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N. Peled
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MA01 - Improvement and Implementation of Lung Cancer Screening (ID 368)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:M. Studnicka, C. Berg
- Coordinates: 12/05/2016, 11:00 - 12:30, Lehar 1-2
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MA01.01 - Detection of Lung Cancer and EGFR Mutations by Electronic Nose System (ID 4867)
11:00 - 11:06 | Author(s): N. Peled
- Abstract
- Presentation
Background:
Early detection of LC has been well established as a significant key point for patient survival and prognosis. New sensitive nanoarray sensors for exhaled Volatile Organic Compounds (VOCs) were developed and coupled with powerful statistical programs; diseases such as LC could be suspected.
Methods:
Breath samples were taken from patients who were evaluated for pulmonary nodules, LC patients before treatment and other control patients. 'Breath-prints' were recognized by nanomaterial based sensor array/Artificial Olfactory System (NaNose®) and Pattern recognition methods were used.
Results:
A total of 139 patients participated in this study, 30 patients with benign nodules, 89 LC patients (16 early and 73 advanced disease) and 20 controls. We revealed significant discrimination between all groups with accuracy of 75.6% to 90.9%. Discrimination of LC from benign nodules had 79% accuracy, while benign nodules could be discriminated from early LC lesions with positive and negative predicted values (PPV and NPV) of 87.7 and 87.5% respectively, and accuracy of 87%. Also, we could discriminate LC patients who harbor EGFR mutations (19) from wild-type (34) with an accuracy of 83%, a sensitivity of 79% and a specificity of 85%. Figure 1
Conclusion:
Breath analysis could discriminate LC patients from benign pulmonary nodules and between EGFR positive and negative mutations. In future, a portable, non-expensive, simple and user-friendly device may support evaluation of pulmonary nodules.
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MA13 - Modern Technologies and Biological Factors in Radiotherapy (ID 395)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Radiotherapy
- Presentations: 1
- Moderators:M. Thomas, P. Mitchell
- Coordinates: 12/06/2016, 16:00 - 17:30, Stolz 1
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MA13.05 - Nivolumab in Non-Small Cell Lung Cancer (NSCLC): The Real-Life Data (ID 5582)
16:30 - 16:36 | Author(s): N. Peled
- Abstract
- Presentation
Background:
Nivolumab has been recently approved by the FDA as a 2[nd]-line treatment of NSCLC. The data regarding its efficacy in the real-life setting is lacking.
Methods:
260 consecutive patients with advanced NSCLC treated with nivolumab at five cancer centers in Israel between January 2015 and March 2016 were observed for OS and toxicity. OS was analyzed by the Cox proportional-hazards regression model.
Results:
Patient baseline characteristics: median age 67y (range 41-99); males 68%; smokers 76%; ECOG PS ≥2 46%; Non-sq/Sq/other 70%/23%/7%; KRASm/EGFRm/ALK+/other genetic aberration/none/NA 7%/5%/0%/4%/42%/42%; brain metastases 21%; liver metastases 21%; treatment (Tx) line: 1st/2nd/3rd+-line/NA 6%/64%/26%/4%. Median duration of follow-up was 4.3 mo (range 0.1-13.8); median Tx duration was 2.7 mo (range 0.1-15.5); median number of Tx cycles delivered was 6 (range 1-26). 130 (50%) patients died; median OS comprised 6.6 mo (95%CI 5.6-8.4). In univariate and multivariate analysis, the only variable which significantly correlated with OS was ECOG PS (table 1). Median OS of patients with ECOG PS 0/1 and ECOG PS ≥2 comprised 8.6 mo and 3.5 mo, respectively. Safety data is presented in table 2. Figure 1Figure 2
Conclusion:
Nivolumab has reasonable efficacy and good safety profile in the real-life setting. ECOG PS ≥2 is associated with poor prognosis.
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MA14 - Immunotherapy in Advanced NSCLC: Biomarkers and Costs (ID 394)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:M. Reck, D.R. Spigel
- Coordinates: 12/06/2016, 16:00 - 17:30, Strauss 2
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MA14.01 - Updated Dataset Assessing Tumor Mutation Burden (TMB) as a Biomarker for Response to PD-1/PD-L1 Targeted Therapies in Lung Cancer (LC) (ID 4011)
16:00 - 16:06 | Author(s): N. Peled
- Abstract
- Presentation
Background:
Immune checkpoint inhibitors (ICPIs) nivolumab and pembrolizumab have been FDA-approved in non-small cell LC (NSCLC). Current IHC based diagnostics are challenged by assay and slide scoring issues and modest predictive value, and more robust and comprehensive biomarkers of ICPI efficacy are needed. A discovery set of 64 NSCLCs treated with ICPIs suggested that high TMB (≥15 mutations/Mb) significantly correlated with longer time on drug (Spigel et al., ASCO 2016, Abstract:9017).
