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José Miguel Sánchez-Torres
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MA 15 - Lung Cancer Biology II (ID 670)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
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MA 15.01 - LungBEAM: A Prospective Multicenter Trial to Monitor EGFR Mutations Using BEAMing Technology in Stage IV NSCLC Patients (ID 10145)
15:45 - 15:50 | Author(s): José Miguel Sánchez-Torres
- Abstract
- Presentation
Background:
Liquid biopsy is a promising approach to improve the management of NSCLC patients, offering a minimally-invasive alternative to tumor tissue testing and enabling timely monitoring of patients on-therapy. The goal of the present study was to evaluate the performance of the OncoBEAM EGFR plasma vs EGFR tissue testing across 19 Spanish hospitals and to examine the timing of T790M mutation emergence in patients during first-line EGFR TKI therapy with respect to radiological progression.
Method:
Blood samples from 112 therapy-naïve advanced NSCLC patients were collected at baseline and throughout EGFR TKI therapy. Results from OncoBEAM EGFR mutation were performed by Sysmex in Hamburg, Germany and then compared to those obtained by the initial EGFR tissue testing obtained at the referring hospital. In addition, the time at which T790M was first detected was compared to the date of progression determined by radiological imaging.
Result:
112 stage IV NSCLC patients (p) were enrolled between Nov 2016 and May 2017. Clinical characteristics: median age 65 y. , 81 female. Smoking pattern: never 70 p (62,5%), former 33 p (29.4%) and active 9 (8%). M1a 28 p (25%), M1b only brain 10 p (8.9%), only bone 17 p (15%). Baseline tissue samples: Exon 19 deletion 74 p (66%) , L858R 38 p (34%). Initial positive percent agreement (PPA) in 69 out of 112 p was 52/69 or 75.4%. Interestingly, the agreement between plasma and tissue EGFR mutation results for patients diagnosed at M0 was 56%, versus 81% with patients diagnosed at M1. In addition, the average number of days between tissue biopsy and blood collection for concordant cases was 128 days, versus 358 days for discordant cases. Currently, the tissue EGFR mutation status of all discordant cases is being re-examined using BEAMing. Preliminary results from serial T790M plasma analyses revealed cases where detection by OncoBEAM was observed several weeks prior to documented progression by imaging. More mature results will be available at the time of the meeting
Conclusion:
Overall, these initial results show high PPA of plasma and tissue EGFR mutation status at baseline. Moreover, early detection of T790M in blood may assist in anticipating resistance to first-line EGFR TKI therapy.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-057 - Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer (NSCLC) (ID 8742)
09:30 - 09:30 | Presenting Author(s): José Miguel Sánchez-Torres
- Abstract
Background:
Nivolumab, a monoclonal antibody against the Programmed Death 1 (PD-1) pathway, has been shown to improve outcome and safety compared to Docetaxel in second-line NSCLC. We evaluated the actual use of Nivolumab in routine clinical practice at a single center in patients with NSCLC.
Method:
Data from patients with a diagnosis of advanced NSCLC who were treated with Nivolumab at standard dose (3mg/kg every 14 days), between January 2016 and March 2017 in our Hospital, were retrospectively collected. We performed a descriptive analysis of multiple demographic, clinical and analytical variables, as well as seeking differences between progression-free survival (PFS) according to squamous (SqCC) and non-squamous (Non-SqCC) histology, ECOG Performance Status (PS) and prior lines received by log-rank, Kaplan-Meier methods and Cox proportional models.
