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Jessica Menis
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ES14 - What First Line in Oncogene Addicted NSCLC (ID 17)
- Event: WCLC 2019
- Type: Educational Session
- Track: Targeted Therapy
- Presentations: 5
- Now Available
- Moderators:Dolores Isla, Jessica Menis
- Coordinates: 9/08/2019, 15:15 - 16:45, Vancouver (2003)
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ES14.01 - First Line in EGFR Mutated Patients (Now Available) (ID 3230)
15:15 - 16:45 | Presenting Author(s): Thanyanan Reungwetwattana
- Abstract
- Presentation
Abstract
Precision medicine is currently applied for almost all cancer types, especially, in NSCLC which is the prototype of successful targeted therapy. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the first effective targeted drug found in NSCLC for treatment in EGFR-mutation positive patients. EGFR (also termed human epidermal growth factor receptor 1 [HER1] or ErbB1) is a member of the ErbB family of cell surface receptor tyrosine kinase1. It is a 170‑kDa RTK with an extracellular ligand‑binding domain, a transmembrane region and an intracellular tyrosine kinase. The RTKs form homodimers and heterodimers after binding to specific ligands, leading to autophosphorylation of tyrosine residues on the intracellular TK domain. This interaction recruits a diverse set of signal transduction cascades including the phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR), signal transduction and transcription (STAT) transcription and RAS/RAF/ mitogen‑activated protein kinase (MAPK) proliferation pathway1. In 2004, somatic mutations in the TK domain of EGFR, found most frequently in adenocarcinomas from patients in Asia who were never or former smokers, were strongly correlated with sensitivity to EGFR-TKIs1. The prevalence of EGFR mutation in NSCLC patients is higher in Asian population compared to the other population (50-55% vs. < 20%). These mutations are mostly distributed in four exons (exon18 to exon21)2. In‑frame deletions of exon19 (44%; E746‑A750deletion) and L858R substitutions in exon21 (41%) are the most prevalent mutations associated with sensitivity to EGFR-TKIs. The point mutations in exon18 (G719C, G719S and G719A) and exon20 (V765A and T783A) are less frequent; 5% and 1%, respectively1.
Presence of the “classical” mutations in exon19 and 21 are the best predictive biomarker for the efficacy of EGFR-TKIs with superior response rate (RR) of 60-70%, progression‑free survival (PFS) of 9-18.9 months, and overall survival (OS) more than 2 years compared with conventional chemotherapy in patients with tumors harboring EGFR‑sensitive mutations making EGFR-TKI is the first-line treatment3. Currently, there are 3 generations of EGFR-TKIs approved in the market. The strategy of first-line treatment in EGFR-positive patients can be categorized into 2 strategies. The first one is treating by the single agent EGFR-TKIs. The first and second-generation EGFR-TKIs have the efficacy in term of PFS of 9-14.7 months in first-line treatment, but if starting with third generation EGFR-TKI, the PFS is longer (18.9 months)3-4. The ORR is similar either starting with 1st, 2nd, or 3rd generation EGFR-TKIs (60-70%). The acquired resistance could be occurred after 9-14 months of treatment by 1st and 2nd-generation EGFR-TKIs and the majority of resistance mechanism is T790M (50-60%) which is now we have the 3rd-generation EGFR-TKI for overcoming this resistance. Moreover, the other bypass tracts (MET amplification, BRAF, HER2 mutation etc.)5 could be the mechanism of resistance as well and we have the potential targeted drugs in the clinical studies which some of them will be approved in the near future. The mechanism of resistance if we start the 1st-line treatment with 3rd-generation EGFR-TKI is different from the previous one. Recently, exploratory data from FLAURA study was reported. They found no T790M detected in the patients whom had progressive disease after 1st-line treatment with 3rd-generation EGFR-TKI. The most common detected acquired resistance genes in the blood were C797S and MET amplification. The other mechanism included HER2 amplification, PIK3CA and RAS mutations. Furthermore, the 3rd-generation EGFR-TKI has the significant strong evidence of better in survival outcome and CNS response in patient whom had the CNS metastases disease6. The second strategy is starting 1st-line treatment with the combination therapy. The recent studies reported in ASCO2018 and ASCO2019 showed the longer PFS (16-19 months) in combination of 1st- generation EGFR-TKI and anti-angiogenesis agents and also longer PFS (16-20 months) in combination of 1st-generation EGFR-TKI with doublet platinum-based chemotherapy compared to single agent 1st-generation EGFR-TKI.7-9 Definitely, there were more adverse events for the combination treatment. The rate of occurring T790M as the acquired resistance and the CNS efficacy are the issues to concern for the combination treatment (Figure 1). The most proper sequence of the treatment in EGFR-positive NSCLC is needed to explore more in the clinical studies. It has pros and cons in each approach and it depends on several factors such as; the patients’ performance status, the location of tumor (CNS metastases?), types of EGFR mutations, acquired resistance, toxicities, treatment after progression, cost of treatment and the reimbursement issue in each country.