Methods:
Comprehensive genomic profiling (CGP) was performed during the course of clinical care. TMB was assessed as the number of somatic, coding, base substitution and indels per Mb of genome. Microsatellite instability-high (MSI-H) or stable (MSS) status was determined using a proprietary algorithm.
Results:
15,529 LCs: 66% adenocarcinoma, 1% sarcomatoid, 14% NSCLC NOS, 11% squamous, 5% small cell, and 2% large cell were assessed. TMB was similar across all lung histologies (median: 6.3, 8.1, 9.0, 9.9, 9.9, and 10.8); the median was 7.6 for all LC cases (TMB ≥15 in 24% of cases), compared to 4.5 for 80,000+ samples of diverse tumor types in the database. Of LCs assessed 0.3% were MSI-H, of which 30/31 were TMB-high; however, 24% of MSS-stable cases were also TMB-high. PD-L1 amplification and DNA repair pathway mutation (MLH1, MSH2, POLE) were found in 1.0% and 1.1% of LC cases analyzed, respectively. Tumors harboring known drivers (ALK, ROS1, EGFR, BRAF V600E, MET splice) had low TMB (median: 2.5, 3.6, 3.8, 3.8, 4.5), whereas tumors with KRAS mutation, non-V600E BRAF mutation, PD-L1 amplification, or DNA repair alterations were more likely to be TMB-high (median: 9.0, 10.8, 14.4, 21.6).
Conclusion:
High TMB may be a predictive biomarker of response to ICPIs. Several factors including lack of a known driver, MSI-H status, PD-L1 amplification, and DNA repair mutation correlated with high TMB (P<0.0001 for all cases). However, 95% of TMB-high cases assessed were MSS and lacked both PD-L1 amplification and DNA repair mutation, and thus would likely not be selected for immunotherapy by assessment of individual genomic alterations or MSI status alone. A validation cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapies including analysis of clinical outcome, TMB, genomic profile, and available clinicopathologic characteristics will be presented. CGP of LC to simultaneously determine TMB, MSI status, PD-L1 amplification, and the presence of driver alterations may provide clinically useful predictors of response to ICPI and other targeted therapies using a single platform, but prospective clinical trials are needed to confirm these observations.
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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): N. Peled
- 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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MTE04 - Screening for Lung Cancer (Ticketed Session) (ID 298)
- Event: WCLC 2016
- Type: Meet the Expert Session (Ticketed Session)
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 07:30 - 08:30, Schubert 5
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MTE04.02 - Screening for Lung Cancer (ID 6545)
08:00 - 08:30 | Author(s): N. Peled
- Abstract
Abstract not provided
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OA10 - EGFR Mutations (ID 382)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
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OA10.01 - Comprehensive Genomic Profiling and PDX Modeling of EGFR Exon 20 Insertions: Evidence for Osimertinib Based Dual EGFR Blockade (ID 4375)
11:00 - 11:10 | Author(s): N. Peled
- Abstract
Background:
EGFR exon 20 insertion mutations (EGFRex20ins) comprise a subset of EGFR activating alterations relatively insensitive to 1[st] and 2[nd] generation EGFR-TKIs. Comprehensive genomic profiling (CGP) integrated with PDX modeling may identify new EGFR-inhibition strategies for EGFRex20ins.
Methods:
EGFRex20ins and co-occurring genomic alterations were identified by hybrid-capture based CGP performed on 14,483 consecutive FFPE lung cancer specimens to a mean coverage depth of >650X for 236 or 315 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. An EGFRex20ins(N771_P772>SVDNP)/EGFR-amplified tumor (24 copies) from this cohort was implanted subcutaneously into the flank of NOD.Cg-Prkdc[scid]Il2rg[tm1Wjl]/SzJ (NSG) mice for tumor growth inhibition studies (TGI) with vehicle, erlotinib (50 mg/kg PO daily), osimertinib (25 mg/kg PO daily), and osimertinib (25 mg/kg PO daily) plus cetuximab (10 mg/kg IV, 2x/week) administered for 21 days.
Results:
CGP identified 263/14,483 cases (1.8%) with EGFRex20ins, which represent 12% (263/2,251) of EGFR activating mutations in this series. 90% (237/263) were NSCLC-adenocarcinoma, 9% (23/263) were NSCLC-NOS, and 1% (2/263) were sarcomatoid carcinoma. Over 60 unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%); 6% (15/263) harbored EGFR A763_Y764insFQEA, an EGFRex20ins typically sensitive to erlotinib. Among EGFRex20ins cases, EGFR-amplification occurred in 22% (57/263). Putative co-occurring driver alterations including EGFR (ex19del and L858R), Her2, MET and KRAS tended to be mutually exclusive, occurring only in 5% (12/263) of cases. The most common co-occurring alterations affected TP53 (56%), CDKN2A (22%), CDKN2B (16%), NKX2-1 (14%) and RB1 (11%). Average tumor mutation burden was low (mean 4.3 mutations/Mb, range 0-40.3 mutations/Mb). Clinical outcomes to 1st and 2nd generation EGFR-TKIs were obtained for a subset of cases with various EGFRex20ins, and 0/6 patients had responses. However, robust TGI was observed with combination osimertinib and cetuximab in a highly EGFR-amplified PDX model with a conserved EGFRex20ins (N771_P772>SVDNP) not associated with response to earlier generation EGFR-TKI, and was superior to vehicle, erlotinib or osimertinib alone (D21 mean tumor size 70 mm[3] vs. 1000, 800, 225 mm[3] respectively; p-values all <0.001).
