Virtual Library
Start Your Search
S. Lu
Moderator of
-
+
OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 8
- Moderators:O.T. Brustugun, S. Lu
- Coordinates: 12/07/2016, 14:20 - 15:50, Stolz 2
-
+
OA23.01 - Anti-EGFR Monoclonal Antibodies plus Chemotherapy in the First-Line Treatment of Advanced NSCLC: A Meta-Analysis (ID 4135)
14:20 - 15:50 | Author(s): G. Stock, P. Aguiar Jr, I. Santoro, H. Tadokoro, R. De Mello, G. Lopes
- Abstract
- Presentation
Background:
Monoclonal Antibodies (mAbs) against the Epidermal Growth Factor Receptor (EGFR) in association with platinum-based doublet chemotherapy have emerged as a potential first-line treatment option for advanced non-small cell lung cancer (NSCLC). This study was conducted to systematically review available data and evaluate the efficacy and toxicity of anti-EGFR mAbs plus chemotherapy vs chemotherapy alone for advanced NSCLC.
Methods:
We carried out a search on network databases and oncology conference abstracts for studies between 1990 and January 2016. Only prospective randomized clinical trials were included. Primary endpoints were overall survival (OS) and toxicity frequency. Secondary endpoints were progression-free survival (PFS) and overall response rate (ORR). Subgroup analysis was performed assessing histological subtypes, EGFR protein expression by immunohistochemistry (IHC), EGFR gene copy number by fluorescence in-situ hybridization (FISH), EGFR mutation status, and smoking status.
Results:
Seven studies (2 with necitumumab and 5 with cetuximab) were included with 5,057 patients. Compared to chemotherapy alone, significant benefits were demonstrated by the addition of anti-EGFR mAb to chemotherapy in OS (HR 0.90; 95%CI 0.84-0.95), PFS (HR 0.93; 95%CI 0.87-0.98), and ORR (OR 1.27; 95%CI 1.06-1.51). In subgroup analyses, the association of anti-EGFR mAb was associated with improved OS among patients with squamous histology (HR 0.84; 95%CI 0.76-0.92), tumours with high EGFR expression by IHC (HR 0.83; 95%CI 0.70-0.98), and smokers (HR 0.87; 95%CI 0.79-0.96). Patients with squamous histology and high EGFR expression by IHC achieved the highest benefit with the association (HR 0.71; 95%CI 0.59-0.86). The OS with the association also seemed to be higher in EGFR FISH negative and in EGFR wild-type tumours, but without statistical significance. Chemotherapy plus anti-EGFR mAb caused more grade 3 or worse adverse events (OR 1.73; 95%CI 1.50-2.00), remarkedly these known to be associated with anti-EGFR therapy, such as acne-like rash (OR 34.13; 95%CI 16.40-71.00) and hypomagnesemia (OR 6.23; 95%CI 3.04-12.77).
Conclusion:
Anti-EGFR therapy plus platinum-based doublet chemotherapy as first-line treatment demonstrated significant efficacy benefits with acceptable toxicity for advanced NSCLC. This benefit is more expressive among squamous histology with high EGFR expression. EGFR protein expression by IHC seems to be a predictive marker for survival in the association group. Further research is needed to corroborate these findings.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA23.02 - Efficacy and Safety of Necitumumab Continuation Monotherapy in Patients with EGFR-Expressing Tumors in SQUIRE, a Phase 3 Study (ID 4283)
14:20 - 15:50 | Author(s): T.E. Ciuleanu, M.A. Socinski, C.K. Obasaju, A.V. Luft, A. Szczęsna, R. Ramlau, B. Bálint, O. Molinier, H. Depenbrock, S. Nanda, L. Paz-Arez, N. Thatcher, P. Bonomi
- Abstract
- Presentation
Background:
SQUIRE (NCT00981058) demonstrated adding necitumumab (N) to gemcitabine/cisplatin (GC) improved survival in patients with Stage IV squamous NSCLC (SQ-NSCLC). Retrospective analysis revealed consistent treatment effect in favor of patients receiving N monotherapy as continuation after chemotherapy (CT) (GC+N continuation patients) versus continuation therapy-eligible GC arm patients (GC non-progressors). In the EU, N is approved for patients with EGFR-expressing tumors. We repeated the analysis in this patient population.
Methods:
Patients with Stage IV SQ-NSCLC were randomized 1:1 for ≤6 cycles of G (1250 mg/m[2] iv, Days [d] 1,8) and C (75 mg/m[2] iv, d1) either with or without N (800 mg iv, d1,8). Patients in GC+N without progression continued N until progressive disease (PD). SQUIRE included mandatory tissue collection. EGFR protein expression was assessed by IHC in a central lab (Dako EGFR PharmDx kit). Analyses were done in EGFR-expressing patients (EGFR >0). Patients who received ≥4 cycles of CT without PD were included. Overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan-Meier method. 95% CIs and hazard ratios estimated using stratified Cox proportional hazards model.
Results:
Of 1093 patients (ITT population), 982 patients (89.8%) had evaluable IHC assay results; 935/982 (95.2%) had EGFR>0. GC+N arm continuation therapy patients included 228 patients with EGFR>0 and 194 patients (EGFR>0) were GC arm non-progressors. Baseline characteristics were similar except gender (Males: 81% in GC+N vs 91% in GC arm). CT exposure was balanced. Median OS from randomization in GC+N vs GC was 16.1 vs 14.9 months; HR 0.76 (95% CI, 0.61, 0.95). Median PFS in GC+N vs GC was 7.4 vs 6.9 months; HR 0.81 (95% CI, 0.66, 1.00). Figure 1
Conclusion:
In patients with EGFR-expressing tumors, a consistent treatment effect in favor of GC+N continuation maintenance compared to GC non-progressors was observed, similar to ITT population with no unexpected increases in AEs.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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): G. Goss, M. Cobo, S. Lu, K. Syrigos, A. Morabito, I. Albert, G. Herodek, S. Chan, G. Ostoros, V. Sarosi, Z. Kiraly, D. Savior, R. Barton, F. Medina, S. Subramanian, A. Ardizzoni, E. Felip, S.M. Gadgeel, V. Georgoulias, J. Love, C. Bühnemann, N. Gibson, E. Ehrnrooth, J. Soria, N. Dupuis
- 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.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA23.04 - Discussant for OA23.01, OA23.02, OA23.03 (ID 6966)
14:20 - 15:50 | Author(s): M. Sebastian
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA23.05 - First-Line Afatinib versus Gefitinib in EGFRm+ Advanced NSCLC: Updated Overall Survival Analysis of LUX-Lung 7 (ID 5347)
14:20 - 15:50 | Author(s): K. Park, E.H. Tan, L. Zhang, V. Hirsh, K. O’byrne, M. Boyer, J.C. Yang, T. Mok, K.H. Lee, S. Lu, Y. Shi, S. Kim, J. Laskin, D. Kim, S.A. Laurie, K. Kölbeck, J. Fan, N. Dodd, A. Märten, L. Paz-Arez
- Abstract
- Presentation
Background:
The irreversible ErbB family blocker afatinib and the reversible EGFR TKI gefitinib are approved for first-line treatment of advanced EGFRm+ NSCLC. This Phase IIb trial prospectively compared afatinib versus gefitinib in this setting.
