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Santiago Ponce
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MS02 - What Molecular Screening for Which Patients? (ID 65)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Targeted Therapy
- Presentations: 4
- Now Available
- Moderators:Rosario Garcia Campelo, Santiago Ponce
- Coordinates: 9/08/2019, 10:30 - 12:00, Vienna (2016)
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MS02.01 - Platform Selection in an Era of Increasing Numbers and Types of Relevant Biomarkers (Now Available) (ID 3446)
10:30 - 12:00 | Presenting Author(s): David P Carbone
- Abstract
- Presentation
Abstract
30 years ago, the selection of therapy for lung cancer patients was simple, with only a few choices available, and very little personalization beyond that which can be defined by standard light microscopy and physical exam. The treatment of lung cancer patients today has greatly improved with the discovery of features of tumors and patients that enable the selection of specific targeted and immunotherapy approaches resulting in substantially improved quality and quantity of life. Selection of the appropriate therapeutic based on these features makes huge differences in the lives of these patients, and many studies are now showing that starting with the matched therapy improves survival over switching to it after trying “one size fits all” therapy.
Scientific advances are introducing more and more of these markers every year, and while this is undoubtedly a good thing for our patients, each of them has sensitivity, specificity, and platform issues that need to be defined, and adds a level of complexity to lung cancer management that is unprecedented. Individually, many of these features are rare so that the vast majority of individual assays performed are negative, further adding to clinical frustration. Technology has advanced to allow the testing of hundreds or thousands of gene sequences in a single analysis, but other markers are not simple gene sequence alterations, but rather gene rearrangements, protein expression alterations, and some RNA expression profiles that require testing on different platforms. As a result, optimal tumor profiling can involve several different analyses, can cost a significant amount of money, and take a significant amount of time to return a result in a disease where both time and resources available are scarce. Biopsy adequacy also becomes an issue with multi-platform testing, and the availability of blood-based testing lessens this issue for certain types of testing, but introduces issues of limited sensitivity and scope of analyses.
Layered upon this are the different health care systems and availability of testing platforms found worldwide, each of which has to make hard decisions about doing the best thing for their patients within these local constraints. However, the impact on patient outcomes and the health care system of missing a key tumor feature and the selection of inappropriate and potentially toxic therapy, in a world where a single dose of a drug costs several times the cost of the testing makes cost of testing less of an issue than sample adequacy, speed of results availability, accuracy of results interpretation, and availability of matching drugs.
In this section, the clinical and technical features of the currently available platforms in use and their advantages and disadvantages will be reviewed and compared.
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MS02.02 - Liquid Biopsy: Who, When, What and How (Now Available) (ID 3445)
10:30 - 12:00 | Presenting Author(s): Christian Rolfo
- Abstract
- Presentation
Abstract
Presentation Title: Liquid Biopsy: Who, When, What and How
Prof. Dr. Christian Rolfo, MD, PhD, MBA, Dr.h.c., Director of Thoracic Medical Oncology and Early Clinical Trials at University of Maryland Medical Center, Greenebaum Comprehensive Cancer Center, 22 S Greene Street Rm. N9E08, Baltimore, MD 21201.
Liquid biopsy (LB) refers to a multitude of biomarkers that can be isolated with minimally invasive methods from human body fluids (blood, saliva, urine, ascites, pleural effusion, etc.) that include cell free DNA (cfDNA), circulating tumor cells (CTCs), microRNAs (miRNAs), long non coding RNAs (lncRNAs), and exosomes (Fig. 1). Plasma genotyping of cfDNA entered clinical practice in non-small cell lung cancer (NSCLC) for detection of EGFRmutations in both treatment-naïve and EGFR-mutated NSCLC after progression to EGFR tyrosine kinase inhibitors (TKIs) as an alternative source to tissue when histological samples are insufficient or when a biopsy is not feasible. Indeed according to the LB IASLC statement1, plasma cfDNA analysis should be offered to the same population candidate for molecular testing using DNA isolated from tissue (all non-squamous NSCLC subjects, or adenosquamous or in patients with clinical features suggestive of the presence of a molecular driver) in cases with insufficient tumor tissue specimens or where tissue specimens are not obtainable. Moreover, LB is indicated for the identification of acquired resistance mutations in EGFR-mutated NSCLCs progressing during treatment with first- or second-generation EGFR TKIs, reserving tissue re-biopsy in case of negative or inconclusive results.
