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J. Soria
Moderator of
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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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ISS09 - Industry Supported Symposium: Targeted Therapy on the Horizon for SCLC - AbbVie (ID 442)
- Event: WCLC 2016
- Type: Industry Supported Symposium
- Track:
- Presentations: 3
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ISS09.02 - Advancing the Study in SCLC – What is the Underlying Biology? (ID 7020)
07:30 - 08:30 | Author(s): J. Soria
- Abstract
Abstract not provided
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ISS09.04 - Panel Discussion: Looking Over the Horizon – Future Treatment of SCLC (ID 7022)
07:30 - 08:30 | Author(s): J. Soria
- Abstract
Abstract not provided
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ISS09.05 - Question & Answer (ID 7023)
07:30 - 08:30 | Author(s): J. Soria
- Abstract
Abstract not provided
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MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:R. Perez-Soler, T. Reungwetwattana
- Coordinates: 12/06/2016, 11:00 - 12:30, Lehar 3-4
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MA08.01 - A Highly Sensitive Next-Generation Sequencing Platform for Detection of NSCLC EGFR T790M Mutation in Urine and Plasma (ID 4637)
11:00 - 12:30 | Author(s): J. Soria
- Abstract
- Presentation
Background:
Non-invasive genotyping of NSCLC patients by circulating tumor (ct)DNA is a promising alternative to tissue biopsies. However, ctDNA EGFR analysis remains challenging in patients with intrathoracic disease, with a reported 26-57% T790M mutation detection rate in plasma (Karlovich et al., Clin Cancer Res 2016; Wakelee et al., ASCO 2016). We investigated whether a mutation enrichment NGS could improve mutation detection in plasma and urine from TIGER-X, a phase 1/2 study of rociletinib in patients with EGFR mutation-positive advanced NSCLC.
Methods:
The therascreen (Qiagen) or cobas (Roche) EGFR test was used for EGFR T790M analysis in tumor biopsies. Urine and plasma were analyzed by trovera mutation enrichment NGS assay (Trovagene).
Results:
Of 174 matched tissue, plasma and urine specimens, 145 (83.3%) were T790M+ by central tissue testing, 142 (81.6%) were T790M+ by plasma, and 139 (79.9%) were T790M+ by urine. Urine and plasma combined identified 165 cases (94.8%) as T790M+. Of 25 cases positive by ctDNA but negative/inadequate by tissue, 16 were double-positive in plasma and urine, unlikely to be false positive (Figure 1). T790M detection rate was higher for extrathoracic (n=119) vs intrathoracic (n=55) disease in plasma (87.4% vs 69.1%, p=0.006) but not urine (81.5% vs 76.4%, p=0.42). Combination of urine and plasma identified T790M in 92.7% of intrathoracic and 95.8% of extrathoracic cases (p=0.47). In T790M+ patients, objective response rate was similar whether T790M mutation was identified by tissue, plasma or urine: 37.4%, 33.1% and 36.6%, respectively. 4 of 9 patients T790M+ by urine but negative by tissue responded, and 2 of 8 patients T790M+ by plasma but negative by tissue responded.
Conclusion:
Mutation enrichment NGS testing by urine and plasma combined identified 94.8% of T790M+ cases. Combination of urine and plasma may be considered before tissue testing in EGFR TKI resistant NSCLC, including patients without extrathoracic metastases. Figure 1
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MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:P. Lara, A. Mohn-Staudner
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 3
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MA11.02 - Mutational Burden in Pulmonary Neuroendocrine Tumors (puNETs) (ID 6099)
14:20 - 15:50 | Author(s): J. Soria
- Abstract
- Presentation
Background:
Tumor mutational load (TML) by whole-exome sequencing (WES) is a potential determinant of response to immune checkpoint blockers. The use of PD-L1 as a predictive biomarker for use of PD-1/PD-L1 inhibitors is limited. To date, there are few data concerning TML in puNETs.
Methods:
WES was performed in fresh-frozen tumor-normal pairs from 35 typical carcinoid (TC), 4 atypical carcinoid (AC) and 9 large-cell neuroendocrine carcinoma (LCNEC) consecutively collected. Exome enriched libraries were sequenced on an Illumina HiSeq 2000 with a paired-end 2 x 100 bp protocol. Reads were aligned to the reference hg19 using an implementation of the Burrows-Wheeler Aligner, and a BAM file was produced for each tumor and normal sample using the Picard pipeline. The MuTect algorithm was used to identify SSNVs in WES data. We used a minimal allelic fraction cutoff of 0.1. Patients' characteristics and TML were described (median and interquartile for quantitative variables and frequencies for qualitative variables). To evaluate the effect of some factors on the TML, an analysis of variance was used. A log transformation was performed according to the distribution of the TML. The median follow-up was estimated using the Schemper's method. The number of relapses and deaths was reported.