Methods:
LUX-Lung 7 assessed afatinib (40 mg/day) versus gefitinib (250 mg/day) in treatment-naïve patients with stage IIIb/IV NSCLC harbouring a common EGFR mutation (Del19/L858R). Co-primary endpoints were PFS (independent review), time to treatment failure (TTF) and OS. Other endpoints included ORR and AEs. In case of grade ≥3/selected grade 2 drug-related AEs the afatinib dose could be reduced to 30 mg or 20 mg (minimum). The primary analysis of PFS/TTF was undertaken after ~250 PFS events. The primary OS analysis was planned after ~213 OS events and a follow-up period of ≥32 months.
Results:
319 patients were randomised (afatinib: 160; gefitinib: 159). At the time of primary analysis, PFS (HR [95% CI] 0.73 [0.57‒0.95], p=0.017), TTF (0.73 [0.58‒0.92], p=0.007) and ORR (70 vs 56%, p=0.008) were significantly improved with afatinib versus gefitinib. The most common grade ≥3 AEs were diarrhoea (13%) and rash/acne (9%) with afatinib and elevated ALT/AST (9%) with gefitinib. 42% of patients treated with afatinib had ≥1 dose reduction due to AEs; dose reductions were more common in females than males (77%/23%) and non-Asians than Asians (64%/36%). Dose reduction of afatinib did not negatively impact PFS (<40mg vs ≥40mg; HR [95% CI]: 1.34 [0.90‒2.00]) but reduced incidence and severity of drug-related grade ≥3 AEs. Treatment discontinuation due to drug-related AEs was the same in each arm (6%). The data cut-off for primary OS analysis occurred on 8 April 2016. At this time, median treatment duration (range) was 13.7 (0‒46.4) versus 11.5 (0.5‒48.7) months with afatinib and gefitinib. 25% (afatinib) and 13% (gefitinib) of patients received treatment for >24 months. 73% and 77% of patients in the afatinib and gefitinib arms had ≥1 subsequent systemic anti-cancer treatment, with 46% and 56% receiving a subsequent EGFR-TKI including osimertinib (14%)/olmutinib (14%). OS data, including subgroup analysis with respect to subsequent therapy will be presented at the meeting.
Conclusion:
Afatinib significantly improved PFS, TTF and ORR versus gefitinib in EGFRm+ NSCLC patients, with a manageable AE profile and few drug-related discontinuations. Dose adjustment of afatinib reduced drug-related AEs without compromising efficacy. Primary OS analysis will be reported.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA23.06 - Overall Survival (OS) of EGFR Mutation Positive Non-Small Cell Lung Cancer Patients: Real-World Treatment Patterns of 1,660 Japanese Patients (ID 5915)
14:20 - 15:50 | Author(s): K. Yoshida, Y. Ohe, A. Inoue, T. Kumagai, M. Takeda, N. Yamamoto, T. Seto, I. Okamoto, N. Tashiro, S. Morita, M. Fukuoka
- Abstract
- Presentation
Background:
Since the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) was launched in Japan, the survival periods of advanced/recurrent EGFR mutation positive (EGFR m+) non-small cell lung cancer (NSCLC) patients have been getting longer. However, clinical factors which contributed to the extension of survival periods of these patients remain unclear. We investigated overall survival, prognostic factors and treatments patterns of EGFR m+ NSCLC patients in real-world clinical practice.
Methods:
This is a multi-center, observational, retrospective study. Histologically or cytologically diagnosed EGFR m+ NSCLC patients who were started first-line treatment from 1/1/2008 to 31/12/2012 were enrolled. The primary objective was the estimated OS. The secondary objectives were to determine prognostic factors, real-world treatment patterns.
Results:
1,660 EGFR m+ NSCLC patients were enrolled from 17 hospitals in Japan (median age 67.0 years, female 64.8%, 38.9% had smoking history, ECOG-performance status 0, 1, 2, 3, 4 were 39.5%, 41.1%, 7.1%, 4.9%, 0.7%, respectively, adenocarcinoma 95.2%, 50.1% exon 19 deletion, 66.7% at stage IV). Median estimated OS was 29.7 months. Cox regression analysis revealed age, smoking history, performance status, histological diagnosis, EGFR mutation type and clinical stage were independently associated with OS. Five year survival rate of stage IV patients was 13.8%. The median number of treatment regimens was two. EGFR-TKI and platinum-doublet chemotherapy were most frequently used as first- and second-line treatments.
Conclusion:
Real world treatment of the large data-set of 1,660 EGFR m+ NSCLC patients was retrospectively investigated. Median OS was 29.7 months and EGFR-TKIs are major components of the treatment regimens for these patients in Japan. (NCT0247520)
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA23.07 - Analysis of Outcomes in US IRESSA Clinical Access Program (ICAP) Patients on Gefitinib for More Than 10 Years (ID 3731)
14:20 - 15:50 | Author(s): F.R. Hirsch, L.V. Sequist, I. Gore, M. Campo, G.R. Simon, E.F. Croft, D. Devincenzo, J. Munley, D. Stein, K. Freivogel, F. Sifakis, P.A. Bunn, Jr.
- Abstract
- Presentation
Background:
In 2011, following gefitinib (IRESSA[®]) NDA voluntary withdrawal, US patients benefiting from gefitinib were eligible to continue gefitinib through the IRESSA Clinical Access Program (ICAP), an IRB-approved protocol. A subset of ICAP investigators subsequently collected additional retrospective data on their ICAP patients through another IRB-approved project (“chart-review subset”).
Methods:
For all enrolled ICAP patients, demographic and serious adverse event (SAE) reports were reviewed. All ICAP investigators were invited to participate in chart review; 47 accepted and collected data on patient/tumor characteristics and safety/tolerability of prolonged gefitinib therapy among their 79 ICAP patients.
