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C. Zhou
Moderator of
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ED11 - Advanced NSCLC: State-of-the-Art Treatment (ID 280)
- Event: WCLC 2016
- Type: Education Session
- Track: Advanced NSCLC
- Presentations: 4
- Moderators:C. Manegold, C. Zhou
- Coordinates: 12/07/2016, 11:00 - 12:30, Hall C8
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ED11.01 - Systemic Therapy for Advanced Oncogene-Driven NSCLC (ID 6485)
11:00 - 12:30 | Author(s): D.R. Gandara, S. Popat, B. Melosky
- Abstract
- Presentation
Abstract:
Oncogene-driven lung cancer remains the embodiment of personalized medicine. Since the first description of EGFR activating mutations found in patients with what was then called bronchiolalveolar carcinoma of the lung (BAC) in 2004, the topic of oncogene-driven lung cancer has grown rapidly and expanded to now encompass a number of additional mutation- and fusion-related entities. Recent updates to molecular testing guidelines, such as those of IASLC, have added several new oncogenes to the initial EGFR and ALK recommendations, including ROS1 and RET fusions, MET amplification or mutation, and HER2 mutations (1,2,3). Although the efficacy of tyrosine kinase inhibitors (TKI) in the treatment of some of these disease subsets is well established, the treatment decision-making process at the time of each relapse is becoming more complex as our knowledge of resistance pathways grows and more treatment options become available, with 2[nd] and 3[rd] generation drugs now in play. Subtping of progressive disease (PD) in oncogene-driven lung cancer into systemic PD versus oligo-PD or CNS-santuary PD can assist in determining the most appropriate therapeutic approach, as shown in Figure 1 below(4).Further, the methods by which we assess tumor at the time of initial or re-biopsy are also rapidly evolving, from single gene or multiplexed gene panels to highly sensitive and specific next generation sequencing (NGS). Lastly, we and others (4,5) have proposed algorithms for possible substitution of plasma cell free DNA by NGS platforms for tissue re-biopsy or for serial monitoring in plasma, as demonstrated in Figure 2.In this presentation we will present a step-wise approach to molecular testing and personalizing treatment for patients with oncogene-driven NSCLC, focusing on EGFR-mutated and ALK-rearranged subsets, since the treatment paradigms are most well established. We will emphasize some of the real world challenges faced by treating physicians. Decision criteria for selecting the best first-line therapy will be reviewed, the importance of re-biopsy upon disease progression to determine the most appropriate next-line therapy highlighted, and third line therapy and beyond discussed. The emerging role of liquid biopsy for assessment of plasma cell free DNA will be discussed, as well as a rationale for substituting liquid biopsy for initial or repeat tumor biopsy in some clinical settings. Algorithms designed to facilitate treatment decision-making will be presented. Two examples in EGFR-mutated lung cancer are shown below.Figure 1: Algorithm for management by Progressive Disease SubtypingEGFR-mutated NSCLCFigure 1Figure 2: Algorithm for Re-Biopsy and/or Plasma cf DNA AnalysisIn EGFR-mutated NSCLCFigure 2 References 1. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J et al: Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2013, 8(7):823-859. 2. Leighl NB, Rekhtman N, Biermann WA, Huang J, Mino-Kenudson M, Ramalingam SS, West H, Whitlock S, Somerfield MR: Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Society for the Study of Lung Cancer/Association of Molecular Pathologists Guideline. Journal of Clinical Oncology 2014. 3. Ettinger, D. S., Akerley, W., Borghaei, H., Chang, A. C., Cheney, R. T., Chirieac, L. R., ... & Grant, S. C. Non–small cell lung cancer, version 2.2013. Journal of the National Comprehensive Cancer Network, 2013, 11(6), 645-653. 4. Gandara DR, Li T, Lara PN, Kelly K, Riess JW, Redman MW, Mack PC: Acquired resistance to targeted therapies against oncogene-driven non-small-cell lung cancer: approach to subtyping progressive disease and clinical implications. Clinical lung cancer 2014, 15(1):1-6. 5. Oxnard, G. R., Thress, K. S., Alden, R. S., Lawrance, R., Paweletz, C. P., Cantarini, M., ... & Jänne, P. A. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non–small-cell lung cancer. Journal of Clinical Oncology, 2014, JCO667162.
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ED11.02 - Systemic Therapy for Advanced Non-Oncogene-Driven NSCLC (ID 6486)
11:00 - 12:30 | Author(s): G.V. Scagliotti
- Abstract
- Presentation
Abstract not provided
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ED11.03 - Management of Oligo-Metastatic NSCLC (ID 6487)
11:00 - 12:30 | Author(s): J. Kuzdzal
- Abstract
- Presentation
Abstract not provided
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ED11.04 - Palliative Radiotherapy of Advanced NSCLC (ID 6488)
11:00 - 12:30 | Author(s): K. Dieckmann
- Abstract
- Presentation
Abstract not provided
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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: 5
- 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 - 09:40 | Author(s): J.R. Brahmer, D. Rodriguez-Abreu, A.G. Robinson, R. Hui, T. Csoszi, A. Fülöp, M. Gottfried, N. Peled, A. Tafreshi, S. Cuffe, M. O’brien, S. Rao, K. Hotta, A.C. Deitz, G.M. Lubiniecki, J. Zhang, R. Rangwala, M. Reck
- 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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PL04a.02 - OAK, a Randomized Ph III Study of Atezolizumab vs Docetaxel in Patients with Advanced NSCLC: Results from Subgroup Analyses (Abstract under Embargo until December 7, 7:00 CET) (ID 5822)
08:45 - 09:40 | Author(s): S.M. Gadgeel, F. Ciardiello, A. Rittmeyer, F. Barlesi, D. Cortinovis, C. Barrios, T. Hida, K. Park, D. Kowalski, M. Cobo Dols, J. Leach, J. Polikoff, C. Matheny, P. He, M. Kowanetz, D.S. Chen, D. Waterkamp, M. Ballinger, A. Sandler, D.R. Gandara, J. Von Pawel
- Abstract
- Presentation
Background:
Atezolizumab inhibits PD-L1 binding to its receptors PD-1 and B7.1, thereby restoring tumor-specific T-cell immunity. Primary analysis of the Phase III OAK study in previously-treated NSCLC revealed superior survival for atezolizumab vs docetaxel in the ITT population (mOS, 13.8 vs 9.6 months; HR, 0.73) and in patients expressing ≥1% PD-L1 on TC or IC (TC1/2/3 or IC1/2/3; mOS, 15.7 vs 10.3; HR, 0.74). Here we present further subgroup analyses.
Methods:
OAK evaluated atezolizumab vs docetaxel in an unselected NSCLC population who had failed prior platinum-containing chemotherapy. Patients were stratified by PD-L1 expression, prior chemotherapy regimens and histology, and randomized 1:1 to atezolizumab (1200 mg) or docetaxel (75 mg/m[2]) IV q3w. PD-L1 expression by IHC and mRNA was centrally evaluated by VENTANA SP142 IHC assay and Fluidigm, respectively. Data cutoff, July 7, 2016.
Results:
For the first 850 of 1225 randomized patients (primary study population), OS was improved with atezolizumab vs docetaxel regardless of histology and this benefit was observed across PD-L1 subgroups within each histology (Table). PD-L1 gene expression showed a similar association with OS as PD-L1 IHC. In nonsquamous patients ORR was 14.4% vs 15.2%; in squamous patients ORR was 11.6% vs 8.2% (atezolizumab vs docetaxel). OS benefit vs docetaxel was seen across subgroups including patients with treated baseline brain metastases (n=85; mOS 20.1 vs 11.9 mo; HR 0.54, 95% CI 0.63-0.89) and never smokers (n=156; mOS 16.3 vs 12.6 mo, HR 0.71, 95% CI 0.47-1.08). Further secondary endpoints and exploratory biomarker analyses for these subgroups and by age and EGFR/KRAS status will be presented.
