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- J. Seoane
- R. Marais
LBA59_PR - Expanding the use of approved drugs: The CPCT’s Drug Rediscovery Protocol (DRUP) (ID 5938)
- D. Van der Velden
- E. Voest
Abstract
Background
Once regulatory drug approval is obtained, patients and pharma would greatly benefit from identifying signals of activity in cancer subsets outside the approved indication. In the Netherlands’ precision oncology-network (), Whole Genome Sequencing (WGS) is offered to systemically treated cancer patients. This allows us to identify a spectrum of potentially actionable genetic aberrations in all types of cancer. The DRUP provides patients with such aberrations access to genetically matched treatment upon central review of the tumor profile.
Methods
Adult patients with solid tumors, glioblastoma, lymphoma or multiple myeloma, with no standard treatment options, are eligible. Patients are enrolled in multiple parallel cohorts, each defined by 1 tumor type, 1 tumor profile and 1 treatment. Efficacy is analyzed per cohort using a Simon-2-stage approach, aimed at ≥ 1 clinical benefit (CR, PR or SD ≥ 16 weeks)/8 patients in stage I, and ≥5/24 in stage II (85% power, α error rate 7.8%). A fresh tumor biopsy for biomarker research is mandatory. There are currently 23 participating hospitals and 19 study drugs, supplied by 10 pharmaceutical companies.
Results
Since study launch Sep 2016, ∼250 cases were submitted for review and about 1/3 of these patients have started study treatment. Clinical benefit was observed in 37% (6% CR, 14% PR, 17% SD ≥ 16 weeks; all CRs and 2/3 of PRs were ongoing at the time of writing and awaiting ≥30 days confirmation). About 2/3 of case submissions were rejected, due to
Conclusions
Execution of a national multi-drug and multi-tumor precision oncology trial is feasible. By performing WGS in many different cancer types, subgroups are identified who may benefit from existing drugs outside of their registered indication. This study hereby accelerates translation of new findings to the clinic and increases the yield of existing therapies.
Clinical trial identification
NCT02925234 (release date: 26-Aug-2016) EudraCT 2015-004398-33 (release date: 01-Oct-2015)
Legal entity responsible for the study
• Governance: Stichting Het Nederlands Kanker Instituut – Antoni van Leeuwenhoek Ziekenhuis, whose registered office is at Plesmanlaan 121, 1066CX, Amsterdam, lawfully represented by Prof. R. Medema, Head of the Board representing the CPCT. • Coordination and running of the study: Prof. E.E. Voest, Netherlands Cancer Institute, division of Molecular Oncology, Amsterdam, the Netherlands.
Funding
• Barcode for Life Foundation (BFL): funding • Dutch Cancer Society (KWF): funding • Hartwig Medical Foundation (HMF): sequencing • Pharmaceutical partners (Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Novartis, Roche): funding and study drugs
Disclosure
F. De Vos: 1. Direct research support to the responsible project lead (Principle Investigator): see 2 2. Novartis, BMS, Roche/Genetech, GSK, Array, AstraZeneca, Merus, Merck E. Cuppen: Board of Directors Hartwig Medical Foundation (not for profit) N. Steeghs: 1. Consulting or Advisory role - Lilly 2. Research Funding - AB Science; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol MS All other authors have declared no conflicts of interest.
1628O - Development of the Manchester Cancer Research Centre Molecular Tumour Board for matching patients to clinical trials based on tumour and ctDNA genetic profiling (ID 3897)
- A. Gupta
Abstract
Background
Advances in Next Generation Sequencing (NGS) are enabling detailed molecular analysis of tumour and circulating tumour DNA (ctDNA). Combined with the expanding development of targeted therapies we are in the era of Precision Medicine. Molecular Tumour Boards (MTB) are needed to interpret genomic data and inform on clinically relevant matched therapies. We describe our experience of setting up a MTB to deliver a world-class genomic driven oncology programme.
