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S. Thongprasert
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SC04 - EGFR Tyrosine Kinase Inhibitors: A Model for Successful Drug Development (ID 328)
- Event: WCLC 2016
- Type: Science Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 4
- Moderators:S. Thongprasert, O. Gautschi
- Coordinates: 12/05/2016, 11:00 - 12:30, Hall C7
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SC04.01 - First- and Second Generation EGFR Tyrosine Kinase Inhibitors (ID 6613)
11:00 - 11:20 | Author(s): J.C. Yang
- Abstract
- Presentation
Abstract not provided
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SC04.02 - Management of Resistance to EGFR Tyrosine Kinase Inhibitors (ID 6614)
11:20 - 11:40 | Author(s): T. Mitsudomi
- Abstract
- Presentation
Abstract:
Discovery of activating mutations of the EGFR gene in adenocarcinoma of the lung in 2004 opened the door to a new era for personalized therapy in thoracic oncology. Lung cancers with EGFR mutation are highly sensitive to EGFR-tyrosine kinase inhibitors (TKI) such as gefitinib, erlotinib, or afatinib, resulting in significantly prolonged progression free survival compared with those treated with platinum doublet chemotherapy. However, acquired resistance inevitably develops usually after a median of 10~12 months. The mechanisms for this resistance have been extensively studied and can be classified into 1) target gene alteration, 2) activation of bypass / accessory pathway, and 3) histologic transformation (Fig.).Figure 1 The most common (50~60%) mechanism for acquired resistance to the EGFR-TKI is a missense mutation at codon 790 of the EGFR gene resulting in substitution of threonine to methionine (T790M). This amino acid change reduces affinity between EGFR kinase and EGFR-TKI compared with that between EGFR-kinase and ATP, leading to reactivation of down-stream pathways. L747S, D761Y, and T854A are also known as secondary mutations that cause acquired resistance, but they are very rare. In these cases, cancer cells are still addicted to or dependent on EGFR pathway. Amplification of the MET gene which codes for a receptor of hepatocyte growth factor (HGF) was the first that was identified as a bypass track resistance mechanism against EGFR-TKI. Following this report, aberrant activation of other receptor tyrosine kinases such as HER2, HER3, AXL, IGF1R, have been reported. It is also shown that some ligands for the receptor tyrosine kinases such as HGF, FGF or IGF cause acquired resistance to EGFR-TKIs. Similarly, alteration of downstream molecule cause resistance. These molecules include BRAF, PTEN, JAK2, CRKL, DAPK, NF-kB, or PUMA. The third mechanism of acquired resistance is histologic transformation that includes small cell lung cancer transformation and epithelial-mesenchymal transition EMT). Exact mechanisms of these histologic changes are not fully understood. However, AXL, Notch-1, TGFb pathway activation as well as down regulation of MED12 ((Mediator Complex Subunit 12) have been proposed as mechanisms of EMT. Then, How are we able to cope with these resistance? For T790M gatekeeper mutations, the third generation EGFR inhibitors that selectively inhibit EGFR-T790M while sparing the wild-type EGFR are active. One of these drugs, osimertinib is already approved and gives a response rate of ~60% and progression free survival of ~11 months. Therefore, identification of T790M at the time of disease progression by rebiopsy is important. We have recently found that three other secondary EGFR mutations implicated in acquired resistance are also sensitive to osimertinib. Tumor resistance caused by activation of accessory pathways can be theoretically coped with by combination of the inhibitor of EGFR and involved molecules. However, because of rarity of each mechanism, there is no clear evidence whether these combination therapies will actually improve patient outcome In other cases, cytotoxic chemotherapy is still an important strategy. According to the IMPRESS study, median progression free survival for patients without T790M who received cisplatin plus pemetrexed was 5.4 months. Eeven with these strategies, cancer cells are smart enough to escape from the therapy using other mechanisms. Heterogeneities in terms of resistant mechanisms within a single patient become evident when specific therapeutic pressure persists. Therefore, we also need to have armamentarium that utilizes other mechanisms to cure lung cancer. Recent advances of immunotherapy targeting immune checkpoints appear attractive in this respect. These mechanism-driven therapeutic approaches will convert this fatal disease into a more chronic disorder, and eventually into a curable disease with the least patient burden.