Conclusion:
Diverse EGFRex20ins were detected in 12% of EGFR-mut NSCLC. Available clinical outcomes data demonstrated lack of response to 1[st] and 2[nd] generation EGFR-TKIs. Identification of co-occurring EGFR-amplification in 22% of cases led to testing of a dual EGFR blockade strategy with an EGFR monoclonal antibody and osimertinib, which demonstrated exceptional tumor growth inhibition in an EGFRex20ins PDX minimally responsive to erlotinib. These findings can rapidly be translated into an ongoing clinical trial of osimertinib and necitumumab.
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OA21 - Palliative and Supportive Care for Lung Cancer Patients (ID 405)
- Event: WCLC 2016
- Type: Oral Session
- Track: Palliative Care/Ethics
- Presentations: 1
- Moderators:C.A. Silva, H. Watzke
- Coordinates: 12/07/2016, 11:00 - 12:30, Schubert 5
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OA21.02 - ALK-Rearranged Non-Small Cell Lung Cancer is Associated with a High Rate of Venous Thromboembolism (ID 4290)
11:10 - 11:20 | Author(s): N. Peled
- Abstract
- Presentation
Background:
Patients with lung cancer are at increased risk for venous thromboembolism (VTE), particularly those receiving chemotherapy. It is estimated that 8-15% of patients with advanced non-small cell lung cancer (NSCLC) experience a VTE in the course of their disease. The incidence in patients with specific molecular subtypes of NSCLC is unknown. We undertook this review to determine the incidence of VTE in patients with ALK-rearranged NSCLC.
Methods:
We identified all patients with ALK-rearranged NSCLC, diagnosed and/or treated at the Princess Margaret Cancer Centre (PM CC) in Canada between July 2012 and January 2015. Retrospective data were extracted from electronic medical records. We then included a validation cohort comprising all consecutive patients with ALK-rearranged NSCLC treated in two tertiary centers in Israel.
Results:
Within the PM CC cohort, of 55 patients with ALK-rearranged NSCLC, at a median follow-up of 22 months, 23 (42%) experienced VTE. Patients with VTE were more likely to be Caucasian (p=0.006). The occurrence of VTE was associated with a trend towards worse prognosis (overall survival HR=2.88, p=0.059). Within the validation cohort (N=43), VTE rate was 28% at a median follow-up of 13 months. Combining the cohorts (N=98) the VTE rate was 36%. Patients with VTE were younger (age 52 vs 58, p=0.04) and had a worse ECOG performance status (p=0.04). VTE was associated with shorter OS (HR=5.71, p=0.01)Figure 1.
Conclusion:
We found the rate of VTE in our ALK-rearranged cohort is 3-5-fold higher than previously reported for the general NSCLC population. This warrants confirmation in larger cohorts.
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P1.01 - Poster Session with Presenters Present (ID 453)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Epidemiology/Tobacco Control and Cessation/Prevention
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.01-027 - Increased Risk of Lung Cancer among Women with Superficial TCC: A Potential Risk Cohort for Lung Cancer Screening (ID 5585)
14:30 - 14:30 | Author(s): N. Peled
- Abstract
Background:
Background: Screening for lung cancer is recommended among heavy current or former smokers at age 55-80. Transitional Cell Carcinoma of the Bladder (TCC) and lung cancer share same risk factors, however the existence of TCC is not indicated as a reason for screening for lung cancer. Patients with invasive TCC undergo full staging and therefore lung cancer is usually detected if it co-exists. However, in superficial TCC, lung evaluation is not routinely done and may be missed. Here, we have studied the incidence of lung cancer among low stage bladder cancer patients aiming to evaluate if this can be defined as a population at risk.
Methods:
Methods: The SEER (Statistics, Epidemiology and End Results) database was used to determine the Incidence and standardized incidence ratio (SIR), and the average time to discovery of lung cancer in Patients with localized TCC of the bladder (AJCC 6 stages T~0~ through T~1a2~) in years 2000-2013, stratified by age and gender, and compare them to the SIR for all solid tumors.