Results:
Cohort included 24 male and 24 female. Median age at diagnosis was 57 [Q1= 46; Q3= 70] years, 38% of carcinoids (TC+AC) and 89% of LCNEC were smokers, 26 (54%) stage I, 16 (34%) stage II, 3 (6%) stage III and 3 (6%) stage IV. All patients underwent surgery and 5 (10%) received neoadjuvant treatment. Median follow-up was 32.6 (min= 4.4; max= 179.9) months; there were 8 (17%) relapses (6/9 LCNEC, 2/39 carcinoids) and 10 deaths. On average, 11.6 Gb of sequence were produced per sample, aiming a mean coverage of 72X. Overall median TML was 0.31/Mb [Q1= 0.22; Q3= 0.67], significantly lower in carcinoids tumors than LCNEC (0.28 [Q1= 0.20; Q3= 0.38]/Mb vs. 2.98 [Q1= 1.20; Q3= 4.84]/Mb, respectively, p<0.0001). Similar findings were observed among smoker vs. non-smoker patients (0.28 [Q1= 0.18; Q3= 0.38]/Mb vs. 0.60 [Q1= 0.28; Q3= 2.98]/Mb, respectively, p=0.04). Both variables were found to be independently correlated with TML within the ANOVA test (p=0.0016).
Conclusion:
Our findings provide a unique portrait of puNETs, revealing different histotype mutational burden. Continued work in harnessing immunological data in puNETs are needed for better understanding immunotherapy-treatment option in this orphan disease.
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OA06 - Prognostic & Predictive Biomarkers (ID 452)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:F. Shepherd, Y. Yatabe
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 1
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OA06.05 - Proteomic Analysis of ERCC1 Predicts Benefit of Platinum Therapy in NSCLC: A Reevaluation of Samples from the TASTE Trial (ID 5361)
14:20 - 15:50 | Author(s): J. Soria
- Abstract
- Presentation
Background:
It is hypothesized that low or absent expression of the excision repair cross-complementation group 1 (ERCC1) protein predicts improved survival in NSCLC patients treated with platinum-based therapy. However, the International Adjuvant Lung Cancer Trial Collaborative Group concluded that current ERCC1 assessment methods are inadequate for clinical decision-making. Due to the unreliability of ERCC1 immunohistochemistry (IHC), the IFCT-0801 TASTE (Tailored Postsurgical Therapy in Early-Stage NSCLC) trial of adjuvant therapy for NSCLC was discontinued. We reevaluated a subset of samples from the TASTE trial using mass spectrometry-based proteomics to quantitate ERCC1 protein. We correlated ERCC1 proteomic status with survival after chemotherapy with cisplatin/pemetrexed and compared it to ERCC1 IHC ranking.
Methods:
Formalin-fixed, paraffin-embedded NSCLC tumor tissues were laser microdissected, solubilized, digested, and proteomically analyzed. A multiplexed, selected reaction monitoring mass spectrometric assay was used to quantitate levels of multiple proteins including ERCC1. The Kaplan-Meier method and univariate Cox analysis assessed overall survival (OS) and relapse-free survival (RFS). A chi-squared test compared binary proteomic levels of ERCC1 (detectable vs. undetectable) with the IHC status assessed using an anti-ERCC1 antibody (8F1) during the TASTE trial.
Results:
Of 146 evaluable patients, 33 (22.6%) had undetectable ERCC1 by quantitative proteomics. Proteomics found no detectable ERCC1 protein in 8/36 (22.2%) IHC-positive patients nor in 8/22 (19.3%) IHC-indeterminate patients. ERCC1 was detected in 71/88 (80.7%) IHC-negative patients (range: 36-137 amol/µg total tumor protein). Undetectable ERCC1 by proteomics was prognostic of OS (hazard ratio [HR]: 5.45; p=0.031). In survival analyses of cisplatin-treated patients (n=122), only one of the 15 deaths occurred among the patients with undetectable ERCC1 protein. These patients had better OS than cisplatin-treated patients with detectable ERCC1, although the difference statistically nonsignificant (HR: 3.98; p=0.102). RFS was similar between patients with and without detectable ERCC1. GARFT protein (predictive of response to pemetrexed) was quantified in 100% of patients (range: 492-4006 amol/µg). The 10 cisplatin/pemetrexed-treated patients with GARFT levels >900 amol/µg had nonsignificantly worse OS than their counterparts with lower GARFT levels (p=0.08).