In summary, EGFR mutation is the crucial oncogenic-driven mutation in NSCLC with effective EGFR-TKI treatment making the patient has good quality of life (QOL) even though they have the advanced-stage disease. The journey of treatment in this group of patients is still underway of development and it is the good prototype for the other targeted drugs development in the clinical studies. I believe that there will be the other effective novel targeted treatments for NSCLC approved in the near future which would improve the long-term survival and QOL for patients.
References:
1. Salomon DS, et al. Crit Rev Oncol Hematol 1995
2. Lynch TJ, et al. N Engl J Med 2004
3. Reungwetwattana T, et al. Journal of Carcinogenesis 2013
4. Soria JC, et al. N Engl J Med 2018
5. Papadimitrakopoulou V, et al. ESMO Congress 2018
6. Reungwetwattana T, et al. J Clin Oncol. 2018
7. Furuya N, et al. ASCO Congress 2018
8. Nakamura A, et al. ASCO Congress 2018
9. Nakagawa K, et al. ASCO Congress 2019
Figure 1: The survival outcome of each approach for EGFR-positive NSCLC
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ES14.02 - First Line in ALK Translocated Patients (Now Available) (ID 3231)
15:15 - 16:45 | Presenting Author(s): Alice T. Shaw
- Abstract
- Presentation
Abstract
Chromosomal rearrangement of ALK defines a distinct subset of non-small cell lung cancer (NSCLC) with marked sensitivity to small molecule ALK tyrosine kinase inhibitors (TKIs). Currently, five ALK TKIs are approved as standard therapies for advanced ALK-positive NSCLC, including the first generation ALK/ROS1/MET inhibitor crizotinib, the second generation ALK inhibitors ceritinib, alectinib and brigatinib, and most recently the third generation ALK/ROS1 inhibitor lorlatinib. In three randomized phase 3 studies (J-ALEX, global ALEX, and ALESIA), alectinib has demonstrated superior efficacy compared to crizotinib, and has replaced crizotinib as the standard first-line therapy for advanced ALK-positive NSCLC. Recently, in a planned interim analysis of the ALTA-1L phase 3 study, brigatinib has also shown superior efficacy to crizotinib as first ALK TKI in advanced ALK-positive NSCLC. In this talk, we will review all the available first-line data with ALK TKIs, with a focus on next-generation ALK inhibitors. In addition to discussing second-generation ALK TKIs, we will also highlight available data with lorlatinib in the first-line setting. The phase 3 study of lorlatinib vs crizotinib as first-line therapy (CROWN) has completed accrual, with results expected within the next year. Finally, we will discuss the potential role of investigational combinations as first-line therapy in advanced ALK-positive NSCLC. These investigational strategies hold the promise of further extending front-line progression-free survival as well as overall survival for this molecular subgroup of patients.
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ES14.03 - First Line in ROS1 Translocated Patients (Now Available) (ID 3232)
15:15 - 16:45 | Presenting Author(s): Frances Shepherd
- Abstract
- Presentation
Abstract not provided
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ES14.04 - First Line for Rare Mutations (RET, BRAF, HER2) (Now Available) (ID 3233)
15:15 - 16:45 | Presenting Author(s): David Planchard
- Abstract
- Presentation
Abstract
Systemic therapy for non-small cell lung cancer (NSCLC) has undergone a dramatic paradigm shift over the past decade. In the recent years a number of other oncogenic drivers beyond EGFR, ALK, and ROS1 inhibition have emerged as novel molecular targets with potential therapeutic implications, including mutations in the genes BRAF, HER2, as well as RET rearrangements. A great number of clinical trials are currently underway, evaluating agents specifically designed to target these alterations. Here, we discuss both established and emerging targeted therapy approaches, as well as ongoing challenges for the treatment of NSCLC patients harboring these oncogenic alterations.