Methods
Patients referred to the Experimental Cancer Medicine Team were consented for analysis of ctDNA and tumour under the TARGET (
Results
From Apr 2015 to Nov 2016 we recruited 100 patients to Part A. Main tumour types were colorectal (24%), breast (20%) and lung (18%). In 41% of patients a potentially actionable aberration was identified. The main challenges were i) optimisation of a bioinformatic pipeline for ctDNA, ii) linking clinical data with genomic data in a single portal, iii) interpretation of unknown variants and iv) linking results to available clinical trials in UK/Europe.
Conclusions
We have successfully implemented a comprehensive molecular profiling programme. The bioinformatic pipeline for ctDNA has evolved through real-life data collection and comparison with tumour/germline DNA. We are developing a web-based interface for linking clinical and genomic data for visualisation and annotation within the MTB. Variant interpretation software packages are being evaluated for data curation and ability to link with matched clinical trials. Recruitment of 450 patients to Part B of TARGET is underway to match patients with early phase trials in real-time.
Clinical trial identification
CFTSp094
Legal entity responsible for the study
Study sponsor is The Christie NHS Foundation Trust
Funding
The Christie NHS Foundation Trust, Manchester Cancer Research Centre, CRUK Major Centre award
Disclosure
A. Wallace: Speaker services for Astra Zeneca and Merck-Serono F. Thistlethwaite: Advisory boards: BMS, Pfizer. Speakers honoraria: Novartis, BMS. Travel support: BMS, Ipsen. Other (service support): Novartis, Pfizer. E. Dean: Currently employed by AstraZeneca. No stock or advisory roles. A. Hughes: Shareholder in AstraZeneca and remunerated consultancy for AstraZeneca, Roche, Leo Pharmaceuticals, Aptus Clinical, Carrick Therapeutics and PCI Biotech M. Krebs: Consultancy for Roche All other authors have declared no conflicts of interest.
1629O - A systematic rapid autopsy program tracks temporal and spatial heterogeneity of human tumors and identifies mechanisms of resistance to targeted therapies (ID 5385)
- C. Walmsley
Abstract
Background
Temporal and spatial heterogeneity of human tumors pose a significant barrier in the identification of effective anticancer therapies. Rapid autopsy, defined as post-mortem examination with collection of tissues for diagnosis and research within 6 hours of death, is a critical tool offering insight into this phenomenon.
Methods
Since January 2014, an on-call rapid autopsy team consisting of a pathologist, medical oncologist, pathology assistant and a tissue collection coordinator performed rapid autopsies on 51 patients with genomically-defined advanced solid tumors. Samples were collected from the primary tumor when present, multiple metastatic lesions, blood, as well as multiple uninvolved sites. All samples were recorded in a centralized database linked to patient’s treatment history, as well as all previously collected tissue and liquid biopsies, under one clinical data and sample collection protocol. Samples meeting minimum viability and tumor cellularity criteria were selected for downstream analyses, including next-generation sequencing and protein-based assays.
Results
In 51 rapid autopsies, a median of 12 tissue samples were collected per autopsy (range 5-24), after a median of 2 hours and 50 minutes post mortem (range 32 minutes - 9 hours). 47 autopsies (92.2%) were completed < 6 hours post mortem, and 4 autopsies (7.8%) were completed > 6 hours post mortem due to delays in the confirmation of the autopsy consent from the patient’s healthcare proxy and transportation delays. Tumor cellularity of collected samples ranged from 0-90% (median 60%), making these samples highly suitable for subsequent genomic analyses. Full analysis of 3 autopsy series revealed molecular alterations driving resistance to PI3K-alpha inhibitors, CDK4/6 inhibitors and FGFR inhibitors in patients with PIK3CA-altered metastatic breast cancer and FGFR2 fusion positive cholangiocarcinoma.