Conclusion:
Although underpowered to detect statistically significant survival differences, this study clearly demonstrates that quantitative proteomics can increase accuracy in identifying NSCLC patients who will respond to platinum-based therapy because they do not express ERCC1. Approximately 28% of such patients were misclassified by ERCC1 IHC in the TASTE trial. Clinicians should be aware that multiplexed quantitative proteomics can quantitate ERCC1 simultaneously with multiple clinically relevant proteins in lung tumors and small biopsies.
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OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:O.T. Brustugun, S. Lu
- Coordinates: 12/07/2016, 14:20 - 15:50, Stolz 2
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OA23.03 - Second-Line Afatinib for Advanced Squamous Cell Carcinoma of the Lung: Analysis of Afatinib Long-Term Responders in the Phase III LUX-Lung 8 Trial (ID 4711)
14:20 - 15:50 | Author(s): J. Soria
- Abstract
- Presentation
Background:
Squamous cell carcinoma (SCC) of the lung is a genetically complex and difficult-to-treat cancer. In LUX-Lung 8, afatinib (40mg/day) significantly improved OS (median 7.9 vs 6.8 months, HR=0.81 [95% CI, 0.69‒0.95], p=0.008), PFS (2.6 vs 1.9 months, HR=0.81 [0.69‒0.96], p=0.010) and DCR versus erlotinib (150mg/day) in patients with relapsed/refractory SCC of the lung (n=795). Notably, 12-month (36 vs 28%; p=0.016) and 18-month survival (22 vs 14%; p=0.016) was significantly higher with afatinib than erlotinib, indicating that some patients derive prolonged benefit from afatinib. Here, we present post-hoc analysis of baseline characteristics and efficacy/safety of afatinib in long-term responders (treatment for ≥12 months). Hypothesis-generating analysis of archived tumor samples and blood serum was undertaken to identify possible molecular/clinical biomarkers.
Methods:
Tumor samples were retrospectively analyzed using FoundationOne[TM] next-generation sequencing (NGS); EGFR expression was determined by immunohistochemistry. Pre-treatment serum samples were analyzed with VeriStrat[®], a MALDI-TOF mass spectrometry test, and classified as VeriStrat-Good or VeriStrat-Poor-risk.
Results:
15/398 patients treated with afatinib were long-term responders. Median duration of treatment was 16.6 months (range: 12.3‒25.8). Patient characteristics were similar to the overall dataset (median age: 65 years [range: 54‒81]; male: 80.0%; Asian: 13.3%; ECOG 0/1: 40.0%/60.0%; best response to chemotherapy CR or PR/SD: 53.3%/46.7%; current and ex-smokers: 80.0%). Median PFS was 16.2 months (range: 2.8‒24.0); median OS was 23.1 months (range: 12.9‒31.5). The most common treatment-related AEs (all grade/grade 3) were: diarrhea (73.3%/6.7%); rash/acne (66.7%/6.7%); stomatitis (13%/7%). AEs generally occurred soon after treatment onset (median onset, days [range]: diarrhea 11 [5‒48]; rash/acne 17 [9‒107]; stomatitis 15 [11‒19]). Four patients required a dose reduction to 30mg/day due to treatment-related AEs (diarrhea, rash, stomatitis, diarrhea/rash). NGS was undertaken in 9 patients and details will be presented at the meeting. Genomic aberrations in the ErbB/FGF gene families were identified in 44.4%/55.6% of long-term responders (overall dataset: 29.4%/58.0%). Of 14 patients assessed by VeriStrat, 85.7% were VeriStrat-Good (overall dataset: 61.6%). Immunohistochemistry data was available for two patients; one overexpressed EGFR (≥10% positive cells; H-score ≥200)
Conclusion:
Baseline characteristics of long-term responders to afatinib were similar to the overall dataset. In this sub-group, afatinib conferred a survival benefit of nearly 2 years. Afatinib was well tolerated with predictable and transient AEs that occurred soon after treatment onset. The dataset was too small to identify any clear NGS/VeriStrat predictive signals. Further studies are required to predict long-term response to afatinib.
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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-050 - Prognostic Value of HLA-A2 Status in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients (ID 4773)
14:30 - 15:45 | Author(s): J. Soria
- Abstract
Background:
The class I human leucocyte antigen (HLA) molecules play a critical role as escape mechanism of antitumoral immunity. Indeed, novel immune-targeting cancer vaccines are currently developped in HLA-A2 positive patients for modulating the T cells response. The HLA-A2 status has been proposed as prognostic factor in lung cancer, but previous evidence is inconsistent. The aim of this study is to evaluate the role of HLA-A2 status as prognostic factor in a large cohort of advanced NSCLC patients.
Methods:
Advanced NSCLC patients eligible to platinum based chemotherapy (CT) were included from Oct. 2009 to July 2015 in the prospective MSN study (IDRCB A2008-A00373-52) in our institute. HLA-A2 status was analysed by flow cytometry. Clinical and pathological data were collected in a Case Report Form (CRF). Statistical analysis was performed with software SAS version 9.3.