The PCR-based cobas EGFR Mutation Test v2 was the first FDA approved LB test for NSCLC, although several limitations on sensitivity of this technique. Fortunately, LB is a rapidly evolving field and several commercial and “in house”NGS platforms have been developed, allowing a more comprehensive plasma genotyping that include genetic rearrangements (such as ALK, ROS1, RET, and NTRK) as well as other relevant oncogene drivers, including mutations of BRAF, HER2, MET, and KRAS. Some of the vendors have a Medicare reimbursement in United States. Recently, the multicenter prospective Noninvasive versus Invasive Lung Evaluation (NILE) study demonstrated that a validated and highly sensitive plasma 73-gene NGS test (Guardant360) used at the time of diagnosis of NSCLC was non-inferior to standard-of-care tissue genotyping in identifying guideline-recommended genomic biomarkers, allowing a guideline-complete genotyping in a higher proportion of patients with a shorter median turnaround time2. These results support the rationale for a “blood-first” approach, reserving tissue for PD-L1 immunohistochemistry or in case of negative liquid biopsy testing. In addition to cfDNA, cfRNA is a novel approach to enhance the comprehensive analysis of circulating biormakers.
Furthermore, the increasing use of more sensitive detection methods, such as NGS, poses novel technical and biological challenges in our clinical practice, including the identification of non tumor-related mutations due to clonal hematopoiesis (CH), increased risk of false positive in presence of low variation allelic fraction (VAF), need for standardization and validation of the analytical methods, definition of requirements for appropriate report and interpretation of the results. Novel technologies such as CH-filtering ultradeep NGS have been tested with promising results3. Moreover, the adoption of molecular tumor board is essential for helping oncologists in interpreting NGS testing results4, using evidence-based scales, such as OncoKB and ESCAT tiers5,6.
Recently, LB use has been advocated in immunotherapy-treated patients as a minimally invasive method that can allow a real time monitoring of treatment response and interpretation of challenging radiographic situations, overcoming the limits of conventional radiological assessment methods7,8. Further prospective studies are needed to better clarify the role of cfDNA as a predictive biomarker for immune checkpoint blockage in NSCLC. LB can also allow the estimation of tumor mutational burden (TMB) in plasma, proving a valuable alternative to tissue. Exploratory analyses of two large randomized phase III studies explored the potential utility of blood TMB (bTMB) as predictive biomarker for immunotherapy, using two different platforms (Foundation Medicine and GuardantOMNI)9,10. The results of these studies support bTMB as potential biomarker for immunotherapy in NSCLC. Further prospective studies will clarify the role of bTMB in treatment selection of patient candidate for immunotherapy, as well as the optimal cut-off value, the minimum number of genes necessary for TMB estimation, and the specific mutations useful.
References
Rolfo C, et al. J Thorac Oncol 2018
Leighl N, et al. Clin Cancer Res 2019
Li BT, et al. Ann Oncol 2019
Rolfo C, et al. ESMO Open 2018
Chakravarty D, et al. JCO Precis Oncol 2017
Mateo J, et al. Ann Oncol 2018
Anagnostou V, et al. Cancer Res. 2019
Guibert N, et al. ASCO-SITC 2019
Peters S, et al. AACR Annual meeting 2019
Gandara DR, et al. Nat Med 2018
Figure 1Liquid biopsy in NSCLC – Who, When, What and How? (Credit: created with BioRender)
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MS02.03 - Achieving Effective Lung Cancer Genotyping While Balancing Constrained Resources (Now Available) (ID 3444)
10:30 - 12:00 | Presenting Author(s): Lynette M Sholl
- Abstract
- Presentation
Abstract
Modern oncologic practice for patients with non-small cell lung carcinoma (NSCLC) demands real time data for an increasing numbers of tumor biomarkers. As a result, laboratories are embracing panel-based approaches to tumor molecular profiling, a trend that is facilitated by the adoption of next generation sequencing (NGS) assays. NGS assays may be designed for highly sensitive and focused detection of hotspot mutations (typically by amplicon sequencing) or broader, more comprehensive profiling for detection of a wide variety of alterations in oncogenes and tumor suppressor genes (typically by hybrid capture technology). There are benefits and drawbacks to both approaches. In general, amplicon sequencing offers speed and sensitivity but limited scope and a propensity for PCR-related artifacts that may adversely affect detection of certain mutation types. In contrast, hybrid capture techniques offer tremendous breadth, enabling capture of 100s of genes to whole genomes, but are limited by sensitivity and longer turnaround time.1 Preanalytic steps including sample acquisition, pathologist review to confirm sample adequacy, and nucleic acid extraction often comprise the majority of the turnaround time required to complete focused tumor tissue molecular profiling. Some assays have been optimized for turnaround times of just a few hours- these assays bypass the separate nucleic acid extraction step,2 but are limited by the few number of mutational targets detected, ultimately requiring the use of multiple simultaneous or sequential focused panels.3 This practice, while perhaps the optimal current model from the standpoint of patient care, may be financially prohibitive for many laboratories. This approach additionally requires careful stewardship of patient tissues, as the use of multiple competing assays and may lead to exhaustion of tumor tissue and incomplete tumor molecular profiling. For patients with limited tissue, a considered plan incorporating input from the treating physician, surgical pathologist, and molecular laboratorian should developed early in order to guide assay priority and ensure adequate tissue is available to confirm any unexpected or contradictory results. When the turnaround time for comprehensive large panel testing is clinically acceptable, this approach may be theoretically more cost effective and in most cases will deliver information for essential and emerging biomarkers.4 It is important to keep in mind, however, that even comprehensive DNA-based assays may lack optimal sensitivity for certain structural variants (fusions, large insertion-deletion events), and it may be necessary to couple these tests with focused RNA-based panels optimized for transcript fusion detection.5
1. Rizzo JM, Buck MJ. Key principles and clinical applications of "next-generation" DNA sequencing. Cancer Prev Res (Phila). 2012;5(7):887-900.