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ES14.05 - Patients Harbouring a Driven-Mutation: Pro and Patient's Perspective (Now Available) (ID 3234)
15:15 - 16:45 | Presenting Author(s): Karen L Reckamp
- Abstract
- Presentation
Abstract
Patients Harbouring a Mutation-Driven NSCLC—Pro and Patient Perspective
Karen L. Reckamp, MD, MS
City of Hope Comprehensive Cancer Center, Duarte, CA, USA
Genomic alterations in non-small cell lung cancer (NSCLC) define distinct subtypes with specific mechanisms leading to constitutive activity of a gene pathway, and tumor growth and metastasis. Targeted therapy for NSCLC with oncogenic driver mutations or alterations, usually with small molecule tyrosine kinase inhibitors (TKIs), has changed the paradigm for treatment of patients. New genetic alterations continue to be described with potential therapeutic interventions, and over 60% of patients with the adenocarcinoma subtype of NSCLC have a defined molecular alteration1. The perspective of the clinician and patient merges on the ideal that treatment for NSCLC should provide a long duration of cancer control (ideally tumor shrinkage) with limited side effects, and improvement in quality of life. Some aspects of treatment with targeted therapy may be more important to the treating physician, while patients may have a differing viewpoint during care. This will be explored.
From a clinician’s lens, the treatment for patients with NSCLC harbouring an alteration that can be treated with a targeted therapy involves an algorithm that includes the ideal sequencing of therapy. This requires determining the best front line therapy based on progression free survival (PFS) and overall survival while including the toxicity profile into the algorithm, and also assessing possible mechanism of resistance and options for subsequent therapy. A front line option should not be withheld based on second line options, but sequencing of therapy to increase survival and quality of life becomes an important part of the treatment decision (Table 1). This may be best exemplified in the case of EGFR mutant NSCLC, in which osimertinib demonstrated clear PFS benefit over erlotinib or gefitinib.2 In this case, mechanisms of resistance are still being elucidated and subsequent therapy becomes chemotherapy combinations. Recent studies have shown PFS benefit with first generation EGFR TKIs in combination with ramucirumab or chemotherapy, but were not directly compared to osimertinib. Furthermore, the toxicity with the combination therapy was also increased. Therefore, the choice of osimertinib as front line therapy is optimal for most patients. Another important aspect in the physician choice of front line therapy is brain penetration, which most TKI therapy is able to achieve, but some are better than others. Importantly, patients will not be treated with novel targeted therapies if they are not tested. Testing can include single gene testing by PCR and FISH, NGS testing and hotspot analysis either on blood or tissue. The utility of liquid biopsies to identify alterations in the metastatic front line setting has been shown,3 and detection has led to actionable therapy.4
Patients expect their physicians to be advocates for their therapy and their lives, and want a reason to hope. Most would like to avoid chemotherapy if possible in the course of treatment. They want the most current, and extensive testing done to determine the right therapy, but also encounter the economic impact of diagnosis and treatment of oncogene-driven NSCLC. Untangling the clinical trial data to provide the therapy most likely to prolong quality of life and survival is essential. Inadequate testing up front can lead to inappropriate treatments, and increased anxiety associated with additional tests and time required to find the right treatment. A NSCLC patient who is also a physician provides valuable insight into the patient perspective, “Everyone with lung cancer needs to have their cancer tissue tested for genetic mutations… That biopsy may lead to identifying mutations that can be successfully targeted. All therapies, whether conventional or targeted, provide bridges to keep you alive for the next therapy, to get to the next bridge. My ultimate goal is not necessarily to cure the disease, but to successfully manage the disease. Very much like the way HIV/AIDS and diabetic patients manage their disease for many, many years….to convert a death sentence to a chronic illness.”5
References
1. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA : the journal of the American Medical Association 2014;311:1998-2006.
2. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25.
3. Leighl NB, Page RD, Raymond VM, et al. Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non-small Cell Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2019.
4. Rothwell DG, Ayub M, Cook N, et al. Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study. Nature medicine 2019;25:738-43.
5. June 7, 2019
Table 1.
