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T. Mok
Moderator of
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ISS04 - Industry Supported Symposium: Treatment Selection Strategies in Advanced NSCLC - A Symphony of Views - Eli Lilly and Company (ID 438)
- Event: WCLC 2016
- Type: Industry Supported Symposium
- Track:
- Presentations: 6
- Moderators:G.V. Scagliotti, T. Mok
- Coordinates: 12/04/2016, 17:15 - 18:45, Hall C1
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ISS04.01 - Welcome & Introduction (ID 6853)
17:15 - 17:20 | Author(s): G.V. Scagliotti, T. Mok
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Abstract not provided
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ISS04.02 - Orchestral Manoeuvres of the Immuno Checkpoints: Targeted or Untargeted Agents? (ID 6854)
17:20 - 17:45 | Author(s): J.G. Aerts
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Abstract not provided
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ISS04.03 - Variation on a Theme: Angiogenesis Inhibition Across Treatment Lines (ID 6855)
17:45 - 18:05 | Author(s): M. Pérol
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Abstract not provided
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ISS04.04 - Keys to Biomarker Driven Choices in 2nd Line (ID 6856)
18:05 - 18:25 | Author(s): L. Paz-Arez
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Abstract not provided
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ISS04.05 - Is the Score Yet Written? (ID 6857)
18:25 - 18:30 | Author(s): G.V. Scagliotti
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Abstract not provided
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ISS04.06 - Discussion: The Unfinished Symphony (ID 6858)
18:30 - 18:45 | Author(s): T. Mok
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Abstract not provided
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PL05 - Closing Plenary Session: A Life in Thoracic Oncology - Reflections from Giants on Milestones in the Treatment Advances in Lung Cancer (ID 433)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 9
- Moderators:P.A. Bunn, Jr., T. Mok
- Coordinates: 12/07/2016, 16:00 - 18:00, Hall C1
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PL05.01 - Pathology (ID 6914)
16:10 - 16:25 | Author(s): A.F. Gazdar
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A life in Thoracic Oncology – Reflections from a pathologist. While many regard a pathologist as a physician involved in laboratory diagnosis, by definition Pathology is the science or the study of the origin, nature and course of diseases. This broader definition of pathology, which basically encompasses all of the study of medicine, is what first attracted me to the field. After my residency I joined the NCI as a research pathologist studying viral oncology in rodents. However a few years later John Minna gave me the opportunity to return to the study of human cancer when he was appointed the head of the NCI-VA Medical Oncology Branch in Washington, DC, with a focus on lung cancer therapy. Our branch was fortunate to have an outstanding lung pathologist, Mary Matthews who taught me most of what I know about lung pathology. Mary also had a profound effect on the understanding and treatment of lung cancer. In 1973 she established that small cell lung cancer (SCLC) was almost always metastatic at the time of diagnosis, and that surgery was unlikely to be curative.[1]These observations, plus the finding that SCLC showed initial responses to the therapy then currently available, helped establish the fundamental distinction of lung cancers into SCLC and NSCLC categories. The Mary Matthew award for Pathology and Translational Research is one of the distinguished awards of the IASLC and I was fortunate and honored to be the fourth recipient in 2003. John Minna assembled an outstanding group of physicians/scientist many of whom became pioneers in the field of lung cancer. Of interest, all three past and present Chief Executive Officers of the IASLC, Heine Hansen, Paul Bunn and Fred Hirsch, spent time at the NCI-VA Medical Oncology Branch. John preached that new approaches for the therapy of lung cancer were needed, that this would require understanding biology, and to understand biology we needed preclinical models. My job was to establish such models and help “translate” them into clinical care. By the early 1980s we had established and characterized large banks of SCLC cell lines and demonstrated that they expressed the entire neuroendocrine (NE) cell program.[2] The cell lines were widely distributed to the scientific community, and in the absence of reliable tumor tissue sources, became the major source of biologic and molecular knowledge of SCLC. Within that decade our group, largely from the use of cell lines, described chromosome 3p loss, MYC family amplification, RB1 and TP53 loss as being characteristics of SCLC and also discovered the MYCL oncogene. The NCI-VA Medical Oncology Branch later relocated to the Bethesda Naval Hospital, MD. In 1991, John Minna accepted a position at the University of Texas Southwestern Medical Center, Dallas, and I was his first recruitment. Thus, during my long career I have only had two employers! I believe this continuity has helped establish strong, long term collaborations and boosted overall productivity. One of the interests of Mary Matthews and me was the heterogeneity of SCLC. It became obvious to us that the so-called oat cell variant was an ischemic artifact. However we were intrigued by the plasticity of SCLC, with a substantial percentage of cases having abnormal (“variant”) morphologies or combined with NSCLC elements, especially after therapy.[3] The variant morphology and its relationship to NEUROD1 as the driver transcription factor (as opposed to ASCL1 as the driver in typical or “classic” SCLC) has recently been highlighted.[4] By the mid 1980s, advances in SCLC biology and therapy had hit a stonewall, and funding dried up. It was time to move onto NSCLC! We established a large collection of NSCLC cell lines and these also formed much of the basis of our understanding of this disease, although tumor tissues were much more readily available. While cell lines have their pluses and minuses, they are excellent for identifying driver mutations and testing targeted therapies. They contributed to the identification of the role of EGFR mutations in lung cancer.[5, 6] Soon after this discovery we used our international fellows and contacts to perform the first large multinational study of geographic and ethnic variations in mutation frequencies, and also demonstrated that mutations were largely absent in tumors other than NSCLC.[7] The advent of Precision Medicine has highlighted the crucial role of the pathologist. Instead of the image of a pathologist looking at microscope slides in isolation in a basement office, he or she plays a crucial role as an integral part of the diagnostic and therapeutic team involved in every aspect of patient management. The pathologist assumes further responsibilities such as tissue procurement and optimal utilization, triaging scant resources for clinical trial requirements, involvement in molecular testing, performing requested or required immunostaining, establishing tissue repositories etc. Previously clinical decision making required the pathologist only to make a diagnosis of SCLC or NSCLC. Precision Medicine has highlighted the importance of accurate classification of NSCLC. Classification is required for mutation testing, therapy selection (or exclusion) and entry onto histology dependent clinical trials. While the introduction of immunostains has greatly facilitated the classification of poorly differentiated NSCLC, the SEER database indicates that up to 14% of NSCLC may remain unclassified throughout the USA. For these reasons we developed a molecular classifier for NSCLC that can be applied to formalin fixed paraffin embedded (FFPE) materials and small core biopsies.[8] The assay is highly accurate and quantitative, and also provides information on grading and survival. While SCLC languished for three decades, its recent designation as a recalcitrant cancer by the US Congress has resulted in a dramatic resurrection of interest, funding and achievement.[9] This has highlighted the importance of preclinical models for SCLC.