- P. Tan
- I. Chau
1O - Comprehensive Genomic Profiling (CGP) of 114,200 advanced cancers identifies recurrent Kinase Domain Duplications (KDD) and novel oncogenic fusions in diverse tumor types (ID 1785)
- S. Ikeda
- S. Ikeda
- L. Gay
- D. Pavlick
- J. Chung
- S. Ramkissoon
- S. Daniel
- J. Elvin
- E. Severson
- T. Bivona
- K. Reckamp
- S. Klempner
- S. Ou
- A. Schrock
- V. Miller
- P. Stephens
- J. Ross
- S. Ganesan
- C. Lovly
- A. Mansfield
- S. Ali
Abstract
Background
Kinase fusions (KFN) are well recognized as targetable drivers in some cancers, and KFN common in one disease can be found in unrelated histologies, as for
Methods
CGP was performed on DNA and/or RNA from 114,200 solid tumors or heme malignancy samples for 184-406 cancer-related genes and select introns from 14-28 genes commonly rearranged in cancer. RNA sequencing for 265 genes was available for some cases. Selected genomic events were confirmed by manual inspection.
Results
KDD were observed in 598 cases (0.62%): BRAF (127), EGFR (115), FGFR3 (94), FGFR1 (40), RET (37), ERBB2 (35), PDGFRA (35), FGFR2 (28) MET (19), ROS1 (14), ALK (13), KIT (8), NTRK1 (8), FLT3 (6), FGFR4 (5), ERBB4 (4), PDGFRB (3), NTRK2 (2). KDD were seen in 2.7% of brain tumors, most often EGFR (66), BRAF (52), PDGFRA (13), and FGFR3 (26). KDD were also common for RET (13-16% of breast, lung, and thyroid KDD+ cases), MET (15-20% of uterine and brain KDD+ cases), and ALK (54% of lung KDD+ cases). KDD possibly related to TKI resistance were seen in BRAF V600E-positive melanoma and ALK-related NSCLC. Table ALK FGFR2 FGFR3 RET ROS1 All Samples FN RE FN RE FN RE FN RE FN RE NSCLC 20868 590 76 10 5 32 5 240 30 189 7 Brain 6317 3 - 7 2 82 5 3 1 24 6 Pancreatobiliary 7934 8 1 178 50 7 2 7 5 2 5 Bladder 1458 - - 1 - 39 10 - - - 2 Thyroid 972 5 - 2 - - - 38 2 1 - All Other 76651 132 27 122 65 89 14 71 34 38 53
Conclusions
KDD are enriched in brain tumors. Diverse KDD are found extracranially and may underlie acquired resistance. Index cases with clinical responses to matched TKIs suggest KDD, KFN and KRE can be targeted therapeutically in many histological subtypes. Recurrent KFN are found widely in cancer, with gene partner varying by subtype.
Legal entity responsible for the study
Foundation Medicine, Inc.
Funding
Foundation Medicine, Inc.
Disclosure
L. Gay, D. Pavlick, J. Chung, S. Ramkissoon, S. Daniel, J. Elvin, E. Severson, A. Schrock, V. Miller, P. Stephens, J. Ross, S. Ali: Employee and stockholder of Foundation Medicine, Inc. All other authors have declared no conflicts of interest.
Invited Discussant 1O (ID 2180)
- P. Tan
- P. Tan
LBA3_PR - Randomized, non-inferiority, phase III trial of second-line chemotherapy for metastatic colorectal cancer (mCRC), comparing the efficacy and safety of XELIRI + bevacizumab versus FOLFIRI + bevacizumab (AXEPT) (ID 1728)
- T. Kim
- T. Kim
- Y. Park
- K. Muro
- R. Xu
- S. Han
- K. Yamazaki
- W. Wang
- J. Ahn
- H. Uetake
- Y. Deng
- S. Cho
- H. Matsumoto
- Y. Ba
- K. Lee
- T. Nishina
- T. Zhang
- S. Iwasa
- S. Morita
- J. Sakamoto
Abstract
Background
Capecitabine and irinotecan combination (XELIRI) regimen has not been recommended by major guidelines due to substantial toxicities. Recently, modified XELIRI (irinotecan 200 mg/m2 on day 1, capecitabine 1600 mg/m2 on days 1–14 every 3 weeks: mXELIRI) has shown favorable tolerability and efficacy with or without bevacizumab (BEV). We conducted “Asian XELIRI ProjecT” (AXEPT) to demonstrate the OS non-inferiority of XELIRI±BEV versus standard FOLFIRI±BEV as second-line chemotherapy for mCRC.
Methods
Patients with histologically confirmed mCRC, ECOG performance status (PS) 0–2, and disease progression or intolerance of the first-line regimen were eligible. Patients were randomized (1:1) to receive standard FOLFIRI±BEV (5 mg/kg on day 1), repeated every 2 weeks (FOLIRI arm) or mXELIRI±BEV (7.5 mg/kg on day 1) repeated every 3 weeks (mXELIRI arm). A total of 464 events were estimated as necessary to show OS non-inferiority with a power of 80% at a one-sided α of 0.025, requiring a target sample size of 600 patients. The 95% confidence interval upper limit of the hazard ratio was pre-specified as less than 1.3. Stratification factors included country, ECOG PS, number of metastatic sites, prior oxaliplatin treatment, and concomitant BEV treatment.