Conclusion:
OAK demonstrated clinically relevant improvements with atezolizumab in the ITT population, including in both histology subgroups regardless of PD-L1 expression (measured by IHC or tumor gene expression), and among other subgroups including never smokers and in patients with baseline brain metastases.OS Atezolizumab Docetaxel HR[a]95% CI n Median, mo n Median, mo Nonsquamous TC3 or IC3 49 22.5 47 8.7 0.35(0.21-0.61) TC2/3 or IC2/3 89 18.7 99 11.3 0.61(0.42-0.88) TC1/2/3 or IC1/2/3 171 17.6 162 11.3 0.72(0.55-0.95) TC0 and IC0 140 14.0 150 11.2 0.75(0.57-1.00) All 313 15.6 315 11.2 0.73(0.60-0.89) Squamous TC3 or IC3 23 17.5 18 11.6 0.57(0.27-1.20) TC2/3 or IC2/3 40 10.4 37 9.7 0.76(0.45-1.29) TC1/2/3 or IC1/2/3 70 9.9 60 8.7 0.71(0.48-1.06) TC0 and IC0 40 7.6 49 7.1 0.82(0.51-1.32) All 112 8.9 110 7.7 0.73(0.54-0.98) [a]Unstratified HRs. TC=tumor cell, IC=tumor-infiltrating immune cell
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PL04a.03 - Durvalumab in ≥3rd-Line Locally Advanced or Metastatic, EGFR/ALK Wild-Type NSCLC: Results from the Phase 2 ATLANTIC Study (Abstract under Embargo until December 7, 7:00 CET) (ID 5336)
08:45 - 09:40 | Author(s): M.C. Garassino, J.F. Vansteenkiste, J. Kim, H. Léna, J. Mazières, J. Powderly, P. Dennis, Y. Huang, C. Wadsworth, N. Rizvi
- Abstract
- Presentation
Background:
Treatment with anti-PD-1/PD-L1 antibodies has demonstrated meaningful clinical benefit in patients with advanced NSCLC. Patients that progress after 2 lines of chemotherapy have few treatment options and poor outcomes. Durvalumab is an engineered human IgG1 mAb targeting programmed cell death ligand-1 (PD-L1).
Methods:
ATLANTIC (NCT02087423) is a Phase 2, open-label, single-arm trial in patients with locally advanced or metastatic Stage IIIB–IV NSCLC (WHO PS 0 or 1; ≥2 prior systemic treatment regimens, including one platinum-based). There was no maximum number of prior treatments. The study initially enrolled all-comers and then was restricted to patients with PD-L1 high tumours (≥25% of tumour cells with membrane staining). The study includes three cohorts; here we report final results in Cohorts 2 and 3 that had EGFR/ALK wild-type or unknown status. Patients enrolled in Cohort 3 had ≥90% of tumour cells with PD-L1 staining. The primary endpoint is ORR (RECIST v1.1), based on independent central review. Secondary endpoints include DCR, DoR, PFS, OS, and safety (CTCAE v4.03).
Results:
As of 3 June 2016, in Cohorts 2/3, 265/68 patients (median age 62/61 years, 67/72% PS 1, 21/29% squamous histology; mean of 3.2/2.6 prior therapies) had received durvalumab (10 mg/kg i.v. q2w). Responses were durable; in Cohort 2, patients with PD-L1 ≥25%, the ORR was similar in patients with squamous and non-squamous histology.
Most AEs were low grade and resolved with treatment delay and/or immunosuppressive interventions. Overall, 10.2% of patients had Grade ≥3 treatment-related AEs and 2.7% had treatment-related AEs leading to discontinuation.Cohort 2 Cohort 3 PD-L1 high (≥25%) PD-L1 low/negative (<25%) PD-L1 ≥90% n=146 n=93 n=68 ORR,* %(95%CI) 16.4(10.8-23.5) 7.5(3.1-14.9) 30.9(20.2-43.3) DCR, %(95%CI) 28.8(21.6-36.8) 20.4(12.8-30.1) 38.2(26.7-50.8) mDoR, months(25[th], 75[th] percentile) 12.3(7.5-NR) NR(7.2-NR) NR; 18/21 responders progression free at DCO n=149 n=94 n=67 mPFS, months(95%CI) 3.3(1.9-3.7) 1.9(1.8-1.9) 2.4(1.8-5.5) mOS, months(95%CI) 10.9(8.6-13.6) 9.3(5.9-10.8) NR(5.9-NC) 1-year OS, %(95%CI) 47.7(39.3-55.5) 34.5(25.0-44.1) 50.8(36.9-63.2) mFollow-up for OS, months 9.4 9.3 7.0 *Confirmed response per independent central review. DCO=data cutoff; DCR=disease control rate (complete response, partial response or stable disease ≥24 weeks); DoR=duration of response; m=median; NC=not calculated; NR=not reached; ORR=objective response rate; OS=overall survival; PFS=progression-free survival
Conclusion:
Durvalumab was active and led to durable responses in a heavily pretreated metastatic NSCLC population; activity was numerically greater for patients whose tumours exceeded the 25% PD-L1 cutoff. The tolerability profile was manageable. Results are consistent with other anti-PD-1/PD-L1 therapies in metastatic, relapsed NSCLC and support further development of durvalumab.
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PL04a.04 - Multicentric French Harmonization Study for PD-L1 IHC Testing in NSCLC (Abstract under Embargo until December 7, 7:00 CET) (ID 4910)
08:45 - 09:40 | Author(s): J. Adam, I. Rouquette, D. Damotte, C. Badoual, C. Danel, F. Damiola, F. Penault-Llorca, S. Lantuejoul
- Abstract
- Presentation
Background:
PD-L1 immunohistochemistry (IHC) is considered as a predictive biomarker for most anti PD-1/PDL-1 therapies in non-small cell lung cancer, but different assays were used in clinical trials. Several studies have compared 4 assays (22C3, 28-8, SP142, SP263) performed in central laboratories on dedicated platforms. In order to harmonise and make PD-L1 testing widely available on most IHC platforms and centers, we compared PD-L1 Dako (22C3, 28-8) and Ventana (SP263) assays and laboratory-developed tests (LDT).
Methods:
IHC with five anti-PD-L1 clones (28-8, 22C3, E1L3N, SP142 and SP263) was performed concomitantly on 41 NSCLC surgical specimens in 7 centers. The IHC platforms used were Ventana BenchMark Ultra (2 centers), Leica Bond (2 centers) or Dako Autostainer Link 48 (3 centers). For each matching platform, 22C3, 28.8 and SP263 assays were performed. For non-matching platforms and other antibodies, LDT were developed in each center and harmonised based on tonsil tissue staining. A total of 35 stainings were performed across different platforms and antibodies for each case. Seven thoracic pathologists trained to PD-L1 scoring in expert courses participated. Each pathologist analysed 6 cases and compared the stainings obtained with the 5 antibodies on all platforms. Tumor cell and immune cell D-L1 stainings were scored semi-quantitatively as recommended in PD-L1 Dako and Ventana assays. For statistical analysis, 1, 5, 25, 50% and 1, 5, 10% thresholds were used for tumor cells and immune cells, respectively.