[10, 11] I feel very humbled and privileged to have lived through and contributed to the seminal advances in our understanding of the biology and therapy of lung cancer. This would not have been possible without the many wonderful and talented people I have worked with. I am reminded of the quote of Isaac Newton: “If I have seen further than others, it is because I have stood on the shoulders of giants”. References 1. Matthews MJ, Kanhouwa S, Pickren J, et al. Frequency of residual and metastatic tumor in patients undergoing curative surgical resection for lung cancer. Cancer chemotherapy reports Part 3 1973;4:63-67. 2. Gazdar AF, Carney DN, Russell EK, et al. Establishment of continuous, clonable cultures of small-cell carcinoma of lung which have amine precursor uptake and decarboxylation cell properties. Cancer Res 1980;40:3502-3507. 3. Gazdar AF, Carney DN, Nau MM, et al. Characterization of variant subclasses of cell lines derived from small cell lung cancer having distinctive biochemical, morphological, and growth properties. Cancer Res 1985;45:2924-2930. 4. Borromeo MD, Savage TK, Kollipara RK, et al. ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs. Cell reports 2016;16:1259-1272. 5. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500. 6. Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169-181. 7. Shigematsu S, Lin L, Takahashi T, et al. Clinical and biological features associated with Epidermal Growth Factor Receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339-346. 8. Girard L, Rodriguez-Canales J, Behrens C, et al. An Expression Signature as an Aid to the Histologic Classification of Non-Small Cell Lung Cancer. Clin Cancer Res 2016. 9. Gazdar AF, Minna JD. Developing New, Rational Therapies for Recalcitrant Small Cell Lung Cancer. J Natl Cancer Inst 2016;108. 10. Gazdar AF, Hirsch FR, Minna JD. From Mice to Men and Back: An Assessment of Preclinical Model Systems for the Study of Lung Cancers. J Thorac Oncol 2016;11:287-299. 11. Gazdar AF, Savage TK, Johnson JE, et al. The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung. J Thorac Oncol 2015;10:553-564.
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PL05.02 - Surgery (ID 6915)
16:25 - 16:40 | Author(s): P. Goldstraw
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WCLC2016 Abstract for Closing Plenary Session A Life in Thoracic Oncology - Reflections on Treatment Advances: Surgery The speaker began his training in Cardiothoracic surgery in 1973 and was appointed as a Consultant in 1979. He will introduce this topic by describing a typical case undergoing surgical treatment for lung cancer in the 1970s, the patient journey and outcomes at that time. From that basis he will detail the changes in the surgical treatment of lung cancer in the last 40 years. This will include: · Changes in the epidemiology of lung cancer. · Improvements in pre-operative selection. · Improvements in the staging process prior to surgery, during surgery and post-surgery. · Differences in surgical approach and the anatomical extent of resection. · Changes in the stage classification over that period. · The establishment of effective adjuvant therapy. · Improved outcomes in morbidity, mortality and survivorship. None of these improvements has been of itself a game changer but collectively they amount to a fundamental change in the surgical management of this disease. A brief mention will be made of advances in the surgical treatment of other thoracic malignancies. Peter Goldstraw
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PL05.03 - Radio-Oncology (ID 6916)
16:40 - 16:55 | Author(s): D. Ball
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When I commenced training in radiation oncology in 1973, there were no CT scanners, calculations were done with slide rules, and chemotherapy, let alone combined modality therapy, had no established role in the treatment of non-small cell lung cancer. An influential trial published in the Lancet in 1971(1) had shown no difference in survival whether patients were randomized to radiotherapy, chemotherapy, a combination of the two or a policy of wait-and–see. Yet within 30 years, the standard of care for patients with inoperable lung cancer being treated for cure, both small cell and non-small cell, had, ironically, become, and remains, concomitant chemotherapy and radiotherapy. The outlook for patients generally regarded as incurable at the outset of my career is that up to one in three selected patients can now expect to live five years as a result of chemoradiation. Patients with stage I non-small cell lung cancer can have their cancer successfully ablated by non-invasive stereotactic radiotherapy in 90% of cases. The developments which led to these changes can be grouped according to three main themes: the impact of the computer revolution; a better understanding of the natural history and biology of the disease, and the introduction of mutimodality therapy. The computer revolution: imaging, treatment planning and delivery Better identification and delineation of the tumor are critical to the success of radiotherapy, in particular avoidance of the catastrophic “geographic miss”. Without computers, the CT and hybrid PET/CT scanners could not have been possible. These dramatically improved the accuracy of staging as well as providing 3D information on the relationship of the soft tissue target to the nearby dose-limiting organs at risk. As computing power increased it became possible to create 4D images of moving tumours, and to image the target with on-board CT scanners attached to the linac immediately before treatment, so making image guided stereotactic ablative radiotherapy possible. Powerful computerised treatment planning systems are now able to create complex dose distributions conforming to the irregularities of any target volume, and to provide dose-volume metrics predictive of risks of normal tissue damage. Improved understanding of the natural history and biology of the disease The recognition that the central nervous system is a sanctuary site which can harbour metastatic disease leading to treatment failure in spite of successful chemotherapeutic eradication of extracranial disease, particularly in small cell lung cancer, led to the introduction of prophylactic cranial irradiation. The British study of continuous hyperfractionated accelerated radiotherapy (CHART) which was given over 12 days to patients with inoperable non-small cell lung cancer resulted in better survival than treatment given over six weeks, even though the total dose was lower. This trial provided clinical support for the notion of treatment induced accelerated repopulation, and reinforced the principle that total treatment times should be kept short in both small cell and non-small cell lung cancer, both when radiotherapy is used alone, and when in combination with chemotherapy. Multimodality therapy The limitations of single modality therapy for a disease with a high propensity for developing genetically determined resistance have long been recognised, and have stimulated the development of strategies simultaneously employing non-cross resistant therapies to maximise tumor cell kill, in line with the principles espoused by Goldie and Coldman.(2) The use of concomitant platinum based chemotherapy with high dose radiotherapy is now well established by meta analysis as improving survival of both non-small cell and small cell lung cancers, but it is also more toxic. Amelioration of these toxicities represents a major challenge for the future. Future directions It is likely that the technical progress in radiation treatment planning and delivery is close to a plateau, and that future progress will depend more on understanding the biology of the disease and its response, and that of the normal tissues, to radiation damage. Biomarkers of response and toxicity, so spectacularly harnessed to advantage by our medical oncology colleagues, are desperately needed to tailor the radiotherapy prescription to the needs of each individual and their cancer. Finally, it is evident that in many jurisdictions, including industrialised wealthy nations, that many patients are either receiving substandard radiotherapy that might increase their chances of cure, or are not receiving treatment at all.(3) Unless these problems can be addressed, the benefits of the remarkable advances in technology and biology documented above will shamefully be restricted to only a fraction of those afflicted with locoregional disease. 1. Durrant KR, Berry RJ, Ellis F, Ridehalgh FR, Black JM, Hamilton WS. Comparison of treatment policies in inoperable bronchial carcinoma. Lancet. 1971;1(7702):715-9. 2. Goldie JH, Coldman AJ, Gudauskas GA. Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat Rep. 1982;66(3):439-49. 3. Vinod SK. International patterns of radiotherapy practice for non-small cell lung cancer. Semin Radiat Oncol. 2015;25(2):143-50.