Conclusions
Rapid autopsies complement serially collected tissue and liquid biopsies, providing invaluable samples for analysis of tumor heterogeneity, evolutionary dynamics and determination of resistance mechanisms to targeted therapies.
Legal entity responsible for the study
Dejan Juric
Funding
Susan Eid Tumor Heterogeneity Initiative
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant LBA59, 1628O and 1629O (ID 5934)
- J. Seoane
84PD - Relationship of PD-L1 and a T-cell inflamed gene expression profile (GEP) to clinical response in a multicohort trial of solid tumors (KEYNOTE [KN]028) (ID 3199)
- P. Ott
Abstract
Background
Antibodies targeting the PD-1 pathway have shown durable clinical benefit in multiple cancers. In the KN028 trial, the antitumor activity and safety of pembrolizumab were investigated in 20 solid tumors. Associations between PD-L1 expression and a T-cell inflamed GEP with response to anti-PD-1 therapy were also evaluated.
Methods
KN028 is a nonrandomized, phase 1b multicenter trial in patients with PD-L1 positive (≥1%, modified proportion score or interface pattern, QualTek IHC) advanced solid tumors treated with pembrolizumab 10 mg/kg Q2W for ≤2 y or until confirmed progression/unacceptable toxicity, death or withdrawal of consent. Response was assessed every 8 wk for 6 mo then every 12 wk. The primary endpoint was ORR (RECIST v1.1, investigator assessment [INV]) in patients who received ≥1 dose of pembrolizumab and had measurable disease. Secondary endpoints included safety, PFS and OS. ORR by central radiology review (IRC). Exploratory endpoints included relationships between GEP score (FFPE extracted RNA analyzed on NanoString nCounter) and PD-L1 expression levels (combined positive score, Dako IHC) with ORR and PFS. Data cutoff date was Feb 20, 2017.
Results
In the total study population (N = 475), there were 66 responders among 471 evaluable patients. ORR (95% CI) by INV ranged from 4.2% (0.1, 21.1) to 33.3% (15.6, 55.3) in 19/20 tumor types; no responders were observed in pancreatic carcinoma. ORR >10% was observed in 13/20 types (58/66 responders). ORR (95% CI) by IRC ranged from 4.3% (0.1, 21.9) to 26.3% (9.1, 51.2) in 18/20 tumor types. Treatment related AEs occurred in 65.5% of patients (14.1% grade 3-5). PD-L1 expression (p = 0.034) and GEP (p = 0.012) were associated with ORR in meta-analysis across tumors. Data for PFS, OS and relationships between PD-L1, GEP and MSI status with ORR will also be presented.
Conclusions
Pembrolizumab demonstrated favorable responses and manageable toxicity in the majority of the tumor types in KN028. Both PD-L1 and GEP score were predictive of clinical response, suggesting the utility of these biomarkers in selecting patients for immunotherapy and other novel therapies across a wide spectrum of tumor histologies.
Clinical trial identification
NCT02054806, originally posted February 3, 2014, KEYNOTE-028; EudraCT Number 2013-004507-39, originally entered May 30, 2014.