Results:
Across 137 US sites, 191 patients enrolled in ICAP. As of September 2016, 75 (39%) remain on gefitinib; discontinuations were due to progression (36%), death (34%), AEs (13%), or other (17%). Sixty-four (34%) patients reported 162 SAEs; 5 (2.6%) patients had 12 SAEs considered to be gefitinib-related by investigators. The chart-review subset included 79 (41%) patients with median age of 69 years at ICAP enrollment, who were predominantly female (70%) and white (84%); 95% had a confirmed NSCLC diagnosis. Due to the evolving understanding of genetic mutations in NSCLC at the time of gefitinib initiation, the majority of patients (79%) never had EGFR sequencing performed. Although tissue is not available for EGFR status confirmation, we assume these patients are nearly exclusively EGFR mutation-positive. Median total length of gefitinib was 11.1 years (6.5-15.1; Table). Long-term gefitinib was well-tolerated; 5% discontinued due to a gefitinib-related AE. Ten-year survival rate from first-ever initiation of gefitinib was 86% and 15-year was 59%. Table. Gefitinib treatment patterns and tolerability among ICAP chart-review patients.Parameter n, % Observed Population (N=79) Total time on gefitinib, prior to and during ICAP Median duration, y, range 11.1 (6.5-15.1) Prior to ICAP Median duration, y, range 7.8 (5.4-10.9) Starting dose 250 mg/day 67 (84.8) No dose changes due to AEs 75 (94.9) During ICAP Median duration, y, range 3.5 (0.04-4.7) Dose: 250 mg/day 76 (96.2) Treatment-related AEs Grade 1-2 Grade ≥3 Grade unknown 13 (16.5) 1 (1.3) 2 (2.5) Dose reductions due to treatment-related AEs 1 (1.3) Discontinuations due to treatment-related AEs 4 (5.1) Discontinuations due to progressive disease 11 (28.9)
Conclusion:
The majority of this subset of patients who participated in ICAP based on long-term clinical benefit from gefitinib continue to do well with gefitinib, demonstrating good tolerance of therapy and survival for a median duration of more than 10 years.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA23.08 - Discussant for OA23.05, OA23.06, OA23.07 (ID 7104)
14:20 - 15:50 | Author(s): M.L. Johnson
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
Author of
-
+
JCES01 - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 413)
- Event: WCLC 2016
- Type: Joint Chinese / English Session
- Track:
- Presentations: 1
- Moderators:F.R. Hirsch, C. Bai
- Coordinates: 12/04/2016, 08:00 - 11:45, Stolz 1
-
+
JCES01.05 - New Clinical Trials on Gene Alteration in China (ID 6814)
08:00 - 11:45 | Author(s): S. Lu
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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
-
+
MA11.01 - Molecular Profiling of Large Cell Neuroendocrine Carcinoma Using Capture-Based Targeted Sequencing (ID 4914)
14:20 - 15:50 | Author(s): S. Lu
- Abstract
- Presentation
Background:
Conventionally, the classification of lung cancer and many other malignancies is determined by the histology of a tumor. Large cell neuroendocrine carcinoma (LCNEC) is traditionally classified as a histological variant of large cell carcinoma (LCC), which is a subtype of non-small cell lung cancer (NSCLC). However, LCNEC exhibits differential cytological, morphological, clinical and biological features than those of classic LCC, thus rendering controversies regarding its classification. In 2015, with the integration of immunohistochemical analyses, the World Health Organization (WHO) has re-classified LCNEC under neuroendocrine tumors. Due to the rareness of LCNEC, few studies have been conducted on the molecular genetic profiling of LCNEC. In this study, we characterized molecular signature associated with a cohort of LCNEC, SCLC and LCC using capture-based targeted sequencing.
Methods:
We performed capture-based targeted sequencing on 30 surgically resected samples from patients with lung cancer using BurningRock Biotech’s OncoScreen Panel. This panel, consisting of all exons and critical introns of 295 genes, covering multiple classes of somatic mutations, including single nucleotide variation (SNVs), rearrangements, copy number variations (CNVs) and insertions and deletions (INDELs), can be used to detect genetic alterations both qualitatively and quantitatively. Among the 30 patients, 15 of them were diagnosed with LCNEC, 5 with LCC and 10 with small cell lung cancer (SCLC).
Results:
While no statistically significant difference was observed in total number of mutations among the three subtypes, LCC carries the most number of somatic mutations followed by LCNEC then SCLC. Overall, we identified 331 mutations with TP53 being the most frequently mutated gene in all three subtypes. Genes with recurrent somatic mutations detected in LCNEC, but not in LCC or SCLC include RUNX1, ERBB4, BRCA1, and EPHA3. Copy number analysis revealed a higher prevalence of CNV in LCNEC, with 60% of cases harboring such alteration. There is no common CNVs shared among all three subtypes. NFкBIA amplification is the only common CNV found in both LCNEC and LCC; and AKT2 amplification is shared by LCNEC and SCLC. Most CNVs are subtype-specific. Interestingly, one RET-fusion was discovered in one LCC sample and one EGFR exon 19 deletion accompanied by EGFR copy number amplification was discovered in one LCNEC sample.
Conclusion:
Targeted deep sequencing reveals distinct genetic profile for LCNEC compared to LCC and SCLC. LCNEC harbors more CNV and contains a panel of genes, including RUNX1, ERBB4, BRCA1 and EPHA3 that are more frequently mutated comparing to LCC and SCLC.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MTE26 - EGFR Targeted Therapies: Lessons Learned (Ticketed Session) (ID 319)
- Event: WCLC 2016
- Type: Meet the Expert Session (Ticketed Session)
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 07:30 - 08:30, Schubert 6
-
+
MTE26.02 - EGFR Targeted Therapies: Lessons Learned (ID 6587)
07:30 - 08:30 | Author(s): S. Lu
- Abstract
- Presentation
Abstract:
Figure 1Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) are the standard therapy for patients with Non-Small-Cell Lung Cancer (NSCLC) harboring activating EGFR mutations. During the last 10 years several trials demonstrated that first and second generation EGFR-TKIs such as erlotinib, gefitinib or afatinib are superior to standard platinum-based chemotherapy in terms of efficacy and tolerability and quality of life. Development of EGFR-TKIs led to a dramatic change in mentality of physicians treating NSCLC. For many years NSCLC has been treated with chemotherapy and platinum-based doublets were offered to all patients irrespective of biological characteristics. Knowledge in the field of molecular biology were limited and even a small cytological sample was sufficient for defining the therapy. Tumor biopsy was recommended only at the time of initial diagnosis and changes in tumor biology as a consequence of therapy exposure were largely unknown. Discovery of EGFR mutations and the impressive activity observed with EGFR-TKIs in EGFR mutated patients led clinicians to understand the relevance of patient selection based on biomarker assessment and therefore the importance of tumor tissue analysis. Since EGFR-TKI approval, EGFR testing entered onto clinical practice and today several biomarkers are routinely tested in NSCLC patients for defining the best therapeutic strategy. In addition to EGFR, other biomarkers such as ALK or ROS1 rearrangements or PD-L1 expression are guiding physician for therapy choice and additional tests are expected to reach the clinic in the next future. As a consequence, tumor biopsy and tissue collection become relevant in clinical practice and also in trial design, since modern studies often claim for tumor tissue. In addition, identification