Results:
28-8, 22C3 and SP263 assays were highly concordant for tumor cell and immune cell stainings across the 5 Dako or Ventana platforms (R2=0.886 to 0.953). LDT demonstrated various levels of concordance as compared to those 3 assays. Notably, LDT using SP263 clone were the most concordant across all platforms for both immune cell and tumor cell stainings, whereas some selected LDT with clones 28-8, 22C3 and E1L3N, but not SP142, showed a good correlation with the 3 assays regarding tumor cells only.
Conclusion:
28-8, 22C3 and SP263 assays gave comparable results across dedicated platforms for tumor cells staining, as well as some selected LDT protocols using 28-8, 22C3, SP263 and E1L3N clones. These results will be further validated at the national level in order to provide recommendations for the use of assays and LDT for PD-L1 testing in NSCLC.
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PL04a.05 - Discussant for PL04a.01, PL04a.02, PL04a.03, PL04a.04 (ID 7158)
08:45 - 09:40 | Author(s): M. Boyer
- Abstract
- Presentation
Abstract not provided
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Author of
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA04.03 - Preliminary Results of a Phase II Study about the Efficacy and Safety of Pyrotinib in Patients with HER2 Mutant Advanced NSCLC (ID 6069)
16:00 - 17:30 | Author(s): C. Zhou
- Abstract
- Presentation
Background:
There is still an unmet need for targeted drugs in non small cell lung cancer (NSCLC) patients with HER2 mutation. Pyrotinib is an oral tyrosine kinase inhibitor targeting both HER-1 and HER-2 receptors. This phase II trial is designed to evaluate the safety and efficacy of pyrotinib in patients with HER2 mutant advanced NSCLC.
Methods:
A single arm prospective phase II trial was undergone to evaluate the efficacy and safety of Pyrotinib in patients with HER2 mutant advanced NSCLC in a single center of Shanghai Pulmonary Hospital, Tongji University(NCT 02535507). Pyrotinib was administrated 320mg or 400mg orally once a day. Next generation sequencing or ARMS was used to identify the patients with HER2 mutation. The primary endpoint was objective response rate and the secondary endpoints were side effect, progression free survival and overall survival.
Results:
From Jul 15 2015 to Jul 21, 2016, 11 patients with her2 mutated advanced NSCLC were enrolled into this study. Among them, the median age was 58 years old, 6 were male, 4 were smoker, ECOG PS 0/1/2 were 5/6 and all of them were adenocarcinoma. None of them received pyrotinib as the first line therapy and the median previous anti-cancer regimen was 2. 9 patients had the details variants of HER2 mutation including 7 with exon 20 776YVMA, 1 with exon 20 770AYVM and 1 with 2326G>ATTT. All of them evaluated the response, including 54.5% with partial response(6/11), 27.3% with stable disease(3/11) and 18.2% with progressive disease(2/11). 1 patient got response to pyrotinib after progressed from afatinib. 5 patients were still on the study and the median PFS was 6.2 months. Side effects were mild including 4 with grade I/II diarrhea, 2 with grade II fatigue, 2 with grade I rash and 1 with dispnea.
Conclusion:
Pyrotinib showed promising results about the ORR and PFS together with mild toxicity in patients with HER2 mutant advanced NSCLC, further multicenter large scale phase II study is initiated to validate the results in this study.
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MA15 - Immunotherapy Prediction (ID 400)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:O. Arrieta
- Coordinates: 12/07/2016, 14:20 - 15:50, Schubert 1
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MA15.03 - The Predictive Value of Mutation/Neoantigen Burden from ctDNA on the Efficacy of PD-1 Blockade in Advanced NSCLC (ID 5884)
14:20 - 15:50 | Author(s): C. Zhou
- Abstract
Background:
Immune checkpoint, PD-1, inhibitors, have been approved to treat advanced NSCLC patients without oncogenic driver in the second-line setting based on durable clinical benefit. It has been demonstrated that the overall mutational burden in tumor tissue was significantly associated with progression free survival (PFS) of advanced NSCLC patients treated with PD-1 inhibitor. However, tumor tissue may not be available from all patients at any time during PD-1 blockade therapy. Therefore, the purpose of this study was to explore the predictive value of mutation/neoantigen burden from ctDNA on efficacy of PD-1 inhibitors.
Methods:
We treated advanced NSCLC patients without oncogenic drivers with PD-1 inhibitor in the second or more line setting. The whole-exome of tumor tissues and ctDNA at baseline and ctDNA at every time of efficacy evaluation from these patients were sequenced by NGS. The hybrid-capture-enriched libraries were sequenced on the Illumina HiSeq 4000 platform with 75-base paired-end reads, sequencing depth was 300 for ctDNA whole-exome sequencing. We compared the results of whole-exome sequencing between patients who achieved objective response to PD-1 inhibitor and patients who experienced disease progression. Besides, we also compared the results of whole-exome sequencing between baseline ctDNA and ctDNA extracted at efficacy evaluation.
Results:
Up to now, a total of 23 patients treated with PD-1 inhibitor received efficacy evaluation at least once in this study. Of them, 4 patients achieved partial response (PR), 3 patients achieved stable disease (SD). Of 4 patients with PR, 3 patients were found to harbor high mutation burden (more than 400 nonsynonymous mutations) from ctDNA and only 1 patient harbored mutation burden of less than 100 from ctDNA at baseline. We found the mutation or neoantigen burden from ctDNA changed during PD-1 blockade therapy. The efficacy of PD-1 inhibitor appeared to be more significantly associated with neoantigen burden rather than mutation burden. Only one ctDNA sample was found positive for MSH6 mutation (C1337X) and all baseline ctDNA samples were negative for microsatellite instability (MSI) status.
Conclusion:
Evaluating nonsynonymous mutation burden/neoantigen burden from ctDNA was feasible in advanced NSCLC patients treated with PD-1 inhibitors. The predictive value of neoantigen burden from ctDNA on the efficacy of PD-1 inhibitor may be better than that of mutation burden in advanced NSCLC. It may not be feasible to determine the status of mismatch-repair deficiency and MSI using ctDNA samples in advanced NSCLC. An expanded study is ongoing. More details will be presented in the conference.
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OA11 - Angiogenesis in Advanced Lung Cancer (ID 387)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:L.M. Montuenga, J. Heymach
- Coordinates: 12/06/2016, 11:00 - 12:30, Stolz 2
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OA11.07 - Combining Anti-Angiogenesis and Immunotherapy Enhances Antitumor Effect by Promoting Immune Response in Lung Cancer (ID 4985)
11:00 - 12:30 | Author(s): C. Zhou
- Abstract
- Presentation
Background:
Increasing studies have shown that anti-angiogenic therapy targeting VEGF/VEGFR2 axis are furnishing demonstrable therapeutic effect on lung cancer，but the treatment benefit is transitory in clinic, generally followed by restoration of tumor growth and disease progression. Blockade of VEGF/VEGFR2 pathway can not only induce anti-vascular effect, but also remodel the immunosuppressive tumor microenvironment probably due to promoting suppressive cells infiltration and enhancing PD-L1 expression, resulting in impairing antitumor immunity. Therefore, the current study aimed to investigate whether combining anti-angiogenic and anti-PD-L1 treatments can induce synergistic antitumor effect by enhancing antitumor immune response in murine lung cancer.