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SC04.03 - Sequencing of EGFR Tyrosine Kinase Inhibitors (ID 6615)
11:40 - 12:00 | Author(s): K. Park
- Abstract
- Presentation
Abstract:
Figure 1. Sequence of EGFR TKIsFigure 1 Sequencing of EGFR Tyrosine Kinase Inhibitors Keunchil Park, MD, PhD Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Treatment of EGFR-mutant(EGFRm) lung cancer with specific EGFR TKIs, such as gefitinib, erlotinib or afatinib, has opened the door to the precision medicine in the management of advanced non-small cell lung cancer with remarkable tumour shrinkage and improvement in progression-free survival (PFS) and quality of life compared to standard chemotherapy. Despite such a remarkable initial clinical response with EGFR TKIs in patients with EGFR+ NSCLC, however, the disease eventually comes back with the emergence of acquired resistance and median PFS is ~ 1 year. The most common mechanism of resistance is acquisition of the T790M gatekeeper mutation and the 3rd-generation EGFR TKIs irreversibly inhibit mutant EGFR, esp. T790M, with sparing wild-type(WT) EGFR. There are several EGFR mutant specific inhibitors(EMSIs) under development including AZD9291, CO-1686, BI1482694 /HM61713, ASP8273, etc. All these 3rd-generation EGFR TKIs have shown a promising early clinical efficacy in T790M(+) EGFRm NSCLC patients with ORR of ca. 60% and PFS of 9.6 – 10.3 months and appear to be well tolerated. Based upon these encouraging early results many confirmatory phase 3 trials(e.g., NCT02151981, NCT02322281) comparing to the standard chemotherapy in the 2nd-line setting are underway. It is very tempting that one might like to move the 3rd-generation EGFR TKI to 1st-line setting. The development of the 3rd-generation agents as the first-line therapy for patients with EGFRm disease has already started. Recently AZD9291 demonstrated an encouraging clinical activity and a manageable tolerability profile in 1st-line: confirmed objective response rate of 77% (95% CI 64, 87) and mPFS of 19.3 months (investigator-assessed). Currently it is being compared with the 1st/2nd-generation EGFR TKI in the 1st-line setting. The Phase III FLAURA study (NCT02296125), comparing AZD9291 80 mg once daily versus current standard of care EGFR-TKIs for treatment-naïve patients, is enrolling. Though the preliminary result in the 1L setting is quite provocative, extreme caution needs to be exerted since the currently available data are not mature enough to determine which agent is the best in its class and only from a small subset of patients. Though it is hoped that the T790M-mediated resistance can be delayed or prevented by using the EMSIs in the TKI-naïve setting, it is also possible that other less well known escape mechanisms might emerge. Given that EMSI works well after failing 1st/2nd-generation EGFR TKI I believe it seems to be a more reasonable approach to investigate if EMSI in the TKI-naïve setting is more effective than 1st/2nd-generation EGFR TKI followed by EMSI when failing 1st/2nd-generation EGFR TKI with acquired resistance. One of the biggest questions to emerge in the era of next-generation inhibitors that have activity against the basic driver oncogene is whether it makes sense to use this approach before the development of acquired resistance to prevent it from occurring in the first place. Can its use in the 1st-line(TKI-naïve) setting prevent the development of acquired resistance and lead to a longterm control of the disease? Considering the well-known genomic heterogeneity with its possible association with resistance to EGFR TKIs we need better understanding of the biology and resistance mechanisms to this class of new generation EGFR TKIs in order to develop better strategies for subsequent therapies to overcome the resistance including how to best sequence the available EGFR TKIs in the clinic as well as combination therapies. It is fair to say that during the past few years we’ve clearly made another progress in the management of NSCLC patients with EGFRm, including those who failed previous EGFR TKIs. However, the currently available data are not mature enough to determine which agent is the best in its class, with the notable differences primarily related to toxicity and we’re not there yet and still lots of unanswered questions remain and further researches are warranted. References 1. DR Camidge, et al. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol 2014;11: 473–481 2. SS Ramalingam, et al. The Next Generation of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Lung Cancer. Cancer 2015;121:E1-E6 3. GR Oxnard et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M. Nature Med 2015;21:560-564 4. LV Sequist et al. Heterogeneity Underlies the Emergence of EGFR T790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor . Cancer Discov 2015;5(7): 713–22 5. CM Lovly et al. Shades of T790M: Intratumor Heterogeneity in EGFR -Mutant Lung Cancer. Cancer Discov 2015;5(7): 694–6. 6. S Ramalingam, et al. ELCC 2016; Abstract LBA1_PR
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SC04.04 - Liquid Biopsies for Dynamic Monitoring of EGFR Mutations in Lung Cancer (ID 6616)
12:00 - 12:20 | Author(s): M. Schuler
- Abstract
Abstract:
Somatic mutations clustering in exons 18 to 21 of the EGFR gene characterize distinct lung cancer biologies. Patients with metastatic EGFR-mutated lung cancer are exquisitely sensitive to targeted agents inhibiting the EGFR tyrosine kinase, which have demonstrated superior progress-free survival and, in some instances, overall survival when compared to platinum-based chemotherapy in first-line treatment. Several studies have shown that EGFR mutations can be detected by highly sensitive assay technology in free DNA circulating in the blood from patients with EGFR-mutated lung cancers 1,2,3. Circulating EGFR-mutated DNA may drop below the level of detection in patients responding to EGFR-TKI, and persistence or reoccurrence of circulating EGFR-mutated DNA may associate with primary and acquired resistance 1,3. In addition, clonal evolution of EGFR-mutated lung cancers under EGFR-TKI therapy can be mirrored by the detection of gatekeeper mutations, such as EGFR T790M or the EGFR C797S, in circulating DNA 4,5. Hence, mutation analysis in circulating free DNA has been suggested as a clinically more feasible and less invasive method for detection of predictive genomic biomarkers and treatment monitoring in advanced lung cancer. The development of more sensitive technologies and bioinformatic algorithms enables the study of comprehensive genomic biomarker panels in blood-derived DNA, which cover a broader spectrum of actionable mutations in treatment-naïve patients and those with acquired TKI resistance. Currently, there are still several limitations to overcome. First, the predictive value of a mutation detected in blood-derived DNA cannot be simply extrapolated from validation studies conducted with tumor-derived DNA. In consequence, prospective clinical validation of blood-based biomarkers is mandatory. Secondly, most studies comparing EGFR mutation detection in tumor and “liquid” biopsies side-by-side reveal inferior sensitivity of blood-based assays. Also, there is a considerable degree of discordance between such assays 4,6,7. Thus, “negative” findings in circulating tumor DNA have to be confirmed by a second assay in tumor-derived DNA. Apart from inflating spending on molecular diagnostics, this may result in further treatment delays, which is hard to bear for patients in particular in the first-line setting. While these obstacles may be soon overcome by technological advances and evolving data from validation studies, “liquid biopsies” focusing on DNA and/or RNA will always miss out on the histopathological information that can be derived from a biopsy of a tumor or metastasis. In the era of immunomodulatory antibody therapy information of tumor-infiltrating immune and stromal cells as well as expression of biomarkers by specific cell populations or with spatial variation become increasingly important. Until this information cannot be reproducibly derived by novel assay technologies the detection of genomic biomarkers in blood-derived DNA will become a highly valuable, additive modality for specific scenarios of primary diagnosis and treatment monitoring. References: 1 N Engl J Med. 2008 Jul 24;359(4):366-77. 2 Clin Cancer Res. 2009 Apr 15;15(8):2630-6. 3 PLoS One. 2014 Jan 21;9(1):e85350. 4 Lung Cancer. 2015 Dec;90(3):509-15. 5 Nat Med. 2015 Jun;21(6):560-2. 6 Clin Cancer Res. 2016 Mar 1;22(5):1103-10. 7 J Clin Oncol. 2016 Jun 27. pii: JCO667162.
Information from this presentation has been removed upon request of the author.