2. Ilie M, Butori C, Lassalle S, et al. Optimization of EGFR mutation detection by the fully-automated qPCR-based Idylla system on tumor tissue from patients with non-small cell lung cancer. Oncotarget. 2017;8(61):103055-103062.
3. Lindeman NI, Cagle PT, Aisner DL, et al. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Mol Diagn. 2018;20(2):129-159.
4. Sireci AN. Single Genes, Panels, and Next-Generation Sequencing Platforms: A Financial Perspective. Arch Pathol Lab Med. 2018;142(7):790-791.
5. Benayed R, Offin M, Mullaney K, et al. High Yield of RNA Sequencing for Targetable Kinase Fusions in Lung Adenocarcinomas with No Mitogenic Driver Alteration Detected by DNA Sequencing and Low Tumor Mutation Burden. Clin Cancer Res. 2019.
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MS02.04 - The Role of Molecular Board (Now Available) (ID 3447)
10:30 - 12:00 | Presenting Author(s): Lara Pijuan
- Abstract
- Presentation
Abstract
The Role of Molecular Board
Lung Tumor Board is a multidisciplinary group of specialists who are responsible for diagnosing and deciding the best treatment for a patient with lung cancer. In cancers with little to no metastatic evidence, the case is handed over to surgeons or sometimes to radiotherapists for local and curative treatment. But in cases of locally advanced or metastatic stages, the patient visits the oncologist alone or in conjunction with the radiotherapists for a more systemic approach. A few years ago, the patient was presented to tumor board immediately, but now because we are in the age of precision medicine, the oncologist can gather more information about the tumour itself to initiate the best personalized treatment for each patient’s cancer. In fact, the oncologist requires 3 types of information: accurate histological diagnosis, molecular characteristics of the tumor, and PD-L1 expression.
Prior to the creation of this molecular tumor board, this information could be given by mail, mobile phone messaging, phone call or in person, since all the information usually arrives a few days after the patient is presented at Lung Tumor Board. If all this information is presented in a room with all the specialists involved in obtaining it, the data can be better analysed and the therapeutic decision making will be much more precise. Hence the idea of creating a MTB with oncologists, pathologists, biologists, bioinformatics, technicians, palliative care, and residents to review the different results for a lung cancer patient.
The type of patients to present in this type of Molecular Tumour Board is widely variable, but usually fall into one of these 6 categories:
1) Newly diagnosed patients with metastatic disease.
The MTB would reaffirm that there is sufficient material and that all the molecular or immunohistochemical techniques are underway (EGFR, BRAF, ALK, ROS1, and PD-L1). Oncologists re-assign the patient for the next MTB to review final results. The pathologist also comments on the percentage of tumour cellularity, so that technicians and biologists can make optimized calculations of the cuts and the type of sample that the biologist has to work with (biopsy and/or cell block and/or cytological smears).
2) Patients with progressive disease with a known molecular marker.
They can be patients where the oncologist repeats sampling. Usually the patient is more familiar to the biologist because he receives liquid biopsies to monitor the disease and the pathologist only knows the patient if he has a re-biopsy.
3) Patients with possible disease progression, pseudoprogression or hyperprogression after immunotherapy.
4) Patients with molecular results received from outside (FM, FOne, clinical trials)
The patient is more familiar to the oncologist who treats him and who has decided to send a sample for a clinical trial or external platform. They are presented in the MTB in order to reaffirm the mutation or translocation found with technology available in the center or maybe it can be consulted outside.
5) Surgical patients with multiple adenocarcinomas that require definitive staging.