Legal entity responsible for the study
Merck & Co., Inc., Kenilworth, NJ, USA
Funding
Merck & Co., Inc., Kenilworth, NJ USA
Disclosure
P.A. Ott: Honoraria from Bristol-Myers Squibb, Merck, Neon Ther, Celldex, Pfizer, CytomX, Novartis, Alexion, Genentech/Roche. Funding from Bristol-Myers Squibb, Merck, Neon Therapeutics, Armo BioSciences, Celldex, MedImmune/AstraZeneca, Pfizer, CytomX. Y-J. Bang: Consultant for MSD. Funding from MSD to the institute. J. Bennouna: Consultant or advisory role, Honoraria from Roche, Boehringer-Ingelheim, AstraZeneca, Shire, MSD, Bristol-Myers Squibb. J-C. Soria: Honoraria from MSD. H.S. Rugo: Consultant for Amgen. Speakers’ bureau for Genomic Health. Travel expenses from Genentech. Funding to the institution from Genentech, Pfizer, Novartis, Lilly, OBI Pharma, Macrogenics, and Merck & Co., Inc. R.B. Cohen: Research funding to the institutiton from Merck & Co., Inc. B.H. O\'Neil: Travel expenses from Amgen. J.M. Mehnert: Advisory board member of Merck & Co., Inc., Genentech, EMD Serono. Consultant for Merck and Amgen. Research funding from Novartis, Merck, Polynoma, AstraZeneca, Immunocore, Macrogenics, Incyte. J. Lopez: Speakers’ Bureau for Roche and travel expenses for Basilea. T. Doi: Consulting/advisory/funding from Lilly Japan, Chugai, Kyowa Hakko Kirin, Nippon Boehringer-Ingelheim, Novartis, MSD, Daiichi Sankyo, Amgen. Funding: Taiho Pharma, Merck Serono, Astellas, Janssen, Takeda, Pfizer, Sumitomo, Bayer, Celgene. D. Levitan, K. Emancipator, A. Joe, M. Ayers, J. Lunceford: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA. Owner of stock or stock options in Merck & Co., Inc. K. Stein: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA and. Owner of stock or stock options in Merck & Co., Inc., Novartis, Sanofi, and Pfizer. G. Zhao: Employee of MSD China. All other authors have declared no conflicts of interest.
1630PD - Association of programmed cell death 1 ligand (PD-L1) expression with molecular alterations in non-small cell lung cancer (NSCLC) patients (pts): Results from the European Thoracic Oncology Platform (ETOP) Lungscape cohort (ID 3780)
- K. Kerr
Abstract
Background
PD-L1 is the only validated predictive biomarker for use with immune checkpoint inhibitors targeting the PD-1 pathway in advanced NSCLC.
Methods
Correlation of PD-L1 expression with that of MET, ALK, PTEN proteins by IHC (MET+:≥2+ and % staining≥50%, ALK+: ≥1+, PTEN+: H-score>0) and mutations in
Results
PD-L1 expression was assessed in 2182 pts, from 15 centers, 51/42/7% adenocarcinomas (AC)/squamous cell carcinoma (SCC)/other, 49/29/22% stage I/II/III, 32/54/11% current/former/never smokers, 4% unknown smoking status. For the 1% cut-off, a significant association was detected between PD-L1 and MET expression both for AC and SCC (PD-L1 positivity in AC: 61% in MET + vs 33% in MET-, p < 0.001; SCC: 57% vs 42%, p = 0.005). PD-L1 positivity was more frequent in PTEN expressing AC (48% vs 37% in PTEN loss subgroup, p = 0.0017), but not in SCC (p = 0.62). The association of ALK expression and PD-L1, explored only in the AC, was not significant (p = 0.42). Significant associations were also detected in AC between PD-L1 and
Conclusions
In this large NSCLC cohort, PD-L1 positivity (with 1%, 5% or 50% cut-off) is found to be significantly associated with IHC MET overexpression, expression of PTEN and
Legal entity responsible for the study
European Thoracic Oncology Platform (ETOP)
Funding
Brystol-Myers Squibb International Corporation
Disclosure
K.M. Kerr: Consulting or advisory role and paid participation in a speakers’ bureau: Astra Zeneca, BMS, Boehringer Ingelheim, Eli Lilly, Merck KGaA, MSD, Novartis, Pfizer, Roche. L. Bubendorf: Member of advisory boards: BI, MSD, Roche K. Monkhorst: Member of 4 advisory boards: Pfizer, Roche, MSD, BMS All other authors have declared no conflicts of interest.