Methods:
We evaluated the antitumor effects of anti-VEGFR2 agent (apatinib) as monotherapy or in combination with anti-PD-L1 monoclonal antibody in a murine lung cancer model using Lewis lung cancer cells (LLCs). The changes of immune components in tumor and spleen were dynamically tested in different treatment groups and time points by flow cytometry and immunohistochemistry.
Results:
The results showed that VEGF/VEGFR2 blockade could retard tumor growth and inhibit tumor neovascularization via eradicating Foxp3[+ ]regulatory T cells (Tregs) and myeloid derived suppressive cells (MDSCs) and reducing the density of microvessels in the first two weeks of treatment. On the third week of apatinib monotherapy, the number of Foxp3[+ ]Tregs and MDSCs had increased again. Although VEGF/VEGFR2 blockade induced more tumor infiltrating lymphocytes (TILs), especially CD8[+] T cells, infiltrating into the tumor mass than control group (P < 0.01), the expression of PD-1 and PD-L1was also significantly upregulated than that control group (P < 0.01). Compared to apatinib monotherapy, combining treatment demonstrated that anti-VEGFR2 plus anti-PD-L1 therapy could significantly inhibit tumor growth (P < 0.01) by persistently eliminating Foxp3[+ ]Tregs and MDSCs. Furthermore, combining anti-VEGFR2 and anti-PD-L1 therapy could not only dramatically increase TILs infiltration, especially CD8[+] T cells, but also significantly reduce the expression of PD-1 and PD-L1.
Conclusion:
Simultaneous blockade of VEGF/VEGFR2 and PD-1/PD-L1 pathways induced a synergistic anti-tumor effect in-vivo, possibly through eliminating immunosuppressive components including Tregs and MDSCs and enhance antitumor immune response.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-031 - Clinical Evaluation of Folate Receptor-Positive Circulating Tumor Cells Detection in Patients with Small Cell Lung Cancer (ID 5480)
14:30 - 15:45 | Author(s): C. Zhou
- Abstract
Background:
Small cell lung cancer (SCLC) is distinguished by extremely high numbers of circulating tumor cells (CTCs) in comparison to other malignancies, however, the role of CTCs in evaluating chemotherapy effect of SCLC is to be further clarified. The purpose of this study was to investigate the predictive and prognostic role of folate receptor–positive CTCs in unresectable SCLC.
Methods:
In this single-center prospective study, blood samples for folate receptor–positive CTCs analysis were obtained from 80 patients with chemotherapy-naive unresectable SCLC at baseline, after two cycles of chemotherapy, and on disease progression. All patients received chemotherapy with EC or EP regimen for at least two cycles. CTCs number at baseline, after chemotherapy and changes with chemotherapy were evaluated as predictive factors for chemotherapy effect, along with clinical characteristics.
Results:
Of all 80 patients, CTCs was detected at baseline as positive (CTCs>8.7 FU/3mL) in 67 patients, with the percentage of 83.8%, which was not associated with age, sex, smoking status or disease stage. In 72 evaluable patients, the disease control rate was 83.9% (52/62) and 50% (5/10) in CTCs positive and negative patients respectively (P=0.004). In CTCs positive patients, those harboring low levels of folate receptor (8.7
Conclusion:
CTCs number at baseline could be used as a useful prognostic biomarker for SCLC. Reduction in CTCs number with chemotherapy could predict better chemotherapy effect of SCLC.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-092 - Predictive and Prognostic Effect of Circulating Tumor Cells in Non-Small Cell Lung Cancer Treated with Targeted Therapy (ID 4815)
14:30 - 15:45 | Author(s): C. Zhou
- Abstract
Background:
We propose a non-invasive, folate receptor (FR)–based circulating tumor cell (CTC) detection approach to interpret treatment response of targeted therapy between baseline and follow-up CTC values and the feasibility whether CTCs as a prognostic factor in advanced NSCLC with EGFR mutation/ALK translocation.
Methods:
This was a prospective, unopen-labeled, single-center trial. From July 25, 2014 to March 11,2016, 308 advanced NSCLC patients were enrolled to quantified CTC level by negative enrichment using immunomagnetic beads in combination with folate receptor-directed polymerase chain reaction(PCR) that allows secondary amplification of tiny amounts of CTCs in 3mL peripheral blood before the start of targeted therapy and after one month, every two months hereafter of treatment. Among whom, 272 NSCLC patients with EGFR mutation (exon 19Del mutation: n=135, L858R mutation: n=137) ,39 ALK translocation or undefined lung cancer patients. Sequential analyses were conducted to monitor CTC values during therapy and correlate radiological effects with treatment outcome.
Results:
There was no significant difference between CTC values and patients’ characristics including stage (P= 0.1015), EGFR mutation status(19 del:14.5 CTCs, L858R:12.6 CTCs, P=0.1868) , age (≤60 versus >60 years), gender, smoking status. Of 272 eligible and evaluable patients received EGFR-TKI, we found that patients harboring lower CTC levels (<20.5)were associated with longer PFS(432days, 95%CI:332.7-541.3) than those with higher CTC levels (≥20.5)(PFS: 308days, 95%CI:245.3-370.7;P=0.017). Patients with CTC <20.5 had a DCR of 77.11% compared with 58.49% in CTC >20.5 groups (P=0.008), patients with CTC <20.5 had a ORR of 51.20% compared with 33.96% in CTC >20.5 groups (P=0.029). Decreased CTC values correlated well with partial response after one month or three months’ treatment of EGFR-TKI (P=0.0082 and P=0.0023),but not with stable disease (P=0.1843 and P=0.8606).Multivariate analysis showed that CTC level was an independent prognostic factor for PFS (CTC level<20.5 vs ≥20.5,hazard ratio, 0.497; P=0.014).
Conclusion:
The change of CTCs correlated significantly with radiological response. This strategy may enable non-invasive, predictive and prognostic, specific biomarker in patients undergoing targeted therapies.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-013 - Afatinib in Patients with Advanced HER2 Mutation-Positive (M+) NSCLC Previously Treated with Chemotherapy (ID 5154)
14:30 - 15:45 | Author(s): C. Zhou
- Abstract
Background:
Afatinib, an irreversible ErbB family blocker, inhibits signalling from all homo- and hetero-dimers of ErbB family members (EGFR [ErbB1], HER2 [ErbB2], ErbB3 and ErbB4). Based on the results of two large Phase III trials (LUX-Lung 3 [LL3] and LL6), afatinib is approved in many countries for first-line treatment of patients with advanced EGFRm+ NSCLC. More recently, following results of the Phase III LL8 trial, afatinib was also approved for treatment of squamous cell carcinoma of the lung after platinum-based chemotherapy. Overexpression/amplification of HER2 has been identified in NSCLC and may have a role in acquired resistance to reversible EGFR tyrosine kinase inhibitors. Afatinib has demonstrated preclinical activity in HER2m+ lung cancer models and clinical activity in HER2m+ NSCLC patients (de Greve et al. Lung Cancer 2012; Mazieres et al. Ann Oncol 2015). This Phase II trial investigates the efficacy and safety of afatinib in patients with advanced NSCLC harbouring HER2 mutations, previously treated with chemotherapy (NCT02597946).