The patient is most familiar to the pathologist who diagnosed the surgical tumor. They are presented in order to know molecular details of multiple synchronous tumours.
6) Patients that wish to utilize stored material for new diagnostic studies/techniques
For reasons of disease progression, the patient may enter a clinical trial or has the option of systemic treatment, so some studies that were not previously performed in are required.
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EP1.01 - Advanced NSCLC (ID 150)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.01-07 - Definitive Results of a Clinical and Molecular Multicentric Characterization of Long-Term Survivors with Advanced Non-Small Cell Lung Cancer (Now Available) (ID 1191)
08:00 - 18:00 | Author(s): Santiago Ponce
- Abstract
Background
Long survivors (LS) in non-small-cell lung cancer (NSCLC), defined as an overall survival (OS) greater than 2 years, are less than 10% in most series. Classical prognosis factors include stage, weight loss and ECOG, but more information is missing in the literature. Recently, EGFR, ALK and ROS 1 population (less than 20%) reach OS longer than 2 years. Immunotherapy has demonstrated very promising results with more LS compared to chemotherapy in first and second line setting. In this study, we focused in the analysis of LS patients with advanced NSCLC EGFR wt (wild type) and ALK nt (non-translocated), defined as those with OS greater than 36 months, in 7 hospitals in Madrid.
Method
In this serie, first of all, we will try to make a clinical, histopathological characterization collecting data from clinical reports according to a previously defined information. In a second step, we will carry out a genetic analysis of these patient samples comparing to an opposite extreme short survivors (SS) samples (OS less than 9 months). Initially, we used a NGS method of RNA-seq technology to identify differentiating profiles of gene expression between the two opposite populations. And finally, we confirmed this preliminary profile by RT-PCR in the rest of samples.
Result
Ninety-six patients were initially included. The majority were men, smokers or former with adenocarcinoma and ECOG 0- 1. We have obtained a differential transcriptome expression between samples from 6 LS and 6 SS, resulting 13 over-expressed and 42 down-expressed genes in LS comparing to SS transcriptome expression. Some of the genes involved in this initial profile belong to different cellular pathways: Secretin Receptor, Surfactant Protein, Trefoil Factor 1, Serpin Family, Ca-bindings Protein channel and Toll like Receptor family. Finally, we carried on by RT-PCR in 40 samples of SS and LS survivors and only four genes were significantly down-regulated in SS compared to LS in the multivariate analysis. These 4 genes were related to Surfactant Proteins: SFTPA1 (p = 0.023), SFTPA2 (p = 0.027), SFTPB (p = 0.02) and SFTPC (p = 0.047)
Conclusion
We present a sequential genetic analysis of a LS population with NSCLC EGFR wt (wild type) and ALK nt (non-translocated), obtaining a differential RNA seq- and RT-PCR gene profile based on different surfactant proteins expression. A further confirmation in a larger sample is ongoing.
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MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:David R Spigel, Roberto Ferrara
- Coordinates: 9/08/2019, 13:30 - 15:00, Vancouver (2003)
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MA07.02 - Early Change of dNLR Is Correlated with Outcomes in Advanced NSCLC Patients Treated with Immunotherapy (Now Available) (ID 2676)
13:30 - 15:00 | Author(s): Santiago Ponce
- Abstract
- Presentation
Background
The [neutrophils/[leucocytes-neutrophils] ratio (dNLR) correlates with immune checkpoint inhibitors (ICI) outcomes in advanced non-small cell lung cancer (aNSCLC) patients. Significance of early dNLR change after the first course of ICI is unknown.
Method
Patients with NSCLC treated with ICI (PD(L)1+/-CTLA4) between Nov. 2012 and Jun. 2018 at 16 EU/US centers were included. A control group treated with chemotherapy (CT) only was also evaluated (NCT02105168). dNLR was collected at baseline (B) and at cycle 2 (C2). Patients were categorized as low vs high dNLR at each timepoint (defined as < vs > 3, as previously done), and the change between B and C2 (good = low at both timepoints, poor = high at both timepoints, mixed = different at each timepoint).
Result
1485 patients treated with ICI were analyzed. PDL1 was negative in 162 (11%), 1-49% in 178 (12%), ≥50% in 201 (14%), and missing in 944 (64%). dNLR at B and C2 did not associate with PD-L1 status.
At baseline, dNLR was high in 509 (34%) patients and associated with worse PFS compared to those patients with low dNLR at baseline (HR 1.56, P<0.0001) and OS (HR 2.02, P<0.0001). At C2, dNLR was high in 484 (34%) and similarly associated with worse outcomes compared to patients with low dNLR at C2 (PFS HR 1.64, P<0.0001; OS HR 2.13, P<0.0001).
