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Enric Carcereny
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-28 - Impact of Afatinib Dosing on Safety and Efficacy Real-World in Patients with EGFR Mutation-Positive Advanced NSCLC (ID 13276)
16:45 - 18:00 | Author(s): Enric Carcereny
- Abstract
Background
Tolerability-guided dose adjustment of afatinib reduced incidence and severity of adverse drug reactions (ADRs) without affecting efficacy in the LUX-Lung (LL) studies in patients with EGFR mutation-positive (EGFRm+) NSCLC. We evaluated the impact of modifying the recommended starting dose of afatinib (40mg) on efficacy and safety in a real-world setting.
a9ded1e5ce5d75814730bb4caaf49419 Method
This non-interventional, observational, multi-country/site study used medical records of TKI-naïve patients with EGFRm+ (Del19/L858R) NSCLC treated with first-line afatinib. Primary outcomes were % patients with ADRs by severity, time on treatment (TT), and time to progression (TTP), relative to LL3. Secondary outcomes were % of patients with/reasons for modified starting dose.
4c3880bb027f159e801041b1021e88e8 Result
228 patients from 13 countries were included. Baseline characteristics were generally similar to LL3, but with more Del19 patients (78% vs 49%) and fewer Asian patients (44% vs 72%); 12% had ECOG PS 2–3. 31% of patients received an afatinib starting dose of <40 mg; 20% of patients starting with <40 mg increased their dose during the study. 67% of 40 mg starters underwent dose reductions, with 86% of those occurring in the first 6 months. Dose reductions were more frequent in females, Eastern Asian patients, and those with lower body weight. The main reason for dose modification was ADRs. In <40 mg starters, overall ADR incidence was similar to that in ≥40 mg starters, with fewer G3 (17% vs 25%) and no G4 ADRs. There were no new safety signals, and fewer ≥G3 ADRs and serious adverse events (SAEs) than in LL3 (28% vs 49% and 5% vs 14%, respectively). >60% of patients received medications to treat diarrhea and manage skin AEs. Median TT and TTP were 18.7 months and 20.8 months, respectively, and were not impacted by reduced starting dose or dose modification (19.4/17.7/19.5 and 25.9/20.0/29.0 months for patients who started on ≤30 mg/reduced to <40 mg/remained on ≥40 mg, respectively). The efficacy of afatinib was demonstrated across all patient subgroups analysed (ECOG PS 0/1 vs 2/3, age <75 yrs vs ≥75 yrs, EGFR mutational status); TT and TTP were significantly longer in patients with ECOG PS0/1 versus PS2/3.
8eea62084ca7e541d918e823422bd82e Conclusion
As in pivotal trials, dose adjustments with afatinib in real-world practice reduced the frequency and intensity of ADRs without impacting efficacy. RealGido demonstrated long TT/TTP regardless of afatinib dose adjustment or reduced starting dose, and an acceptable safety profile. The results highlight the benefit of tailoring afatinib dose based on individual patient characteristics and ADRs to optimize outcomes.
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-29 - Overall Response Rate of Nintedanib and Docetaxel in Combination with the Nutraceutical Use of Silibinin in Advanced NSCLC (ID 13239)
16:45 - 18:00 | Author(s): Enric Carcereny
- Abstract
Background
The bioactive flavonolignan silibinin, the main component of standardized extracts from the seeds of the milk thistle herb Silybum marianum, has been shown to exhibit significant anticancer activity in preclinical models. Silibinin is a direct inhibitor of pSTAT3, a signal transducer and key transcription factor that is associated with chemoresistance in cancer cells. Our group has shown that oral administration of the silibinin-containing nutraceutical Legasil® could represent the first silibinin formulation with proven clinical benefit as an adjunct cancer treatment in patients with brain metastases. Nintedanib is an orally administered, small-molecule triple angiokinase inhibitor of VEGF1–3, PDGFa and b, and FGFR1–3. The LUME-Lung 1 trial showed that nintedanib significantly extended progression-free survival (PFS) and overall survival (OS) in patients with NSCLC adenocarcinoma when added to docetaxel chemotherapy, with no differences in response rate.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with stage IV NSCLC who failed ≥1 prior treatment were eligible for nintedanib/docetaxel combination. We present retrospective data analysis regarding patients that received nintedanib/docetaxel with or without combination with up to 5 capsules (630 mg)/day of Legasil®.