Methods:
In this Phase II, open-label, single-arm trial, eligible patients are aged ≥18 years, with ECOG PS 0/1, histologically or cytologically confirmed stage IV NSCLC, confirmed HER2m+ tumour tissue, and measurable disease (RECIST v1.1), following failure of one or two prior chemotherapy regimens, of which one is platinum-based. Prior radiotherapy (except palliative treatment), chemotherapy or immunotherapy within 4 weeks, hormonal therapy within 2 weeks, or EGFR/HER2-targeted therapy is not allowed. In Part A of this two-part trial, patients will receive continuous oral afatinib monotherapy at the approved starting dose of 40 mg/day. The dose may be escalated to 50 mg/day after 4 weeks in patients with minimal drug-related adverse events (AEs); dose reduction by 10-mg decrements to a minimum of 20 mg/day will occur in case of drug-related grade ≥3 or selected grade 2 AEs. In Part B, patients with ECOG PS ≤2 experiencing >12 weeks of clinical benefit with afatinib monotherapy before disease progression will continue treatment with afatinib plus weekly intravenous paclitaxel 80 mg/m[2]. In Parts A and B, treatment will continue until disease progression or intolerable AEs. The primary endpoint is objective response in Part A. Secondary endpoints include: disease control, progression-free survival, time to progression, and duration of response in Part A; and overall survival. Safety will also be assessed. Target enrolment is 40 patients, and participating countries will be listed in the full presentation.
Results:
Section not applicable.
Conclusion:
Section not applicable.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 6
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-047 - Co-Activation of STAT3 and YAP1 Signaling Pathways Limits EGFR Inhibitor Response in Lung Cancer (ID 4168)
14:30 - 15:45 | Author(s): C. Zhou
- Abstract
Background:
EGFR tyrosine kinase inhibitors (TKIs) induce early activation of several signaling pathways. Interleukin-6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) hyper-activation occur following EGFR TKI therapy in EGFR-mutant NSCLC cells. We explored the relevance of co-targeting EGFR, STAT3 and Src-YES-associated protein 1 (YAP1) signaling in EGFR-mutant NSCLC.
Methods:
We combined in vitro and in vivo approaches to explore whether concomitant activation of STAT3 and Src-YAP1 can limit the effectiveness of EGFR TKIs in EGFR-mutant NSCLC cells and xenograft models. In two cohorts of EGFR-mutant NSCLC patients, we examined messenger RNA (mRNA) gene expression within signaling pathways, leading to EGFR TKI resistance.
Results:
Gefitinib suppressed EGFR, ERK1/2 and AKT phosphorylation but increased STAT3 phosphorylation (pSTAT3-Tyr705). In EGFR mutant cells, gefitinib plus TPCA-1 (STAT3 inhibitor) abolished pSTAT3-Tyr705 but not the YAP1 phosphorylation on tyrosine 357 by Src family kinases (SFKs). The triple combination of gefitinib, TPCA-1 and AZD0530 (SFK inhibitor) ablated both STAT3 and YAP1 phosphorylation and was highly synergistic, according to the combination index. In two EGFR mutant xenograft mouse models, the triple combination of gefitinib, TPCA-1 and AZD0530 markedly and safely suppressed tumor growth. High levels of STAT3 or YAP1 mRNA expression were associated with worse outcome to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free survival (PFS) was 9.6 (95%CI, 5.9-14.1) and 18.4 months (95%CI, 8.8-30.2) for patients with high and low STAT3 mRNA, respectively (p<0.001), (HR for disease progression, 3.02; 95% CI, 1.54-5.93; p=0.0013). Median PFS was 9.6 (95%CI, 7.7-15.2) and 23.4 months (95%CI, 13.0-28.1) for patients with high and low YAP1 mRNA, respectively (p=0.005), (HR for disease progression, 2.57; 95%CI, 1.30-5.09; p=0.0067). The results were similar in the validation cohort of 55 EGFR-mutant NSCLC patients treated with first-line EGFR TKI in the Department of Oncology of Shanghai Pulmonary Hospital.
Conclusion:
Our study reveals that STAT3 and Src-YAP1 signaling activation occurs following single EGFR TKI in EGFR-mutant NSCLC. STAT3 and YAP1 mRNA levels were significantly predictive of progression-free survival in the original as well as in the validation cohort of EGFR-mutant NSCLC patients. Co-targeting STAT3 and Src in combination with EGFR TKI could substantially improve survival.
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P3.02b-075 - Addition of Bevacizumab for Malignant Pleural Effusion as the Manifestation of Acquired EGFR-TKI Resistance in NSCLC Patients (ID 4053)
14:30 - 15:45 | Author(s): C. Zhou
- Abstract
Background:
This study aimed to investigate the clinical value of bevacizumab in EGFR mutant non-small cell lung cancer (NSCLC) patients who had developed acquired resistance to EGFR-TKIs therapy that manifested as malignant pleural effusion (MPE).
Methods:
A total of 86 patients were included. Among them, 47 patients received bevacizumab plus continued EGFR-TKIs (B+T) and 39 patients received bevacizumab plus switched chemotherapy (B+C).
Results:
The curative efficacy rate for MPE in B+T group was significantly higher than that in B+C group (89.4% vs. 64.1%, P = 0.005). Patients in B+T group had longer progression-free survival (PFS) than those in B+C group (6.3 vs. 4.8 months, P = 0.042). While patients with acquired T790M mutation in B+T group had a significantly longer PFS than those in B+C group (6.9 vs. 4.6 months, P = 0.022), patients with negative T790M had similar PFS (6.1 vs. 5.5 months, P = 0.588). Overall survival (OS) was similar between two groups (P = 0.480). In multivariate analysis, curative efficacy was the independent prognostic factor for these patients (HR 0.275, P = 0.047). Figure 1 Figure 2
Conclusion:
B+T could be a valuable treatment for NSCLC patients presenting with MPE upon resistant to EGFR-TKIs therapy, especially for those with acquired T790M mutation.
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P3.02b-076 - Bisphosphonates Enhance Effect of EGFR-TKIs in NSCLC Patients with EGFR Mutation and Bone Metastases (ID 4817)
14:30 - 15:45 | Author(s): C. Zhou
- Abstract
Background:
Whether bisphosphonates could enhance the treatment outcome of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation and bone metastases (BM) remains controversial.
Methods:
251 NSCLC patients with EGFR mutation and BM were identified. As first-line treatment, 44 patients received EGFR-TKIs alone and 56 patients received EGFR-TKIs plus bisphosphonates therapy.
Results:
Comparing to TKIs alone, EGFR-TKIs plus bisphosphonates had significant longer progression-free survival (PFS: 11.5 vs 10.5 months; HR = 0.64, P = 0.030), but similar overall survival (OS: 20.2 vs 20.8 months; HR = 0.95, P = 0.847) in NSCLC with EGFR mutation and BM. Although the incidence of skeletal-related events in combined treatment group was lower than that in EGFR-TKIs alone group, there is no statistical significance (32.1% vs. 45.5%, P = 0.173). Chemotherapy plus bisphosphonates had similar PFS (6.4 VS 6.7 months; HR = 1.09, P = 0.684) and OS (15.5 vs 14.1 months; HR = 0.87, P = 0.486) to chemotherapy alone in patients with EGFR of wild type. In multivariate analysis, EGFR mutation was found to be a significant independent prognostic factor for OS in NSCLC patients with BM (HR = 0.722, P = 0.019). Figure 1
Conclusion:
The addition of bisphosphonates to EGFR-TKIs could enhance the effect of EGFR-TKIs in NSCLC patients with EGFR mutation and BM. Bisphosphonates did not bring additional benefit to chemotherapy in BM patients with EGFR of wild type. EGFR mutation was the significant independent prognostic factor for OS in NSCLC patients with BM.