Result:
Forty patients were treated. Median age was 67; 67.5% were male; 80% were smokers. Histologies: Non-SqCC 42.5%, SqCC 52.5%, 5% NOS. ECOG PS: 50% ECOG 2, 45% ECOG 1, 5% ECOG 0. Twenty patients were treated as second-line (50%), and 20 had received ≥ 2 prior systemic therapies (50%). Median PFS was 3 months. Response rate: 35% (2.5% of patients had complete response); 42.5% of patients had stable disease and 22.5% progression disease. Adverse events were mostly grade 1 and 2, as expected, just one patient discontinued treatment due to grade 4 inmuno-mediated colitis. Patients with SqCC achieved a longer median PFS than Non-SqCC patients (4.9 vs 2.8 months, HR 2.14, 95% CI 1.1-4.6, p <0.05). Median PFS in patients who received 1 prior line was 2 months vs 3.5 months in patients who received ≥2 prior lines (log-rank, p=0.5). PFS in ECOG PS 0-1 patients was 3 months vs 2 months in ECOG PS 2 (log-rank, p=0.2).
Conclusion:
Nivolumab in NSCLC routine clinical practice is a safe and active alternative to chemotherapy. Nivolumab achieve a good outcome in both histologies, SqCC and Non-SqCC, but we detected a longer PFS in SqCC. Adverse events were as expected, grade 1 and 2.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-027 - Are Inflammatory Markers Predictive of Nivolumab Efficacy in Advanced Non-Small-Cell Lung Cancer (NSCLC)? (ID 8042)
09:30 - 09:30 | Presenting Author(s): José Miguel Sánchez-Torres
- Abstract
Background:
Elevated neutrophile-to-lymphocyte ratio (NLR) is a systemic inflammatory marker that has been associated with poor prognosis in NSCLC (Bar-Ad, 2016). There is, however, limited data of the effect of inflammatory markers on Nivolumab efficacy. We assessed whether there is an association between NLR and efficacy of Nivolumab in NSCLC. We also evaluated the value of neutrophil count percentage (NCP). Finally, to establish if the effect was predictive of Nivolumab or prognostic of a therapeutic effect, we studied also NLR and NCP in a cohort of chemotherapy-treated NSCLC.
Method:
Data from NSCLC patients treated with Nivolumab (N=40) in routine clinical practice in our Hospital between January 2015 and May 2017 were retrospectively collected. Population was dichotomized according to whether they had NLR≥5 or <5. Cut-off for NCP was established at 80% using the minimum p-value method. The association between NLR or NCP and progression free survival (PFS) and overall survival (OS) was analyzed by log-rank, Kaplan-Meier method and Cox proportional models. A cohort of chemotherapy-treated NSCLC patients (N=54) were also analyzed.
Result:
In Nivolumab cohort, median age was 67. Thirteen patients (32.5%) were NLR≥5 and five (12.5%) were NCP≥80%. In chemotherapy cohort, median age was 69. Thirty-one patients (57%) were NLR≥5 and ten (18.5%) were NCP≥80%. In Nivolumab cohort, PFS and OS were longer with NLR<5 (log-rank p<0.0001). This effect was also observed with NCP<80% (log-rank p<0.0001 -PFS-, p=0.01 -OS-). In chemotherapy-treated patients, a similar effect was observed. Complete data of median PFS and OS, and Cox proportional models is shown in table 1.Treatment Inflammatory marker Median PFS (months) Cox proportional models median PFS Median OS (months) Cox proportional models median OS Nivolumab NLR<5 ≥5 6 2 HR 6.7 CI 95% 2.9-15.3 p<0.000001 25 10.5 HR 4.4 CI 95% 1.9-9.2 p<0.0000001 Nivolumab NCP<80% ≥80% 6 1.5 HR 0.09 CI 95% 0.02-0.34 p<0.0000001 21 9.5 HR 0.2 CI 95% 0.09-0.84 p=0.02 Chemotherapy NLR<5 ≥5 15.5 6.5 HR 6.7 CI 95% 3.0-15.1 p<0.0000001 24 17 HR 8.9 CI 95% 3.6-21.9 p<0.0000001 Chemotherapy NCP<80% ≥80% 4 2.5 HR 0.45 CI 95% 0.2-0.9 p=0.03 14 9.5 HR 0.35 CI 95% 0.16-0.75 p=0.007
Conclusion:
Systemic inflammation biomarker NLR, and to a lesser extent NCP are prognostic, but not predictive, factors of Nivolumab efficacy in NSCLC. NLR<5 and NCP<80% are associated with improved PFS and OS in NSCLC regardless of treatment evaluated.