Results:
Results: based on 89691 patients (F:M ratio 1:3.3), the SIR for all solid tumors was 1.95[CI95%:1.87-2.04] for women and 1.87[1.83-1.9] for men. The SIR for lung cancer in women was significantly higher, 2.40[2.19-2.62], with significance persisting among all age groups >50y. The SIR for men was 1.81[1.73-1.9], not significantly different from the risk for all solid tumors in any age group. The median latency period until discovery of lung cancer was 5.41, 3.54, 2.74 and 0.08 years in women, and 4.41, 3.59, 2.96 and 0.96 in men, for age groups 50-59, 60-69, 70-79 and 80+, respectively.
Conclusion:
Conclusion: Incidence of lung cancer is higher in localized TCC patients than among the general population, and among women it appears to be significantly higher than the general risk of solid tumors. Early stage TCC patients may therefore stand to gain from lung cancer screening, and should be considered as potential screening candidates.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 3
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-033 - Clinical Effectiveness of Hybrid Capture-Based Massive Parallel Sequencing in Therapeutic Strategy Planning in Lung Cancer (ID 5735)
14:30 - 14:30 | Author(s): N. Peled
- Abstract
Background:
Personalized medicine significantly increases survival of lung adenocarcinoma patients. Currently, existing diagnostic guidelines include only EGFR and ALK testing, although other oncogenic drivers can be detected and targeted as well. Massive parallel sequencing (MPS) detects a wider spectrum of actionable genomic alterations (GAs) compared to regular molecular diagnostic procedures. Studies on the influence of hybrid capture-based (HC-based) MPS on therapeutic strategy are limited. In this study, we explored its impact on therapy management and clinical outcomes.
Methods:
A retrospective cohort of patients who were diagnosed with advanced stage lung cancer, and performed HC-based MPS between 11/2011 and 10/2015. Two platforms of HC-based MPS were included: a tissue based assay, and a blood based assay of circulating free DNA (cfDNA, "liquid biopsy") for tissue-exhausted cases. Demographic and clinico-pathologic characteristics, treatments, and outcome data were collected and analyzed.
Results:
One hundred and one patients were analyzed in this study: median age, 63 years; 53% females; 45% never smokers; 85% with adenocarcinoma, 19/101 performed a blood-based assay of cfDNA. HC-based MPS was carried-out upfront and after EGFR/ALK testing yielding negative or uncertain results in 15% and 85% of cases, respectively. HC-based MPS was performed before 1[st]-line therapy in 51.5% cases, and in 48.5%, after treatment failure. HC-based MPS recognized clinically actionable, National Comprehensive Cancer Network (NCCN) recommended drivers in 50% of cases, most commonly in EGFR (18%), RET (9%), ALK (8%), MET (6%) and ERBB2 (5%). EGFR/ALK aberrations were identified in 16 patients by HC-based MPS after negative prior regular testing. Therapeutic strategy was changed for 43 patients (42.6%). A higher fraction of tissue-based assays changed therapeutic strategies (n=37/82, 45%) compared to blood-based cfDNA assays (n=6/19, 32%), although not significantly. The overall response rate after treatment change to targeted therapy was 65% (complete response, 14.7%; partial response, 50%), and 62% if excluding not-previously tested patients. Median duration of targeted treatment was 26 weeks (range: 1-227). Median survival was not reached. Immunotherapy was administered in 33 patients, mostly without a detected actionable driver, presenting disease control rate of 32% and an association to tumor mutational burden.
Conclusion:
HC-based MPS changed therapeutic strategy in close to half of the patients with lung cancer, and was associated with high overall response rate, which may translate into a survival benefit.
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P2.03b-042 - MET exon 14 Mutations Encode a Hyperactive Kinase and Therapeutic Target in Lung Adenocarcinoma (ID 5252)
14:30 - 14:30 | Author(s): N. Peled
- Abstract
Background:
Activation of the MET tyrosine kinase receptor can drive oncogenesis and metastasis in certain cancer types. Somatic mutations at or around the splice junctions for MET exon 14 (METΔ14) are a recurrent mechanism of MET activation. METΔ14 mutations lead to aberrant messenger RNA (mRNA) splicing resulting in a METΔ14 protein lacking the juxtamembrane domain.
Methods:
We analyzed RNAseq data across 12 cancer types to define the prevalence of METΔ14 in solid tumors. We explored the driver role of METΔ14 both in vitro and in vivo. Finally, we explored acquired resistance mechanisms in a patient treated with crizotinib.
Results:
The METΔ14 mutation and aberrant mRNA transcript are most common in lung adenocarcinoma and also identified in other cancers. Endogenous levels of METΔ14 transcript transform human epithelial lung cells in an HGF-dependent manner. This allele also induces lung cancer in mice that is responsive to a clinically available MET inhibitor. Finally, we document clinical response to crizotinib in a patient with a METΔ14-driven NSCLC lung cancer. Upon clinical progression on crizotinib, indicating acquired resistance, we detected acquired MET mutations in cell-free DNA from the patient that converge on critical drug-binding residues in the MET activation loop.