1631PD - Prominent immune suppressive tumor microenvironment in female never-smoker lung cancer patients with EGFR mutations (ID 2460)
- B. Park
Abstract
Background
According to genetic and genomic analysis as well as previous clinical research, lung cancer in never-smokers might have pathogenesis and progression different from that of lung cancer among smokers. There has been indirect evidence that different types of mutations in tumors might be related to the altered immune functions.
Methods
Tissues from 110 female patients with lung adenocarcinoma (never-smokers: 102 & smokers: 8) at the Samsung Medical Center, were analyzed by next-generation genomic sequencing including whole-exome seq and RNA-seq. Somatic mutations and gene expression levels of immune signature genes were profiled. The significance for clinical outcome of the selected genes was plotted using Kaplan-Meier method and log-rank test.
Results
Expression biomarkers of immune suppressive cells such as mast cells, macrophage and Treg were prominent in female never-smokers compared to female smokers of lung adenocarcinoma. The data suggest that cells of cytotoxic functions are deactivated in smokers, whereas cells of immune suppressive functions are activated in never-smokers. Specifically as expression of immune markers specific for B-cells, dendritic cells, mast cells and Treg was especially up-regulated (p<.05) in tumors from patients with EGFR mutation (42%), its mutation status may play an important role in augmenting the immune suppressive activity. EGFR mutation–positive adenocarcinoma was significantly associated with low level of expression of an immune checkpoint molecule, programmed death-ligand 1 (PD-L1), in contrast with high level of cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) in female never-smokers.
Conclusions
This overall immune suppression in lung adenocarcinoma patients with EGFR mutation might explain the lower response rate of anti-PD-1/PD-L1 blockade to the female never smokers, which suggests that other approaches to block the immune suppressive microenvironment would be necessary.
Legal entity responsible for the study
The Institutional Review Board of Samsung Medical Center
Funding
Samsung Cancer Research Institute
Disclosure
All authors have declared no conflicts of interest.
1632PD - A novel radiomic based imaging tool to monitor tumor lymphocyte infiltration and outcome of patients treated by anti-PD-1/PD-L1 (ID 4205)
- R. Sun
Abstract
Background
Tumor infiltrating lymphocytes (TIL) appears necessary to trigger anticancer activity of anti-PD-1/PD-L1. Radiomics consists in the analysis of quantitative data extracted from standard medical imaging to generate imaging biomarkers. We developed a radiomics-based predictor of TIL and investigated whether such signature could predict the outcome of patients treated by anti-PD1/PD-L1.
Methods
We first developed a predictive model of tumor infiltrating CD8 T cells with RNA-Seq and raw imaging data (CT –Scan) using random forest in 69 HNSCC patients from the TCGA (The Cancer Genome Atlas)/TCIA (The Cancer Imaging Archive) database. CD8 T cells were estimated by the Microenvironment Cell Populations-counter signature. To validate our tool, this signature was applied to a first independent cohort of 100 patients for which the pathologic TIL was assumed as either high (lymphoma, melanoma, lung, bladder, renal and MSI+ cancers; 30 patients) or low (adenoid cystic carcinoma, low-grade neuroendocrine tumors, uterine leiomyoma; 70 patients). Finally, we applied our signature on a second cohort of 139 patients prospectively enrolled in anti-PD-1/PD-L1 phase 1 trials to infer its relation with patient outcome (Overall Survival).
Results
We developed a CD8 radiomics-based signature with six out of the 80 extracted features from CT-scans. As an internal validation, the correlation of this signature with the estimated TCGA CD8 was: spearman’s rho=0.81 (P < 1e-5). In the first external cohort, this signature was associated with the assumed lymphocyteness (Wilcoxon test, P < 0.001). When validating our signature in the second external cohort, the median of the CD8 signature predicted score was used to separate patients into two groups. Patients with high predicted CD8 score had significantly better OS (HR = 0.55, 95%CI=0.36-0.86, P = 0.009) and the CD8 signature remained significant after multivariate analysis including RMH score and the number of previous lines of treatment (HR = 0.48, 95%CI=0.31-0.76, P = 0.002).