4c3880bb027f159e801041b1021e88e8 Result
Fifty-nine patients were enrolled in the study: median age, 60y (range: 43–79); male, 46 (78%). All the cases had adenocarcinoma histology. All patients had received first line therapy and 13 (22%) patients had >2 prior lines of treatment. A higher overall response rate (ORR) was observed in the group receiving Legasil® supplementation: ORR 55.5% versus 22%, p=0.02. No statistically significant differences in the median PFS were observed in the two arms: 2.34 months (95% confidence interval [CI] 1.83–2.91) for nintedanib/docetaxel combination (n=41) versus 4.99 (95%CI 0.94–9.05) for nintedanib, docetaxel and Legasil® triple combination (n=18) (p=0.241) at the data cut-off of January 2018. In the control group (n=41), ORR was greater in patients with known KRAS (n=8) or EGFR (n=3) mutations: 45% versus 13%, p=0.028.
8eea62084ca7e541d918e823422bd82e Conclusion
The inhibition of pSTAT3 with silibinin may increase tumor responses to nintedanib/docetaxel combination. In addition, patients with known KRAS or EGFR mutations may show higher tumor responses to nintedanib/docetaxel combination.
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P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-09 - Targetable Genomic Alterations in KRAS Mutant Lung Adenocarcinoma by Targeted Next Generation Sequencing (ID 13705)
16:45 - 18:00 | Author(s): Enric Carcereny
- Abstract
Background
KRAS mutant (m) non-small cell lung cancer (NSCLC) represents 25% of cases. Despite the common mutation, biological and clinical behaviour of this disease is diverse. The aim of our study was to analyze co-occurring genomic alterations in advanced KRASm lung by next-generation sequencing (NGS) and compare them to a KRAS wild-type (WT) population.
a9ded1e5ce5d75814730bb4caaf49419 Method
Advanced lung adenocarcinoma patients treated with a platinum doublet with KRAS mutation by Sanger were submitted to targeted NGS with the Oncomine Solid Tumor kit (DNA) and compared to a KRAS WT population of clinically similar patients. Association with outcome of the genomic alterations was evaluated.
4c3880bb027f159e801041b1021e88e8 Result
32 KRASm patients and 18 WT patients were analyzed. The most frequent KRAS mutation was p.Gly12Cys (45%), followed by p.Gly12Val (24%). TP53 mutation was observed in 55% of KRASm tumors and 60% of WT cases (Table 1). Mutations in STK11 were found in 10% of cases in the KRAS mutant cohort while none in the WT. 3 out of the 4 cases of STK11 mutations coexisted with TP53 mutations. FGFR3, SMAD4 and DDR2 mutations were more frequently found in cases with KRAS mutations, although at low frequencies. Neither KRAS nor TP53 mutations had an impact in OS. We then selected the KRAS mutant cohort and evaluated the impact of co-mutations. TP53 or STK11 did not significantly affect OS of KRAS mutant patients.
Table 1. Co-ocurring alterations in KRAS mutant and WT tumors
8eea62084ca7e541d918e823422bd82e ConclusionMutations/CNG
KRAS mutant % (N: 38)
KRAS WT % (N: 15)
TP53 mut
55%*
60%*
STK11 mut
10%**
0%
FGFR3 mut
13%
6%
SMAD4 mut
8%
0%
DDR2 mut
5%
0%
MYC mut
5%
6%
KRAS CNG
8%
6%
KRASm lung adenocarcinoma is genomically diverse. NGS provides biologically relevant information and druggable targets in this subset of patients.
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P2.03 - Biology (Not CME Accredited Session) (ID 952)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.03-02 - Cell-Free DNA (cfDNA) Testing in Lung Adenocarcinoma (LUAC) Patients: Spanish Lung Liquid Versus Invasive Biopsy Program (SLLIP) (ID 12561)
16:45 - 18:00 | Author(s): Enric Carcereny
- Abstract
Background
Liquid biopsies are a revolution in cancer diagnostics as a minimally invasive alternative to tissue biopsy. cfDNA is used for the detection of biomarkers in LUAC patients if a tumor tissue sample is not available. We conducted the SLLIP study to prospectively validate Guardant360 for the detection of 7 targetable activating alterations (EGFR, ALK, ROS1, BRAF, MET, RET, and ERBB2) in LUAC.
a9ded1e5ce5d75814730bb4caaf49419 Method
Blood samples from treatment-naïve stage IIIB-IV LUAC patients were analyzed using Guardant360, a next-generation sequencing panel covering 73 genes. The assay includes complete exon sequencing for 19 cancer genes, sequencing of critical exons in 54 genes, and detection of amplifications (18 genes), fusions (6 genes), and indels (23 genes) with high overall clinical sensitivity rates (85%) and ultra-high specificity (>99.9%). Indels and point mutations can be detected at a mutant allele fraction as low as 0.1%. Guardant360 was compared with tissue genotyping performed as standard of care, using a variety of “real life” techniques. The primary objective was to demonstrate the non-inferiority of Guardant360 versus tissue analysis for the detection of the 7 genetic alterations. The study is registered with ClinicalTrials.gov, number NCT03248089.