of mechanisms responsible for acquired resistance led to repeat tumor biopsies. Unfortunately, in NSCLC, the amount of tissue obtained at the time of primary diagnosis is often not abundant and tumor re-biopsy if feasible in the minority of patients. Such limitations are leading to development of the so-called “liquid biopsy”, allowing physicians to obtain biomarker information in circulating tumor DNA. In addition, new technologies are implementing the possibility to test for multiple biological events using a single experiment, with a significant reduction in amount of tissue needed, reducing time and costs. Development of EGFR inhibitors also led to a different approach for treating lung cancer. For the first time physicians faced with oligo-progressing diseases, consisting in disease slowly progressing under EGFR-TKI therapy. Often the disease remains asymptomatic and it is still partially sensitive to the therapy. The possibility to control disease outcome by continuing the targeted agent led to the concept of “treatment beyond progression”, an approach that is preserving patient quality of life with also a favorable impact on duration of life. Finally, anti EGFR therapies also highlighted the new opportunity for treating brain metastases. Brain metastases (BM) are a frequent complication of NSCLC, with 25–40% of patients developing BM during the course of the disease, often within the first 2 years after the primary tumor diagnosis. A review of 1,127 NSCLC patients found that those with EGFR mutations were more likely to develop BM than those without such mutations. The frequency of BM was thus 31.4% for the mutation-positive patients but only 19.7% for the negative ones. Improvements in neurologic symptoms and performance status have been reported with whole-brain radiation therapy (WBRT) in combination with steroid therapy in these patients. However, due to their poor performance status, many patients with BM are not eligible for surgery or radiosurgery. Furthermore, the role of systemic chemotherapy for the treatment of BM is controversial due to the impenetrable nature of the blood brain barrier (BBB), with reported response rates to chemotherapy ranging from 15–30% (overall survival [OS] 6–8 months). Response rates of brain metastases to EGFR tyrosine kinase inhibitor (TKI) treatment (e.g. gefitinib, erlotinib, afatinib) in patients with NSCLC harboring EGFR mutations reach 60–80%, with a complete response rate as high as 40%. Median OS is 15–20 months, and progression-free survival in the brain reaches 6.6–11.7 months, demonstrating improved clinical outcome (Table I). Nevertheless, first and second generation EGFR-TKI may have limited BBB penetration. New EGFR-TKIs including the third-generation EGFR-TKI osimertinib and AZD3759, an oral reversible inhibitor of EGFR activating mutations, recently showed impressive activity in presence of BM. The possibility to obtain a long lasting brain disease control together with the positive impact on duration of life is also impacting on the strategy of BM treatment, with preference for therapies not or modestly impacting on cognitive functions, such as stereotaxic radiotherapy, and a lower usage of WBRT. Reference: 1. Porta R, et al. Eur Respir J 37: 624-631, 2011. 2. BPark SJ, et al. Lung Cancer 77: 556-560, 2012. 3. Li Z. J Clin Oncol 29 (Suppl): abstract e18065, 2011. 4. Kim JE, et al. Lung Cancer 65: 351-354, 2009. 5. Welsh JW, et al. J Clin Oncol 31: 895-902, 2013. 6. Iuchi T, et al. Lung Cancer 82: 282-287, 2013. 7. Hoffknecht P, et al.. J Thorac Oncol 10: 156-163, 2015.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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
-
+
OA11.03 - A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with Advanced Non-Small Cell Lung Cancer (ID 4571)
11:00 - 12:30 | Author(s): S. Lu
- Abstract
- Presentation
Background:
Targeting the tumor microenvironment, such as tumor angiogenesis, has led to the successful development and approval of a number of targeted therapies thereby changing the standard of care for many types of cancer. However, treatment options are limited in third-line non-small cell lung cancer (NSCLC) patients. Fruquintinib is a potent and highly selective oral kinase inhibitor targeting vascular endothelial growth factor receptors and is currently in late stage development for multiple cancers. This Phase II study was designed to evaluate the efficacy and safety of fruquintinib in third-line NSCLC patients (NCT02590965).
Methods:
A total of 91 patients were randomized to receive best supportive care (BSC) plus fruquintinib or BSC plus placebo in a 2:1 ratio from 12 Chinese clinical centers. Fruquintinib initial dose was 5 mg once daily and treatment was given in every 4-week cycle (3 weeks treatment followed by 1 week off). The primary objective was to compare progression free survival (PFS) between the two treatment groups. Secondary efficacy parameters included objective response rate (ORR), disease control rate (DCR), overall survival (OS). Tumor response was assessed per RECIST 1.1.
Results:
As of August 7, 2015, median PFS was 3.8 months for the fruquintinib group comparing with 1.2 months for the placebo group (hazard ratio=0.27, p<0.001). The ORR was 16.4% for the fruquintinib group comparing with 0% for the placebo group (p=0.02). The DCR of the fruquintinib group was significantly higher than that of the placebo group with a difference of 53.8% (36.3, 71.4; 95% CI, p<0.001). OS was not mature and initial analysis revealed 3- and 6-month OS rates of 90.2% and 68.3% for the fruquintinib group, and 73.3% and 58.2% for the placebo group, respectively. Adverse event was reported in 68.9% and 60.0% patients in fruquintinib and placebo group, respectively. The incidence of serious adverse events was 3.3% in the fruquintinib group and 6.7% in the placebo group.
Conclusion:
Fruquintinib in third-line NSCLC met the primary efficacy endpoint of PFS and demonstrated superiority in the secondary endpoints of ORR and DCR as compared with placebo. OS has yet to mature. Fruquintinib was generally well tolerated and safety profile consistent with previously reported. These results support further development of fruquintinib in third-line NSCLC patients. A randomized, double-blind, multi-center Phase III registration study was initiated in December 2015 (NCT02691299). Clinical trial information: NCT02590965.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:O.T. Brustugun, S. Lu
- Coordinates: 12/07/2016, 14:20 - 15:50, Stolz 2
-
+
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): S. Lu
- 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.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
OA23.05 - First-Line Afatinib versus Gefitinib in EGFRm+ Advanced NSCLC: Updated Overall Survival Analysis of LUX-Lung 7 (ID 5347)
14:20 - 15:50 | Author(s): S. Lu
- Abstract
- Presentation
Background:
The irreversible ErbB family blocker afatinib and the reversible EGFR TKI gefitinib are approved for first-line treatment of advanced EGFRm+ NSCLC. This Phase IIb trial prospectively compared afatinib versus gefitinib in this setting.
Methods:
LUX-Lung 7 assessed afatinib (40 mg/day) versus gefitinib (250 mg/day) in treatment-naïve patients with stage IIIb/IV NSCLC harbouring a common EGFR mutation (Del19/L858R). Co-primary endpoints were PFS (independent review), time to treatment failure (TTF) and OS. Other endpoints included ORR and AEs. In case of grade ≥3/selected grade 2 drug-related AEs the afatinib dose could be reduced to 30 mg or 20 mg (minimum). The primary analysis of PFS/TTF was undertaken after ~250 PFS events. The primary OS analysis was planned after ~213 OS events and a follow-up period of ≥32 months.