Conclusions
The radiomics-based signature of TIL was validated in two external cohorts. It appears a promising tool to estimate TIL and to infer the outcome of metastatic patients treated with anti-PD1/PD-L1.
Legal entity responsible for the study
Ferté Charles
Funding
None
Disclosure
L. Verlingue: consulting Adaptherapy J-C. Soria: Consultancy fees from AstraZeneca, Astex, Clovis, GSK, Gammamabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, Pharmamar Pierre Fabre, Roche-Genentech, Sanofi, Servier, Symphogen, Takeda. All other authors have declared no conflicts of interest.
Invited Discussant 84PD, 1630PD, 1631Pd and 1632PD (ID 5935)
- S. Singh
Questions to discussant (ID 5936)
85PD - Ultrasensitive detection of EGFR T790M mutation by droplet digital PCR (ddPCR) in TKI naïve non-small cell lung cancer (NSCLC) harboring EGFR mutation: Results of the nationwide program Biomarkers France of the French Cooperative Thoracic Intergroup (IFCT) (ID 3719)
- M. Beau-Faller
Abstract
Background
The presence of T790M mutation in
Methods
We analyzed 343
Results
ddPCR identified a T790M mutation in 23/256 specimens (9%). T790M Fractional Abundance (FA) was ≥10%; ≥1% <10%; ≥0.1% <1%, ≥0.03% <0.1%, in 5 (22%), 7 (30%), 6 (26%) and 5 (22%) patients, respectively. The presence of a T790M mutation was not correlated with a specific type of
Conclusions
Ultrasensitive detection of T790M is related in 9% of
Clinical trial identification
NCT01700582
Legal entity responsible for the study
French Cooperative Thoracic Intergroup (IFCT)
Funding
Institut National du Cancer (INCa), AstraZeneca, IFCT (Alain Depierre Award 2015)
Disclosure
P-P. Bringuier: Research funding from Institut National du Cancer (INCa) and honoraria from AstraZeneca, Roche. F. Barlesi: Honorarium from Bristol-Myers Squibb. D. Moro-Sibilot: Personal fees from Roche, Eli Lilly, Pfizer, Novartis, AstraZeneca, Bristol-Myers Squibb, MSD, Boehringer Ingelheim. J. Cadranel: Personnal fees from AstraZeneca, Bristol-Myers Squibb and Roche for participating to board of experts. All other authors have declared no conflicts of interest.
86PD - Biomarker prevalence study and phase I trial of afatinib in children with malignant tumours (ID 4576)
- K. Nysom
Abstract
Background
Dysregulation of the ErbB pathway may play a role in the development of paediatric neuroectodermal and mesenchymal tumours, suggesting that afatinib, an oral, irreversible ErbB family blocker, could be an effective treatment. A biomarker prevalence study assessed the frequency of ErbB-deregulations; in parallel, a Phase I trial (NCT02372006) was conducted.
Methods
Archived tissue samples from 277 neuroectodermal tumours and rhabdomyosarcomas were tested for protein expression of HER1–HER4, gene amplification of HER1/HER2 and mRNA expression of ErbB receptors and ligands. A Phase I afatinib trial in children aged 2 to < 18 years used a rolling 6 dose escalation design to determine the MTD/RP2D, starting at 18 mg/m2/d (80% of the BSA-equivalent adult MTD dose), increasing to 23, 29, and 35 mg/m2. PK was analysed after 1st dose and at steady state. Anti-tumour activity was assessed as per disease standards.