Conclusion:
These findings qualify METΔ14 mutations as drivers of lung adenocarcinoma, deomstrate the utility of a new animal model of MET-driven disease and identify a subpopulation of patients who may benefit from further development of targeted MET/HGF therapies.
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P2.03b-047 - The Clinical Impact of Multiplex ctDNA Gene Analysis in Lung Cancer (ID 5758)
14:30 - 14:30 | Author(s): N. Peled
- Abstract
Background:
Next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) enables a non-invasive option for comprehensive genomic analysis of lung cancer patients. Currently there is insufficient data in regard to the impact of ctDNA analysis on clinical decision making. In this study, we evaluated the clinical utility of ctDNA sequencing on treatment strategy and progression-free survival.
Methods:
In this retrospective study, data was collected from files of 90 NSCLC patients monitored between the years 2011-2016 at the Thoracic Center Unit at Davidoff Cancer Center, Rabin Medical Center, Israel. The patients performed liquid biopsy NGS analysis by a commercial test (Guardant 360), in which ctDNA was extracted from plasma and analyzed by massively parallel paired end synthesis by digital NGS. This test allows the detection of somatic alterations such as point mutations, indels, fusions and copy number amplifications.
Results:
Age at diagnosis ranged between 31 and 89 years, with median age of 63 years. Sex ratio was 1:2.2. Out of 90 patients, 38 consecutive patient files have already been reviewed for clinical impact. 82% (31/38) were diagnosed with Adenocarcinoma. 5% (2/38) performed ctDNA at initial diagnosis, 48% (17/38) performed ctDNA after 1[st] line therapy due to progressive disease and the remaining 50% performed the test after multiple lines of treatment. Liquid biopsy NGS analysis allowed the detection of actionable mutations, according to NCCN guidelines, in 68% (26/38). Treatment decision was changed subsequent to NGS analysis in 34% (13/38) which received tailored targeted therapy. Interestingly, 13% (5/38) were detected with EGFR activating mutation following wild type result by standard local molecular testing based on RT-PCR from tissue biopsy. Based on the RECIST criteria of response evaluation, 30% of the patients had partial response after switching to targeted therapy, 15% had stable disease, 15% experienced progressive disease and ~40% were not evaluated yet. Survival rates will be calculated further in the study based on data availability.
Conclusion:
Our interim results analysis showed that liquid biopsy ctDNA testing revealed possible treatment options for more than two-thirds of patients analyzed, including FDA-approved drugs as well as eligibility for clinical trials. Most of the patients that were evaluated showed a positive response to treatment. Although this topic needs to be further assessed in large randomized controlled trials, these positive results emphasize the utility of liquid biopsy analysis to guide clinicians to select the right therapy for the right patient.
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P3.02a - Poster Session with Presenters Present (ID 470)
- 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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P3.02a-037 - Lung Cancer in Young Patients: Higher Rate of Driver Mutations, Brain Involvement and Better Survival (ID 5998)
14:30 - 14:30 | Author(s): N. Peled
- Abstract
Background:
Young patients with lung cancer represent a distinct subset of patients with this disease. Studies show that younger patients are more likely to be women and non-smokers. They are diagnosed at a later stage; the histologic type is more likely to be adenocarcinoma and more driver mutations such as in the EGFR gene are found. Prognosis and survival of the younger patients has mostly been shown to be better in the younger population.
Methods:
Retrospective data was collected in a single tertiary hospital between 1/2010 and 12/2015. Patients were divided into 2 age groups: patients who were diagnosed aged younger than 50 years and patients aged older than 60 years. We analyzed demographic characteristics, disease course and survival.
Results:
The younger cohort included 77 patients, with a median age of 45 years. The older group included 107 patients, median age of 68 years. Both groups had similar female to male ratio and had similar ratio of smokers, although the younger had significantly lower median pack years (40 vs. 60, P<0.001). Adenocarcinoma was the most common histopathology in both age groups (64% vs. 71%) and a larger proportion of small cell lung cancer histology was found in the younger cohort (12% vs. 3%, P<0.001). EGFR mutations were more common in the young cohort (18% vs. 13%, P=0.06), as well as ALK translocations (9% vs. 1%, P<0.001) and accordingly, they were treated by more targeted therapies (25% vs. 16%, P=0.015). Although young patients had more brain metastasis (38% vs. 21%, P=0.002), their median survival was not significantly different than the older cohort (24.8 vs.18.2 months p=0.5). yet after performing sub-stratification it was found that patients under 40 years had better median survival (70.8 months P=0.05). Among patients with a driver mutation, median survival was better for younger patients (31.9 vs. 17.0 months, P=0.003).
Conclusion:
Young patients with lung cancer have better median survival; their tumors harbor a higher rate of driver mutations and they have a higher percentage of brain involvement.