Results
Between Dec 2013 and Aug 2015, 650 patients were enrolled and randomized either to receive mXELIRI±BEV (n = 326) or FOLFIRI±BEV (n = 324). After a median follow-up of 15.8 months (IQR; 8.7–24.9), median overall survival was 16.8 months in the mXELIRI arm and 15.4 months in the FOLFIRI arm (HR 0.85, 95% CI 0.71–1.02, non-inferiority test p < 0.0001). Overall, the incidence of grade 3/4 adverse events with mXELIRI was significantly lower than that with FOLFIRI (53.9% vs 72.3%; p < 0.0001). The most common grade 3/4 adverse event was neutropenia 16.8% and 42·9% patients in mXELIRI and FOLFIRI ams, respectively; p < 0·0001). The incidences of grade 3/4 diarrhea were low in both arms (7.1% vs 3.2%; p = 0.0443).
Conclusions
mXELIRI±Bev is well-tolerated and non-inferior to FOLFIRI±Bev in terms of OS. mXELIRI could be an alternative to FOLFIRI as a standard second-line backbone treatment for mCRC.
Clinical trial identification
NCT01996306; UMIN000012263
Legal entity responsible for the study
This trial is supported by Epidemiological and Clinical Research Information Network (ECRIN: global sponsor).
Funding
This trial was funded by Chugai Pharmaceutical Co., Ltd. and F. Hoffmann-La Roche Ltd.
Disclosure
T.W. Kim: Research Fund: Roche, Merck Serono, Bayer. K. Muro: Research grants from MSD, Daiichi Sankyo, Ono, Shionogi, Kyowa Hakko Kirin, and Gilead Sciences, and also honoraria from Chugai, Takeda, Eli Lilly, Merck Serono, Taiho, and Yakult. K. Yamazaki: Honoraria: Takeda, Chugai, Taiho, Yakult, Merck Serono, Bristol Myers Squib, Lily, Sanofi, S. Morita: Honoraria from Chugai and Daiichi-Sankyo. All other authors have declared no conflicts of interest.
Invited Discussant One LBA TBC (ID 2182)
- I. Chau
- I. Chau
193O - Prognostic gene expression signature in chemotherapy treated patients from the MAGIC trial (ID 1685)
- E. Smyth
- E. Smyth
- G. Nyamundanda
- D. Cunningham
- I. Tan
- E. Fontana
- C. Ragulan
- A. Okines
- S. Lin
- A. Wotherspoon
- M. Nankivell
- C. Peckitt
- N. Valeri
- R. Langley
- P. Tan
- A. Sadanandam
Abstract
Background
Transcriptomics has defined novel molecular subgroups of gastroesophageal cancer (GC), however the prognostic value of these classifications has not been evaluated in the context of standard treatment. We hypothesised that gene expression on post-chemotherapy resection specimens from patients treated in the MAGIC trial could be used to create prognostic groups with different survival outcomes.
Methods
RNA was extracted from FFPE resections and analysed with the NanoString Technologies’ nCounter system. The gene panel included 200 genes associated with different GC characteristics. Penalised Cox regression was used to identify genes that predict overall survival (OS) followed by computing risk scores (GC-Assigner) for each patient using standard Cox regression. Finally, unsupervised analysis was used to cluster patients into GC-Assigner risk groups associated with OS.
Results
Gene expression data from 82 chemotherapy treated MAGIC trial patients were used to generate a 7 gene signature that predicts OS. Using GC-Assigner scores, three groups were defined; 3 year OS from surgery was 0% (95% 0 – 0%) for high risk patients, 40% (95% CI 27.0% - 64.0%) for intermediate risk patients and 80% (95% CI 63.8% - 99.8%) for low risk patients (p < 0.000001). Multivariate analysis demonstrated that GC-Assigner risk groups were independent of lymph node metastasis in predicting OS (HR lymph node positive 3.46, p 0.025; HR intermediate risk GC-Assigner 0.18, p = 1.00E-05; HR low risk GC-Assigner 0.072, p = 5.23E-06). GC-Assigner group status was not prognostic in patients treated with surgery alone (n = 117; p > 0.05).
Conclusions
These data suggest that risk score and GC-Assigner groups are independent predictors of prognosis in GC patients treated with neoadjuvant chemotherapy in the MAGIC trial . As risk is assigned using post-treatment resection tissue which is less limited than diagnostic biopsies, pending our ongoing validation of this signature and these risk groups, GC-Assigner could be used as stratifier for future clinical trials evaluating personalised post-chemotherapy and resection treatment approaches for GC patients.
Clinical trial identification
ISRCTN93793971.
Legal entity responsible for the study
Medical Research Council Clinical Trials Unit at University College London
Funding
The TransMAGIC study was supported by CRUK grant (CRUKE/07/049).
Disclosure
E.C. Smyth: Honoraria for advisory role from Bristol Meier-Squibb, Five Prime Therapeutics and Gritstone Oncology. D. Cunningham: Research Funding from: Amgen (Inst); AstraZeneca (Inst); Bayer (Inst); Celgene (Inst); MedImmune (Inst); Merck Serono (Inst); Merrimack (Inst); Sanofi (Inst). A. Sadanandam: Licensor for a patent number PCT/IB2013/060416. Research funding from from Bristol-Myers Squibb. All other authors have declared no conflicts of interest.
Invited Discussant 193O (ID 2183)
- F. Lordick
- F. Lordick