Results:
Five hundred forty-five advanced NSCLC patients were included. Three hundred forty-four patients (63%) were male, median age was 61 years (21-84); 466 (85%) were smokers. Four hundred seven (75%) were adenocarcinoma, 69 (13%) squamous and 69 (13%) others histologies. Among 259 patients with known molecular profile, 113 (43.6%) NSCLC were KRASmut, 50 (19.3%) EGFRmut, 30 (11.6%) ALK positive, 9 (3.5%) BRAFmut and 8 (3.1%) FGFR1amp. Four hundred forty-seven (83%) patients had performance status 0-1 at diagnosis. Five hundred eight patients (93%) were stage IV, and 37 (7%) stage IIIB. All received platinum-based CT (49% cisplatine, 42% carboplatin and 9% both). No association was observed between HLA-A2 status and patient or tumor characteristics. The median progression free survival to platinum-based CT (PFS) was 5.6 months [confidence interval (CI) 95% 5.20-6.10]. In HLA-A2 positive patients, the median PFS was 5.6 months [CI 95% 5.1-6.4] vs. 5.7 months [CI 95% 4.9-6.2] in HLA-A2 negative patients (HR 1, Wald test, p=0.8).The median overall survival (OS) was 12.6 months [CI 95% 11.3-14.3]. The median OS was 12.8 months [CI 95% 11-14.6] in HLA-A2 positive vs. 12.5 months [CI 95% 10.4- 15.3] in HLA-A2 negative patients (HR 1, Wald test p=0.61). No significant differences were found between HLA-A2 status and PFS and OS in advanced NSCLC patients.
Conclusion:
Our study has observed no prognostic role of HLA-A2 status in advanced NSCLC patients.
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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-025 - PROs With Ceritinib Versus Chemotherapy in Patients With Previously Untreated ALK-rearranged Nonsquamous NSCLC (ASCEND-4) (ID 5128)
14:30 - 15:45 | Author(s): J. Soria
- Abstract
Background:
Here, we present the patient-reported outcomes (PROs) of ceritinib versus chemotherapy as first-line treatment for advanced ALK+ NSCLC.
Methods:
Untreated, ALK+, advanced, nonsquamous NSCLC patients (N=376) were randomized (1:1) to ceritinib 750 mg/day (n=189) or chemotherapy (n=187; [pemetrexed 500 mg/m[2 ]plus cisplatin 75 mg/m[2] or carboplatin AUC 5-6] for 4 cycles followed by maintenance pemetrexed). PROs were assessed using EORTC quality-of-life questionnaire (QLQ-C30), the lung cancer module (QLQ-LC13), Lung Cancer Symptom Scale (LCSS), and EQ-5D.
Results:
Median treatment exposure was 66.4 weeks for ceritinib and 26.9 weeks for chemotherapy. PRO compliance was high, ≥80% at most timepoints. Ceritinib significantly prolonged time to deterioration of lung cancer-specific symptoms (pain, dyspnea, and cough) versus chemotherapy in both LCSS and QLQ-LC13 instruments (composite endpoints for LCSS, HR=0.61 [0.41, 0.90]; and QLQ-LC13, HR=0.48 [0.34, 0.69]). Time to deterioration in LC13 questionnaire was significantly longer with ceritinib versus chemotherapy (23.6 [20.7, NE] vs 12.6 [8.9, 14.9] months) (Table). In the QLQ-C30 instrument, 4 of 5 functional domains and 6 of 9 symptom scales improved with ceritinib (P< 0.05); 2 scales related to gastrointestinal symptoms indicated deterioration for ceritinib. In agreement with most other scales showing symptom improvement, ceritinib demonstrated significant improvements in Global Health Status/QoL in the same instrument (QLQ-C30, P<0.001) as well as for EQ-5D-5L index (P<0.001) and EQ-5D-5L VAS (P<0.05 from cycle 13 until 49). Figure 1
Conclusion:
Untreated ALK+ NSCLC patients experienced significantly greater improvements in lung cancer-specific symptoms on treatment with ceritinib. General health status was significantly improved with ceritinib versus chemotherapy. Overall, PRO results from all 4 instruments independently showed improvements highlighting the consistency and robustness of these findings.
