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Poster display session

2157 - Exome Sequencing of Tumor Samples from S1107 “Randomized Phase II Evaluation of Tivantinib and Tivantinib in Combination with Erlotinib in Patients with Papillary Renal Cell Carcinoma (pRCC)"

Date

10 Sep 2017

Session

Poster display session

Presenters

Przemyslaw Twardowski

Citation

Annals of Oncology (2017) 28 (suppl_5): v295-v329. 10.1093/annonc/mdx371

Authors

P. Twardowski1, X. Wu2, M. Plets3, C. Tangen3, E.R. Plimack4, N. Agarwal5, N.J. Vogelzang6, J. Wang2, S. Tao2, I. Thomson7, P. Lara8

Author affiliations

  • 1 Department Of Medical Oncology And Experimental Therapeutics, City of Hope, 91010 - Duarte/US
  • 2 Molecular And Cellular Biology, City of Hope, 91010 - Duarte/US
  • 3 Swog Statistical Center, Fred Hutchison Cancer Research Center, 98109 - Seattle/US
  • 4 Medical Oncology, Fox Chase Cancer Center, 19111-2497 - Philadelphia/US
  • 5 Medical Oncology, Huntsman Cancer Institute, 84112 - Salt Lake City/US
  • 6 Medical Oncology, US Oncology Research c/o Comprehensive Cancer Crts of NV, 89169 - Las Vegas/US
  • 7 Urology, University of Texas, San Antonio, 78229 - San Antonio/US
  • 8 Medical Oncology, University of California Davis Cancer Center, 95817 - Sacramento/US
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Resources

Abstract 2157

Background

pRCC is associated with activation of MET pathway, overexpression of EGFR and inferior responses to VEGF inhibition than clear cell RCC. In S1107 we randomized patients (pts) with advanced pRCC and 0-1 prior systemic therapy to MET inhibitor tivantinib at 360 mg BID (Arm 1) or tivantinib 360 mg BID plus EGFR inhibitor erlotinib at 150 mg daily (Arm 2). 66% of pts had no prior systemic therapy; 6% had type 1 pRCC, 42% had type 2, and 52% had no subtype assigned. The study was closed at interim analysis after 55 pts were enrolled and 0% RR was noted. Median PFS was 2.0 and 3.3 months, and OS was 10.3 and 11.3 months in Arms 1 and 2 respectively. These results were inferior to previously reported clinical trials with pRCC. To better understand these outcomes we performed whole exome sequencing of tumor samples collected from pts participating in this study.

Methods

Exome of 16 pts were successfully sequenced using Agilent SureSelect probes. The mean coverage of target regions ranged from 45x to 91x. Only reads aligned to unique genomic location were retained. The single point mutations and small indels were identified using GATK HaplotypeCaller. Copy number analysis was performed using Bioconductor package “DNACopy” and customized R scripts.

Results

Most of the mutations were unique to individual pts indicating high diversity of variants in this patient cohort. Only 1 MET mutation was ascertained affecting tyrosine kinase domain (K1198I). Other mutations associated primarily with type 2 pRCC included CDKN2A, PBRM1, SETD2, KDM6A, FAT1, NF2, CUL. No EGFR and FH mutations were detected. The most affected pathways included WNT, cadherin and mitotic G2-G2/M phase. Somatic copy number variation was challenging to obtain since no matching normal tissues were collected, but MET amplification was suspected in minority of cases.

Conclusions

S1107 patient cohort had a high proportion of pts with molecular subtypes not driven by MET abnormalities and would not be expected to respond well to MET inhibition. Although MET remains a reasonable therapeutic target in pRCC, careful selection of pts exhibiting MET alterations is required to better benefit from therapy with MET inhibitors.

Clinical trial identification

NCT01688973

Legal entity responsible for the study

Southwest Oncology Group

Funding

(NIH/NCI NCTN CA180888;CA180819;CA180820).

Disclosure

P. Twardowski: Consulting/Speakers Bureau: Sanofi Aventis, Medivation, Astellas, Dendreon, Roche, Janssen, Bayer, Pfizer. E. Plimack: Consulting/Scientific Advisory: AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Exelexis, Genentech, Horizon Pharma, Inovio, Novartis, Pfizer, Roche Grant/Trials: Acceleron, Agensys, AstraZeneca, Bristol-Myers Squibb, Merck, Peloton, Pfizer. All other authors have declared no conflicts of interest.

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