Results:
319 patients were randomised (afatinib: 160; gefitinib: 159). At the time of primary analysis, PFS (HR [95% CI] 0.73 [0.57‒0.95], p=0.017), TTF (0.73 [0.58‒0.92], p=0.007) and ORR (70 vs 56%, p=0.008) were significantly improved with afatinib versus gefitinib. The most common grade ≥3 AEs were diarrhoea (13%) and rash/acne (9%) with afatinib and elevated ALT/AST (9%) with gefitinib. 42% of patients treated with afatinib had ≥1 dose reduction due to AEs; dose reductions were more common in females than males (77%/23%) and non-Asians than Asians (64%/36%). Dose reduction of afatinib did not negatively impact PFS (<40mg vs ≥40mg; HR [95% CI]: 1.34 [0.90‒2.00]) but reduced incidence and severity of drug-related grade ≥3 AEs. Treatment discontinuation due to drug-related AEs was the same in each arm (6%). The data cut-off for primary OS analysis occurred on 8 April 2016. At this time, median treatment duration (range) was 13.7 (0‒46.4) versus 11.5 (0.5‒48.7) months with afatinib and gefitinib. 25% (afatinib) and 13% (gefitinib) of patients received treatment for >24 months. 73% and 77% of patients in the afatinib and gefitinib arms had ≥1 subsequent systemic anti-cancer treatment, with 46% and 56% receiving a subsequent EGFR-TKI including osimertinib (14%)/olmutinib (14%). OS data, including subgroup analysis with respect to subsequent therapy will be presented at the meeting.
Conclusion:
Afatinib significantly improved PFS, TTF and ORR versus gefitinib in EGFRm+ NSCLC patients, with a manageable AE profile and few drug-related discontinuations. Dose adjustment of afatinib reduced drug-related AEs without compromising efficacy. Primary OS analysis will be reported.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P1.02-056 - Tumor Heterogeneity in Lesion Specific Response Creates ROS1 Fusion Mediating Resistance to Gefitinib in EGFR 19 Deletion Lung Adenocarcinoma (ID 6207)
14:30 - 15:45 | Author(s): S. Lu
- Abstract
Background:
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer related death worldwide. In recent years molecular characterisation of NSCLC has led to the identification of several driver events including EGFR constitutive activation, ALK-rearrangement and ROS1 fusion. Whilst there are several mechanisms of EGFR-mutation stated in the literature, how genomic heterogeneity related with acquired EGFR resistance to second targeted agent affects response to subsequent therapy has not been noted.
Methods:
We studied EGFR-TKI, gefitinib, in an EGFR 19 deleted lung adenocarcinoma patient to assess whether tissue and liquid biopsy could be integrated with radiologic imagings to demonstrate the impact of individual actionable driver mutation on lesion specific response.
Results:
A 60-year old female, with no previous or family history of malignancy initially presented with EGFR 19 deletion mutation, ROS1 fusion negative and ALK rearrangement negative stage IV, T2aN3M1a lung adenocarcinoma detected in primary lung cancer tissue at the first diagnosis. Biopsy of this patient’s metastatic right cervical lymph node following prolonged response to gefitinb led to the loss of detection of EGFR mutation, and the novel mechanism of acquired resistance with EZR-ROS1 fusion where crizotinib was demonstrated to have good efficacy in all lesions, especially the enlarged lymphadenopathy, and also including diminishing efficacy on metastatic brain lesions. In circulating tumor DNA (ctDNA), mutant EGFR levels disappeared followed by gefitinib treatment, and a recognized EZR-ROS1 fusion was meanwhile identified before crizotinib therapy.
Conclusion:
This case displays tumor heterogeneity in action, where targeted therapy selects against primary drivers, allowing for the establishment of sub-colonies with new drivers within the specific lesion. Parallel analysis of tumor biopsies when disease progressed and ctDNA monitoring showed that lesion specific radiographic responses to subsequent targeted therapies could be driven by district resistant mechanism in the separate tumor lesions within the same patient. This demonstrates that the importance of molecular heterogeneity surveillance ensuing from acquired resistance in managing NSCLC, and the usage of liquid biopsies to allow for a holistic viewpoint of the molecular landscape of this heterogeneous disease.
-
+
P1.04 - Poster Session with Presenters Present (ID 456)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Pulmonology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P1.04-023 - Thrombomodulin Inhibits the Growth and Angiogenesis of Human Lung Cancer via Blocking VEGFR2-Mediated JAK/STAT3 Signaling Pathway (ID 4520)
14:30 - 15:45 | Author(s): S. Lu
- Abstract
Background:
Angiogenesis has been an attractive target for drug therapy because of its key role in the growth and metastatic spread of malignant tumor. Thrombomodulin has been shown to possess anti-inflammatory and vascular endothelial protection activities. However, its roles in tumor angiogenesis are unknown. The aim of this study was to investigate the roles of thrombomodulin in tumor angiogenesis and its anticancer activities.
Methods:
ex vivo aortic ring angiogenesis sprouting assay was used to detect neo-vascularization. Western blotting was performed to examine STAT3 signaling cascade.
Results:
Thrombomodulin significantly inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, migration and tube formation in vitro and blocked vascular endothelial growth factor (VEGF)-triggered neo-vascularization. VEGF receptor (VEGFR) 2 mediated-Janus Kinase 2/STAT3 signaling pathway was significantly inhibited by thrombomodulin in endothelial cells. In addition, the constitutively activated STAT3 protein, and the expression of STAT3-dependent target genes, including cyclin D1, c-Myc, Bcl-xL, and VEGF were also down-regulated in response for thrombomodulin in human lung cancer cells. Consistent with the above findings, thrombomodulin inhibited tumor cell cycle progression and induced cell apoptosis in vitro.
Conclusion:
Therefore, our provided the first evidence that thrombomodulin inhibited tumor angiogenesis and growth via inhibiting VEGFR2-mediated JAK/STAT3 signaling pathway with the potential of a drug candidate for cancer therapy.
-
+
P1.05 - Poster Session with Presenters Present (ID 457)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P1.05-025 - Prognostic Significance of Hepatitis B Virus to Stage IB Non-Small Cell Lung Cancer Patients in China (ID 5474)
14:30 - 15:45 | Author(s): S. Lu
- Abstract
Background:
Hepatitis B virus (HBV) is considered to be a major cause of hepatocellular carcinoma. However, little is known about the role of chronic HBV infection in other malignancies. We aimed to determine HBV infection with other well established prognostic factors and performed multivariate survival analyses to evaluate its value in Chinese non-small cell lung cancer (NSCLC) patients.