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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-030 - Use of a 200-Mg Fixed Dose of Pembrolizumab for the Treatment of Advanced Non–Small Cell Lung Cancer (NSCLC) (ID 6129)
14:30 - 14:30 | Author(s): N. Peled
- Abstract
Background:
Previous analyses showed no clinically significant exposure-efficacy relationship for pembrolizumab doses of 2-10 mg/kg. Population pharmacokinetics (popPK) modeling suggested weight-based or fixed pembrolizumab doses could maintain exposures within the established safety/efficacy bounds. Fixed dose advantages include increased convenience, reduced dosing error risk, and less discarded product. Pembrolizumab 200 mg Q3W was evaluated in the KEYNOTE-024 study of pembrolizumab versus platinum-doublet chemotherapy for treatment-naive advanced NSCLC with PD-L1 TPS ≥50% (NCT02142738).
Methods:
Pembrolizumab serum concentration was quantified with an electrochemiluminescence-based immunoassay (lower limit of quantitation, 10 ng/mL). The existing 2-compartment popPK model derived from studies of weight-based pembrolizumab dosing was extended with KEYNOTE-024 concentration-time data. Correlation between pembrolizumab exposure (ie, area under the serum-concentration curve over 6 weeks [AUC~ss-6weeks~]) and efficacy was assessed.
Results:
Median (range) weight was 69.7 kg (38-110) in KEYNOTE-024 and 75 kg (35.7-210) in the existing popPK model studies. In treatment-naive advanced NSCLC, there was a flat relationship between pembrolizumab exposure and efficacy for the 200-mg fixed dose and weight-based doses (linear regression P>0.05). Observed pembrolizumab concentrations for 200 mg (median 1976 μg·d/mL, 90% CI 1124-3322) were consistent with predictions (median 1751 μg·d/mL, 90% prediction interval 955-3136) and fell within the previously observed therapeutic window for 2 and 10 mg/kg (Figure). There was considerable overlap in exposures for 2 mg/kg and 200 mg, regardless of whether weight was >90 or <90 kg for 200 mg (Figure). Figure 1
Conclusion:
Pembrolizumab exposure at 200 mg Q3W is similar to that of 2 mg/kg Q3W. Including data from patients with advanced NSCLC treated with 200 mg did not change the flat exposure-efficacy relationship. Along with the superior PFS and OS provided by pembrolizumab over platinum-doublet chemotherapy as first-line therapy for advanced NSCLC with TPS ≥50%, these data support 200 mg Q3W as an alternative to the approved 2-mg/kg Q3W dose.
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P3.02c-053 - Clinical and Plasma Biomarkers for Disease Control with Nivolumab Treatment for Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 4715)
14:30 - 14:30 | Author(s): N. Peled
- Abstract
Background:
Anti-PD1 antibodies have become the treatment of choice for most advanced NSCLC patients after failure of first line platinum-based chemotherapy. Responses are seen in roughly 20% of treated patients. PDL1 expression level and mutational burden might be predictive factors but are not always available and their predictive accuracy is limited. Predictive biomarkers are urgently needed. We hypothesized that clinical data and baseline blood tests might be predictive for benefit from nivolumab.
Methods:
A chart review was performed of patients with advanced NSCLC who received at least one cycle of nivolumab, at one of three cancer centers during 2015-2016. Additional inclusion criteria were: available baseline clinical data, evaluation of response and availability of blood test results. Blood test results collected were: Absolute Lymphocyte Count (ALC), Absolute Neutrophil Count (ANC), White Blood Cells (WBC), Hemoglobin (Hb), Platelets (PLT), Albumin (ALB), Lactate Dehydrogenase (LDH). Blood test results were collected at baseline and before the second and third treatment. Disease control (DC) was defined as any tumor shrinkage, or stable disease for at least 6 months, as assessed by the treating physician by computerized tomography scans. Patients with DC were compared with patients with progressive disease (PD, patients progressing within the first 6 months). Uni- and multivariate regression analyses were performed using Stata (version 11.2, StataCorp).
Results:
A total of 70 patients treated with nivolumab were included, median age 67 years, 66% males, 27% with DC. DC patients compared to PD patients were younger (61.6 vs 69.3 yr, p<0.001), more females (42% vs 27%, p<0.05), and had a lower baseline WBC (6.9 vs 9.2 K/microL, p<0.05). The difference in WBC between DC and PD patients increased during treatment (2.3 K/microL at baseline, 2.6 prior to third treatment). Lower baseline neutrophil count was associated with DC (p=0.02). Neither performance status nor LDH predicted outcome on uni-variate analysis. On multivariate analysis age (p=0.050) and baseline WBC (p=0.02) were associated with outcome. Patients less than 67 years of age with baseline WBC<8.04 K/microL (n=18) had DC rate of 50%, while DC rate was 4% in patients 67 years or more, with WBC >=8.04 K/microL (n=23).
