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A. Santo
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MA14 - Immunotherapy in Advanced NSCLC: Biomarkers and Costs (ID 394)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:M. Reck, D.R. Spigel
- Coordinates: 12/06/2016, 16:00 - 17:30, Strauss 2
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MA14.06 - Nivolumab in Never Smoker Patients with Advanced Squamous NSCLC: Results from the Italian Expanded Access Programme (EAP) (ID 4765)
16:36 - 16:42 | Author(s): A. Santo
- Abstract
- Presentation
Background:
Nivolumab is the first checkpoint inhibitor approved for the treatment of Sq-NSCLC to show a survival benefit vs the standard of care docetaxel in the randomised, phase III, CheckMate 017 study. In the nivolumab development program, a greater clinical benefit was shown in current and former smokers than in never smokers. Nevertheless, no data are available in this respect from a real world setting. For this reason, we decided to use the data collected in the EAP in order to assess the effectiveness and tolerability of nivolumab treatment in the never smoker patient population.
Methods:
Nivolumab was provided upon physician request for patients aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for stage IIIB/stage IV Sq-NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks for <24 months. Patients included in the analysis had received ≥1 dose of nivolumab and were monitored for adverse events using Common Terminology Criteria for Adverse Events.
Results:
Of 372 patients with Sq-NSCLC participating in the EAP in Italy, 38 (10.2%) were never smokers, a proportion very similar to the one observed in Checkmate 017 (10%). With a median number of doses of 8 (range, 1–22) and a median follow-up of 5.6 months, the disease control rate in this group was 50%, including 9 patients with a partial response and 10 with stable disease. Eight patients were treated beyond RECIST-defined progression, with 4 of them achieving disease control. As of April 2016, median progression-free survival and overall survival were 3.5 months and not reached, respectively. 17 patients (44.7%) discontinued treatment for any reason except toxicity and 5 (13.1%) discontinued due to AE.
Conclusion:
These preliminary results, although obtained from a small sample size, suggest that nivolumab is effective and well tolerated in a never smoker group of patients with advanced Sq-NCLCS in the real life and warrant further investigation in this area.
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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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OA06.06 - Druggable Alterations Involving Crucial Carcinogenesis Pathways Drive the Prognosis of Squamous Cell Lung Carcinoma (SqCLC) (ID 5342)
15:15 - 15:25 | Author(s): A. Santo
- Abstract
- Presentation
Background:
We previously built and validated a risk classification model for resected SqCLC by combining clinicopathological predictors to discriminate patients’ (pts) prognosis (Pilotto JTO 2015). Here we (AIRCMFAG project no. 14282) investigate the molecular portrait of prognostic outliers to identify differentially expressed, potentially druggable alterations.
Methods:
Based on the published 3-class model, 176 and 46 pts with good and bad prognosis, respectively, were identified. Somatic Mutations (SM) and Copy Number Alterations (CNA) were evaluated with Next Generation Sequencing (NGS) for 59 genes (Ion Proton system, Ion Ampliseq custom panel). Moreover, RNA expression assays, immunohistochemistry (IHC) and immunofluorescence (FISH) were performed. Descriptive statistic was adopted and continuous variables were dichotomized according to AUC or medians.
Results:
Herein, the analysis of 60 pts (good/poor 27/33) is reported. In the overall population, the median rate of SM (3.3%) is lower compared to the median rate of CNA (28.3%), without significant differences between the two prognostic groups. The most frequent SM resulted to be missense (66.7%) and nonsense (20.3%) mutations, whereas the copy number gain is the most common CNA (76.7%), The distribution of relevant alterations in the main carcinogenesis pathways in term of SM, CNA and expression (by RNA, IHC and FISH), according to the prognostic subgroups, are reported in the table.Pathway Gene [method] Good [%] Poor [%] p-value Squamous differentiation SOX [CNA] 74.1 51.5 0.11 TP63 [CNA] 37.0 21.2 0.25 Epithelial to mesenchymal transition SNAI1 [RNA] 59.2 90.9 0.006 Vimentin [RNA] 44.4 69.7 0.07 mTOR PI3KCA [SM] 0 9.0 0.24 RICTOR [CNA] 3.7 27.3 0.017 p-mTOR [IHC] 11.1 18.1 0.5 Tyrosine kinase receptors DDR2 [SM] 11.1 0 0.085 FSR2 [CNA] 3.7 18.1 0.12 MET [FISH] 11.1 24.2 0.32 FGFR3 [FISH] 25.9 42.4 0.28 Cell cycle regulators CDKN2A [CNA] 22.2 3.0 0.38 SMAD4 [CNA] 33.3 57.6 0.074 Immune checkpoints PD-L1 [IHC] 18.5 6.1 0.23 PD-1 [RNA] 51.8 93.9 <0.0001
Conclusion:
Although performed on a limited number of pts, such comprehensive analysis of DNA, RNA and proteins, using different methodologies, is feasible and allow identifying potentially druggable prognostic modulators, such as RICTOR/PI3K/mTOR signaling pathway. The possibility to inhibit this pathway with selective agents is currently under investigation in in vitro preclinical models.
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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)
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P1.05-050 - External Validation of a Prognostic Model for Squamous-Cell Lung Cancer and Impact of Adjuvant Treatment in >1,300 Patients (ID 5297)
14:30 - 14:30 | Author(s): A. Santo
- Abstract
Background:
A risk classification model able to powerfully discriminate the prognosis of resected squamous-cell lung cancer (R-SqCLC) patients (pts) was developed (Pilotto JTO 2015). Herein, we validate the model in a larger multicenter series of >1,300 R-SqCLC pts (AIRC project 14282).