Author of
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SC29 - Access, Value Assessments and Affordability of Novel Therapies (ID 353)
- Event: WCLC 2016
- Type: Science Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:M. Krzakowski, E. Richardet
- Coordinates: 12/07/2016, 11:00 - 12:30, Strauss 1
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SC29.05 - The Thai Experience to Overcome High Cost Drug in Cancer (ID 6725)
12:15 - 12:30 | Author(s): S. Thongprasert
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With limited resources for health, Low and Middle Income Countries (LMICs) struggle to guarantee all members of their society toget cancer treatments, especially the innovative but expensive cancer medicines[1, 2]. Cancer is a leading cause of deathin Thailand, which is an upper-middle income country in South-East Asia. From 2003 to 2011, the mortality rate from cancer rose from 79 to 95 per100,000 populations. [3].Since the Thai health care reform in 2001[4, 5] several stakeholders have initiated policies andprogramsto facilitate access to medicines. The Thai NLEM is different from the one listed by WHO, due to the fact that WHO listed only the minimum required medicine, while the Thai list included an optimum list. At the present, the Thai NLEM has more than 700 items of active ingredients and 1000 dosage forms [6, 7]. When the NLEM was first introduced in 1981, only cost, safety, and efficacy were considered as criteria for inclusion whereas effectiveness was added to the list of criteria in 2004. Since 2008, economic evidence has become important for the Sub-committee of the NLEM to justify the new costly medicines such as type E2 to be included in the list of NLEM. As of 2009, the NLEM can be divided into six categories, which are A, B, C, D, E1, and E2. Type A: Basic medicines that every health facility must make available Type B: Alternative, second line medicines of those in category A Type C: Medicines prescribed only by specialists TypeD: Medicines used only for particular indications and diseases Type E1: Medicines used only for special or vertical programs Type E2: Medicines that are high costs but are important for particular groups of patients Heath Care Coverage for Thai residences are divided into 3 categories 1. Universal Coverage Scheme (UCS) Cover 75% of Thai population 2. Social Security Scheme (SSS) Cover 19%, Private sector employees, excluding dependants 3. Civil Servant Medical Benefit Scheme (CSMBS) Cover 9%, Government employees plus dependants (parents, spouse and up to two children age <20) The CSMBS has covered most of the cancer drugs including the expensive drugs, however UCS and SSS have covered only drugs listed in the NELM; thus there are unmet need for cancer patients with these two healthcare schemes. Thai government set up several policies to enable access to the cancer drugs such as Compulsory Licensing, Pooled purchasing (price negotiation), Special marketing arrangement (price negotiation), and E2 access program. Several pharmaceutical companies provide their own scheme for patients who are willing to pay for the drug by themselves (patient access program) Even with all the programs available, the problem of accessibility of costly anticancer drugs still persists. There should be more input into this problem. References 1. Kanavos P, Das P, Durairaj V, Laing R, Abegunde DO (2010) Options for financing and optimizing medicines in resource-poor countries World Health Organization. 2. American College of Physicians (2011) How can our Nation Conserve and Distribute Health Care Resources Effectively and Efficiently? Philadelphia: American College of Physicians. 3. MoharaA,YoungkongS,PérezVelascoR,WerayingyongP,PachaneeK,etal.(2012)UsinghealthtechnologyassessmentforinformingcoveragedecisionsinThailand.JComparEffectRes.1:137–146. 4. Damrongplasit K, Melnick GA (2009) Early results from Thailand's 30 Baht Health Reform: something to smile about. Health Aff (Millwood). 28: w457–466. doi: 10.1377/hlthaff.28.3.w457 PMID: 19336469 5. Towse A, Mills A, Tangcharoensathien V (2004) Learning from Thailand's health reforms. BMJ. 328: 103–105. PMID: 14715608 6. Yoongthong W, Hu S, Whitty JA, Wibulpolprasert S, Sukantho K, et al. (2012) National drug policies to local formulary decisions in Thailand, China, and Australia: drug listing changes and opportunities. Value Health. 15: s126–131. doi: 10.1016/j.jval.2011.11.003 PMID: 22265059 7. Turongkaravee S, Rattanavipapong W, Khampang R, Leelahavarong P, Teerawattananon Y, et al. (2012) Evaluation of high-cost medicine scheme (Category E2) under the 2008 National List of Essential Medicines. Nonthaburi: Health Intervention and Technology Assessment Program.