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P3.02b - Poster Session with Presenters Present (ID 494)
- 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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P3.02b-003 - Second-Line Afatinib versus Erlotinib for Patients with Squamous Cell Carcinoma of the Lung (LUX-Lung 8): Analysis of Tumour and Serum Biomarkers (ID 5627)
14:30 - 15:45 | Author(s): J. Soria
- Abstract
Background:
LUX-Lung 8 compared second-line afatinib (40 mg/day; n=398) and erlotinib (150 mg/day; n=397) in patients with stage IIIB/IV squamous cell carcinoma (SCC) of the lung. PFS (median 2.6 vs 1.9 months, HR=0.81 [95% CI, 0.69–0.96], p=0.010) and OS (median 7.9 vs 6.8 months, HR=0.81 [0.69–0.95], p=0.008) were both significantly improved with afatinib versus erlotinib. Here we report exploratory molecular (n=245) and immunohistochemical (n=288) analyses of tumour samples to assess the frequency of short variants (SVs) and copy number alterations (CNAs) in cancer-related genes and whether these tumour genomic alterations, or EGFR expression levels, have clinical utility as prognostic/predictive biomarkers in patients with SCC of the lung. We also assessed the predictive utility of the prospectively validated VeriStrat®, a serum protein test (n=675).
Methods:
Archived tumour samples were retrospectively analysed using next-generation sequencing (FoundationOne™). Tumour EGFR expression was assessed by immunohistochemistry; EGFR positivity was defined as staining in ≥10% of cells. Pretreatment serum samples were assigned as VeriStrat-Good or VeriStrat-Poor according to a mass spectrometry signature. Cox regression analysis was used to correlate OS/PFS with genomic alterations (individual or grouped into gene families e.g. ErbB family), EGFR expression levels and VeriStrat status.
Results:
The frequency of ErbB family alterations was low (SVs: EGFR 6.5%, HER2 4.9%, HER3 6.1%, HER4 5.7%; CNAs: EGFR 6.9%, HER2 3.7%). No individual genetic alterations, or grouped ErbB family aberrations, were prognostic of OS/PFS. Treatment benefit from afatinib versus erlotinib was consistent in all molecular subgroups. Most tumours were EGFR-positive by immunohistochemistry (afatinib: 82%; erlotinib: 86%). EGFR expression was not predictive of OS or PFS benefit (EGFR-positive PFS: HR=0.76 [0.57‒1.02]; OS: HR=0.84 [0.63‒1.12]; EGFR-negative PFS: HR=0.87 [0.45‒1.68]; OS: HR=0.77 [0.40‒1.51]). In afatinib-treated patients, both PFS (HR=0.56 [0.43‒0.72], p<0.0001) and OS (HR=0.40 [0.31‒0.51], p<0.0001) were improved in the VeriStrat-Good versus the VeriStrat-Poor group. VeriStrat-Good patients had significantly longer OS and PFS when treated with afatinib versus erlotinib (median OS: 11.5 vs 8.9 months, HR=0.79 [0.63‒0.98]; PFS: HR=0.73 [0.59‒0.92]). In VeriStrat-Poor patients there was no significant difference in OS between afatinib and erlotinib (HR=0.90 [0.70‒1.16]). However, there was no significant interaction between treatment arms and VeriStrat classification.
Conclusion:
Despite comprehensive, multifaceted analysis, no biomarkers were identified that predicted the benefit with afatinib over erlotinib in patients with SCC of the lung. Afatinib is a treatment option in this setting irrespective of patients’ tumour genetics or EGFR expression levels. However, patient outcome strongly depends on VeriStrat status.
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P3.02b-102 - Osimertinib Benefit in ctDNA T790M Positive, EGFR-Mutant NSCLC Patients (ID 5472)
14:30 - 15:45 | Author(s): J. Soria
- Abstract
Background:
The third generation tyrosine kinase inhibitors (TKIs) osimertinib is approved for patients with acquired epidermal growth factor receptor (EGFR) T790M mutations in advanced non-small cell lung cancer (NSCLC) patients. New tissue biopsy to detect T790M cannot always be performed, due to the size or location of the lesions and risk of complications to the patient. As an alternative, liquid biopsies based on circulating cell-free tumor DNA (ctDNA) analysis have been described. We assess the efficacy of osimertinib in ctDNA T790M-positive, EGFR-mutant NSCLC patients with progression under first- or second-generation EGFR TKIs ineligible for tissue biopsy at progression; and the feasibility of identifying T790M mutations in ctDNA isolated from blood samples in this cohort of patients.
Methods:
ctDNA analysis using enhanced eTAm-Seq™ assay (Inivata), and enhanced version of the Tam-Seq ® assay was conducted in 48 eligible patients treated in a single center between April 2015 and April 2016. Patients determined to have T790M mutation were prescribed osimertinib (80mg daily). Objective response rate (ORR) by RECIST 1.1 criteria was centrally reviewed and correlated with (A) T790M allele fraction, (B) EGFR activating mutation allele fraction, and (C) T790M by EGFR activating mutation allele fraction ratio.