Conclusion:
We have identified clinical biomarkers (age and baseline WBC) that are associated with DC under nivolumab treatment. Validation on an independent data set is warranted. The association of a low peripheral WBC/ANC with increased response rate raises the possibility that acute inflammatory responses are counteractive to anti-PD1 therapy.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-040 - Long Term Outcomes Following IMRT for Mesothelioma Post EPP and Unresectable (ID 4594)
14:30 - 14:30 | Author(s): N. Peled
- Abstract
Background:
Malignant Pleural Mesothelioma (MPM) is an uncommon thoracic malignancy which remains a challenge in management. In recent years the use of surgery has been widely debated especially the use of extrapleural pneumonectomy. (EPP) Following EPP radiotherapy has been widely used to reduce local control with varied results. In patients that are not surgical candidates definitive intensity modulated radiotheapy (IMRT) based treatment has become an option in addition to systemic therapy (Zaruder et al.). We sought to report our results in a unique middle-eastern population with low-level asbestos exposure for both: IMRT – post – EPP and with IMRT used as definitive therapy for patients who were unresectable.
Methods:
Complete medical records of MPM patients (n=28) treated with IMRT at the Davidoff Center were reviewed with Helsinki committee approval. Patients were divided into two groups: post- EPP(n=17) and without surgery(n=11). Patients following EPP were treated with IMRT to 54Gy to the entire hemithorax. Patients without surgery were treated with pleural IMRT (P-IMRT) to the entire hemithorax to 54Gy. cisplatinum\pemetrexed chemotherapy was used in 18\28 patients. Patients were grouped by asbestos exposure (9/28-32%) and Mediterranean/Arabic (58%) vs. caucasian ethnicity(42%). Patients were followed for outcomes and toxicity until death.
Results:
28 patients, predominately male, (82%) were treated at a single center in Israel between 8/2007 and 3/2016. For patients post-EPP 56% received sequential chemotherapy with IMRT. 94% had epitheliod histology. 11/17 (65%) had disease progression with a median time TTP of 12 months(range 1-72mos) . 23% of remain alive without evidence of disease. Only 2/17 (11%) experienced local failure. The Median OS for this group is 23.6 months(1- 100 months) . For the 11 patients treated with definitive P-IMRT, 90% received platinum based chemotherapy. 81% were epitheliod histology. 54% have experienced progression with median TTP of 12 months. Median overall survival for the cohort is 13.5 months (range 8-49months) . Of note no episodes of grade 3 or greater radiation pneumonitis were seen in the entire cohort.
Conclusion:
This is the first Israeli report of outcomes following definitive therapy for mesothelioma. IMRT was delivered without toxicity. The local control following EPP was excellent with encouraging OS. P-IMRT can be delivered to unresectable patients with encouraging overall survival and time to progression. Further work must be done to sequence systemic therapy with IMRT.
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P3.07 - Poster Session with Presenters Present (ID 493)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Regional Aspects/Health Policy/Public Health
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.07-004 - Nivolumab for Non-Small Cell Lung Cancer (NSCLC): An Economic Model for Risk Sharing Based on Real-Life Data (ID 5452)
14:30 - 14:30 | Author(s): N. Peled
- Abstract
Background:
Increasing costs of novel immunotherapy requires risk sharing between manufacturers and payers. Aside from the cost per dose of the compound, the total treatment cost (TTC) is affected by the duration of treatment (DOT). DOT in real life may differ significantly from that observed in the randomized clinical trials. The objective of this study was to develop a risk sharing strategy based on real world data for the use of nivolumab in NSCLC.
Methods:
We analyzed DOT for 260 consecutive patients with advanced NSCLC treated with nivolumab at five Israeli cancer centers between January 2015 and March 2016. We developed a model to incorporate the number of cycles delivered and to calculate the TTC for each patient. We calculated the “mid-point” (MP) to estimate the number of cycles for all patients to comprise half of the TTC for the population.
Results:
Median age 67y (range 41-99); males 68%; ECOG PS ≥2 46%; Non-squamous (Non-sq)/Squamous(Sq)/other histology 70%/23%/7%; treatment line: 1[st]/2[nd]/3[rd]+-line/NA 6%/64%/26%/4%. All patients received nivolumab as standard of care or within the compassionate use program. Median duration of follow-up was 4.3 mo (range 0.1-13.8); 27% of patients continued the treatment at the time of data cut-off. Median DOT was 2.7 mo (range 0.1-15.5). Median number of treatment cycles delivered calculated from a total of 206 patients was 6 (range 1-26 and 1-23 for Sq and Non-sq NSCLC, respectively). TTC distribution according to the treatment cycle and MP for Non-sq and Sq NCSLC are presented in Figure 1 (A and B), respectively. Figure 1
Conclusion:
Based on current list prices in Israel, the estimated mid-point for total treatment cost is the 5[th] cycle for Non-Sq NSCLC and the 4[th] cycle for Sq NSCLC. Our data may represent a basis for risk sharing discussion between the payers and the manufacturers.