Methods:
It is a retrospective evaluation of the impact of HBV infection status in 366 patients who underwent complete surgical resection for stage IB NSCLC NSCLC patients in Shanghai Chest Hospital from 1998 to 2008. All the patients were Shanghai Niece and all the stage IB NSCLC patients didn’t receive adjuvant chemotherapy. The patients’ blood samples were tested with chemiluminescent immunoassay for the presence of HBV surface antigen (HBsAg), antibodies against HBV core antigen (anti-HBc), and antibodies against HBsAg (anti-HBs) before operation. Other variables in the analysis included age, gender, history of smoking and pathologic type. HBsAg positive was definite as HBV infection.
Results:
Figure 1 51 HBV infection cases (13.93%) were positive in stage IB NSCLC. The 5-year overall survival of patients without or with chronic HBV infection were 71.25% and 50.98% (P=0.028). Multivariate analyses revealed that gender, chronic HBV infection were significant predictive factors for overall survival (P< 0.05).
Conclusion:
The chronic HBV infection is a significant independent prognostic factor in stage IB non-small cell lung cancer.
-
+
P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P2.01-001 - Enrichment-Free, Rapid Metabolic Assay for Detection of Tumor Cells in Pleural Effusion and Pheripheral Blood (ID 3790)
14:30 - 15:45 | Author(s): S. Lu
- Abstract
Background:
Current methods for circulating tumor cell (CTC) detection are mostly include an enrichment step and the subsequent immunostaining-based identification of CTCs by epithelial and leukocytes markers. These methods are limited by loss and damage of CTCs during the enrichment and fail to determine the malignancy and drug targets of putative CTCs.
Methods:
We describe an enrichment-free, metabolic-based assay for rapid detection of tumor cells in the pleural effusion and peripheral blood samples. All nucleated cells are plated on microwell chips that contain 200,000 addressable microwells. These cells are labeled with a fluorescent anti-CD45 antibody (leukocyte marker), a fluorescent glucose analog (2-NBDG) and a dead cell marker (EthD-1). The microwell chips are imaged by a computerized high-speed fluorescent microscope in three colors and the bright filed. A computation algorithm analyzes the images and identify candidate tumor cells that are viable, CD45 negative, and exhibit high glucose uptake (EthD-1[-]/CD45[-]/2-NBDG[high]). A micromanipultor is then utilized to retrieve single tumor cells based on recorded addresses for single-cell sequencing.
Results:
EthD-1[-]/CD45[-]/2-NBDG[>100] cells are identified as candidate tumor cells. Single-cell sequencing based on a small panel of driver oncogenes (EGFR, KRAS, PIK3CA) shows that >60% of candidate tumor cells are true tumor cells harboring mutations in the panel. Single-cell whole exome sequencing results show all candidate tumor cells have high mutation frequency in dirver oncogenece and tumor suppressors from Qiagen's Human Lung Cancer Panel. Meanwhile, CD45[-]/EthD-1[-]/2-NBDG[>100] tumor cells show heterogenieity in cytokeratin (CK) expression, and only ~40% of these tumor cells are found CK positive. Figure 1
Conclusion:
We have developed a simple and functional-based method to rapidly identify tumor cells with high glucose uptake in the clinical liquid samples without enrichment. These tumor cells are addressable, enabling single-cell manipulation and sequencing. Clinical feasibility of this assay has been established by testing samples from a cohort of patients.
-
+
P2.03a - Poster Session with Presenters Present (ID 464)
- 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)
-
+
P2.03a-058 - Is There a Place for Pemetrexed Rechallenge in Advanced Lung Adenocarcinoma? (ID 4537)
14:30 - 15:45 | Author(s): S. Lu
- Abstract
Background:
There is a lot of lung cancer patients progressing beyond the third or fourth line of treatment still suitable for further therapy .And some patients choose to receive previous chemotherapy rechallenge,particularly in patients who had previously responded.So the role of chemotherapy rechallenge is worth discussing.Pemetrexed is known to be a potent chemotherapeutic agent with high efficacy and low toxicity in the treatment of advanced lung adenocarcinoma.In clinical practice,it is used to rechallenge by certain patients,according to previous efficacy and tolerance, as long as it was stopped for reasons other than progression. Therefore, the aim of this retrospective study is to evaluate the efficacy and safety of pemetrexed rechallenge strategy in lung adenocarcinoma.
Methods:
We retrospectively identified patients with the following criteria:(i) clinical benefit (stable disease(SD) or partial response(PR)) from previous line of pemetrexed-based chemotherapy (ii) discontinuation for a reason other than progression (iii) rechallenge with pemetrexed after a minimal pemetrexed-based chemotherapy-free interval of 3 months.The main objectives were to evaluate disease control rate (DCR),progression-free survival (PFS), overall survival (OS) and toxicity of pemetrexed rechallenge .
Results:
62 patients were enrolled into this study. Initial pemetrexed-based therapy was used as 1[st] or 2[nd] line of chemotherapy in 46(74.2%), and 16(25.8%)of cases. 43(69.4%) patients achieved SD, 19 (30.6%) achieved PR. Pemetrexed was rechallenged as a 2nd, 3rd,or further line of chemotherapy in 43.5%, 37.1% and 19.4% of cases.4 patients (6.5%) achieved PR ,41 (66.1%) achieved SD and 17 (27.4%) experienced progressive disease.The median PFS was 3.9 months with the pemetrexed rechallenge.The median OS from the beginning of pemetrexed rechallenge was 8.2 months (95% CI: 5.0-11.3months).38(61.3%) patients had chance to receive further therapy after pemetrexed challenge failure.Next,we associated DCR,PFS,OS of pemetrexed rechallenge with the cllicial outcomes of initial pemetrexed treatment. We found that patients who had longer PFS (P=0.036)or achieved PR response(P=0.022) to initial pemetrexed were more likely to get benefit from rechallenge.The patients with longer PFS of initial treatment exhibited longer PFS of rechallenge (P=0.008). However, the interval time between initial and rechallenge treatment did not affect efficacy of pemetrexed rechallenge.25 patients (40%) reported grade 1/2 toxicity, 4 patients (6%) experienced grade3/4 toxicity, mostly neutropenia (65%) and hepatobiliary disorder (24%).
Conclusion:
It is a pragmatic strategy to retreat patients with pemetrexed when this drug has shown previous activity.The rechallenge treatment is generally well tolerated.
-
+
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)
-
+
P3.02a-030 - ROS1 Fusion Chinese Lung Adenocarcinoma Patients Treated with Crizotinib Detected Using Next-Generation Genotyping from ctDNA (ID 6163)
14:30 - 15:45 | Author(s): S. Lu
- Abstract
Background:
Chromosomal rearrangements involving the c-ros oncogene 1 (ROS1) have been described as a subset of non-small cell lung cancer (NSCLC). Recently Crizotinib has exhibited marked therapeutic efficacy in the treatment of the ROS1 fusion NSCLC. However, resistance often occurs and repeated biopsy is necessary for tumor genotyping and underlying resistant mechanism. Circulating tumor DNA (ctDNA) represents a promising way to assess tumor genetic profile non-invasively. This study aims to assess whether liquid biopsies accurately screen disease diagnosis and reflect the response to Crizotinib treatment through analysis of ctDNA for ROS1 fusions in patients with lung adenocarcinoma, and to elucidate the underlying mechanisms of ROS1 targeted drug resistance.