Results:
T790M status in ctDNA was assessed in 48 EGFR-mutant NSCLC patients. Median age was 65 years (range 37-83); 36 (75%) patients were women and 58% were never-smoker. EGFR mutation status was Del19 in 33 (69%) and L858R in 15 (31%) NSCLC patients. The ctDNA T790M mutation was positive in 24 out of 48 (50%) patients, and 23 out of 24 T790M-positive samples maintained the original activating EGFR mutation in ctDNA analysis. Among evaluable patients (n=16), osimertinib gave a partial response rate of 62.5% and a stable disease rate of 37.5%. Neither correlation between ctDNA T790M AF and RECIST radiological response was observed, nor with the other parameters evaluated. Of the seven cases with best response (decrease of 50% or more in size), 3 cases had T790M detected at <0.25%.
Conclusion:
Osimertinib efficacy in a real-world setting among T790M-positive tumours detected in ctDNA from liquid biopsy support the use of such liquid biopsies as a surrogate marker for T790M in tumour tissue, avoiding the need for invasive tumor biopsies for personalising treatment in lung cancer patients
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P3.02b-115 - Clinical Activity of Osimertinib in EGFR Mutation Positive Non Small Cell Lung Cancer (NSCLC) Patients (Pts) Previously Treated with Rociletinib (ID 4893)
14:30 - 15:45 | Author(s): J. Soria
- Abstract
Background:
Both osimertinib and rociletinib were developed to target the EGFR resistance mutation T790M. Sequist, et al reported clinical activity with osimertinib in 9 pts previously treated with rociletinib[1]. We conducted a retrospective analysis at 8 institutions of pts treated with rociletinib, who discontinued the drug due to disease progression or intolerable toxicity and subsequently received osimertinib.
Methods:
We identified pts treated with rociletinib followed by osimertinib, as part of osimertinib's US expanded access program or via commercial supply. Clinical characteristics and outcomes were assessed. Frequency of clinical and radiologic assessments on osimertinib was at the discretion of the treating physician. For this retrospective review, reverse KM method was used to calculate the median follow-up; KM method was used for time-to-event endpoints.
Results:
45 pts were included in this analysis. Median age at the start of osimertinib was 66 years (43-86) and 71% were female. 28 pts had exon 19 deletions and 16 had L858R. Median duration of therapy on front line EGFR TKI was 18 months (5-54). Median starting dose of rociletinib was 625 mg bid (range 500-1000). The response rate (RR) and disease control rate (DCR; Response+Stable Disease) with rociletinib were 38% and 91%; median duration of rociletinib therapy was 6.2 months. 32 (71%) pts discontinued rociletinib for disease progression. 23 (51%) pts received other therapies (1-4) before starting osimertinib. 25 (56%) pts were known to have brain metastases at osimertinib initiation. RR and DCR with osimertinib were 33% and 82%. DCR in the brain was 88%. With a median follow-up of 7.1 months, median duration of osimertinib therapy in all patients was 8 months (95%CI- 6.6-NR; 64% censored). The 1-year overall survival (OS) rate on osimertinib was 70% (54%-91%). In the 32 pts who discontinued rociletinib due to progression, DCR with osimertinib was 75% and median duration of therapy was 7.8 months (4.6-NR). Neither duration of,or response to rociletinib treatment, nor interval between the two the drugs was associated with duration of osimertinib or OS after osimertinib using a Cox model adjusted for age and sex.
Conclusion:
Osimertinib can provide clinical benefit in EGFR mutation positive NSCLC patients previously treated with rociletinib. The clinical activity of osimertinib in these patients may be related to more potent inhibition of T790M mutation or ability to overcome resistance to rociletinib. Reference- 1. Sequist, et al. JAMA Oncology 2016
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P3.02c - Poster Session with Presenters Present (ID 472)
- 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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P3.02c-031 - Immune Checkpoint Inhibitors (IC) and Paradoxical Progressive Disease (PPD) in a Subset of Non-Small Cell Lung Cancer (NSCLC) Patients (ID 5448)
14:30 - 15:45 | Author(s): J. Soria
- Abstract
Background:
In non-squamous NSCLC PD-L1 negative patients (pts), IC might increase the risk of early death compared to docetaxel in the phase III study Checkmate 057. Tumor Growth Rate (TGR) is calculated using 2 CTscans and the time interval between the 2 exams. It integrates tumor dynamics and kinetics. We hypothesized that TGR could identify a subset of pts named PPD, in which IC could accelerate tumor progression, leading to early death.