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PL05.04 - Translational Lung Cancer Research (ID 6917)
16:55 - 17:10 | Author(s): N. Saijo
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Lung cancer is a leading cause of cancer death in the world. The survival benefit of chemotherapy was rarely observed in NSCLC until the development of Cisplatin. Platinum doublets including 2nd/3rd generation cytotoxic drugs showed minor prolongation of survival but the effect reached a plateau. JCOG conducted key RCTs to develop new standards against SCLC but a breakthrough has not been observed yet. Two recent major therapeutic advancements in NSCLC are immunotherapies to inhibit immune checkpoints and development of targeted drugs for driver mutations. Translational Research in Immune Checkpoint inhibitors Immunotherapy of cancer has a long history without success because of wrong strategy of immune stimulation with non-specific immunostimulators, biological response modifiers and recently by peptide antigens. After introduction of idea on immune checkpoint inhibition by Dr. James Allison, the studies of this fields were dramatically activated. Currently two anti-PD-1 antibodies such as Nivolumab and Pembrolizumab have been approved for the treatment of NSCLC based on reproducible effects of tumor shrinkage and survival benefit. In second line treatment, both antibodies significantly improved survival compared with standard care of cytotoxic chemotherapy irrespective of patient selection. Recent press release announced that Nivolumab failed to demonstrate benefit for PFS compared to cytotoxic chemotherapy (CheckMate-026), on the other hand Pembrolizumab demonstrated superior PFS and OS (KEYNOTE-024). Both of the trials patient selection was done based on PD-L1 expression in lung cancer cells. In spite of positive data on survival, RR in various trials against advanced NSCLC with or without prior chemotherapy ranges from 15-25% for both drugs and median survival is almost same in anti-PD1 Ab and cytotoxic drugs. The most important issue will be how to concentrate responsive patient population or how to eliminate in effective patients. Although there is a tendency of correlation between PD-L1 expression and objective response/survival, responders to Ab are experienced even in PD-L1 negative patients. There are many problems in PD-L1 screening. There is no comparative data of various PD-1 tests used in various clinical trials. Each PD-1 test uses different antibody. Each test uses a different definition and cut off point that defines PD-1 positivity. There is no data on best sample, paraffin-fixed vs fresh tissue, primary site tumor vs metastatic tissue. PD-1 expression is not stable and influenced by many factors. There is no reliable validation and standardization. In tumor cells, mutation burden may influence on antigenicity. In colorectal cancer, microsatellite instability has related with response to anti-PD-1 antibody, but it is not yet clear whether mutation burden really increases antigenicity. CD8 lymphocytes infiltration is also considered to be one of the biomarkers for anti-PD-1 Ab response. However, it is too objective and seems to be quite difficult to quantify CD 8 lymphocytes infiltration. The most important thing will be the function of killer T lymphocytes which can respond to target antigens and to kill tumor cells. The best method may be quantitative measurements of cytotoxicity in killer T cell on tumor cells. The techniques to demonstrate this process are mandatory for successful patient selection in the treatment with anti-PD-1 antibody. Translational Drug Development for Precision Medicine Recent development of molecular target drugs in lung cancer really reflects progress of translational studies. EGFR-TKIs are one of the most important drugs and changed concept of treatment of lung cancer. Finding on many rare driver mutations forced to reclassify lung cancer to various genomic subtypes. Innovative technologies for genomic medicine changes one size fit medicine to precision medicine. For discovery of drugs to each genomic subtype of lung cancer, nationwide and global screening network should be mandatory. In Japan LC-SCRUM Japan leaded by Dr. Koichi Goto, National Cancer Center Hospital East, started in February 2013 to find out new seeds against lung cancer by the support of government.. At the beginning, tumor tissues were analyzed for ALK/ROS1/RET fusions using RT-PCR in EGFR –Mt negative patients and the detected fusions were confirmed by FISH. From March 2015, multiplex diagnostic kit using NGS was introduced and this project expanded as SCRUM-Japan including other histological types of lung cancer such as SQ and SM as well as GI malignancy. 14 pharmaceutical companies started to support this project. No. of institutions joined in the network increased to 200 In Non-SQ NSCLC, 159 and 96 for SQ and SM, respectively on March, 2016. More than 2,500 samples were analyzed. Rare mutations including ROS(91), RET(54) and ALK(40) fusions, ERB2 mutation/amplification(48), BRAF mutation(16), MET amplification/ex14 skip(16) and PIK3A mutation(22) have been screened in 287 Non-SQ-NSCLC patients and 67(23%) have been accrued to more than 12 clinical trials. In LURET trials against RET fusion gene + patients, 19 patients have been accrued and 17 are eligible. The response rate of vandetanib was 53%and PFS was 4.7 months. In 0012-01 trial against ROS fusion gene + patients, 129 patients (74 from china, 26 from Japan, 15 from Taiwan and 12 from Korea)has been accrued. Response rate of crizotinib was 69%in 127 evaluable patients. J-AlEX trial was a phase III randomized controlled trial comparing alectinib(ALE) and crizotinib(CRI) in ALK-positive NSCLC. Response rates for ALE and CRI were 85.4% and 70.2% respectively. PFS was not reached and 10.2 months(P<0.0001), respectively. Other clinical trials are ongoing. Samples from SQ and SM are increasing and interesting mutations and amplifications have been detected in these materials. Accordingly this nationwide and population enrichment screening system enabled various rare driver mutations to be efficiently detected in lung cancer, contributing to the rapid accrual of matched patients in translational clinical trials.