Methods:
Twelve plasma samples were collected from a cohort of 4 patients with ROS1 fusion advanced stage lung adenocarcinoma, confirmed by fluorescent in situ hybridization (FISH) in tissue. A prospective-retrospective analysis on ctDNA was further performed from archived plasma samples using our ctDNA panel with concurrent CT or MRI imaging at the baseline and 8-week intervals during responsive Crizotinib treatment, and at progressive disease.
Results:
All patients showed detectable levels of ROS1 fusion in ctDNA at baseline. Upon treatment with Crizotinib, response rate is inversely correlated with levels of ROS1 fusion. One patient with progressive disease, patient 1, exhibited a detectable CD74-ROS1 fusion with 13.5% concentration at baseline; it was undetectable at partial response and re-elevated to 8.2% accompanied by an acquired G2032R mutation when disease progressed.
Conclusion:
Our ctDNA panel could be applied clinically to detect ROS1 fusion from plasma for accurate screening and convenient monitoring where detection correlates with disease status, and could distinguish mutations associated with Crizotinib induced resistance in patients with NSCLC, thus facilitating personalized cancer therapy.
-
+
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)
-
+
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): S. Lu
- 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.
-
+
P3.02b-031 - T790M: A Favorable Mutation? (ID 5681)
14:30 - 15:45 | Author(s): S. Lu
- Abstract
Background:
Patients with lung adenocarcinoma harboring somatic activating mutations in the epidermal growth factor receptor (EGFR) gene have benefited significantly from EGFR tyrosine kinase inhibitors (TKIs). However, a vast majority would eventually develop resistance to such TKIs, resulting in disease progression. T790M, a secondary mutation in exon 20 of the EGFR gene, has been identified as the major mechanism responsible for acquired EGFR-TKI resistance, accounting for roughly 50% of resistance. However, the association of T790M status and clinical outcome remains elusive. Here, we conducted a retrospective study examining the association between T790M status and prognosis on clinical samples obtained from 43patietns with EGFR-mutant lung adenocarcinoma and later acquired resistance to EGFR-TKIs.
Methods:
We performed capture-based targeted ultra-deep sequencing on either tumor biopsies or blood samples of 43 lung adenocarcinoma patients, who harbored EGFR mutations, and subsequently developed resistance to EGFR TKIs. We used BurningRock Biotech’s panels, consisting of critical exons and introns, covering multiple classes of somatic mutations, including single nucleotide variation (SNVs), rearrangements, copy number variations (CNVs) and insertions and deletions (INDELs) to detect genetic alterations both qualitatively and quantitatively.
Results:
We investigated the mutation spectrum after the development of resistance to EGFR-TKIs. Our analysis revealed 64% (18/28) of patients, harboring exon 19 deletions at baseline, acquired T790M at the time of progression. In contrast, only 33% (5/15) of patients, harboring exon 21 L858R substitutions at baseline, acquired T790M, indicating T790M mutation is more commonly found in patients with exon 19 deletions (p=0.052). Next, we associated T790M status with cumulative EGFR-TKI exposure time, and found patients had longer TKI exposure are more likely to acquire T790M mutation. The median TKI exposure time for patients who eventually acquired T790M was 19.20m ±1.86. In contrast, the median exposure time for patients who never acquired T790M 12.20m±1.20m (P =0.017). Furthermore, we investigated the presence of T790M mutation with progression free survival (PFS). Our data revealed that 68% (15/22) of patients with PFS≥12 months acquired T790M mutation after TKI exposure. In contrast, among patients with PFS< 12 months, only 38% of them acquired T790M mutation (p=0.048).
Conclusion:
Patients who eventually acquired T790M mutation have longer cumulative TKI exposure and are associated with longer PFS before the emergence of drug resistance. In addition, we also discovered that patients harboring exon 19 deletions are more likely to develop T790M mutation. Therefore, T790M status can be used as a potential biomarker for prognosis.
-
+
P3.02b-041 - Genome-Wide Screen of DNA Methylation Changes Reveals GABBR2 as a Novel Potential Target for EGFR 19 Deletion Adenocarcinoma with Erlotinib (ID 6219)
14:30 - 15:45 | Author(s): S. Lu
- Abstract
Background:
Lung cancer is the leading cause of cancer related death around the world. The last decade has witnessed the rapid development of epidermal growth factor receptor (EGFR) directly targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). However, the challenge of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) has been an issue when talking with activating EGFR mutations, which makes it crucial to elucidate the mechanism of EGFR-TKI targeted drug resistance.
Methods:
Methyl-sensitive cut counting sequencing (MSCC), one of the most commonly used whole-genome DNA methylation sequencing technology, was applied to investigate the changes of paired tissue DNA methylation before and after TKI (erlotinib) treatment lasting two cycles with partial response (PR) for stage IIIa (N2) lung adenocarcinoma patients (N=2) with activating EGFR 19 deletion. Sequenom EpiTYPER assay method was further analyzed to double confirm the changed methylated candidate genes in these two patients, through comparing the methylated changes in paired tissues before and after TKI treatment. Western blotting, cell cycle and apoptosis analysis by the up/down regulation of a candidate gene (GABBR2) were performed in three lung adenocarcinoma cell lines, A549 (EGFR wild type), HCC4006 (EGFR 19 deletion, DelL747-E749) and HCC827 (EGFR 19 deletion, DelE746-A750), to elucidate the mechanism of GABBR2 gene in the regulation of EGFR-TKI treatment.
Results:
Sixty aberrant methylated genes were firstly discovered using MSCC method in these two patients harboring EGFR 19 del mutation treated with erlotinib. Two aberrant methylated genes, CBFA2T3 and GABBR2, were clearly validated by the Sequenom EpiTYPER assay subsequently. GABBR2 was significantly down regulated in HCC4006 and HCC827 cells harboring EGFR 19 mutations but remained conservative in A549 cells with EGFR wild-type after erlotinib treatment by Western blotting. The phenomenon was in line with the obvious apoptosis of HCC4006 and HCC827 cell lines after erlotinib treatment, but not in A549 cells. GABBR2 was further induced down regulation after erlotinib exposure through apoptosis method silenced by siRNA using RNAi technology. Meanwhile, GABBR2 gene was demonstrated up regulation rescued the apoptosis significantly, when overexpressing GABBR2 in HCC827 cell lines along with erlotinib treatment.