Methods:
We performed a retrospective case study of all NSCLC pts treated by IC in a single institution between Dec. 12 and Feb. 16. CT scan were centrally reviewed by a senior radiologist and assessed according to RECIST 1.1 criteria. We calculated TGR at baseline of IC (baseline CTscan (n) vs n-1 CTscan) and TGR during IC (n+2 CTscan vs n+1 CTscan). We further estimated the difference (deltaTGR) between TGR during IC and TGR at baseline. DeltaTGR>0 means IC speeds up tumor growth. PPD was defined as deltaTGR>50%, corresponding to an absolute increase in TGR greater than 50% per month. PDL1 expression was assessed with the SP142 clone.
Results:
89 pts were eligible. 58% were male, median age 60 (41-78); 15% never smokers. 62 pts had adenocarcinoma, 21 squamous and 6 other histologies. Mutational status was unknown for 14 pts; 36% wild type, 9 pts EGFRmut, 25 pts KRASmut. PDL1 expression was positive in 25 pts, unknown in 57 pts. 52 pts (58%) received nivolumab, 25 pembrolizumab and 12 atezolizumab. Treatement was received as 1-3[rd] line in 52 pts, and as ≥ 4[th] line in 37 pts. Overall, 25 pts (28%) had a response according to RECIST 1.1 criteria, 31 (35%) a stable disease. Median OS was 14.7 months. During IC, deltaTGR was <0 in 79 pts and >0 in 20 pts. Among the 20 pts with deltaTGR>0, 9 had a PPD. Characteristics (age, sex, smoking status, pathology, number of previous line, PDL1 status) of the 9 pts were not different from other pts. None of the PPD were pseudoprogression. Median OS of PPD vs others was 3.2 and 23 months, respectively. PPD was not more frequent in tumors with high baseline TGR.
Conclusion:
Our results suggest that PPD is a new subset of response criteria in which IC may increase tumor progression, leading to a poorer survival. Rapidly growing disease at study entry nor RECIST criteria could predict the occurrence of PPD.
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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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PL03.07 - First-line Ceritinib Versus Chemotherapy in Patients With ALK-rearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-4) (Abstract under Embargo until December 6, 7:00 CET) (ID 4987)
08:35 - 10:25 | Author(s): J. Soria
- Abstract
- Presentation
Background:
Here, we report results of ceritinib versus chemotherapy as first-line treatment for advanced ALK+ NSCLC.
Methods:
Untreated ALK+ (IHC confirmed), advanced, nonsquamous NSCLC patients (N=376; median age, 54 years) were randomized (1:1) to ceritinib 750 mg/day (n=189 [59 with brain metastases (BM)]) or chemotherapy (n=187 [62 with BM]; [pemetrexed 500 mg/m[2] plus cisplatin 75 mg/m[2] or carboplatin AUC 5-6] for 4 cycles followed by maintenance pemetrexed), stratified by WHO PS (0 vs 1-2), BM at screening, and prior neo-/adjuvant chemotherapy. Crossover from chemotherapy to ceritinib was allowed at progression (n=80 crossed-over).
Results:
Median treatment exposure was 66.4 weeks for ceritinib and 26.9 weeks for chemotherapy. Median follow-up duration was 19.7 months (randomization to cut-off date). The study met its primary objective, with ceritinib demonstrating statistically significant improvement in BIRC PFS (RECIST 1.1; median, 16.6 [12.6, 27.2] vs 8.1 months [5.8, 11.1], HR=0.55, P<0.001) versus chemotherapy. OS was immature (HR, 0.73 [0.50, 1.08]; P=0.056) with 42.3% of required events at interim analysis. ORR (BIRC, 72.5% vs 26.7%) and DOR (BIRC, median, 23.9 vs 11.1 months) were also higher with ceritinib versus chemotherapy. Among patients with measurable baseline BM and ≥1 postbaseline assessment, intracranial ORR (BIRC neuroradiologist; modified RECIST v1.1) was higher with ceritinib (72.7% [49.8, 89.3] vs 27.3% [10.7, 50.2]) versus chemotherapy (Table). Most common AEs (>50%) with ceritinib were diarrhea (84.7%), nausea (68.8%), vomiting (66.1%), ALT increase (60.3%), and AST increase (52.9%). Overall, 5.3% ceritinib- and 11.4% chemotherapy-treated patients discontinued due to AEs suspected to be drug-related. Figure 1
Conclusion:
First-line ceritinib achieved statistically significant and clinically meaningful improvement in median PFS with an estimated 45% risk reduction in advanced ALK+ NSCLC versus chemotherapy including maintenance. Moreover, ceritinib achieved high and durable systemic responses and high OIRR in patients with measurable BM. Safety profile of ceritinib is consistent with previously reported.