Between B and C2, dNLR remained low in 804 (56%, « good ») or high in 327 (23%, « poor ») or changed in 310 pts (22%, « intermediate »). Those with a good dNLR demonstrated mPFS 5.3, mOS 18.6 mo), followed by those intermediate with mixed dNLR (mPFS 3, mOS 9.2 mo), and finally poor dNLR (mPFS 2, mOS 5mo). Outcomes were independant of PD-L1 expression (adjusted HR for PFS 1.94 for intermediate and 3.16 for poor groups, compared to good dNLR group, P<.001; adjusted HR for OS was 2.08 for intermediate and 3.67 for poor groups, P<0.001).A bootstrap tested the stability of OS/PFS prediction (P<0.001).
In the chemo-cohort (n=173), high C1-dNLR (n=81, 47%) was not associated with OS (P=0.84).
Conclusion
dNLR at baseline, at cycle 2, and the change between these two timepoints associated with outcomes in patients treated with immunotherapy independent of PD-L1, but not in patients treated with chemotherapy alone. dNLR is specifically prognostic in the context of immunotherapy.
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OA03 - Systemic Therapies for SCLC: Novel Targets and Patients' Selection (ID 121)
- Event: WCLC 2019
- Type: Oral Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Christine Lee Hann, Makoto Nishio
- Coordinates: 9/08/2019, 13:30 - 15:00, Hilton Head (1978)
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OA03.03 - Initial Efficacy and Safety Results of Irinotecan Liposome Injection (nal-IRI) in Patients with Small Cell Lung Cancer (Now Available) (ID 1985)
13:30 - 15:00 | Author(s): Santiago Ponce
- Abstract
- Presentation
Background
SCLC accounts for ~15% of lung cancers, with 5-year survival <10%. 50-90% of patients with extensive disease respond to initial treatment; many rapidly relapse due to acquired resistance to front-line platinum-based chemotherapy. Limited treatment options are available for second-line patients. nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor), utilizing intraliposomal stabilization technology to enable high drug load and in-vivo stability.
Method
RESILIENT (NCT03088813) is a two-part Phase 2/3 study assessing the safety, tolerability, and efficacy of monotherapy nal-IRI in SCLC patients who progressed on/after a front-line platinum regimen: Part 1 includes dose-finding then dose-expansion. Key eligibility criteria included ECOG PS 0-1 and adequate organ function, with prior exposure to immunotherapy allowed. Eligible patients received nal-IRI 70mg/m2 or 85mg/m2 (free-base equivalent) q2w. Primary endpoints were safety and tolerability. Efficacy assessments included objective response rate (ORR), best overall response (BOR), progression-free survival (PFS), and overall survival (OS).
Result
30 patients were treated for >12 weeks in Part 1 (male, 43%; median age, 60.4y; platinum-resistant, 40%) with tumor assessments q6w. During dose-finding, 5 patients received nal-IRI 85mg/m2 (deemed not tolerable: dose-limiting toxicity) and 12 patients received nal-IRI 70mg/m2 (deemed tolerable: selected for dose expansion). At data cut-off** (median follow-up, 4.4mo), 25 patients had received nal-IRI 70mg/m2. Diarrhea was the most common gastrointestinal adverse events (AEs) (Gr3, 20%). Hematologic AEs included neutropenia (Gr3, 8%; Gr4, 8%), anemia (Gr3, 8%), febrile neutropenia (Gr3, 4%), thrombocytopenia (Gr3, 4%; Gr4, 4%). Preliminary efficacy identified 11 patients with partial responses (ORR 44%), BOR (PR+SD) of 72%, and 12-week disease control rate (DCR12wks PR+SD) of 48%. PFS and OS are not yet mature.
Conclusion
Part 1 demonstrated encouraging anti-tumor activity for nal-IRI 70mg/m2 in patients with SCLC (ORR: 44%, BOR: 72%). nal-IRI 70mg/m2 was generally well tolerated. Future research is warranted to assess nal-IRI in second-line SCLC.