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P2.02-034 - PD-L1 Expression Can Be a Prognostic Marker in EGFR Mutant NSCLC Patients Treated with Erlotinib (ID 8933)
09:30 - 09:30 | Author(s): José Miguel Sánchez-Torres
- Abstract
Background:
INF-gamma secreted by CD8+ lymphocytes upregulates PD-L1 expression in cancer cells. We recently identified STAT3 and YAP1 as compensatory mechanisms of resistance to EGFR tyrosine kinase inhibition in EGFR mutant cells. STAT3 and YAP1 up-regulate CCL5 (Rantes) and CXCL5, respectively, with both chemokines attracting the myeloid-derived suppressor cell. STAT3 stimulates DNMT1 by repressing STAT1 and retinoic acid-inducible gene-I (RIG-I) expression. STAT1 and RIG-I are key mediators in INF-gamma signaling. We assume that alterations in the INF-gamma signaling pathway could be present in EGFR mutant NSCLC.
Method:
Total RNA from 53 EGFR mutant NSCLC patients was reversed transcribed and analyzed by qRT-PCR. STAT3, YAP1, RIG-I, STAT1, PD-L1, DNMT1 and CXCL5 mRNA were examined with specific primers/probes in triplicates. Progression-free survival (PFS) and overall survival (OS) were estimated.
Result:
Fifty-three EGFR mutant NSCLC patients treated with erlotinib were analyzed, 72% were female, 62% never-smoked, 70% had exon 19 deletion and 36% brain metastases. A positive correlation was found between RIG-1 and STAT1 (r=0.42, p=0.003). An anti-correlation trend was noted between STAT3 and PD-L1, YAP1 and PD-L1 and DNMT1 and STAT1. Median PFS was 22, 12.9 and 8.6 months for patients with high, intermediate and low PD-L1 mRNA, respectively (P=0.04). Median PFS was numerically longer for patients with low levels of DNMT1, RIG1 STAT1 and CXCL5, although the differences were not statistically significant. A similar trend was observed for OS.
Conclusion:
PD-L1 mRNA could be a prognostic marker in EGFR mutant NSCLC patients. Down-modulation of PD-L1 indicates alterations in pattern-recognition receptors (PRRs), like RIG-1 or downstream interferon signaling factors. The dysregualtion of the pathway is multifactorial, and the role of STAT3 and YAP1 hyperactivation merits further research. DNMT1 overexpression ablates STAT1. Since the cyclin-dependent kinase 4 (CDK4) interacts with DNMT1, therapies with CDK4 inhibitors can directly neutralize the main defects in the INF-gamma signaling pathway.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-073 - TPX-0005 with an EGFR Tyrosine Kinase Inhibitor (TKI) Overcomes Innate Resistance in EGFR Mutant NSCLC (ID 8956)
09:30 - 09:30 | Author(s): José Miguel Sánchez-Torres
- Abstract
Background:
Overexpression of several receptor tyrosine kinases (RTKs) substitutes EGFR signaling in EGFR-mutant NSCLC. The MET ligand hepatocyte growth factor (HGF) provides an alternative signaling mechanism for EGFR by inducing inter-receptor cross talk with EphA2, CUB domain-containing protein-1 (CDCP1) or AXL. SHP2, a non-receptor protein tyrosine phosphatase is central in signal transduction downstream of RTK signaling and in Src activation. We previously demonstrated that STAT3 and Src-YAP1 signaling limits EGFR TKI efficacy in EGFR-mutant NSCLC. We are now exploring the possibility of multiple RTK activation through a Src-YAP1-mediated transcriptional program. We are evaluating whether combined EGFR inhibition with TPX-0005, a novel orally available multikinase inhibitor and potent Src/FAK and JAK2 inhibitor, can be more efficient than EGFR inhibition alone in EGFR-mutant NSCLC cells.