4c3880bb027f159e801041b1021e88e8 Result
186 LUAC patients were enrolled over a period of 11 months (August 2016-July 2017). Median age 64, 65% male, 72% smoker/ex-smokers, 85% ECOG performance status 0-1. Targetable activating alterations were detected by the Guardant360 assay and by tissue analysis in 25% (n=47) and 26% (n=49) of patients, respectively (non-inferiority P=0.268). Thirty patients (16%) had alterations identified by both modalities. None of the 186 patients was successfully tested in tissue for all 7 alterations. Of the 17 patients who were negative in tissue but for whom Guardant360 identified targetable alterations, 3 had BRAF V600E mutations. For none of these patients was BRAF tested in tissue. Clinical efficacy per biomarker and treatment modality are awaited.
8eea62084ca7e541d918e823422bd82e Conclusion
Guardant360 cfDNA and tissue analysis detect relevant somatic tumor alterations at similar rates in LUAC patients. Under-genotyping in tissue is common but can be mitigated by the use of cfDNA next generation sequencing assays.
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P2.03-15 - Integrin-Linked Kinase (ILK), Protein Tyrosine Phosphatase SHP2 and B lymphoma Mo-MLV Insertion Region 1 Homolog (Bmi-1) in EGFR-Mutant NSCLC (ID 12557)
16:45 - 18:00 | Author(s): Enric Carcereny
- Abstract
Background
The clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is jeopardized by the activation of multiple signaling pathways. ILK regulates the expression of Bmi-1, a well-known epithelial mesenchymal transition-inducing transcription factor. SHP2 function is required for MAPK pathway activation, and also plays a role in receptor tyrosine kinase signaling pathways.
a9ded1e5ce5d75814730bb4caaf49419 Method
Clinical data were assessed in accordance with the protocol approved by the institutional review board and de-identified for patient confidentiality. Pretreatment tumor specimens from advanced EGFR-mutant NSCLC patients (pts) were collected from eight sites in Spain, France, Italy and Colombia. mRNA gene expression analysis was performed by TaqMan (qRT-PCR). We examined the mRNA levels of ILK, SHP2 and Bmi-1.
4c3880bb027f159e801041b1021e88e8 Result
With a median follow-up of 26.7 months, median progression-free survival (PFS) was 9.3 (95% CI, 7.6-14.2) and 15.7 months (95%CI, 12.3-30.1) for pts with high and low ILK mRNA, respectively (P=0.0002), (HR for disease progression, 2.4; 95% CI, 1.3-4.5; P=0.002). Median PFS was 11.4 (95% CI, 8.2-14) and 24.1 months (95% CI, 8.2-30.9) for pts with high and low SHP2 mRNA, respectively (P=0.009), (HR, 2.4; 95% CI, 1.2-4.7; P=0.01). Median PFS was 8.2 (95% CI, 4.8-13.1) and 24.1 months (95% CI, 14.2-36.5) for pts with high and low SHP2 mRNA, respectively (P=0.001), (HR, 2.9; 95% CI, 1.4-5.9; P=0.002). Median overall survival (OS) was 17.9 (95% CI, 13.2-33) and 34.4 months (95% CI, 18.5-44.2) for pts with high and low ILK mRNA, respectively (P=0.200), (HR, 1.5; 95% CI, 0.79-3; P=0.200). Median OS was 18.5 (95% CI, 14-33) and 36.7 months (95% CI, 16.7-47.1) for pts with high and low SHP2 mRNA, respectively (P=0.018), (HR, 2.5; 95% CI, 1.1-5.8; P=0.020). Median OS was 17.6 (95% CI, 8.6-39.1) and 36.7 months (95% CI, 19.1-64.1) for pts with high and low Bmi-1 mRNA, respectively (P=0.004), (HR, 2.2; 95% CI, 1.0-5.1; P=0.040).
8eea62084ca7e541d918e823422bd82e Conclusion
The disturbance of RTKs, including ILK-SHP2-Bmi-1 axis, occurs frequently in EGFR mutant NSCLC patients, significantly limiting the PFS and OS. The levels of ILK, SHP2 and Bmi-1 could be predictive for upfront combinatory therapy of EGFR TKI plus a MAPK pathway inhibitor (SHP2 or MEK inhibitors).
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P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.04-27 - Ph II Study of Oral Selective AXL Inhibitor Bemcentinib (BGB324) in Combination with Pembrolizumab in Patients with Advanced NSCLC (ID 14307)
16:45 - 18:00 | Author(s): Enric Carcereny
- Abstract
Background
Bemcentinib (BGB324) is a first-in-class, highly selective oral inhibitor of the AXL tyrosine kinase currently in phase II clinical development across several cancer types. AXL overexpression has been observed in pts failing anti-PD-1 therapy in several cancers whereas AXL inhibition via bemcentinib has shown synergistic effect with checkpoint blockade in pre-clinical models of NSCLC.