Table 1. Baseline Demographic, Patient Disposition, Safety & Tolerability, and Clinical Efficacy for Part 1 of the RESILIENT studyDose-Finding /
Dose-Exploration PhaseIrinotecan
Liposome
Injection
85mg/m2
(N=5)Irinotecan
Liposome
Injection
70mg/m2
(N=25)Baseline Characteristics Gender, Male, n (%) 3 (60.0) 10 (40.0) Age (Years, median) 62.0 59.0 Baseline ECOG 0 1 (20.0) 3 (12.0) 1 4 (80.0) 22 (88.0) Time Since Most Recent Progression (Weeks, median) 3.4 3.2 Disease Location, n (%) Locally Advanced 0 2 (8.0) Metastatic 5 (100.0) 23 (92.0) Disposition, n (%) Patient Completed Study 4 (80.0) 12 (48.0) Patient Currently Ongoing* – 7 (28.0) Deaths 2 (40.0) 6 (24.0) Disease Related 1 3 Adverse Event Not Related to Study Drug 1 1 Cardiac Arrest 1 - Hepatic Failure - 1 Adverse Event Related to Study Drug 0 2 Abdominal Sepsis - 2 Patient Discontinued Treatment 5 (100.0) 18 (72.0) Safety & Tolerability, n (%) Any Treatment-Emergent Adverse Event (TEAE) 5 (100.0) 25 (100.0) Grade 3 or Higher TEAE (≥ 2 patients) 5 (100.0) 15 (60.0) Neutropenia 1 (20.0) 4 (16.0) Anemia – 2 (8.0) Thrombocytopenia – 2 (8.0) Diarrhea 3 (60.0) 5 (20.0) Asthenia – 2 (8.0) General Physical Health Deterioration – 2 (8.0) Pneumonia 2 (40.0) 1 (4.0) Abdominal Sepsis – 2 (8.0) Hypokalemia 1 (20.0) 2 (8.0) Renal Failure – 2 (8.0) Best Overall Response Complete Response (CR) – – Partial Response (PR) 2 (40.0) 11 (44.0) Stable Disease 1 (20.0) 7 (28.0) Progressive Disease 1 (20.0) 5 (20.0) Non-evaluable 1 (20.0) 2 (8.0) Objective Response Rate CR + PR 2 (40.0) 11 (44.0) Non-responder 3 (60.0) 14 (56.0) ** Data Cut-off: May 8, 2019. * Per RECIST v1.1 or RANO criteria. Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-113 - Phase 1b Trial of Cabozantinib or Cabozantinib Plus Atezolizumab in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 1455)
09:45 - 18:00 | Author(s): Santiago Ponce
- Abstract
Background
Cabozantinib is an inhibitor of tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, RET, ROS1, and TAM family kinases (Tyro3, AXL, MER). Preclinical and clinical studies suggest that cabozantinib promotes an immune-permissive tumor environment, which may enhance response to immune checkpoint inhibitors (ICIs) such as the anti–PD-L1 mAb atezolizumab. Cabozantinib has demonstrated clinical activity in phase 1/2 studies of advanced NSCLC. Atezolizumab is approved for select patients with advanced NSCLC as monotherapy or as part of a combination regimen. Clinical studies in solid tumors, including NSCLC, indicate that the combination of a VEGF-targeting agent with an ICI may reverse ICI resistance.Here we present the study design of an ongoing phase 1b trial of cabozantinib alone or in combination with atezolizumab that includes cohorts with advanced non-squamous (nsq) NSCLC.
Method
This global, phase 1b, open-label trial (COSMIC-021) is evaluating the safety, tolerability, preliminary efficacy, and pharmacokinetics of cabozantinib alone or in combination with atezolizumab (NCT03170960). The study consists of a dose-escalation stage (completed) and an expansion stage. In the expansion stage, 18 cohorts are being enrolled at the recommended expansion dose of cabozantinib (40 mg po qd) + a standard dose of atezolizumab (1200 mg q3w IV), including 3 advanced NSCLC cohorts: (1) nsqNSCLC with prior ICI therapy, (2) nsqNSCLC without prior systemic anticancer therapy for metastatic disease, and (3) EGFR-mutant nsqNSCLC with prior EGFR-targeting therapy. Thirty patients are being enrolled per cohort, with potential for extended enrollment pending Study Oversight Committee review. Two exploratory single-agent cohorts (N=30) are being enrolled to receive a 60-mg dose of cabozantinib, including a cohort of patients with nsqNSCLC who received prior ICI therapy. Patients will continue treatment as long as they experience clinical benefit per investigator or until unacceptable toxicity. The primary endpoint of the expansion stage is the objective response rate for each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers and immune cell profiles with clinical outcome.
Result
Section not applicable
Conclusion
Section not applicable
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P1.12 - Small Cell Lung Cancer/NET (ID 179)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.12-03 - Antitumor Activity of Single Agent Lurbinectedin in Patients with Relapsed SCLC Occurring ≥30 Days After Last Platinum Dose (ID 1710)
09:45 - 18:00 | Author(s): Santiago Ponce
- Abstract
Background
Lurbinectedin (L) inhibits activated transcription and induces DNA double-strand breaks, leading to apoptosis.
