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J. De Castro
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ORAL 04 - Adjuvant Therapy for Early Stage Lung Cancer (ID 99)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:E. Vallieres, Y. Ohe
- Coordinates: 9/07/2015, 10:45 - 12:15, 205+207
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ORAL04.05 - Results Ph III Trial Customized Adjuvant CT after Resection of NSCLC with Lymph Node Metastases SCAT: A Spanish Lung Cancer Group Trial (ID 2983)
10:45 - 12:15 | Author(s): J. De Castro
- Abstract
- Presentation
Background:
Postop platinum-based CT improves outcomes in completely resected NSCLC with nodal involvement (St II-IIIA) but compliance and outcomes remain limited. Analysis of expression of genes involved in DNA repair could be used to individualize optimal CT. BRCA1 is primarily involved in the repair of double strand DNA breaks and functions as a differential regulator of response to cisplatin (Cis) and antimicrotubule agents. BRCA1 defficiency can enhance Cis resistance. Loss of BRCA1 function is associated to sensitivity to DNA-damaging CT and may also be associated with resistance to spindle poisons
Methods:
Randomized phase III multicenter trial. After surgery patients (p) with St II and III NCSLC were random 1:3 to control arm (3 cycles Cis-Docetaxel) or to experimental arm with treatment assigned according BRCA1 expression levels (low levels: Cis-Gemcitabine; intermediate levels: Cis-Doc; high levels: Docetaxel alone). Stratifification factors: N1 vs N2; age < or > 65 y; non-Squamous vs Squamous (Sq) histology; lobectomy vs pneumonectomy). Planned PORT in N2. Primary end-point OS. Secondary end-points DFS, toxicity profile (CTCAE v 3.0) /compliance, recurrence pattern. Statistical hypothesis: increase 20% 5y survival rate control group (45%)
Results:
From June/2007 to May/2013, a total of 591 p were screened and 500 of them were randomized in the study, 108 in control arm, 392 in experimental arm. In experimental arm 110 p received Cis-Gem, 127 Cis-Doc and 110 Doc alone. There were no significant differences between arm for known prognostic factors: Median age 64 y; 79% males, 21% females; 43% Sq, 49% Adenoca, 8% others; 57% former smokers, 32% current smokers, 11% never smokers; pneumonectomy 26%; N1 58%, N2 48%. Median tumor size 4.4 cm (0.8-15.5 cm). Median mRNA BRCA1 levels 15.78 (0.73-132). Mean BRCA1 levels 6.95 in Adenoca vs 20.29 in Sq (p<0.001). P with Sq histology showed a longer DFS (HR 0.73; p=0.05) but without differences in OR (HR 1) Median follow-up 28 months (0-79 m), with a cut-off of March 15[th] 2015, median survival has not reached both arms and no significant differences have been seen for OS with hazard ratio (HR) 0.866 (p=0.45) or DFS with HR 1. In experimental group HR for OS was 0.842 (NS) comparing low with high-BRCA1 levels. In p with high-BRCA1 levels control treatment (Cis-Doc) was superior to experimental (Doc) with HR 1.24 (NS).In non-Sq histology experimental treatment was superior to control with HR 0.75. For p receiving all planned treatment HR is 0.63 with p = 0.043 compared with p not able to complete treatment.
Conclusion:
Overall survival data are still immature because median survival is not reached with a median f-u 28 m for this N+ population. At this time analysis BRCA1 based adjuvant CT does not improve overall OS. In p with high BRCA1 levels Doc alone is inferior to Cis-Doc. BRCA-1 levels are higher in Sq and in non-Sq histology a trend to better survival in experimental arm was found. Full dose of planned treatment confers a survival advantage, however, longer follow-up is still warranted.