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P3.02b-091 - Liver Metastases Is the Negative Predictive Factor for First-Line EGFR TKIs Therapy in NSCLC Patients with EGFR Mutation (ID 4054)
14:30 - 15:45 | Author(s): C. Zhou
- Abstract
Background:
Whether liver metastases (LM) could predict the treatment outcome of patients with non-small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutation receiving first-line EGFR tyrosine kinase inhibitors (TKIs) remains controversial.
Methods:
A total of 598 patients with advanced NSCLC receiving EGFR detection were included. 99 NSCLC patients had LM and 56 of them with EGFR mutation received EGFR-TKIs as first-line therapy.
Results:
In EGFR mutation group, patients with LM had shorter progression-free survival (PFS: 7.4 vs. 11.8 months, P = 0.0002) and overall survival (OS: 20.8 vs. 31.5 months, P = 0.0057) compared to patients without LM when they received first-line EGFR-TKIs therapy. EGFR-mutated patients with LM received first-line chemotherapy had similar PFS and OS to patients without LM (PFS, 4.7 vs. 5.9 months, P = 0.3051; OS, 12.7 vs. 14.5 months, P = 0.3783). In EGFR wild type group, PFS and OS were also similar in patients with LM vs. without LM (PFS, 6.3 vs. 5.1 months, P = 0.2092; OS, 12.6 vs. 16.2 months, P = 0.4885). Univariate cox regression analyses identified only never smoking (HR = 0.536, P = 0.012) were significantly associated with better OS in NSCLC patients with LM. Figure 1
Conclusion:
Liver metastases is not only the negative predictive factor for first-line EGFR-TKIs therapy in NSCLC patients with EGFR mutation but also predicts poor effect of chemotherapy in NSCLC patients with EGFR wild type.
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P3.02b-096 - Osimertinib (AZD9291) in Asia-Pacific Patients with T790M Mutation-Positive Advanced NSCLC: Open-Label Phase II Study Results (ID 4282)
14:30 - 15:45 | Author(s): C. Zhou
- Abstract
Background:
Osimertinib (AZD9291) is an oral, potent, irreversible EGFR-TKI, selective for both EGFR-sensitizing (EGFRm) and T790M resistance mutations. Following positive outcomes from recent Phase I and II trials, osimertinib is now recommended for patients with EGFR T790M mutation-positive advanced non-small cell lung cancer (aNSCLC).
Methods:
AURA17 (NCT02442349) is an open-label, single arm, Phase II study investigating the efficacy and safety of osimertinib in an Asia-Pacific patient population with EGFRm T790M mutation-positive locally advanced or metastatic NSCLC, who had progressed following EGFR-TKI therapy or EGFR-TKI and chemotherapy. T790M-positive status was confirmed via central testing of biopsy samples using the cobas[®] EGFR Mutation Test. Inclusion required measureable disease, performance status (PS) 0/1, and acceptable organ function; asymptomatic brain metastases were allowed. Patients received osimertinib 80 mg once daily until disease progression. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 (by blinded independent central review, BICR). Secondary objectives included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival, and safety and tolerability.
Results:
As of 4 March 2016 data cut-off, 171 patients were enrolled, with 166 evaluable for response: median age, 60.0 years; female, 69%; Asian, 98%; never smokers, 78%; PS 0/1, 15%/85%; EGFR Exon 19 and L858R mutations, 64% and 34% patients, respectively; second-/≥third-line, 32%/68%; median treatment exposure, 5.6 months. Confirmed ORR and DCR (95% CI) by BICR were 60% (52, 68) and 88% (82, 92), respectively. DoR and PFS are not calculable as data is immature. Causally-related adverse events (AEs) grade ≥3 were reported in eight (5%) patients. AEs leading to dose interruption or dose reduction occurred in seven (4%) and two (1%) patients, respectively. Six (4%) patients discontinued treatment due to AEs, two (1%) causally-related AEs as assessed by investigator. The most commonly reported AEs (%, [grade ≥3]) were diarrhoea (29%, [0]), rashes and acnes (grouped terms) (20%, [0]), and dry skin (grouped terms) (17%, [1%]). Interstitial lung disease-like events were reported in three (2%) patients.
Conclusion:
AURA17 demonstrated clinical efficacy of osimertinib in Asia-Pacific patients with EGFR T790M mutation-positive aNSCLC, with an ORR of 60% and DCR of 88% that are comparable to global Phase II trials. Osimertinib was well tolerated, with a low frequency of AEs grade ≥3. No new safety signals were seen and the pattern of AEs was consistent with global studies
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P3.02b-104 - Rebiopsy for Patients with Non-Small-Cell Lung Cancer after Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Failure (ID 5808)
14:30 - 15:45 | Author(s): C. Zhou
- Abstract
Background:
All non-small cell lung cancer patients (NSCLC) with mutant epidermal growth factor receptor (EGFR) eventually develop resistance to EGFR tyrosine kinase inhibitors (TKIs). Rebiopsy and retesting plays more important role in clinical application for exploring resistant mechanisms and determining further therapy strategies. This retrospective study was be performed to determine the percentage of patients who underwent rebiopsy and retesting, and the rebiopsy and retesting effect on clinical strategies and patients prognosis.
Methods:
From October 2011 to March 2016, patients with advanced NSCLC who developed resistance to EGFR-TKIs were included into this study. EGFR mutation detection were performed by ARMS PCR in our institution.
Results:
A total of 539 patients were enrolled in this study with a median progression-free survival time (PFS) of 11.1 months according to RECIST criteria. In all, 297 (55.1%) patients underwent rebiopsy for 178 computed tomography (CT)-guided needle biopsies, 87 serous cavity effusion (including 80 pleural effusion, 3 ascitic fluid and 4 pericardial effusion), 21 superficial lymph node biopsy, 11 other procedures. 354 (65.7%) patients after EGFR-TKIs failure were performed EGFR mutation testing used by 288 rebiopsy and 66 plasma samples. 181 (51.5%) had T790M mutation. In 66 plasma samples, 29 (43.9%) hardored T790M mutation, 23 (34.8%) with mutation in accordance with before EGFR-TKIs treatment, 14 with wild-type EGFR. In all patients, 341 recieved further treatment in our hospital; 236 (69.2%) patients treated with chemotherapy, 43 (12.6%) recieved TKI combined local treatment, 42 (12.3%) changed second or third generation TKIs, 30 switched to other treament. But this part of data still underdone.
Conclusion:
Rebiopsy is feasible in patients after EGFR-TKIs failure. Rebiopsy could effect on further treatment strategies after especially third generarion EGFR-TKI in clinical application. While plasma is also an available surrogate of EGFR mutation testing for patients without suitable lesions for rebiopsy after disease progression.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 3
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-025 - Safety and Efficacy of Apatinib in Patients with Previously Heavily Treated Advanced Non-Squamous Non-Small-Cell Lung Cancer (ID 4559)
14:30 - 15:45 | Author(s): C. Zhou
- Abstract
Background:
Apatinib is a tyrosine kinase inhibitor which selectively inhibits VEGFR-2 and also represents mild inhibition to PDGFR, c-Kit and c-src. It is an orally bioavailable, small molecule agent which is thought to inhibit angiogenesis and tumor cell proliferation. Previous clinical trials have demonstrated its obvious antitumor activity in various cancer type. Thus we designed this phase II, open-label, single-armed, prospective study (NCT02515435) to investigate the efficacy and safety of apatinib for heavily treated, advanced non-squamous NSCLC patients who are not applicable to current standardized therapy or other clinical trials.