Results
In the biomarker prevalence study, ErbB deregulation markers were defined as: (A) HER1 gene amplification: HER1/Cen7 ≥2.0; ≥10% of cells with ≥15 copies; ≥40% of cells with ≥4 copies; or gene cluster in ≥ 10% of cells; (B) HER2 gene amplification: HER2/CEP17 ≥2.0; Protein expression (membrane); (C) EGFR H-score >150; and (D) HER2 H-score >0. Patients (pts) with tumours positive for ≥2 markers (A–D) will be selected to enrich the trial expansion cohorts. In the Phase I trial, 23 pts were screened, 17 treated and 12 evaluable for MTD. 1/7 pts experienced DLTs at 18 mg/m2 and 2/5 at 23 mg/m2. DLT events were decreased appetite, diarrhoea, dehydration, hypernatraemia, hypokalaemia, cheilitis, rash. Diarrhoea (12 pts) and dry skin (6 pts) were the most frequently reported drug-related AEs. Exploratory PK analysis suggested that exposure at 18 mg/m2 in children was in a similar range as in adults treated with 40 mg/d. 1 pt with ependymoma had stable disease for 8 treatment cycles.
Conclusions
Afatinib was tolerable in children, with a safety profile similar to adults. The MTD was established at 18 mg/m2/d and resulted in drug exposure considered effective in adults. The biomarker prevalence study identified exploratory screening markers being used to enrich patient selection in the ongoing expansion cohort.
Clinical trial identification
NCT02372006
Legal entity responsible for the study
Boehringer Ingelheim
Funding
Boehringer Ingelheim
Disclosure
D. Frappaz: Advisory board: BMS. P. Varlet: Advisory board: Roche (Herby trial), Novartis (dabrafinib trial), Boehringer (afatinib trial), Nanostring Technologies. D. Hargrave: Payments for being part of an advisory board in relation to the development of afatinib in childhood cancer. S. Gallego: Advisory board: Loxo Oncology. M. Kieran: Advisory board for Afatinib but do not receive any funds or payments. M. Casanova: Advisory board: Boehringer Ingelheim Pharma GmbH & Co. KG, Roche, Lilly, Bayer, Loxo Oncology. A. Lahogue, S. Wind, B. Stolze, D. Roy, M. Uttenreuther-Fischer: Employee of Boehringer Ingelheim. B. Geoerger: Advisory board: Boehringer Ingelheim. All other authors have declared no conflict of interest.
87PD - Prospective study assessing the expression of angiogenesis-related genes as markers of anti-VEGFR2 response in advanced renal cell carcinoma (ID 5193)
- J. Garcia-Donas
Abstract
Background
Since different therapeutic alternatives are reaching the clinic, we need biomarkers to guide treatment decissions in advanced Clear Cell Renal Cancer. This study explores the tumor expression of angiogenesis-related genes as potential markers of anti-VEGFR2 response.
Methods
Through an observational prospective study carried by the Spanish Oncology Genitourinary Group (SOGUG) FFPE tumor samples were collected from 159 RCC patients. A nCounter® Custom CodeSets (NanoString Technologies) was designed to measure the expression of a selected set of genes involved in angiogenesis (n = 23), immune response (n = 5) and RCC mutational landscape (n = 4), together with 4 house keeping genes. This technology was successfully applied to 135 primary tumors (81% clear cell histology), 4 metastasis, and 10 normal kidney tissues from patients treated with anti-VEGFR2 therapy. The association between the expression of the genes and PFS and OS was analyzed through cox-regression. Data provided correspond to multivariable analyses adjusted for MSKCC prognosis group, RCC histology and age.
Results
The 135 patients studied had been treated with sunitinib (91%), pazopanib (7%) or sorafenib (1%); most in first line (98%) and the median PFS was 21.0 months (95%CI=14.5-27.4). The strongest associations found corresponded to
Conclusions
We propose that the basal tumor expression of VEGF isoforms influences the survival of the patients treated with anti-VEGFR2 drugs.
Legal entity responsible for the study
Spanish Oncology Genitourinary Group (SOGUG)
Funding
Spanish Oncology Genitourinary Group (SOGUG)
Disclosure
All authors have declared no conflicts of interest.