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ORAL 32 - EGFR WT and MT Targeting (ID 144)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K.J. O'Byrne, D.R. Gandara
- Coordinates: 9/09/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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ORAL32.02 - Long-Term Survivors with EGFR Wild-Type Advanced NSCLC Treated with Second-Line Erlotinib: Subgroup Analysis from WILT Study (ID 1661)
16:45 - 18:15 | Author(s): J. De Castro
- Abstract
- Presentation
Background:
The overwhelming majority of advanced NSCLC p worldwide is wild-type (WT) EGFR. The results reported so far are difficult to interpret due to the heterogeneous nature of this large group of p. There is a variation in terms of efficacy considering known prognostic factors; however, other characteristics, as yet undefined, might further explain this variability. In the clinical setting, prolonged second-line treatment with Erlotinib (E) has been identified in a small group of p with WT EGFR leading to a long-term survival. The role of E in this special subset needs to be further determined in order to identify who might be most likely to benefit.
Methods:
WILT is a multicentre, open-label, observational study. WT EGFR (if rarely unknown, both squamous tumour and current/former smoking status as mandatory criteria) advanced NSCLC p treated with second-line E (150mg/d, until unacceptable toxicity/progressive disease) were included. Using a prognostic index model, the aim of this study is to identify subgroups of p with specific clinical and laboratory parameters that are likely to derive clinically meaningful and statistically significant benefit from E. Here we present the results of patients’ subgroups with long-term E treatment in second-line setting (PFS≥6 months and PFS≥9 months).
Results:
355 p were included in the study and preliminary reported data showed an overall median PFS of 2.3 months, finding 40% of p with a median PFS>2.5 months. Baseline subgroups characteristics of 52 p (14.6%) with a PFS≥6 months and 30 p (8.5%) with a PFS≥9 months are shown in Table 1. Efficacy data in PFS≥6 months subgroup: Median PFS of 10.8 months (95% CI: 9.2-12.3). Objective Response Rate of 21.6% and Disease Control Rate of 82.4%. Main related grade≥3 toxicities were rash (1.9%) and diarrhoea (3.8%). Efficacy data in PFS≥9 months subgroup: Median PFS of 13.5 months (95% CI: 12-15). Objective Response Rate of 17.2% and Disease Control Rate of 82.8%. Main related grade≥3 toxicities were rash (3.3%) and diarrhoea (6.7%). Table1: Patient characteristics
*Unknown: Squamous and current/former smokersSLP ≥6 months (N=52) SLP ≥9 months (N=30) Median age ( years) 65 67 Male/Female (%) 69/31 67/33 ECOG 0/1/2 (%) 21/62/17 23/64/13 Histology (%) Adenocarcinoma/Squamous 48/39 43/50 Stage (%) IV 75 67 EGFR status (%) WT Unknown* 85 15 80 20 Smoking status (%) Current/Never/Former 19/17/64 17/16/67 Metastases (%) Yes Lung/Bone/CNS/Pleura/Liver 83 44/21/14/12/9 77 39/22/9/13/13 Prior platinum-based doublet (%) Yes 94 93 Prior Maintenance Treatment (%) Yes 27 17 Best response to first-line (%) CR+PR/SD 48/31 40/37 Weight loss during first-line (%) Yes 22 23 Anaemia (%) Yes 69 63
Conclusion:
Global efficacy results of E, in terms of PFS, match with previously reported data for second-line setting. A long-term survivors group has been identified, whom the administration of E resulted in an extraordinary prolonged response. Highlighting the heterogeneity of this subgroup, it was not possible the identification of standardized prognostic factors. Potentially molecular variables for long-term survival with E in WT EGFR NSCLC could play a role in the determination of different evolutions.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-104 - Regulating the Response to Cisplatin in Lung Cancer Cells through the Transcription Factor TCF4: A New Potential Role for Wnt Signaling (ID 1647)
09:30 - 17:00 | Author(s): J. De Castro
- Abstract
Background:
The standard treatment for non-small cell lung cancer (NSCLC) is Platinum-based chemotherapy, although the main clinical problem associated is the progression of the disease to a platinum-resistant state. This fact has limited its efficacy in these tumor types, which is one of the first causes of cancer deaths in developed countries. Thus, it is of great interest to identify predictive molecular biomarkers that could help in the patient treatment selection.
Methods:
In this study we used array-CGH to analyze the cytogenetic alterations that arise in NSCLC and ovarian cancer cells after cisplatin treatment, by using four paired sensitive(S) and resistant(R) cell lines: H23S/R, H460S/R, A2780S/R and OVCAR3S/R.