Methods:
R-SqCLC pts in 6 different institutions (01/2002 - 12/2012) were considered eligible. Each patient was assigned with a prognostic score to identify the individual risk of recurrence, on the basis of the clinico-pathological data according to the develop model (age, T-descriptor according to TNM 7th edition, nodes, and grading). Kaplan-Meier analysis for disease-free/cancer-specific/overall survival (DFS/CSS/OS) was performed according to the published 3-class risk model (Low: score 0-2; Intermediate: score 3-4; High: score 5-6). Harrell’s C-statistics was adopted for model validation. The effect of adjuvant chemotherapy (ACT) was adjusted with the Propensity Score (PS).
Results:
Data from 1,375 pts from 6 institutions were gathered (median age: 68 years; male/female: 86.8%/13.2%; T-descriptor 1–2/3–4: 73.3%/26.7%; nodes 0/>0: 53.4%/46.6%; stages I-II/III-IV: 71.7%/28.3%); 384 pts (34.5%) underwent ACT. With a median follow-up of 55 months (95% CI 51-59), pts at Low-Risk had a significantly longer DFS in comparison with Intermediate- (HR 1.67, 95% CI 1.40-2.01) and High-Risk (HR 2.46, 95% CI 1.90-3.19) pts, as well as for CSS (HR 1.79, 95% CI 1.48-2.17; HR 2.33, 95% CI 1.76-3.07) and OS (HR 2.46, 95% CI 1.80-3.36; HR 4.30, 95% CI 2.92-6.33). C-statistics was 68.3 (95% CI 63.5-73.1), 68.0 (95% CI 63.2-72.9), and 66.0 (95% CI 61.6-71.1), for DFS, CSS and OS, respectively. 60-months DFS for Low-, Intermediate- and High-Risk pts was 51.0%, 33.5% and 25.8%, respectively (p<0.0001). 60-months CSS for Low-, Intermediate- and High-Risk pts was 82.7%, 64.7% and 53.3%, respectively (p<0.0001). 60-months OS for Low-, Intermediate- and High-Risk pts was 56.7%, 37.9% and 30.9%, respectively (p<0.0001). A significant benefit in DFS was found in favor of ACT (p=0.005), with no difference in CSS (p=0.57), although a trend in OS (p=0.16). Overall, no significant differences for ACT were found in DFS, CSS and OS when survival was corrected with PS analysis, although CSS and OS curves visually separate with a trend for ACT in Intermediate- and High-Risk pts.
Conclusion:
The prognostic performance of the previously developed model was validated in a larger R-SqCLC pts’ series. Considering the overall dismal prognosis of such disease, the efficacy of ACT requires to be clearly established for Intermediate- and High-Risk pts, as well as that should be questioned for Low-Risk pts.
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P1.06 - Poster Session with Presenters Present (ID 458)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.06-017 - Observational Study on Prolonged Disease Stabilization in Advanced NSCLC EGFR WT/Unknown Patients Treated with Erlotinib in Second Line (ID 4998)
14:30 - 14:30 | Author(s): A. Santo
- Abstract
Background:
In advanced NSCLC, erlotinib treatment was shown to improve survival independently of EGFR status and induce high rates of prolonged stable disease (SD). It has previously been reported that, after second-/third-line erlotinib, PFS and OS are long-lasting and similar between patients with SD ≥8 months and those attaining partial/complete response (PR/CR). The present study investigated the clinical value of SD in a real-world setting of advanced NSCLC.
Methods:
This Italian multicenter observational study enrolled patients with stage IIIB-IV NSCLC on second-line erlotinib and wild-type/unknown EGFR mutational status, with SD, CR or PR per RECIST v1.1 lasting for ≥4 weeks. Patients were observed from the beginning of erlotinib for approximately 8 months or until death. Primary end-points were the rate and duration of SD (i.e. time interval from erlotinib start to the last evidence of SD by RECIST) or CR+PR. Secondary end-points were OS and PFS (i.e. time interval from the erlotininb start to the first evidence of progression), estimated by the Kaplan-Meier method and calculated by response duration or disease stabilization. Adverse events occurring during the observation period were also recorded.
Results:
At the cut-off date of 30/04/16, 144/172 (83.7%) enrolled patients were evaluable for response (mean age 69.1 years, 61.8% males). At the start of erlotinib treatment, 85.4% were non-smokers, 89.6% had an ECOG-PS of 0-1, and 84.7% had stage IV NSCLC (83.3% adenocarcinoma and 11.8% squamous cell carcinoma). Following second-line erlotinib, 82.6% (119/144) of patients achieved SD and 17.4% (25/144) PR. Notably, SD was maintained for ≥8 months in 27% (39/144) of cases. At the end of the observation period, 12 (8.3%) patients had deceased, none with SD ≥8 months. Median OS had not been reached by the entire population. According to SD duration, median OS was 4.3 months if <2 months, 6.8 if between 2 and 5 months, and not reached if ≥5 months or if PR. Median PFS was 9.0 months in the entire population, 8.7 among patients with SD and 10.8 with PR. According to SD duration, PFS was 1.4 if <2 months, 4.4 months if between 2 and 5 months, 7.5 if between 5 and 8 months and 10.5 if ≥8 months. No unexpected toxicities were observed.
Conclusion:
In advanced NSCLC, second-line erlotinib yielded a high rate of SD, lasting ≥8 months in 27% of cases, with PFS similar to PR patients and low mortality rate.