Conclusion:
Genome-wide screen of DNA methylation changes demonstrated that GABBR2 gene might be as a novel potential treatment target for stage IIIa (N2) EGFR 19 deletion adenocarcinoma with erlotinib treatment. Our research provides a new theoretical basis for the epigenetic study of EGFR mutated lung adenocarcinoma treatment.
-
+
P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P3.02c-007 - Assessment of Dianhydrogalactitol in the Treatment of Relapsed or Refractory Non-Small Cell Lung Cancer (ID 4639)
14:30 - 15:45 | Author(s): S. Lu
- Abstract
Background:
Non-small cell lung cancer (NSCLC) is treated with surgery and chemotherapy with either tyrosine kinase inhibitors (TKIs) or platinum-based regimens, but drug-resistance is frequent and long-term prognosis poor. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent with proven activity against NSCLC in clinical studies. VAL-083 has demonstrated superior activity to cisplatin in both in vitro and in vivo NSCLC models, including TKI-resistant NSCLC, and circumvents cisplatin-resistance in ovarian cancer cells. VAL-083 is approved for the treatment of lung cancer in China; however, clinical adoption is limited by lack of modern data related to mechanism-of-action and utility in the context of standard-of-care platinum-based chemotherapy. Here we aimed to investigate in vitro i) the distinct mechanism-of-action of VAL-083, ii) VAL-083 cytotoxicity in a panel of NSCLC cell-lines with varying p53 status, and iii) the combination of VAL-083 with cisplatin or oxaliplatin.
Methods:
VAL-083 cytotoxicity was investigated in a panel of 11 human NSCLC cell-lines: 3 wild-type (H460, A549, H226), 6 mutant (H1975, SkLU1, H2122, H157, H1792, H23) and 2 null (H838, H1299) for p53. Cell-cycle and DNA damage was investigated by propidium iodide and immunofluorescent staining in synchronized cultures of H2122, H1792, A549. Cytotoxicity was determined by MTT assay. Combination potential for VAL-083 with cisplatin or oxaliplatin was investigated in H460, A549, H1975 (TKI-resistant) by determining superadditivity and synergy using the combination index (CI)<1 criteria.
Results:
VAL-083 treatment caused persistent S/G2 cell-cycle arrest and cell-death. Furthermore, one-hour pulse treatment led to phosphorylation of DNA double-strand break sensors ATM, single-strand DNA-binding Replication Protein A (RPA32), and histone variant H2A.X, suggesting activation of the homologous repair pathway. S/G2 phase cell-cycle arrest and increased γH2A.X in cancer cells persisted >72 hours after treatment, indicating irreversible DNA lesions. Importantly, VAL-083 was active against all cell-lines tested, irrespective of their p53 status, suggesting a mechanism-of-action that differs from other alkylating agents, including cisplatin. When combined with either cisplatin or oxaliplatin in vitro, VAL-083 demonstrated significant superadditivity (p<0.05) and synergism (CI<1) for both combinations in all NSCLC cell-lines. This strongly suggests non-overlapping modes-of-action between the platinum drugs and VAL-083 and demonstrates synergism in TKI-resistant cell-lines.
Conclusion:
This preclinical data strongly suggests VAL-083 as a potential treatment for platinum and TKI-resistant NSCLC. An open-label post-market clinical trial in China will investigate the activity of VAL-083 in relapsed/refractory NSCLC. Results will provide guidance to physicians under the context of VAL-083’s current approval in China, as well as serve as proof-of-concept for expanded development worldwide.
-
+
P3.02c-093 - A Prospective, Randomized, Multicenter, Phase Ⅲ Study, Comparing rhTPO with rhIL-11 Treating CIT (NCT02344979) (ID 4891)
14:30 - 15:45 | Author(s): S. Lu
- Abstract
Background:
Chemotherapy-induced thrombocytopenia (CIT) is a common dose limiting toxicity of clinical chemotherapy drugs, which may lead to reduced dose chemotherapy or delay chemotherapy time, and even terminate chemotherapy treatment. This is the first randomized, open-label, multicenter, phase Ⅲ study to compare the efficacy and safety of prophylactic treatment for thrombocytopenia in China. We tried to investigate the efficacy and safety of preventive application with rhTPO or rhIL-11 to protect against CIT in advanced non-small-cell lung cancer (NSCLC) patients.
Methods:
From June 2009 to July 2016, 108 patients with NSCLC who were receiving the first-line platinum-based chemotherapy suffered from severe thrombocytopenia(the nadir of platelet counts＜50×10[9]/L) during the prior chemotherapy cycle. They were randomized to rhTPO arm or rhIL-11 arm in the following chemotherapy cycle, and the chemotherapy regimens and drug doses were consistent with that in the prior and following cycle (GC Gemcitabine 1000-1250 mg/m[2], D1 and D8; Carboplatin dosing by AUC value=5, D1; Q3W) or GP (Gemcitabine 1000-1250 mg/m[2], D1 and D8; Cisplatin 75 mg/m[2], D1; Q3W). 77 patients (56males, 21 females) were enrolled in rhTPO arm and 31 patients (18 males, 13 females) were enrolled in rhIL-11 arm. There were no statistical difference between two arms in terms of gender, age and the nadir of platelet counts during prior chemotherapy cycle(P＞0.05). rhTPO (15000U/d) was injected subcutaneously on the 2[nd], 4[th], 6[th], 9[th ]Day after the initiation of chemotherapy, and IL-11(3mg/d) was injected subcutaneously per day from Day 9 to Day15 after the initiation of chemotherapy. Blood routines were conducted to test before chemotherapy initiation and the 3[th], 5[th], 7[th], 9[th], 11[th], 13[th], 15[th], 17[th], and 21[th] day after chemotherapy. Toxicity and efficacy were monitored.
Results:
In the following chemotherapy cycle there were no statistical difference between rhTPO arm and rhIL-11 arm on the following indexes: the nadir of platelet counts(62.6±39.4×10[9]/L vs. 52.8±36.8×10[9]/L, P＞0.05) , the maximum platelet counts (223.5±127.3×10[9]/L vs. 245.8±158.7×10[9]/L, P＞0.05) , duration of platelet counts less than 50×10[9]/L[Median (95%CI): 4.0(3.0-5.0) days vs. 4.5(3.0-9.0) days, P＞0.05], time of platelet count recovered to 75×10[9]/L [Median(95%CI): 5(3-7) days vs. 6(4-8) days, P＞0.05] and to 100×10[9]/L[median(95%CI): 6(6-8) days vs. 6(5-9) days, P＞0.05]. Drug-related adverse events in rhTPO arm were less than those of rhIL-11 arm (5 cases (6.49%) in rhTPO arm, 8 cases (25.8%) in rhIL-11 arm, P<0.05).
Conclusion:
Although there is no statistical difference on efficacies, prophylactic administration of rhTPO is safer and more convenient than that of rhIL-11 in advanced NSCLC patients.
-
+
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)
-
+
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): S. Lu
- 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).
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
