In conclusion, the triplet cisplatin/ pemetrexed/bevacizumab may be a new first line standard of care for patients eligible for bevacizumab, and not candidate to multimodal treatment trials. Second line and further lines treatments are very limited with no validated options except pemetrexed in case of late relapse after platinum/pemetrexed. But exciting drugs and strategies were tested in this testing, in particular ICI. But remaining key questions include which predictive biomarkers for these innovative, thrilling but expensive treatments to target the best patients for each drug? And how to potentially combine these drugs versus, or in combination with, standard chemotherapy? Thus real hopes seem closer for our MPM patients with new systemic treatments. Keywords: Mesothelioma, chemotherapy, Immunotherapy, systemic treatment ED13: TREATMENT OF MALIGNANT PLEURAL MESOTHELIOMA WEDNESDAY, DECEMBER 7, 2016 - 11:00-12:30 ED13.06 MESOTHELIOMA IN A SETTING OF GERMLINE BAP1 MUTATIONS Michele Carbone 1 , Harvey Pass 2 , Haining Yang 1 1 Thoracic Oncology, University of Hawaii Cancer Center, Hawaii/HI/United States of America, 2 Department of Cardiothoracic Surgery, NYU Langone Medical Center, New York/NY/United States of America Individuals that are born with germline BAP1 mutations are affected by the BAP1 cancer syndrome. All individuals affected by this cancer syndrome have developed one or more malignancies in the course of their life. Mesothelioma, uveal and cutaneous melanomas –tumors often associated with exposure to environmental carcinogens-, are the most common malignancies, although almost any tumor type has been detected in carriers of this cancer syndrome. In addition, BAP1 mutant carriers develop multiple benign melanocytic tumors –histologically different from other SPITZ-like tumors- that we have called melanocytic BAP1 associated intradermal tumors (MBAITs) that can S30 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017 alert the physician that the patients is a carrier of the BAP1 cancer syndrome. Most malignancies develop after the 4 th decade of life, although cancers in individuals as young as 19 years old have been detected. Because many of these malignancies, for example melanomas, can be cured by early detection, it is important to identify BAP1 mutant carriers that can be screened for early detection and curative resection. Moreover, carriers of germline BAP1 mutation may be at increased risk of developing mesothelioma and melanoma following exposure to low doses of asbestos, sunlight and X-Rays, thus cancer preventive measures can be implemented. When cancer develops in a setting of BAP1 germline mutations, these patients have a much better prognosis compared to patients with the same malignancies when they occur sporadically (i.e., not in carriers of BAP1 mutations). Familial mesotheliomas in these individuals occur in either the pleura or peritoneum (frequency ratio 1:1) at a median age of 56.3 years, have a male-to-female ratio of 0.73:1, and are associated with prolonged survival of 5 to 10 or more years, compared with a median age at diagnosis of 72, a pleural-to-peritoneal ratio of 86:14, a male-to-female ratio of 4:1, and a median survival of less than 1 year in sporadic mesothelioma. About 100 families with this mutated BAP1 cancer syndrome have been described in the United States, Europe, and New Zealand. Genetic studies demonstrated that these mutations are transmitted across multiple generations over the course of several centuries, and some US families carrying BAP1 mutations descend from a Swiss family that immigrated in the US in the early 1700s. An International Consensus Meeting sponsored by the IASLC supported medical screening for at-risk people who are carriers of BAP1 germline mutations as follows: (1) annual dermatological screening for early detection of melanoma at age 18 or younger; (2) annual eye examination/ ophthalmoscopy for uveal melanoma at age 18 or younger; and (3) skin and eye examinations every 6 months after age of 30, when the frequency of cancer among carriers of germline BAP1 mutations starts to increase. It was also recommended that genetic counseling should be offered to all individuals tested for BAP1. Moreover, those with BAP1 germline mutations should be ncouraged to participate in studies to improve early detection of mesothelioma (Carbone M. et al., Journal of Thoracic Oncology 11, 1246-1262, 2016). Keywords: BAP1, mesothelioma, germline SESSION ED14: SMALL CELL LUNG CANCER WEDNESDAY, DECEMBER 7, 2016 - 14:30-15:45 ED14.01 CHEMOTHERAPY OF SMALL CELL LUNG CANCER Primo Lara Internal Medicine/Hematology-Oncology, University of California Davis Comprehensive Cancer Center, Sacramento/CA/United States of America 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. Keywords: sclc, small cell, neuroendodrine ED14: SMALL CELL LUNG CANCER WEDNESDAY, DECEMBER 7, 2016 - 14:30-15:45 ED14.02 THORACIC RADIOTHERAPY OF SCLC Berend Slotman Radiation Oncology, VU University Medical Center, Amsterdam/Netherlands 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 Copyright © 2016 by the International Association for the Study of Lung Cancer S31
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