In pts with advanced, pre-treated NSCLC, bemcentinib monotherapy led to disease stabilisation in 2 out of 8 pts including evidence of tumour reduction. Combination therapy of bemcentinib with EGFR inhibition indicated the potential of AXL blockade to reverse resistance to targeted therapy in advanced EGFR therapy resistant NSCLC. Evidence of immune activation following bemcentinib monotherapy was observed in AML patients.
This open label, single-arm, two-stage Phase 2 study was designed to test whether AXL inhibition may increase the efficacy of pembrolizumab in patients with advanced, previously treated adenocarcinoma of the lung.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with documented Stage IV adenocarcinoma of the lung who had progressed on previous platinum chemotherapy and – if applicable – at least one line of licensed EGFR or ALK targeted therapy, received 200 mg/d bemcentinib po and 200 mg/q3wk pembrolizumab iv. Patients were required to consent to a fresh pre-treatment biopsy. Tumour assessments were done 9-weekly. The primary endpoint was ORR. Tumour biopsies were analysed for PD-L1 and AXL as well as immune cell populations. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) in patients pre-dose and at C2D1.
4c3880bb027f159e801041b1021e88e8 Result
As of time of writing, the study had fully recruited its first stage. Of 24 patients enrolled, 14 were ongoing. 6 of 10 patients who had reached their first scan showed evidence of tumour shrinkage including 3 pts with partial responses in their target lesions. 2 patients had stable disease. There were no grade 4 treatment-related events. Dose reduction from 200 to 100 mg/d of bemcentinib as a consequence of adverse events was required in 12% of patients. Correlation of AXL and PD-L1 expression with response was evaluated. Soluble AXL plasma levels were increased following one cycle of treatment indicative of target engagement.
8eea62084ca7e541d918e823422bd82e Conclusion
A preliminary analysis of response to combination treatment during the first stage of this study as well as biomarker correlation will be presented at the meeting. Clinical trial information: NCT03184571
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P2.15 - Treatment in the Real World - Support, Survivorship, Systems Research (Not CME Accredited Session) (ID 964)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.15-25 - NIVEX TRIAL (GECP 1605): Nivolumab in the Real World: Spanish Expanded Access Program Experience in Pretreated Advanced NSCLC Patients (ID 13030)
16:45 - 18:00 | Author(s): Enric Carcereny
- Abstract
Background
Nivolumab is a standard treatment for pretreated patients with advanced non-small cell lung cancer (NSCLC). Real world data about toxicity and efficacy of nivolumab is needed.
a9ded1e5ce5d75814730bb4caaf49419 Method
We have analyzed patients from the Expanded Access Program in Spain that included patients with advanced pretreated NSCLC. We have retrospectively analyzed 665 patients that had received at least 1 dose of nivolumab 3mg/kg q2w from 01/2015 for squamous ﴾Sq﴿ and 06/2015 for non‐Sq NSCLC, to 11/2017.
4c3880bb027f159e801041b1021e88e8 Result
Median age was 61 (32-85) years, 73% were men, 85% had ECOG 0-1, 88% were current or former smokers and 15% presented brain metastases. 128 (19,2%) patients presented Sq NSCLC and 537 (80,8%) patients Non‐Sq NSCLC. 7% of patients presented EGFR mutation. PD-L1 was ≥ 1% in 32,9% of analyzed patients.
Best response was complete response 1,7%, partial response 22,4%, stable disease 24,1%, and progressive disease 37,1%, and was not assessed in 14,7% of patients. No differences in response rate were observed according to histology.
After a median follow‐up of 8,2 months, the median OS was 8,97 (95%CI 7,69-10,24) months, and the median PFS was 3,23 (95%CI 2,77-3,70) months. Estimated 1-year OS was 42,4% (95%CI 38,5-42,8%) and estimated 1-year PFS was 22,2% (95%CI 19,1-25,3%). No differences in OS or PFS according to histologies were observed.
296 (44,5%) patients presented toxicity related to Nivolumab, that was grade ≥3 in 69 (10,4%) patients. Grade ≥3 diarrhea was reported in 1,2% of patients and pneumonitis occurred in 1,2% of patients (1 patient presented a grade 5 pneumonitis). According to the presence of grade ≥3 toxicity, the median OS was 14,57 (CI95% 8,45-20,68) months for patients with grade ≥3 toxicity and 8,73 (CI95% 7,50-9,96) months for patients without grade ≥3 toxicity (p= 0,074).
Additional efficacy data including treatment lines, presence of immune-related adverse events, PS2, brain metastasis, response to first line, or post-nivolumab treatment will be presented.
8eea62084ca7e541d918e823422bd82e Conclusion
Efficacy and safety of nivolumab was in line with previously shown data. There was a trend to a better OS for those patients experiencing grade ≥3 toxicity.
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