Method:
We studied the mRNA expression levels of stromal HGF and tumor RTKs, AXL, CDCP1, MET, and EphA2, as well as SHP2, and clinical outcome in baseline samples of 64 EGFR-mutant NSCLC patients treated with first-line EGFR TKI. We combined in vitro approaches to explore whether gefitinib or osimertinib combined with TPX-0005 can abolish STAT3 and Src-YAP1 and downregulate the expression of RTKs.
Result:
High levels of AXL, CDCP1 and SHP2 mRNA expression were associated with worse outcome to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free survival (PFS) was 14.5 and 23.4 months for patients with high and low AXL mRNA, respectively (p=0.0359). Median PFS was 9.1 and 20.2 months for patients with high and low CDCP1 mRNA, respectively (p=0.0179). Tumoral EPHA2 and MET or stromal HGF levels did not affect PFS. Median PFS was 11.4 and 24.1 months for patients with high and low SHP2 mRNA, respectively (p=0.0094). The combination of gefitinib/osimertinib with TPX-0005 resulted in highly synergistic suppression of cell viability and reduced colony formation in two EGFR-mutant cell lines. The combination abolished the EGFR inhibition-induced STAT3 and YAP1 phosphorylation, as confirmed by western blotting and immunofluorescence. The results of TaqMan quantitative-PCR assay revealed that gefitinib/osimertinib plus TPX-0005 reduced the mRNA levels of AXL, CDCP1 and MET, an effect that could not be obtained with EGFR inhibition alone. In vivo experiments are ongoing.
Conclusion:
AXL and CDCP1 are adverse predictive markers of PFS in EGFR-mutant NSCLC patients. STAT3 and Src-YAP1 signaling limits the efficacy EGFR TKI. Combined EGFR inhibition with TPX-0005 (currently in phase I clinical testing) is a particularly attractive strategy
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PL 02 - Presidential Symposium including Top 3 Abstracts and James Cox Lectureship Award Presentation (ID 585)
- Event: WCLC 2017
- Type: Plenary Session
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:Hisao Asamura, Keunchil Park
- Coordinates: 10/17/2017, 08:15 - 09:45, Plenary Hall (Exhibit Hall D)
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PL 02.04 - SCAT Ph III Trial: Adjuvant CT Based on BRCA1 Levels in NSCLC N+ Resected Patients. Final Survival Results a Spanish Lung Cancer Group Trial (ID 9523)
08:40 - 08:50 | Author(s): José Miguel Sánchez-Torres
- Abstract
- Presentation
Background:
Postop platinum-based CT is considered standard of care in resected NSCLC with lymph node involvement. BRCA1 and BRCA2 are important DNA repair factors primarily involved in the repair of double strand DNA breaks. BRCA-1 functions may act as a differential regulator of response to cisplatin (Cis) and antimicrotubule agents. BRCA1 defficiency enhances Cis resistance and loss of BRCA1 function is associated to sensitivity to DNA-damaging CT and may also be associated with resistance to spindle poisons.
Method:
SCAT randomized phase III multicenter trial tests individualized optimal CT based on expression of BRCA1. 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). Stratification 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: 5y survival rate control group (45%) could be increase 20% in experimental arm.
Result:
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). Compliance of CT was better in experimental arm with less dose-reductions and without differences according extent of surgery. CT compliance was lower in patients older 70 y. Median PFS: 38.7 m (control), 32.2 m Cis-Gem, 34.3 m Cis-Doc and 41 m Doc. At 5 years, event-free rate is 54% in control arm and 56% in experimental arm and median OS 73.3 m (control) vs 77.5 m (exp) (p=0.75). In experimental arm: Docetaxel alone 80.2 m, Cis-Doc 80.5 m and Cis-Gem 74 m.
Conclusion:
Higher survival than expected in patients with lymph node involvement. No significant difference in survival achieved with the experimental arm. In case of high levels BRCA CT treatment without cisplatin is not detrimental. (Eudract:2007-000067-15; NCTgov: 00478699)
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