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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

4062 - Olaparib plus paclitaxel sensitivity in biomarker subgroups of gastric cancer

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Presenters

Yu-Zhen Liu

Citation

Annals of Oncology (2018) 29 (suppl_8): viii14-viii57. 10.1093/annonc/mdy269

Authors

Y. Liu1, D. Hodgson2, G. Locker3, Z. Lai4, D. Balcerzak2, A. Sharpe2, J.C. Barrett4, M. Orr2, T.S. Gutjahr2, B. Dougherty4, M.P. Roudier2, X. Shi3, R. Miller5, W.H. Kim6, X. Zeng7, A. Ochiai8, S. Im9, R. Xu10, N. Boku11, Y. Bang9

Author affiliations

  • 1 ,, AstraZeneca, , - Cambridge/GB
  • 2 ,, AstraZeneca, Cambridge/GB
  • 3 ,, AstraZeneca, Gaithersburg/US
  • 4 ,, AstraZeneca, Waltham/US
  • 5 ,, Ventana Medical Systems, Tucson/US
  • 6 ,, Seoul National University College of Medicine, Seoul/KR
  • 7 Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing/CN
  • 8 ,, National Cancer Center Hospital East, Chiba/JP
  • 9 Cancer Research Institute, Seoul National University College of Medicine, Seoul/KR
  • 10 ,, Sun Yat-sen University Cancer Center, Guangzhou/CN
  • 11 ,, National Cancer Center Hospital, Tokyo/JP
More

Resources

Abstract 4062

Background

Study 39 (NCT01063517) showed a significant improvement in overall survival (OS) following olaparib plus paclitaxel (OP) vs paclitaxel (P) alone in advanced gastric cancer, with improvements greatest in patients (pts) with low or undetectable tumour ATM protein levels. The Phase III GOLD study (NCT01924533) also showed a survival benefit trend for OP vs P. We investigated biomarker subgroups, candidate genes and homologous recombination repair (HRR) deficiency using pre-defined and post-hoc exploratory analyses, to determine if a predictive relationship exists between such biomarkers and clinical outcome in gastric cancer pts treated with OP.

Methods

Candidate genes, HRR deficiencies, loss of heterozygosity (LoH) and microsatellite insufficiency (MSI) were assessed in formalin-fixed, paraffin-embedded gastric tumour samples from GOLD by next-generation sequencing. HRR deficiencies were identified as carrying pathogenic mutations in any 15 HRR genes and LoH using allele-specific copy number information coupled with assessed tumour purity. ATM protein level was assessed by immunohistochemistry (IHC). Clinical outcomes analyzed were OS, PFS and ORR.

Results

Efficacy in the genetics evaluable population (n = 400) was broadly consistent with the overall GOLD population (n = 525) for each outcome investigated. ATM-negative patients by IHC had better prognosis independent of treatment. No statistically significant associations with clinical outcomes were identified (Table). Post-hoc exploratory analyses indicated good prognosis (OS) in pts with an ATM mutation, and poor prognosis in pts with CDH1, FGFR2 or KRAS mutations.Table: 83P

Pre-specified subgroupPatients/events in OS, PFS, ORR, respectivelyOSPFSORR
Hazard ratioHazard ratioOdds ratio
[<1 favours OP][<1 favours OP][>1 favours OP]
(P value)(P value)(P value)
Overall population525/381, 449, 720.80 (0.026)*0.84 (0.065)1.68 (0.057)
Evaluable for genetics400/284, 342, 570.80 (0.065)*0.87 (0.214)1.40 (0.256)
ATM IHC status+ve324/233, 281, 420.79 (0.076)0.96 (0.737)1.06 (0.870)
-ve76/51, 61, 150.72 (0.292)0.61 (0.081)3.41 (0.082)
ATM IHC nullNot null381/273, 327, 520.82 (0.094)0.89 (0.315)1.25 (0.551)
Null19/11, 15, 50.55 (0.426)0.28 (0.090)6.46 (0.141)
ATMWt378/274, 326, 550.80 (0.062)0.86 (0.175)1.43 (0.244)
Mut22/10, 16, 20.83 (0.803)0.91 (0.875)0.83 (1.00)
ATM/BRCAWt369/266, 317, 540.81 (0.090)0.85 (0.160)1.52 (0.185)
Mut31/18, 25, 30.94 (0.908)1.11 (0.795)0.39 (0.578)
HRRWt354/254, 302, 520.79 (0.066)0.83 (0.122)1.54 (0.177)
Mut46/30, 40, 51.05 (0.903)0.96 (0.921)0.58 (0.659)
ARID1aWt332/232, 287, 460.82 (0.133)0.86 (0.216)1.28 (0.526)
Mut68/52, 55, 110.65 (0.326)0.91 (0.741)2.06 (0.335)
TP53Wt136/90, 113, 170.80 (0.322)0.98 (0.918)2.03 (0.197)
Mut264/194, 229, 400.77 (0.074)0.76 (0.042)1.16 (0.732)
MSIStable381/269, 325, 530.81 (0.081)0.87 (0.216)1.32 (0.377)
High19/15, 17, 40.41 (0.198)0.83 (0.784)3.22 (0.582)
LoH scoreLOH evaluable ≤6198/139, 175, 32 137/101,119, 210.73 (0.064) 0.73 (0.122)0.75 (0.062) 0.80 (0.222)1.11 (0.847) 1.32 (0.638)
>661/38, 56, 110.62 (0.175)0.71 (0.246)0.84 (1.00)

ATM IHC null, 0% tumour cells expressed ATM; HRR, homologous recombination repair; LoH, loss of heterozygosity; MSI, microsatellite instability status; Mut, mutation; ORR, objective response rate; OS, overall survival; PFS, progression free survival; Wt, wild type Analyses represent the HR for olaparib vs placebo in the stated subgroups *Significant difference for OP vs P was set at P < 0.025 Assessed using the Ventana ATM (Y170) assay (ATM negative defined as < 25% nuclei staining)

Conclusions

None of the pre-specified molecular subgroups had a better outcome from adding olaparib to paclitaxel than the overall GOLD population. Additional studies are required to understand the OS signal observed with OP treatment in pts with advanced gastric cancer in the GOLD study. Yu-Zhen Liu and Darren Hodgson are joint first authors.

Clinical trial identification

NCT01924533.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Editorial Acknowledgement

Claire Routley, Mudskipper Business Ltd.

Disclosure

D. Hodgson, Z. Lai, D. Balcerzak, A. Sharpe, J.C. Barrett, M. Orr, T.S. Gutjahr, B. Dougherty, X. Shi: Employee and stockholder: AstraZeneca. G. Locker: Employee: AstraZeneca. M.P. Roudier: Employee and shareholder: AstraZeneca. R. Miller: Employee and share/stockholder: Roche. W.H. Kim: Grant: Seoul National University Hospital. S-A. Im: Preclinical research grant: AstraZeneca. N. Boku: Grant and personal fees: Taiho, Ono; Personal fees: Chugai, Eli Lilly. Y-J. Bang: Advisory/consulting role, honorarium, research funding: AstraZeneca. All other authors have declared no conflicts of interest.

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