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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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SC05.02 - Novel Cytotoxic Drugs in Lung Cancer (ID 6618)
11:00 - 12:30 | Author(s): J. Soria
- Abstract
- Presentation
Abstract:
Even in the era of precision medicine and immunotherapy, cytotoxic chemotherapies remain an essential component of lung cancer treatment, both in resectable disease as well as in advanced/metastatic lung cancer. We have chosen to focus on 2 new cytotoxic compounds, which are likely to emerge as new players in the field of lung cancer management. One (named PM1183) has activity in small-cell lung cancer (SCLC), the other TAS-114 has activity in non-small cell lung cancer (NSCLC). PM1183 is a DNA-binding chemotherapy with a new mechanism of action. PM1183 acts as an inhibitor of transcription. Binding of PM1183 to CG-rich motifs, triggers sequential phosphorylation of Pol II and stalling of elongating Pol II. This leads to recruitment of the ubiquitin-proteasome machinery, RNA Pol II degradation, and recruitment of XPF, generation of DNA breaks and induction of apoptosis. PM1183 has been tested in a phase IB trial in combination with doxorubicine. In the dose-finding part: recommended dose (RD) was defined at PM1183 4.0 mg flat dose (FD) or 2.0 mg/m2 + DOX 50 mg/m2 both on day (D)1 every three weeks (q3w). Myelosuppression was dose-limiting (DLT). Compelling activity was observed during escalation phase. It was especially remarkable as 2nd line in SCLC patients: 5 of 7 evaluable pts (71%) had objective partial response (PR) as per RECIST v.1.1. In an expansion cohort of 20 patients, PM1183 and DOX showed outstanding clinical activity: 67% response rate, including 10% of CRs, as 2nd line treatment in SCLC patients. A randomized phase III trial testing PM1183 + DOX is planned and will compare this combination with topotecan or CAV. TAS-114 is a first-in-class oral deoxyuridine triphosphatase (dUTPase) inhibitor that acts as a modulator of the pyrimidine nucleotide metabolic pathway by blocking the conversion of 2’‑deoxyuridine-5’-triphosphate (dUTP; FdUTP) into 2’-deoxyuridine-5’-monophophate (dUMP; FdUMP) through reversible inhibition of dUTPase (gatekeeper protein), resulting in the enhanced incorporation of both uracil and fluorouracil into DNA. The activity of TAS-114, administered in combination with thymidine synthase (TS) inhibitors, 5-FU, S-1 or capecitabine, has been studied pre-clinically in various cancer cell lines and animal models. TAS-114 selectively inhibited dUTPase and showed a higher affinity than the substrates of dUTPase, dUTP and FdUTP, inhibition constant values of TAS-114 were 0.13 μM and 0.10 μM, respectively. The antitumor effect of TAS-114 combined with S-1 as compared to that of S-1 alone was investigated in vivo using a xenograft mouse model with NCI-H2228 (human NSCLC). Both regimens were administered orally (TAS-114: 600 mg/kg/day and S-1: 8.3 mg/kg/day vs S-1: 8.3 mg/kg/day through day 1 to 28) and resulted in relative tumor volumes of 1.61% vs 3.04%, p<0.01, inhibition rates of 52.7% vs 10.8%, and body weight changes of 6.8% vs 3.3%, respectively. A phase 1 clinical study of TAS-114 and S-1 combination treatment is currently ongoing to investigate the safety and to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in patients (pts) with advanced refractory solid tumors. TAS-114 and S-1 are administrated orally twice a day for 14 days followed by 7 days resting period for a 21-days cycle at the starting dosage of 5 mg/m² with the fixed dosage of 25 mg/m², respectively. To date, a total of 96 pts were enrolled with 37 pts in the dose escalation and 59 pts in the MTD expansion stages. TAS-114 and S-1 were escalated up to 240 mg/m² and 36 mg/m², respectively, with 2 DLTs observed at the highest dose level (1 patient with G3 rash and 1 patient with G2 rash/G2 HFS), therefore TAS-114 at 240 mg/m² and S-1 at 30 mg/m² was determined to be the MTD and RD. The most common treatment related adverse events were anemia and rash. There were 4 confirmed partial responses observed in 2 non-small cell lung (NSCLC) pts, 1 pancreas pt and 1 colorectal cancer patient to date. Amongst 6 evaluable NSCLC pts to date, there was an overall response rate of 33% (2/6) with 2 confirmed PR and a disease control rate of 100% (6/6). Pharmacodynamics analysis performed on patient tumor specimens treated at MTD indicated TAS-114 target engagement by reductions in the amount of intra-tumoral dUMP, a “surrogate” metabolite indicative of dUTPase inhibition, following TAS-114/S-1 combination as compared to S-1 alone administration. When TAS-114 is administered in combination with S-1, an additional cytocidal antitumor effect to TTP depletion by TS inhibition is expected as TAS-114 inhibits a gatekeeper protein, thereby allowing increased DNA incorporation of both uracil and 5-FU resulting in DNA damage.
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