Results:
Our experimental approach revealed the presence of a common deletion of the gene TCF4 in a mosaic manner in at least 50% of the resistant cells in both tumor types, while a decrease in TCF4 expression was confirmed through qRT-PCR in the same cells. As TCF4 is a downstream transcription factor of Wnt signaling, we analyzed its potential role regulating the CDDP response in resistant cells through its action in the Wnt pathway. Combination of Top-Fop vectors and TCF4-cDNA overexpression plasmids showed firstly, that resistant cells responded easily to the activation of Wnt pathway, an effect in part mediated by the decrease in TCF4 expression; secondly the overexpression of TCF4 induced an increase in the Cisplatin sensitivity. These results indicate that TCF4 could be acting as a Wnt transcriptional repressor, maintaining the sensitivity to Cisplatin in A2780-S cells.
Conclusion:
Our translational approach in a total of 40 ovarian and lung primary tumors and in 14 normal tissues confirmed that TCF4 expression is frequently downregulated in these tumor types. Altogether we present a novel role for Wnt signaling pathway, regulating the response to CDDP, which could be a potential target for cancer treatment. Supported by ISCIII PI12/00386, ISCIII PI12/01463 and the Miguel Servet II program (CP08/00068) to I. Ibáñez de Cáceres
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-064 - Erlotinib in EGFR-Positive NSCLC: Efficacy, Safety and Feasibility for Rebiopsy (ID 830)
09:30 - 17:00 | Author(s): J. De Castro
- Abstract
Background:
First-line Erlotinib (E) delays progression in 10-14 months in patients (p) harboring EGFR mutations (EGFRm+). Understanding the resistance mechanisms in order to personalize treatment justify the need for rebiopsy. However, undergoing this procedure could be not feasible on a daily basis. Due to different clinical courses and progression patterns, NCCN guidelines recommend strategies according to symptomatology, extent and site of metastasis in recurrent setting. Nowadays, identifying tumour recurrence patterns and evaluating the potential limitations of rebiopsy are relevant in clinical practice.
Methods:
ASPET is an ongoing, multicentre, observational study. Eligible p are chemonaïve with EGFRm+ advanced NSCLC treated with E (150mg/d, until unacceptable toxicity or progressive disease). Primary endpoint is to correlate PFS and tumour localization/characteristics at progression. The evaluation of potential feasibility of rebiopsy (questionnaires completed by physicians and p at diagnosis) is one of the secondary endpoints.
Results:
Baseline characteristics of 100 p included in this preliminary analysis: mean age 66 yrs; 65% female; 89% adenocarcinoma; 91% stage IV; 69% PS-ECOG 0-1; 60% never smokers; 31% central tumours; 57% Del19, 35% L858R, 8% other mutations. Different metastatic locations according to type of mutation have been reported (Figure 1). Objective Response Rate of 63.33% and Disease Control Rate of 90% (60 p evaluable). Main related grade≥3 toxicities were skin disorders (7%) and diarrhoea (2%). Questionnaires completed by 80 physicians: 81.2% considered technically feasible repeat biopsy, 66.25% believe that p would be willing to undergo rebiopsy and 72.5% would direct changes in therapy with rebiopsy results. Results from questionnaires completed by 69% of p are shown in Table 1. Table 1: Results from patient-reported questionnaires (N=69)
Figure 1Before the biopsy procedure, you thought that it would be N (%) Not uncomfortable 13 (18.84) Uncomfortable 31 (44.93) Painful 22 (31.88) Insufferable 3 (4.35) The punctures of each lesion have been N(%) Not uncomfortable 23 (33.33) Uncomfortable 34 (49.28) Painful 9 (13.04) Insufferable 3 (4.35) Overall, you consider the procedure N(%) Not uncomfortable 20 (28.99) Uncomfortable 37 (53.62) Painful 9 (13.04) Insufferable 3 (4.35) If you would have to repeat another biopsy N(%) I will do it 52 (75.36) I will not repeat it again 4 (5.80) I would need anesthesia 13 (18.84)
Conclusion:
Rebiopsy is considered feasible for physicians in clinical practice and the majority of p would undergo a second biopsy. No new safety data have seen so far and efficacy results in terms of responses match with previously reported data.