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PL05.05 - Chemotherapy (ID 6918)
17:10 - 17:25 | Author(s): T. Le Chevalier
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Chemotherapy has long been the only available systemic treatment for Non-Small Cell lung Cancer. In the late 70’s, there were a multitude of triplets and quadruplets with response rates ranging from 20-35% in patients with stage IV disease. In 1980, cisplatin, a cytotoxic agent initially developed for germ-cell tumors, showed some activity, mostly when combined with a vinca-alkaloïd or with etoposide. At the time Vinorelbine was registered by the FDA in 1994, alone or in combination with cisplatin, only 3 drugs were approved for NSCLC, nitrogen mustard, methotrexate and doxorubicin! Metastatic Disease The individual data-based meta-analysis published in 1995 established the superiority of chemotherapy over supportive care in patients with advanced NSCLC. These results have been recently updated and confirmed in 2714 patients from 16 trials with an overall survival benefit of 9% at 1 year. Chemotherapy also improves quality of life and symptom control in patients with good performance status. It is classically recommended to use platin compounds (mostly cisplatin and carboplatin) in combination with third generation agents including vinorelbine, gemcitabine, taxanes (paclitaxel, docetaxel, nab-paclitaxel) or pemetrexed (in non-squamous NSCLC). Integrating palliative care at an early stage of the treatment also prolongs survival and improves quality of life. Second line chemotherapy with docetaxel or pemetrexed has also been demonstrated active even if the benefit on overall survival remains modest. The use of biological markers such as ERCC1, RRM1, beta-tubulin or thymidilate synthase has not yet proven efficacy on the choice of cytotoxic agents. Maintenance: Up to 2009, it was generally accepted that 4 to 6 cycles of induction chemotherapy followed by a rest till progression were the standard. The switch to a new drug as maintenance after 4 cycles of a platin-based doublet showed a benefit for PFS and OS. Maintenance is now considered a standard in the management of metastatic NSCLC. Chemo-radiotherapy for locally advanced disease: The benefit obtained with radiotherapy and chemotherapy given sequentially in locally advanced inoperable NSCLC is modest but significant and well established. Several randomized trials comparing radiotherapy-chemotherapy given sequentially or concomitantly have suggested a better outcome when both modalities were given early and simultaneously. A meta-analysis based on individual patient data from published and unpublished randomised trials which compared radiotherapy alone with the same radiotherapy combined with concomitant cisplatin- or carboplatin-based chemotherapy was recently performed. The analysis was based on 9 trials including 1764 patients. The hazard ratio of death among patients treated with radio-chemotherapy compared to radiotherapy alone was 0.89 (CI 95%: 0.81-0.98; P = 0.02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years. There was some evidence of heterogeneity among trials and sensitivity analyses did not lead to consistent results. The available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy in combination with radiotherapy. Adjuvant chemotherapy: In the meta-analysis published in 1995, a 13% reduction in the risk of death was observed, suggesting an absolute benefit of 5% at 5 years with adjuvant chemotherapy. These results constituted the rationale for a new generation of randomized studies with platinum-based regimens. The LACE meta-analysis, which was reported at ASCO 2006, pooled a total of 4584 patients accrued in the five largest cisplatin-based adjuvant trials launched after the results of the meta-analysis. It confirmed the benefit of adjuvant chemotherapy with a 5.3% improvement of survival at 5 years (p=0.0043). Disease-free survival was also improved (5.2% at 5 years, p<0.0001). There was a negative effect of adjuvant chemotherapy for stage IA. The risk reduction was 8% for stage IB, 17% for stages II and III. The effect of chemotherapy did not vary according to age, gender, PS, type of surgery and histology. In parallel, the adjuvant UFT meta-analysis also confirmed a significant advantage of the drug compared to control in 2003 Japanese patients (p<0.001). The individual-data-based meta-analysis was updated in 2007. It confirmed the significant effect of postoperative chemotherapy, with or without postoperative radiotherapy. Neoadjuvant chemotherapy : Several phase II trials have been carried out in the 80’s to evaluate the benefit of preoperative chemotherapy in operable NSCLC with encouraging results. In the mid 90’s, two randomized phase III trials had a significant impact on the medical community due to their impressive results. Both trials randomized 60 stage IIIA patients and were interrupted after positive interim results were observed. Only two published randomized phase III studies comparing front-line surgery to pre-operative chemotherapy followed by surgery accrued the number of patients that were initially planned: a French study that included 373 patients and the Medical Research Council LU22 trial that included 519 patients. None of the large randomized studies could demonstrate a significant advantage in favor of pre-operative chemotherapy. A recent individual patient data-based meta-analysis of pre-operative chemotherapy trials has included 2385 patients from 15 trials. A HR of 0.87 (CI 95%: 0.7_–0.96, p=0.007) was observed, equivalent to an absolute improvement in survival of 5% at five years, similar to the benefit observed with postoperative chemotherapy. Preoperative or postoperative chemotherapy? A comparison of preoperative versus postoperative chemotherapy has been did not show any difference. In fact, the key issue may be to determine which patients should be treated with adjuvant and/or neo-adjuvant therapy. The neo-adjuvant approach offers a unique opportunity to test new drugs and to compare the tumor characteristics prior to and following induction therapy. Developing molecular based therapeutic strategies will certainly be one of the major challenges over the next few years. Several randomized adjuvant studies have recently been initiated in Europe and in America, based on the molecular characteristics of patients tumor. In conclusion, chemotherapy remains the main systemic treatment for most patients with lung cancer and the only one able to increase the cure rate. Unfortunately, very few drugs have been developed in the last decade in spite of a clear unmet medical need. A better individual selection of drugs/drug combinations according to pharmacogenomic data might encourage the community to optimize the use of cytotoxic agents.