1633PD - Co-amplification of KIT/KDR/PDGRA in over 100,000 advanced cancer cases (ID 4039)
- U. Disel
Abstract
Background
The 4q12 amplicon (4q12amp) which harbors the tyrosine kinases KIT, KDR and PDGFRA has been thought to occur as frequently as 3-7% in lung adenocarcinoma (LA) (Ramos et al, 2009) and 5-15% in glioblastoma (GBM) (Holtkamp, 2006; Szerlip, 2012) as assessed by a variety of techniques. As 4q12amp is hypothesized to be an oncogenic driver, it remains unclear whether all three kinases participate equally in oncogenesis, or if one kinase can be preferentially targeted by a tyrosine kinase inhibitor (TKI) for patient benefit. We undertook a large-scale genomic analysis to describe the frequency of 4q12 across solid tumors.
Methods
We prospectively analyzed 114,200 primarily advanced stage solid tumors in the course of clinical care using hybrid-capture based comprehensive genomic profiling (CGP) of 186 to 315 genes plus introns from 14 to 28 genes commonly rearranged in cancer.
Results
4q12amp was present in 0.65% of all cases (740/114,200), with a median copy number of 10, and was most abundant in the following cancers: 4.8% of GBM (155/3,222), 0.83% of lung cancers (191/22,857, 2/3 approximately being LA), 1.9% of sarcomas (106/5,391), and 0.77% of breast cancers (92/11,980). Of sarcomas, 7.1% of osteosarcomas (26/367) and 2.82% of soft tissue sarcomas NOS (22/780) harbored 4q12amp. Of 4q12amp lung cancer cases, the supramajority (86%) did not harbor known oncogenic drivers of NSCLC (alterations of EGFR/HER2/MET, ALK/ROS/RET fusions, or BRAF V600E). Index cases of durable responses to pazopanib and imatinib will be described in undifferentiated sarcoma, synovial sarcoma, and head and neck/salivary cancers.
Conclusions
4q12amp is significantly less frequent in GBM and lung cancer than previously reported by non-sequencing techniques, but is enriched in osteosarcoma and undifferentiated sarcomas. The driver status of 4q12amp is supported both by the predominant mutual exclusivity with other known drivers in lung cancer, and responses to various multi-TKIs. The specificities of the latter may help shed insight into whether singly or multiply targeting KIT/KDR/PDGFRA is a preferred approach for patient benefit.
Legal entity responsible for the study
Foundation Medicine
Funding
Foundation medicine, Inc funded a small part of the study
Disclosure
U. Disel: Research agreement with Foundation Medicine, which provided funding to run a small number of genomic profiling assay (<15). R. Madison, J. Chung, A. Oztan, A. Benson, J. Webster, P.J. Stephens, A.B. Schrock, V.A. Miller: an employee of and has equity interest in Foundation Medicine Inc M. Gounder: No COI for this specific work. Advisory board or compensations: Tracon, Daiichi, Karyopharm, Epizyme, Amgen S.J. Klempner: Honoraria – Foundation Medicine, Inc. Consulting/Advisory Board – Lilly Oncology, Boston Biomedical S-H.I. Ou: Stock ownership Yes Membership of an advisory board or board of directors Genentech/Roche, Ariad, Pfizer, Novartis, Astra Zeneca Corporate sponsored research S. Ganesan: COI: Merck: Spouse is employee and owns equity Inspirata Inc.: am on SAB, own equity and have IP Novartis: consultant J.S. Ross: Employee of and has equity interest in Foundation Medicine Inc. paid speaker for several pharmaceutical companies. has equity interest in Sypher Inc. S. Ali: Employee of and have equity interest in Foundation Medicine. I own <5000 USD in stock in epizyme and exelexis. All other authors have declared no conflicts of interest.
Invited Discussant 85PD, 86PD, 87PD and 1633PD (ID 5937)
- R. Marais