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P3.07-007 - Compassionate Use Program for New Cancer Drugs in Israel - Shortcut for Reimbursement Approval (ID 4873)
14:30 - 14:30 | Author(s): N. Peled
- Abstract
Background:
Drug accessibility and reimbursement remains a major challenge across the globe. The Israeli Ministry of Health (MOH) approves drugs based on previous approval by the FDA and EMA-EU. Compassionate use programs (CPU) represent the use of a compound approved by the FDA/EMA-EU before its approval by local regulatory authorities. CPU provides accelerated access to novel compounds to patients otherwise unable to get the treatment.
Methods:
This is a retrospective analysis of 102 patients treated with nivolumab, osimertinib, or nintedanib within a CPU in a single tertiary Israeli cancer center. Basic patient demographics, different logistic treatment aspects and the time from FDA/EMA-EU approval to reimbursement approval for these compounds in Israel were analyzed.
Results:
We started Nintedanib program by July 2014 when the official MOH approval was 16 months later in Nov 2015. Osimertinib program was started a year before the official approval by MOH and was approved for reimbursement 4 months prior to drug registration. Nivolumab for Non-squamous was started 6 months before approval, while for Squamous the label was approved by MOH 2 months after starting the compassionate program. Reimbursement approval was received 6 months thereafter for nivolumab (Squamous NSCLC). Two out of the three drugs in the program were approved for reimbursement, one of them even before MOH registration. Figure 1
Conclusion:
Compassionate use programs allow access to new cancer drugs prior to their approval by the regulatory authorities, increases physicians' experience with novel compounds and may affect reimbursement approval.
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PL04a - Plenary Session: Immune Checkpoint Inhibitors in Advanced NSCLC (ID 430)
- Event: WCLC 2016
- Type: Plenary
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:J. Soria, C. Zhou
- Coordinates: 12/07/2016, 08:45 - 09:40, Hall D (Plenary Hall)
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PL04a.01 - Health-Related Quality of Life for Pembrolizumab vs Chemotherapy in Advanced NSCLC with PD-L1 TPS ≥50%: Data from KEYNOTE-024 (Abstract under Embargo until December 7, 7:00 CET) (ID 7153)
08:45 - 08:55 | Author(s): N. Peled
- Abstract
- Presentation
Background:
In KEYNOTE-024 (NCT02142738), pembrolizumab provided superior progression-free survival (PFS) over platinum-based chemotherapy as first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) with PD-L1 expression on ≥50% of tumor cells (ie, PD-L1 tumor proportion score [TPS] ≥50%) and no sensitizing EGFR or ALK aberrations (HR 0.50, P < 0.001). Despite a 44% crossover rate from chemotherapy to pembrolizumab, pembrolizumab also significantly improved overall survival (OS) (HR 0.60, P = 0.005). Any-grade (73% vs 90%) and grade 3-5 (27% vs 53%) treatment-related adverse events were less frequent with pembrolizumab. Health-related quality of life (HRQoL) is an important consideration for anticancer therapy, particularly in the first-line setting. We present data from the prespecified exploratory patient-reported outcomes (PRO) analysis of KEYNOTE-024.
Methods:
305 patients were randomized to pembrolizumab 200 mg Q3W or investigator-choice platinum-doublet chemotherapy plus optional pemetrexed maintenance therapy for nonsquamous disease. The EORTC QLQ-C30 and QLQ-LC13 were administered at cycles 1-3 and every 9 weeks thereafter. The key PRO end points were change from baseline to week 15 in the QLQ-C30 global health status/QoL score and time to deterioration in the QLQ-LC13 composite of cough, chest pain, and dyspnea. PROs were analyzed for all patients who received study treatment and completed ≥1 PRO instrument (n = 299).
Results:
Across treatment arms, PRO compliance was >90% at baseline and ~80% at week 15. Least squares (LS) mean (95% CI) change from baseline to week 15 in QLQ-C30 global health status/QoL score was 6.95 (3.29 to10.58) for pembrolizumab (n = 151) and –0.88 (–4.78 to 3.02) for chemotherapy (n = 148). The difference in LS means was 7.82 (95% CI 2.85-12.79; nominal 2-sided P = 0.002). The proportion of improved global health status/QoL score at week 15 was 40.0% for pembrolizumab and 26.5% for chemotherapy. Fewer patients in the pembrolizumab arm had deterioration in the QLQ-LC13 composite of cough, dyspnea, and chest pain (30% vs 39%), and time to deterioration was also prolonged with pembrolizumab (HR 0.66, 95% CI 0.44-0.97; nominal 2-sided P = 0.029).
Conclusion:
Pembrolizumab was associated with a clinically meaningful improvement in HRQoL compared with platinum-based chemotherapy. Combined with the superior PFS and OS and manageable safety profile, these data suggest pembrolizumab may be a new standard of care for first-line treatment of PD-L1–expressing advanced NSCLC.
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