Method
This multicenter, single agent, phase II Basket trial treated a cohort of 105 SCLC patients (pts) with ECOG PS 0-2 who had received one prior chemotherapy line. L 3.2 mg/m2 was administered as a 1-hour i.v. infusion on Day 1 q3wk. Primary endpoint, confirmed overall response rate (ORR) by RECIST v.1.1 according to investigator assessment, was met (ORR=35.2%; 95% CI, 26.2-45.2%). A sub-analysis excluding the 21 pts with disease relapse < 30 days after last platinum dose is reported here.
Result
Median age of 84 evaluated pts was 60 years (range, 41-83), 58.3% were male, ECOG PS 0-1/2 in 96/4%, liver metastasis in 36.9%, history of CNS involvement in 4.8%, prior platinum in 100%, median chemotherapy-free interval (CTFI)=3.9 months (1.1-16.1); prior immunotherapy in 8.3%. A median of 5.5 cycles (range, 1-24) was administered.
ORR, % (95% CI) (confirmed responses) (n=84)
40.5 (29.9-51.7)*
CTFI≥90d (n=60)
45.0 (32.1-58.4)
CTFI 30-89d (n=24)
29.2 (12.6-51.1)
Disease Control Rate at 6 months, % (n=84)
48.8
Median duration of response (months) (95% CI) (n=34)
5.3 (3.5-6.4)
CTFI≥90d (n=27)
6.2 (3.5-7.3)
CTFI 30-89d (n=7)
4.1 (2.6-5.3)
Median overall survival (months) (95% CI) (n=84)**
10.9 (7.8-14.9)
CTFI≥90d (n=60)**
11.9 (9.7-16.2)
CTFI 30-89d (n=24)**
(4.1-7.6)
*4 of 7 pts who failed prior immunotherapy had confirmed response
**Preliminary data
L was well tolerated. Neutropenia was the most common adverse event (AE) (G3:21.5% and G4:25%), whereas febrile neutropenia was reported in 2.4%. Most common non-hematological AEs included fatigue (G3: 7.1%), nausea and vomiting (all G1-2: 32.1% and 16.7%) and transaminase increase (G3:7.2%). There was no death due to treatment related AE.
Conclusion
L is an active agent for second-line treatment of SCLC. The highest ORR (45.0%) was reported for pts with CTFI≥90d. Notable antitumor activity (ORR=29.2%) was also observed in pts with CTFI 30-89d, for whom no therapy is currently approved. Hence, L is a valuable therapeutic option for SCLC pts with disease relapse after first-line platinum-based therapy.
Updated trial results will be presented at the conference.
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P2.12 - Small Cell Lung Cancer/NET (ID 180)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.12-13 - Lurbinectedin (L) Combined with Paclitaxel (P) or Irinotecan (I) in Relapsed SCLC. Results from Two Phase Lb Trials (ID 1588)
10:15 - 18:15 | Presenting Author(s): Santiago Ponce
- Abstract
Background
L is a new agent that exerts antitumor activity through inhibition of trans-activated transcription and modulation of tumor microenvironment. Preclinical evidence of synergism was observed for L in combination with P and I.
Method
Activity of combinations with LP and LI in small cell lung cancer (SCLC) was reviewed in two phase Ib trials. Patients were enrolled following a 3+3 dose escalation design. SCLC patients with ECOG performance status (PS) 0-1 and pretreated with at least one platinum-based chemotherapy are presented. Extensive pharmacokinetic (PK) sampling for L and P or I was performed.
Result
19 pts were treated: 7 with LP and 12 with LI. Baseline characteristics (LP/LI) were: males, 57%/45%; median age, 55/57 years; ECOG PS score 1, 57%/92%; chemotherapy-free interval (CTFI) >90 days, 43%/67%; median (range) prior lines, 1 (1-3)/2 (1-3); liver metastases, 29%/33%.
Lurbinectedin-Paclitaxel
(L: 2.2 mg/m2 – 5 mg FD +
P: 60-80 mg/m2) *
(n=7)
Lurbinectedin-Irinotecan
(L: 1-2.4 mg/m2 + I: 75 mg/m2) **
(n=12)
ORR (CR+PR)
CR
PR
71% (n=5)
14% (n=1)
57% (n=4)
25% (n=3)
0%
25% (n=3)
ORR in CTFI >90d
67%
38%
CB (CR+PR+SD≥4m)
71%
67%
Median DOR
2.3 m 95% CI (2.0-NR)
4.6 m 95% CI (3.0-6.8)
Median PFS
4.8 m 95% CI (1.8-12.5)
5.6 m 95% CI (1.4-8.3)
* Combination with P given for up to 6 cycles, followed by single-agent L 2.2 mg/m2.