Oncogene
Mutation prevalence
Approved drugs
First-line drug of choice
Driver-oncogenes with approved agents
EGFR
Asian 30-40%/ Caucasian 10-20%
Erlotinib
Gefitinib
Afatinib
Osimertinib
Osimertinib
ALK
1-7%
Crizotinib
Ceritinib
Alectinib
Brigatinib
Lorlatinib
Alectinib
ROS1
1.7%
Crizotinib
Ceritinib
Crizotinib
BRAF
2%
Dabrafenib/trametinib
Dabrafenib/trametinib
NTRK
<1%
Larotrectinib
Larotrectinib
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Author of
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MA08 - Pawing the Way to Improve Outcomes in Stage III NSCLC (ID 127)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Now Available
- Moderators:Simon Ekman, Helena A Yu
- Coordinates: 9/08/2019, 15:15 - 16:45, Tokyo (1982)
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MA08.02 - Durvalumab Impact in the Treatment Strategy of Stage III Non-Small Cell Lung Cancer (NSCLC): An EORTC Young Investigator Lung Cancer Group Survey (Now Available) (ID 608)
15:15 - 16:45 | Author(s): Jessica Menis
- Abstract
- Presentation
Background
Stage III NSCLC represents a very heterogeneous population with extremely different treatment modalities including surgery, chemotherapy (CT) and radiotherapy (RT), mostly in combination. The results of the PACIFIC trial have now been reported in full including an overall survival (OS) benefit with durvalumab in addition to concomitant CT-RT. An electronic European survey was circulated to evaluate the impact of durvalumab in the staging and treatment strategy of stage III disease.
Method
A Young Investigator EORTC Lung Cancer Group survey containing 31 questions, was distributed between 31/01/18 and 31/03/19 to EORTC LCG and several European thoracic oncology societies’ members
Result
206 responses were analyzed (radiation oncologist: 50% [n=103], pulmonologist: 26.7% [n=55], medical oncologist: 22.3% [n=46]; 81.5% with >5 years experience in treating NSCLC). Italy (27.7%, n=57), Netherlands (22.8%, n=47), France (13.6%, n=28), and Spain (11.6%, n=24) contributed most. 83.5% (n=172) confirmed that they had access to durvalumab at the time of the survey. 97.6% (n=201) report that treatment decision is made by a multidisciplinary board. Regarding staging, 76.7% (n=158) support the need of a mediastinal pathological staging in case of suspect lymph-nodes, with a preference for EBUS/EUS (61.2%, n=126). 81.6% (n=168) treated more than half of patients with a concomitant CT-RT with the 1st cycle of chemotherapy in 39.7% (n=81). 95.1% consider durvalumab as practice changing, especially given the OS results (77.9%, n=152/195). 30% (n=119/395) will give patients concomitant CT-RT if PD-L1 >1%, and in borderline resectable cases 17.7% (n=70/395) will propose concomitant CT-RT instead of surgery. Durvalumab administration will be given regardless of PDL1 status in 13.1% (n=27) and 28.6% (n=59) would consider the possibility of a rebiopsy after CT-RT in case of negative PD-L1. 38.8% (n=80) foresee some problems with PD-L1 testing in this population due to availability of cytologic or small histologic samples. About 53.8% (n=105/195) normally will start durvalumab within 6 weeks after CT-RT and 48.5% (n=100) would also use durvalumab after sequential CT-RT
Conclusion
Durvalumab results are changing the treatment approach to stage III unresectable (and maybe resectable) NSCLC and planned strict adherence to the patient population as recruited to the PACIFIC study, was not demonstrated. This survey was released after the EMA approval of durvalumab and PD-L1 status seems to play a role in the treatment strategies, but surprisingly almost half of the clinicians will use durvalumab after sequential CT-RT without safety or efficacy data.
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YI02 - Clinical Trials (ID 108)
- Event: WCLC 2019
- Type: Young Investigator Session
- Track: Young Investigators
- Presentations: 1
- Now Available
- Moderators:Laura Mezquita, Frances Shepherd
- Coordinates: 9/07/2019, 09:00 - 10:30, Dublin (1997)
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YI02.02 - Basket and Umbrella Trial Designs in Oncology (Now Available) (ID 3697)
09:00 - 10:30 | Presenting Author(s): Jessica Menis
- Abstract
- Presentation
Abstract
Cancer treatment has made gigantic improvements in patients’ prognosis in multiple cancer types, by virtue of major steps forward in the concept of personalized medicine. This involves scientific progress in tumour biology, genomics technology, computational analysis and drug discovery that has propelled advances in both translational and clinical cancer research.
In particular, rapid development, decreased cost, and increased availability of next-generation genomic sequencing and other methods for both molecular and, more recently, immunological tumor classification have changed the paradigm for understanding and treating cancer.
Until recently, drug development has been conducted separately for different histological tumor types since the histological type was the primary known determinant of drug efficacy. However, this histology focus has been integrated by new knowledge on genomic alterations and immunological profile. Therefore, clinical trials have been evolving in parallel, from the traditional two-arm comparison of an experimental treatment vs. a control, to accelerate identification of promising therapies, to increase throughput and to allow for the increasing use of molecular and immunological classification of patients into smaller sub-groups.