Methods:
We prospectively enrolled 40 patients with previously heavily treated advanced non-squamous NSCLC. All patients received apatinib with a dose of 500mg, q.d., p.o. Efficiency was evaluated initially 4 weeks later and then every 8 weeks until disease progression, death, or unacceptable toxicity. The primary end point of this study was overall response rate (ORR). The secondary end points were progression-free survival (PFS), overall survival (OS).
Results:
Forty patients were enrolled in the study with a median age of 61. 15% of patients received apatinib as second-line therapy, 40% of patients received apatinib as third-line therapy, and 60% as forth-line to twelfth-line therapy. Nine patients were found with activated EGFR mutation. Among all the enrolled patients, 38 patients had clinical evaluation and the other 2 received treatment of apatinib less than one month. Within 33 patients who had available image efficiency, 6 were identified as PR,17 SD and 10 PD, no CR was observed. The ORR was 18.18 %, the DCR was 69.69 %. The ORR for patients with EGFR mutation positive and negative were 25% and 16% separately. The median PFS was 3.22 months (95% CI, 2.20-4.17 months). Among them, 6 patients received the treatment of apatinib more than five months. The 6-month OS rate was 76.98% (95% CI, 61.68%-92.27%), the 12-month OS rate was 57.48% (95% CI, 28.75%-86.20%). Common treatment-related adverse events were proteinuria (25%), hypertension (17.5%), and hand-foot-skin reaction (HFSR)(27.5%). Severe adverse events included grade 3 hypertension (5%), HFSR (5%), and thrombocytopenia (5%), no grade 4 or 5 adverse events were observed. No un-expected adverse events were found.
Conclusion:
Apatinib as a monotherapy had a promising overall response together with an acceptable side effect in patients with previously heavily treated advanced non-squamous NSCLC. A phase III study comparing apatinib monotherapy with placebo as 3rd/4th setting in advanced non-squamous NSCLC is ongoing to further evaluated the efficacy of apatinib (NCT02332512).
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P3.02c-049 - Dendritic Cells Modified with Tumor-Associated Antigen Gene Demonstrate Enhanced Antitumor Effect against Lung Cancer (ID 4411)
14:30 - 15:45 | Author(s): C. Zhou
- Abstract
Background:
Immunotherapy involving dendritic cells (DCs) vaccine has the potential to overcome the bottleneck of cancer therapy.
Methods:
Here, we engineered Lewis Lung cancer cells (LLC) and bone marrow derived DCs to express tumor-associated antigen (TAA), ovalbumin (OVA) via lentiviral vector plasmid encoding OVA gene. We then tested the anti-tumor effect of modified DCs both in vitro and in vivo.
Results:
The results demonstrated that in vitro modified DCs could dramatically enhance T cells proliferation (P < 0.01) and kill LLC significantly than control groups (P < 0.05). Moreover, modified DCs can reduce tumor size and prolong the survival of tumor-bearing mice than control groups (P < 0.01, P < 0.01; respectively). Modified DCs enhanced homing to T-cell-rich compartments and triggered naïve T cells to become cytotoxic T lymphocytes, which exhibited significant infiltration into the tumors. Interestingly, modified DCs also markedly reduced tumor cells harboring stem cell markers in mice (P < 0.05), suggesting the potential role of eliminating cancer stem-like cells in vivo. Figure 1
Conclusion:
These findings indicated that DCs bioengineered with TAA may enhance antitumor effect against murine lung cancer through novel mechanism that is worth further exploration.
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P3.02c-050 - IMpower010: Phase III Study of Atezolizumab vs BSC after Adjuvant Chemotherapy in Patients with Completely Resected NSCLC (ID 6098)
14:30 - 15:45 | Author(s): C. Zhou
- Abstract
Background:
Early-stage non-small cell lung cancer (NSCLC) is treated surgically, but 30%-70% of patients experience post-resection recurrence and succumb to disease. Adjuvant chemotherapy is the standard of care for fully resected NSCLC (stages IB [tumors ≥4 cm]-IIIA), and although cisplatin-based chemotherapy provides some benefit, the 5-year absolute survival benefit is ≈5%, underscoring the unmet need. Atezolizumab is an anti-PD-L1 monoclonal antibody that inhibits PD-L1 from binding to its receptors PD-1 and B7.1, thereby restoring anti-tumor immune response. Atezolizumab monotherapy has demonstrated promising efficacy and tolerable safety in patients with previously-treated advanced NSCLC, with a survival benefit observed across all PD-L1 expression levels. Given the need to improve survival for patients with early-stage NSCLC, IMpower010 (NCT02486718), a global Phase III randomized, open-label trial, has been initiated to compare the efficacy and safety of atezolizumab with best supportive care (BSC), following adjuvant cisplatin-based chemotherapy in patients with resected stage IB (tumors ≥4 cm)-IIIA NSCLC.
Methods:
Eligibility criteria include complete tumor resection 4-12 weeks prior to enrollment for pathologic stage IB (tumors ≥4 cm)–IIIA NSCLC. Patients must have adequately recovered from surgery, be eligible to receive cisplatin-based adjuvant chemotherapy and have an ECOG PS 0-1. Exclusion criteria include the presence of other malignancies, use of hormonal cancer or radiation therapy within 5 years, prior chemotherapy, autoimmune disease or exposure to prior immunotherapy. Approximately 1127 patients, regardless of PD-L1 expression status, will be enrolled. Eligible patients will receive up to four 21-day cycles of cisplatin-based chemotherapy (cisplatin [75 mg/m[2] IV, day 1] + either vinorelbine [30 mg/m[2] IV days 1, 8], docetaxel [75 mg/m[2] IV day 1] or gemcitabine [1250 mg/m[2] IV days 1, 8], or pemetrexed [500 mg/m[2] IV day 1; non-squamous NSCLC only]). Adjuvant radiation therapy is not permitted. Following adjuvant treatment, eligible patients will be randomized 1:1 to receive atezolizumab (1200 mg q3w, 16 cycles) or BSC. Stratification factors will include sex, histology (squamous vs non-squamous), extent of disease (stage IB vs II vs IIIA) and PD-L1 expression by IHC (TC, tumor cell; IC, tumor-infiltrating immune cell; TC2/3 [≥5% expressing PD-L1] and any IC vs TC0/1 [<5%] and IC2/3 [≥5%] vs TC0/1and IC0/1 [<5%]). The primary endpoint is disease-free survival, and secondary endpoints include overall survival and safety. Exploratory endpoints include PD-L1 status, immune and tumor related biomarkers before, during and after treatment with atezolizumab and at radiographic disease occurrence or confirmation of new primary NSCLC.
Results:
Section not applicable
Conclusion:
Section not applicable
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PL03 - Presidential Symposium (ID 428)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 1
- Moderators:D.P. Carbone, R. Pirker
- Coordinates: 12/06/2016, 08:35 - 10:25, Hall D (Plenary Hall)
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PL03.05 - BRAIN: A Phase Ⅲ Trial Comparing WBI and Chemotherapy with Icotinib in NSCLC with Brain Metastases Harboring EGFR Mutations (CTONG 1201) (Abstract under Embargo until December 6, 7:00 CET) (ID 4570)
08:35 - 10:25 | Author(s): C. Zhou
- Abstract
- Presentation
Background:
Non-small cell lung cancer (NSCLC) with brain metastases （M） had a poor prognosis. Whole brain irradiation (WBI) is a standard of care for this critical medical condition. The median survival is only 4-6 months. Small molecule inhibitors of epidermal growth factor receptor (EGFR) including icotinib achieved very successful results in advanced NSCLC with EGFR mutations. There were no prospective randomized clinical trials to explore the efficacy of EGFR tyrosine kinase inhibitors (TKIs) on brain M.