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PL05.06 - Targeted Therapy (ID 6922)
17:25 - 17:40 | Author(s): F. Shepherd
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Abstract not provided
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PL05.07 - A Wise Man’s Conclusion (ID 6919)
17:40 - 17:55 | Author(s): L. Einhorn
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The past decade has seen more advances in diagnosis and management of lung cancer than were available in the previous 30 years. Fifty years ago, the association of cigarette smoking in lung cancer was firmly established by the Surgeon General's report in the United States. During the past decade, major efforts by IASLC and other organizations have greatly reduced the use of tobacco and, thus, we will be seeing a decrement in morbidity and mortality from lung cancer. However, in the United States last year, there were still 228,000 new cases and 160,000 deaths from lung cancer. It remains the number one cause of cancer death in both American men and women, and the same is true in most developed and developing countries. Over 28% of all cases of cancer death in the United States are due to lung cancer. IASLC has been a leader in updating the TNM classification for non-small cell lung cancer. This allows for uniformity of data results in surgical and adjuvant studies. Cisplatin-based adjuvant chemotherapy has been demonstrated to improve the surgical cure rate by 5-10%. In the future, we hope to be able to identify by molecular, rather than just clinical characteristics, those patients with resected lung cancer who are cured with surgery and do not need to be subjected to adjuvant chemotherapy, as has been similarly accomplished in breast cancer. Also, we hope to have better definition of tumors that are inherently platinum resistant and, therefore, would need alternative strategies to try to improve the surgical cure rate. For the last two decades of the 20th century, chemotherapy has been the backbone for treatment of stage IVB lung cancer. Most studies have been built around platinum combination chemotherapy. Earlier studies pre-platinum utilized inactive drugs such as cyclophosphamide and doxorubicin. In the 1980s, cisplatin and etoposide was a common platinum doublet, and in the 1990's, carboplatin + paclitaxel. A review of phase III trials in North America from 1973-1994 demonstrated very sobering results. Thirty-three trials in 8,434 patients were performed and 23 of these 33 included a platinum compound. Only 5 of the 33 trials demonstrated a statistically significant difference in survival with a median increase of 2 months (range 0.7 to 2.7 months). It thus became clear that we need to personalize therapy rather than giving all patients the same chemotherapy. Modest success was seen by adding Bevacizumab to carboplatin + paclitaxel. Major advances have been made during the past decade with the identification of specific mutations that can be therapeutically exploited. EGFR and ALK were the first to be identified and subsequently ROS-1. Molecular targeted agents demonstrated spectacular responses in the great majority of patients, compared to the usual 25% brief responses that were achieved previously with platinum-based combination chemotherapy. These driver mutations were predominantly in adenocarcinomas and non-smokers or never smokers. More recent mutations have included smokers and non-smokers such as BRAF V600E and MET Exon-14 skipping mutation which can be seen in smokers as well as non-smokers. During the past five years, immunotherapy has been an exciting new addition to the armamentarium for treatment of patients with metastatic lung cancer. Immune checkpoint inhibitors are still in the nascent phase and the optimal duration of therapy for stage IVB disease, combination with other immunotherapeutic agents, chemotherapy, or radiotherapy, as well as use of adjuvant therapy, will be awaited with eager anticipation. Exciting new technology such as CRISPR-cas9 to gene edit PD-1 holds great potential future promise to make these immune checkpoint inhibitors more effective in a larger percentage of patients with lung cancer, as well as those responses being more durable.
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PL05.08 - Welcome to Yokohama for WCLC 2017 (ID 6920)
16:00 - 16:10 | Author(s): H. Asamura
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Abstract not provided
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PL05.09 - Farewell (ID 6921)
17:55 - 18:00 | Author(s): R. Pirker
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Abstract not provided
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PR03 - Press Conference: Accurate Diagnosis (ID 477)
- Event: WCLC 2016
- Type: Press Conference
- Track:
- Presentations: 4
- Moderators:T. Mok
- Coordinates: 12/06/2016, 10:30 - 11:45, Schubert 1
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PR03.01 - Lung Cancer Staging – Changing the Clinical Practice (ID 7209)
10:30 - 10:30 | Author(s): R. Rami-Porta
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Abstract not provided
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PR03.02 - Randomised Phase III Study of Osimertinib vs Platinum-Pemetrexed for EGFR T790M-Positive Advanced NSCLC (AURA3) (ID 7210)
10:30 - 10:30 | Author(s): V. Papadimitrakopoulou
- Abstract
- Presentation
Abstract not provided
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PR03.03 - BRAIN: A Phase Ⅲ Trial Comparing WBI and Chemotherapy with Icotinib in NSCLC with Brain Metastases Harboring EGFR Mutations (CTONG 1201) (ID 7211)
10:30 - 10:30 | Author(s): Y.-. Wu
- Abstract
- Presentation
Abstract not provided
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PR03.04 - First-line Ceritinib Versus Chemotherapy in Patients With ALK-rearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-4) (ID 7212)
10:30 - 10:30 | Author(s): G. De Castro Jr
- Abstract
- Presentation
Abstract not provided
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Author of
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ISS04 - Industry Supported Symposium: Treatment Selection Strategies in Advanced NSCLC - A Symphony of Views - Eli Lilly and Company (ID 438)
- Event: WCLC 2016
- Type: Industry Supported Symposium
- Track:
- Presentations: 2
- Moderators:G.V. Scagliotti, T. Mok
- Coordinates: 12/04/2016, 17:15 - 18:45, Hall C1
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MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:R. Perez-Soler, T. Reungwetwattana
- Coordinates: 12/06/2016, 11:00 - 12:30, Lehar 3-4
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MA08.03 - Osimertinib vs Platinum-Pemetrexed for T790M-Mutation Positive Advanced NSCLC (AURA3): Plasma ctDNA Analysis (ID 4733)
11:12 - 11:18 | Author(s): T. Mok
- Abstract
- Presentation
Background:
AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib, a T790M directed EGFR-TKI, vs platinum-based doublet chemotherapy in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on previous EGFR-TKI therapy. Concordance between plasma and tissue testing, and efficacy outcomes by baseline plasma T790M status, were evaluated.
Methods:
Eligible patients were randomised 2:1 to osimertinib 80 mg orally once daily or platinum-pemetrexed (pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC5) every three weeks for up to six cycles. Patients were tumour tissue T790M-positive (by cobas[®] EGFR Mutation Test v2) from a biopsy after disease progression prior to study entry. Blood samples were taken at baseline for retrospective analysis of T790M mutation status by plasma ctDNA using the cobas[®] EGFR Mutation Test v2.