** One patient received L 3 mg/m2 + I 15 mg/m2.
CB, clinical benefit; CR, complete response; CTFI, chemotherapy-free interval; d, days; DOR, duration of response; FD, flat dose; I, irinotecan; L, lurbinectedin; m, months; NR, not reached; ORR, overall response rate; P, paclitaxel; PFS, progression-free survival; PR, partial response; SD, stable disease.
Adverse events (AEs): grade (G) 4 neutropenia LP/LI 43%/27% of patients; no episodes of febrile neutropenia in LI, one (G3) in LP; no G4 anemia or G4 thrombocytopenia in either study. Non-hematological toxicity was mild and mainly consisted of G3 fatigue (18%) and G3 nausea (7%) in LI; no G3/4 toxicities were found in LP. No toxic deaths and no discontinuations were due to AEs. PK: mean clearance of L (12 L/h in combo with P, and 9.5 L/h in combo with I), of P (31.5 L/h) and of I (32.2 L/h) are comparable with reported data (11.2 L/h, 31.4/h and 25 L/h, respectively).
Conclusion
LP and LI combinations showed promising activity after first-line therapy in SCLC. This activity seems consistent with that observed in other trials with L given alone or in combination. Both combinations showed acceptable safety profile. So far, no evidence of major PK drug-drug interactions has been observed. Further development of these combinations is warranted.
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PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)
- Event: WCLC 2019
- Type: Plenary Session
- Track:
- Presentations: 1
- Now Available
- Moderators:Giorgio Vittorio Scagliotti, Ramon Rami-Porta
- Coordinates: 9/09/2019, 08:00 - 10:15, Barcelona (2005)
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PL02.11 - Overall Survival with Durvalumab Plus Etoposide-Platinum in First-Line Extensive-Stage SCLC: Results from the CASPIAN Study (Now Available) (ID 2265)
08:00 - 10:15 | Author(s): Santiago Ponce
- Abstract
- Presentation
Background
Extensive-stage (ES)-SCLC is a recalcitrant disease associated with a median OS of ~10 months following etoposide-platinum (EP); new treatments that prolong survival are needed. CASPIAN (NCT03043872) is an open-label, phase 3 study of durvalumab (anti-PD-L1), ± tremelimumab (anti-CTLA-4), combined with EP as first-line treatment for patients with ES-SCLC. Here we report results for durvalumab + EP (D+EP) versus EP from a planned interim analysis.
Method
Patients with previously untreated ES-SCLC (ECOG PS 0/1) were randomised (1:1:1) to durvalumab 1500 mg + EP q3w; durvalumab 1500 mg + tremelimumab 75 mg + EP q3w; or EP q3w. Patients in immunotherapy arms received up to 4 cycles of EP followed by maintenance durvalumab until progression. Patients in the EP arm received up to 6 cycles of EP and prophylactic cranial irradiation (PCI), at the investigator’s discretion. Investigator’s choice of cisplatin or carboplatin was allowed across all arms and was a stratification factor at randomisation. The primary endpoint was OS. Data cutoff: 11 March 2019.
Result
268 patients were randomised to D+EP and 269 to EP. Baseline characteristics were well balanced between arms. In the EP arm, 56.8% of patients received 6 cycles of EP. At the interim analysis, D+EP significantly improved OS compared to EP with a HR of 0.73 (95% CI, 0.591-0.909; p=0.0047); mOS 13.0 versus 10.3 months, respectively. 33.9% of patients were alive at 18 months with D+EP versus 24.7% with EP. Secondary endpoints of PFS and ORR were also improved with D+EP compared to EP: PFS HR 0.78 (95% CI, 0.645-0.936); mPFS 5.1 versus 5.4 months; 12-month PFS rate 17.5% versus 4.7%; investigator-assessed ORR (RECIST v1.1; unconfirmed) 79.5% versus 70.3% (odds ratio, 1.64 [95% CI, 1.106-2.443]). The incidences of grade 3/4 AEs (61.5% versus 62.4%) and AEs leading to discontinuation (9.4% each) were similar between arms; the incidence of haematological toxicities was numerically higher in the EP arm. The durvalumab + tremelimumab + EP arm continues blinded to final analysis.
Conclusion
The addition of durvalumab to EP as first-line treatment for ES-SCLC significantly improved OS (27% reduction in risk of death) versus a robust control arm that permitted up to 6 cycles of EP and PCI. Of note, this chemo-immunotherapy regimen offers flexibility in platinum choice (carboplatin or cisplatin), reflecting current clinical practice for this challenging disease. No new safety signals were identified.
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