Also cost-efficiency need to be considered: classical phase I, II and III models for drug development require large resources, limiting the number of experimental agents that can be tested and making the evaluation of targeted agents inefficient.
On the other hand, methodology and quality assurance need to be preserved since the validation of biomarkers is generally affected by several challenges, such as the multitude of assessment methods (i.e. immunohistochemistry, fluorescence in situ hybridisation, next-generation sequencing, etc.), reliability in terms of sensitivity and specificity, reproducibility of the test, feasibility of obtaining an adequate and representative tumour sample and, finally, the overall related costs.
All these considerations, added to the strong collaboration with the regulatory agencies, approving novel agents based on data obtained from phase 1/2 trials, have led to an evolution in the design of early-stage clinical trials.
The enrichment design can require many fewer patients, i.e. only those patients hypothesized to benefit, to be randomized relative to the “all comers” randomized design. The choice between an unselected versus enriched design should always be made also based on the existing level of evidence for the predictive biomarker.
Two main enrichment strategies can be used to avoid over-treatment and save valuable resources, by matching the right drug to the right subgroup of patients. They can be defined as: basket trials and umbrella trials.
Basket trials allow patients with multiple diseases and one or more target to be enrolled in cohorts or groups in one trial (the basket). They are often viewed as parallel phase II trials within the same entity, designed on the basis of a common denominator. Researchers are therefore allowed to separately analyse the patients’ responses as each tumour type can be put in one cohort, and assess the impact of the drug on all of the patients as one group. If one group shows a good response, this group will be expanded to immediately assess whether others could benefit from the new therapy. If another group does not show evidence of effectiveness, this group may be closed and the other cohort can continue the recruitment. Basket trials can be further sub-classified in three groups: basket trials on one drug in several tumour types (1), basket trials on one drug for one molecular alteration in several tumour types (2), and basket trials on one drug in several molecular alterations in several tumour types.
Umbrella trials are built on a centrally performed molecular portrait and molecularly selected cohorts with matched drugs, and can include patients’ randomisation and strategy validation. In the umbrella design, a separate enrichment trial is conducted for each bio- marker stratum. The enrichment design for a given stratum uses as the test regimen a drug expected to be active for the alteration defining that stratum.
Beyond new designs, new end-points and new evaluation techniques are also warranted to finally achieve methodology and clinical improvements, in particular within immunotherapy trials.
As clinicians continuously learn from their patients, applying knowledge gained from one set of patients to their forthcoming patients, in adaptive designs, modifications of some aspects of the trial can be prospectively planned so that changes (‘‘adaptations’’) may take place while the study is ongoing (for example: a treatment arm or a subgroup of patients could be dropped; the trial size could be increased, etc). Planning for such types of studies would allow to overcome the challenge related to the limited available information in the literature describing the targeted sub-populations.
Alongside the growing complexity of these clinical trials, new frameworks for stronger and faster collaboration between all stakeholders in drug development, including academic institutions and frameworks, clinicians, pharma companies and regulatory agencies, has to be further encouraged.
In the current era, the main goal should be to identify large and meaningful differences in small, molecularly and immunologically selected groups of patients and to develop rapidly new compounds. Basket and umbrella trials respond to the need of ‘‘trials designed to learn’’, that can evolve into ‘‘trials designed to conclude’’.
Menis J, Hasan B, Besse B. New clinical research strategies in thoracic oncology: clinical trial design, adaptive, basket and umbrella trials, new end-points and new evaluations of response. Eur Respir Rev 2014; 23: 367–78
Simon R. Critical Review of Umbrella, Basket, and Platform Designs for OncologyClinical Trials. Clin Pharmacol Ther. 2017; 102(6):934-41
Renfro LA, Sargent DJ. Statistical controversies in clinical research: basket trials, umbrella trials, and other master protocols: a review and examples. Ann Oncol. 2017;28(1):34-43
Garralda E, Dienstmann R, Piris-Giménez A, Braña I, Rodon J, Tabernero J. New clinical trial designs in the era of precision medicine. Mol Oncol. 2019;13(3):549-57
Renfro LA, Mandrekar SJ. Definitions and statistical properties of master protocols for personalized medicine in oncology. J Biopharm Stat. 2018;28(2):217-228
Rashdan S, Gerber DE. Going into BATTLE: umbrella and basket clinical trials to accelerate the study of biomarker-based therapies. Ann Transl Med. 2016;4(24):529
Morrell L, Hordern J, Brown L, et al. Mind the gap? The platform trial as a working environment. Trials. 2019; 20(1):297
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