Results:
Concordance data are reported in the table. Within the intent-to-treat (ITT) population (n=419), patients plasma T790M-positive and randomised to treatment (n=172) had markedly improved progression-free survival (PFS) by investigator assessment (IA) with osimertinib vs platinum-pemetrexed: hazard ratio 0.42 (95% CI: 0.29, 0.61); median 8.2 vs 4.2 months. Objective response rate (ORR) by IA was also distinctly improved with osimertinib vs platinum-pemetrexed: 77% vs 39% (odds ratio 4.96 [95% CI: 2.49, 10.15]; p<0.001). This is consistent with the ITT population: PFS hazard ratio 0.30 (95% CI: 0.23, 0.41); p<0.001 (median 10.1 vs 4.4 months); ORR 71% vs 31% (odds ratio 5.39 [95% CI: 3.47, 8.48]; p<0.001). Figure 1
Conclusion:
In plasma T790M-positive patients the clinical benefit of osimertinib was superior to platinum-pemetrexed, consistent with the ITT T790M-positive population selected by tumour tissue test. PFS with osimertinib was similar regardless of selection by tissue or plasma T790M-positive status. Based on these, and AURA Phase II data, routine biopsy testing is recommended for patients with a plasma T790M-negative test where feasible.
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.03 - Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers (ID 4325)
14:26 - 14:32 | Author(s): T. Mok
- Abstract
- Presentation
Background:
GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.
Methods:
A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).
Results:
165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.
Conclusion:
RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.
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OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:O.T. Brustugun, S. Lu
- Coordinates: 12/07/2016, 14:20 - 15:50, Stolz 2
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OA23.05 - First-Line Afatinib versus Gefitinib in EGFRm+ Advanced NSCLC: Updated Overall Survival Analysis of LUX-Lung 7 (ID 5347)
15:05 - 15:15 | Author(s): T. Mok
- Abstract
- Presentation
Background:
The irreversible ErbB family blocker afatinib and the reversible EGFR TKI gefitinib are approved for first-line treatment of advanced EGFRm+ NSCLC. This Phase IIb trial prospectively compared afatinib versus gefitinib in this setting.
Methods:
LUX-Lung 7 assessed afatinib (40 mg/day) versus gefitinib (250 mg/day) in treatment-naïve patients with stage IIIb/IV NSCLC harbouring a common EGFR mutation (Del19/L858R). Co-primary endpoints were PFS (independent review), time to treatment failure (TTF) and OS. Other endpoints included ORR and AEs. In case of grade ≥3/selected grade 2 drug-related AEs the afatinib dose could be reduced to 30 mg or 20 mg (minimum). The primary analysis of PFS/TTF was undertaken after ~250 PFS events. The primary OS analysis was planned after ~213 OS events and a follow-up period of ≥32 months.
Results:
319 patients were randomised (afatinib: 160; gefitinib: 159). At the time of primary analysis, PFS (HR [95% CI] 0.73 [0.57‒0.95], p=0.017), TTF (0.73 [0.58‒0.92], p=0.007) and ORR (70 vs 56%, p=0.008) were significantly improved with afatinib versus gefitinib. The most common grade ≥3 AEs were diarrhoea (13%) and rash/acne (9%) with afatinib and elevated ALT/AST (9%) with gefitinib. 42% of patients treated with afatinib had ≥1 dose reduction due to AEs; dose reductions were more common in females than males (77%/23%) and non-Asians than Asians (64%/36%). Dose reduction of afatinib did not negatively impact PFS (<40mg vs ≥40mg; HR [95% CI]: 1.34 [0.90‒2.00]) but reduced incidence and severity of drug-related grade ≥3 AEs. Treatment discontinuation due to drug-related AEs was the same in each arm (6%). The data cut-off for primary OS analysis occurred on 8 April 2016. At this time, median treatment duration (range) was 13.7 (0‒46.4) versus 11.5 (0.5‒48.7) months with afatinib and gefitinib. 25% (afatinib) and 13% (gefitinib) of patients received treatment for >24 months. 73% and 77% of patients in the afatinib and gefitinib arms had ≥1 subsequent systemic anti-cancer treatment, with 46% and 56% receiving a subsequent EGFR-TKI including osimertinib (14%)/olmutinib (14%). OS data, including subgroup analysis with respect to subsequent therapy will be presented at the meeting.
Conclusion:
Afatinib significantly improved PFS, TTF and ORR versus gefitinib in EGFRm+ NSCLC patients, with a manageable AE profile and few drug-related discontinuations. Dose adjustment of afatinib reduced drug-related AEs without compromising efficacy. Primary OS analysis will be reported.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-022 - First-Line Durvalumab plus Tremelimumab vs Platinum-Based Chemotherapy for Advanced/Metastatic NSCLC: Phase 3 NEPTUNE Study (ID 4610)
14:30 - 14:30 | Author(s): T. Mok
- Abstract
Background:
Current first-line therapy for advanced EGFR and ALK wild-type NSCLC is associated with poor survival and there remains a significant need for more effective treatments in this population. Blockade of immune checkpoints programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) represents a promising anticancer therapeutic strategy. In preclinical models, targeting both PD-1 and CTLA-4 provides for non-redundant pathway blockade and potential synergy. Durvalumab (MEDI4736) is a selective, high-affinity, engineered human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to PD-1 (IC~50~ 0.1 nM) and CD80 (IC~50~ 0.04 nM). Tremelimumab is a selective human IgG2 mAb inhibitor of CTLA-4. A Phase 1b study of durvalumab + tremelimumab demonstrated encouraging clinical activity and a manageable tolerability profile in advanced NSCLC, with activity observed in patients with high and low/no tumour PD-L1 expression (NCT02000947).
Methods:
NEPTUNE (NCT02542293) is a randomised, open-label, multicentre, global, Phase 3 study. Immunotherapy- and chemotherapy-naïve patients with advanced/metastatic EGFR and ALK wild-type NSCLC (with either PD-L1 high expression [≥25% tumour cells staining for PD-L1 at any intensity] or PD-L1 low/negative expression [<25% tumour cells staining for PD-L1 at any intensity] ) will be randomised (1:1) to durvalumab (20 mg/kg i.v. every 4 weeks [q4w] for up to 12 months) + tremelimumab (1 mg/kg i.v. q4w for up to 4 doses); or standard-of-care platinum-based doublet chemotherapy. The primary endpoint is overall survival (OS). Secondary endpoints are progression-free survival (PFS), objective response rate (ORR), duration of response and proportion of patients alive and progression free at 12 months by investigator assessment (RECIST v1.1); time from randomisation to second progression; OS, PFS and ORR in patients with PD-L1 low/negative NSCLC; safety (CTCAE v4.03) and tolerability; pharmacokinetics; and immunogenicity. Exploratory outcomes include potential biomarkers of response to treatment and impact of subsequent anticancer therapies on OS. Recruitment is ongoing. Figure 1
Results:
Not-applicable
Conclusion:
Not-applicable
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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-044 - Afatinib versus Gefitinib as First-Line Treatment for EGFR Mutation-Positive NSCLC Patients Aged ≥75 Years: Subgroup Analysis of LUX-Lung 7 (ID 5327)
14:30 - 14:30 | Author(s): T. Mok
- Abstract
Background:
The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of advanced EGFRm+ NSCLC. In the Phase IIb LUX-Lung 7 trial, afatinib significantly improved median progression-free survival (PFS; HR=0.73 [95% CI, 0.57–0.95], p=0.017), objective response rate (70% vs 56%, p=0.008) and time to treatment failure (TTF; HR=0.73 [95% CI, 0.58–0.92], p=0.007) versus gefitinib in this setting (Park et al. Lancet Oncol 2016). Here we evaluated the efficacy and safety of afatinib versus gefitinib in patients aged ≥75 years in a subgroup analysis of LUX-Lung 7 (NCT01466660).