Methods:
Advanced NSCLC with EGFR sensitive mutations and brain M were randomized to WBI plus chemotherapy (chemo) or icotinib. Patients in WBI arm received radiotherapy with 30Gy/3Gy/10 fractions plus concurrent or sequential doublet chemo of 4-6 cycles. Patients in EGFR TKI arm received icotinib 125mg orally tid until disease progression. Icotinib could be continued beyond progression if clinical benefit was observed by the investigator. Crossover to icotinib from WBI could be permitted. Key inclusion criteria were EGFR mutations and radiologically confirmed brain M with at least 3 lesions. The primary endpoint was intracranial progression-free survival (iPFS) by investigator assessments according to RECIST v1.1. The secondary endpoints included objective response rate (ORR), PFS and overall survival (OS). Safety and tolerability were assessed by measuring adverse events （AEs） (CTCAE v4).
Results:
From Dec. 2012 to June 2015, 176 patients from 17 sites were randomized to WBI+Chemo arm (N=91) or icotinib arm (N=85). The baseline clinicopathologic factors were balanced between the two groups. Median age was 58, PS 1 was 87.2%, non-smoker 70.9%, adenocarcinoma 96.8%, symptomatic brain M were 16.5%. Icotinib significantly improved median iPFS compared with WBI+chemo: hazard ratio [HR] 0.56; 95% CI: 0.36-0.90; p=0.014 (10.0 vs 4.8 months). Median PFS was 6.8 vs 3.4 months, (HR 0.44, 95% CI 0.31-0.63, P<0.001). Median OS had no significant difference between the arms (18.0 vs 20.5 months, HR 0.93, 95%CI 0.60-1.44, P=0.734). Intracranial ORR was significantly improved with icotinib than WBI+Chemo (67.1% vs 40.9%; p<0.001); Overall ORR was 55.0% vs 11.1% (P<0.001). Grade ≥3 AEs assessed by the investigators were reported in 8.2% (N=7) of patients treated with icotinib and 26.2% (N=28) treated with WBI+Chemo. Most common causally related AEs in the icotinib arm were increased liver transaminase & rash; in the WBI+Chemo arm were hematologic toxicity.
Conclusion:
Icotinib demonstrated superior iPFS, PFS and ORR over WBI+Chemo in EGFR mutant advanced NSCLC with brain M, and well-tolerated safety profile. Icotinib would be a treatment option for EGFR mutant patients with brain M (NCT01724801).
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SC05 - Novel Drugs in Thoracic Cancers (ID 329)
- Event: WCLC 2016
- Type: Science Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
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SC05.03 - Novel Tyrosine Kinase Inhibitors in Lung Cancer (ID 6619)
11:00 - 12:30 | Author(s): C. Zhou
- Abstract
- Presentation
Abstract:
The invited talk will firstly talk about the recent advances in novel TKIs overcoming resistance during EGFR-TKI and ALK-TKI treatment. Afterwards, several novel TKIs with CNS penetration that may substantially change the prognosis and treatment strategy of patients with brain metastases will be discussed. Finally, we will take an overview about targeted therapy against rare and novel, potentially druggable oncogenic drivers either in preclinical settings or early-stage clinical trials. As we know, the presence of EGFR activating mutations and ALK chromosomic rearrangements with corresponding tyrosine kinase inhibitors (TKIs) has revolutionized the treatment strategies of patients with non-small cell lung cancer (NSCLC) [1, 2]. Although tremendously initial response and manageable toxicity profiles, however, acquired resistance inevitably develops after approximately 1 year treatment with EGFR-TKIs (erlotinib and gefitinib) and ALK inhibitor (crizotinib). Encouragingly, third-generation EGFR-TKIs including AZD9291, CO1686 and HM61713 have showed striking efficacy overcoming acquired resisitance driven by T790M secondary mutations [3, 4]. In patients who get acquired resistance to first-generation EGFR-TKIs with T790M mutations, the objective response rate (ORR) of AZD9291 was 61% and median progression-free survival (PFS) was 9.7 months [4]. Other novel third-generation EGFR-TKIs such as ASP8274, EGF816, PF-06747775 and avitinib are also being investigated in early-stage clinical trials and the survival and safety data will be released in the near future. Another promising novel EGFR-TKI, namely AZD3759 has showed promising response in patients with brain metastases and leptomeningeal disease, a major case leading to treatment failure. In BLOOM study, 11 out of 21 patients with measurable brain metastases and heavily pre-treated progressed both extracranially and intracranially had tumor shrinkage in the brain at dose ≥50mg BID. Recently, EAI045, an EGFR allosteric inhibitor, in combination with cetuxmab exhibit antitumor activity in mouse models of lung cancer driven by L858R/T790M/C797S, a common resistant mechanism of AZD9291 [5]. Meanwhile, second-generation ALK inhibitors (ceritinib, alectinib and brigatinib) have entered clinical applications for NSCLC patients with ALK rearrangements after failure of crizotinib and third-generation ALK inhibitors (lorlatinib and ASP3026) are also being evaluated in clinical trials overcoming known ALK resistant mutations[6, 7]. In patients who progress on crizotinib, the ORR and PFS of brigatinib at 180mg was 54% and 12.9 months. Lorlatinib, a third-generation ALK inhibitor, also demonstrated robust clinical activity in ALK-rearrangement patients with NSCLC. The ORR was 57% in patients who received 1 prior ALK-TKI and 42% in patients who received ≥2 prior ALK-TKIs. On the other hand, with the development of high-throughput sequencing, called next-generation sequencing (NGS) and genomic technologies, more novel molecular targets such as MET 14 exon skipping splicing mutations[8]have been identified as potential therapeutic targets and simultaneously analyzing hundreds of molecular alterations have turned out reality with limited tumor tissues. In the recent years, the emergence of numbers of oncogenic drivers other than EGFR mutations and ALK rearrangements has divided NSCLC into multiple distinct subtypes amenable to corresponding targeted therapy, including ROS1 rearrangement, RET arrangement, BRAF-V600E mutations, HER2 mutations and MET 14 exon skipping mutations et al. For instance, dabrafenib either as monotherapy or in combination with MEK inhibitor (trametinib) has displayed promising antitumor activity and manageable safety profile in patients with BRAF V600E mutations [9, 10]. In 57 previously treated metastatic NSCLC patients with BRAF-V600E mutations, 63.2% patients (36/57) achieved an overall response [9]. Other novel molecular targets maybe serving as oncogenic drivers including mutations in HER2 (neratinib and pyrotinib) and PI3KCA (BKM120 and GDC0941), ROS1 (entrectinib, foretinib and lorlatinib), RET (XL184) and NTRK (entrectinib) rearrangements and FGFR1 gene amplification (AZD4547, Lenvatinib and FP-1039) are being evaluated either in preclinical settings or early-stage clinical trials. Reference: 1. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361: 947-957. 2. Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371: 2167-2177. 3. Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med 2015;372: 1700-1709. 4. Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372: 1689-1699. 5. Jia Y, Yun CH, Park E, Ercan D, Manuia M, Juarez J, et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 2016;534: 129-132. 6. Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol 2016;34: 661-668. 7. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370: 1189-1197. 8. Paik PK, Drilon A, Fan PD, Yu H, Rekhtman N, Ginsberg MS, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov 2015;5: 842-849. 9. Planchard D, Besse B, Groen HJ, Souquet PJ, Quoix E, Baik CS, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 2016;17: 984-993. 10. Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, et al. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol 2016;17: 642-650.
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