Methods:
Treatment-naïve patients with stage IIIB/IV EGFRm+ NSCLC were randomized (1:1) to oral afatinib (40 mg/day) or gefitinib (250 mg/day), stratified by EGFR mutation type (Del19/L858R) and presence of brain metastases (Yes/No). Co-primary endpoints were PFS, TTF, and overall survival. Subgroup analyses of PFS and adverse events (AEs) by age (≥75/<75 years) were exploratory.
Results:
Of 319 patients randomised in LL7, 40 (13%) were aged ≥75 years (afatinib n=19, gefitinib n=21). Median PFS for both age groups was in line with the overall population and favoured afatinib versus gefitinib (patients ≥75 years: 14.7 vs 10.8 months, HR=0.69 [95% CI, 0.33–1.44]; patients <75 years: 11.0 vs 10.9 months, HR=0.76 [95% CI, 0.58–1.00]). The incidence of treatment-related AEs (grade 3/4) was slightly higher in the older subgroup (afatinib: 42%/0%; gefitinib: 24%/5%) than in the younger subgroup (afatinib: 28%/2%; gefitinib: 15%/<1%). There were no unexpected safety findings. The most common treatment-related AEs (all grade [grade 3]) with afatinib in the older patient subgroup were diarrhoea (89% [21%]), rash (63% [5%]), dry skin (37% [0%]), and decreased appetite (32% [0%]). Dose reduction/discontinuation of afatinib due to treatment-related AEs was required in 53%/16% and 40%/5% of the older and younger subgroup, respectively.
Conclusion:
A small subgroup of patients in the LUX-Lung 7 trial were ≥75 years old (13%). In exploratory subgroup analyses of patients aged ≥75 and <75 years old, advancing age did not adversely affect the PFS benefit and tolerability observed with afatinib versus gefitinib in treatment-naïve EGFRm+ NSCLC patients. These findings suggest that afatinib can provide an effective and tolerable treatment for older patients with EGFRm+ NSCLC.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-038 - First-Line Atezolizumab plus Chemotherapy in Chemotherapy-Naïve Patients with Advanced NSCLC: A Phase III Clinical Program (ID 4956)
14:30 - 14:30 | Author(s): T. Mok
- Abstract
Background:
First-line treatments for patients with advanced NSCLC include targeted therapies and platinum-based doublet chemotherapy±bevacizumab and/or pemetrexed. Although immunotherapies targeting the PD-L1/PD-1 pathway are available for advanced NSCLC beyond the first line, chemotherapy is a key first-line option for patients, despite poor survival outcomes, highlighting the need for additional treatment options. Atezolizumab, a monoclonal anti–PD-L1 antibody, inhibits the binding of PD-L1 to its receptors PD-1 and B7.1, restoring tumor-specific T-cell immunity. Clinical efficacy has been reported with atezolizumab monotherapy in patients with squamous and nonsquamous NSCLC, with a survival benefit observed across all PD-L1 expression levels. Additionally, Phase Ib data showed the potential for chemotherapy to further enhance responses to atezolizumab, with tolerable safety, in patients with NSCLC. Bevacizumab in combination with atezolizumab may enhance efficacy in non-squamous NSCLC by inhibiting VEGF-mediated immunosuppression. Four global, Phase III, randomized, open-label trials are evaluating atezolizumab+platinum-based chemotherapy±bevacizumab in chemotherapy-naive patients with stage IV NSCLC.
Methods:
Eligible patients must have stage IV NSCLC, measurable disease (RECIST v1.1) and ECOG PS 0-1 and be chemotherapy naive. Exclusion criteria include untreated CNS metastases, autoimmune disease and prior exposure to immunotherapy. Patients will be enrolled regardless of PD-L1 expression status. Patients randomized to the experimental arm will receive atezolizumab 1200 mg with standard platinum-based chemotherapy in IMpower130 and 131 and also ±bevacizumab in IMpower150 for four or six 21-day cycles, then maintenance with atezolizumab in IMpower130 and 131 and atezolizumab+bevacizumab in IMpower150. In IMpower132, experimental-arm patients will receive atezolizumab+platinum-based chemotherapy+pemetrexed, then maintenance with atezolizumab+pemetrexed. Patients receiving atezolizumab may continue until loss of clinical benefit. Co-primary endpoints are progression-free survival and overall survival. Secondary endpoints include objective response rate and safety. Evaluation of predictive biomarkers associated with efficacy will be performed.
ECOG PS, Eastern Cooperative Oncology Group performance status; IHC, immunohistochemistry.Trial IMpower130 IMpower131 IMpower132 IMpower150 Histology Nonsquamous Squamous Nonsquamous Nonsquamous Planned enrollment(N) 650 1025 568 1200 Experimental Atezolizuma +carboplatin +nab-paclitaxel Atezolizuma +carboplatin +paclitaxel or Atezolizumab +carboplatin +nab-paclitaxel Atezolizuma +carboplatin or cisplatin +pemetrexed Atezolizumab +carboplatin +paclitaxel or Atezolizumab +carboplatin +paclitaxel +bevacizumab Comparator Carboplatin +nab-paclitaxel Carboplatin +nab-paclitaxel Carboplatin or cisplatin +pemetrexed Carboplatin +paclitaxel +bevacizumab Stratification factors Sex Liver metastases Centrally assessed PD-L1 expression by IHC Sex Liver metastases Centrally assessed PD-L1 expression by IHC Sex ECOG PS Chemotherapy type (carboplatin vs cisplatin) Smoking status Sex Liver metastases Centrally assessed PD-L1 expression by IHC Identifier NCT02367781 NCT02367794 NCT02657434 NCT02366143
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.02c-041 - IMpower133: A Phase I/III Study of 1L Atezolizumab with Carboplatin and Etoposide in Patients with Extensive-Stage SCLC (ID 4789)
14:30 - 14:30 | Author(s): T. Mok
- Abstract
Background:
Platinum-based chemotherapy with etoposide is the current first-line (1L) standard of care for the majority of patients with extensive-stage small cell lung cancer (ES-SCLC). Although initial response rates with chemotherapy range from 50% to 70%, survival outcomes remain poor (median overall survival [mOS] < 1 year), and new treatment approaches are needed. Atezolizumab is an anti–PDL1 monoclonal antibody that inhibits the binding of PD-L1 to its receptors PD-1 and B7.1, thereby restoring anti-tumor T-cell activity. In a Phase Ia study, single-agent atezolizumab demonstrated a tolerable safety profile and promising durability of response in patients with ES-SCLC: confirmed ORR was 6% (n = 1/17 [partial response]; DOR of 7 months) by RECIST v1.1 and 24% by immune-related response criteria (irRC) (n = 4/17, with 2 patients on atezolizumab for ≥ 12 months). In addition, pre-clinical and Phase I data suggest that atezolizumab plus platinum-based chemotherapy in NSCLC may be synergistic, resulting in durable responses that could potentially translate into improved survival over monotherapy alone. Taken together, these findings provide a rationale to investigate whether atezolizumab + carboplatin + etoposide can improve survival compared with carboplatin + etoposide in the 1L treatment of ES-SCLC.
Methods:
IMpower133 (NCT02763579) is a global, Phase I/III, randomized, multicenter, double-blinded, placebo-controlled trial comparing the efficacy and safety of atezolizumab + carboplatin + etoposide with that of placebo + carboplatin + etoposide in treatment-naive patients with ES-SCLC. Patients will be enrolled regardless of PD-L1 expression status. Exclusion criteria include untreated CNS metastases, autoimmune disease or prior anti-cancer therapy for ES-SCLC. The study stratification factors include sex, ECOG performance status and presence of CNS metastases. Eligible patients will be randomized 1:1 to receive four 21-day cycles of atezolizumab (1200 mg IV) or placebo in combination with carboplatin (AUC 5 mg/mL/min IV, day 1) and etoposide (100 mg/m[~2~], days 1-3), followed by maintenance with atezolizumab or placebo until PD per RECIST v1.1. Patients can continue with treatment until persistent radiographic PD, symptomatic deterioration or unacceptable toxicity. Co-primary endpoints of investigator-assessed progression-free survival per RECIST v1.1 and OS will be evaluated. Secondary efficacy endpoints include ORR and DOR. Safety and tolerability will also be assessed. Approximately 400 patients will be enrolled in this trial.
Results:
Section not applicable
Conclusion:
Section not applicable
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PL03 - Presidential Symposium (ID 428)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 1
- Moderators:D.P. Carbone, R. Pirker
- Coordinates: 12/06/2016, 08:35 - 10:25, Hall D (Plenary Hall)
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PL03.03 - Randomised Phase III Study of Osimertinib vs Platinum-Pemetrexed for EGFR T790M-Positive Advanced NSCLC (AURA3) (Abstract under Embargo until December 6, 7:00 CET) (ID 4452)
09:05 - 09:15 | Author(s): T. Mok
- Abstract
- Presentation
Background:
Osimertinib is a potent, irreversible, CNS active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for sensitising (EGFRm) and T790M resistance mutations. Osimertinib is indicated for the treatment of patients with locally advanced or metastatic EGFR T790M-positive NSCLC. AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib versus platinum-based chemotherapy plus pemetrexed in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on first-line EGFR-TKI therapy.
Methods:
Eligible patients were ≥18 years with documented EGFRm, radiological disease progression following first-line EGFR-TKI and centrally confirmed T790M-positive (by cobas® EGFR Mutation Test) from a tissue biopsy after disease progression. Asymptomatic, stable CNS metastases were allowed. Patients were randomised 2:1 to osimertinib 80 mg orally, once daily or platinum-pemetrexed (pemetrexed 500 mg/m[2] plus either cisplatin 75 mg/m[2] or carboplatin AUC5) every three weeks for up to six cycles; pemetrexed could be continued as maintenance treatment. Primary endpoint was progression-free survival (PFS) by investigator assessment according to RECIST v1.1; sensitivity analysis was by blinded independent central review (BICR).
Results:
A total of 419 patients were randomised to treatment (osimertinib, n=279; platinum-pemetrexed, n=140). Baseline characteristics were generally balanced across treatment groups: female 64%, Asian 65%, never smoker 68%, CNS metastases 34%, EGFR exon 19 deletion 66%. Osimertinib significantly improved PFS compared with platinum-pemetrexed: hazard ratio [HR] 0.30; 95% CI: 0.23, 0.41; p<0.001 (median 10.1 months vs 4.4 months). The result was consistent with PFS analysis by BICR: HR 0.28; 95% CI: 0.20, 0.38; p<0.001 (11.0 months vs 4.2 months). Objective response rate was significantly improved with osimertinib (71%) vs platinum-pemetrexed (31%); odds ratio 5.39 (95% CI: 3.47, 8.48; p<0.001). Median duration of response was 9.7 months (95% CI 8.3, 11.6) with osimertinib and 4.1 months (95% CI 3.0, 5.6) with platinum-pemetrexed. Grade ≥3 causally-related adverse events (AEs) as assessed by the investigator were reported in 6% of patients (n=16) treated with osimertinib and 34% (n=46) treated with platinum-pemetrexed. Most common causally-related AEs in the osimertinib group: diarrhoea (29% [grade ≥3, 1%]), rash (28% [<1%]); in the platinum-pemetrexed group: nausea (47% [3%]), decreased appetite (32% [3%]).
Conclusion:
In patients with EGFR T790M-positive advanced NSCLC following progression on EGFR-TKI treatment, osimertinib demonstrated a superior clinically-meaningful efficacy over platinum-pemetrexed, with a 70% reduction in the risk of disease progression, and well-characterised safety profile, establishing the new standard of care for these patients.
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SC12 - Anticancer Drug Development in the 21st Century (ID 336)
- Event: WCLC 2016
- Type: Science Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:L. Einhorn, K. Kubota
- Coordinates: 12/05/2016, 16:00 - 17:30, Hall C2
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SC12.01 - Establishment of EGFR Tyrosine Kinase Inhibitors: History and Lessons Learned for Future Drug Development (ID 6645)
16:00 - 16:25 | Author(s): T. Mok
- Abstract
- Presentation
Abstract not provided
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