In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5012-5012
Abstract:
Background: To investigate clinical activity, safety and biomarkers of a pan-PI3K inhibitor BKM120 in R/M-SCCHN and identify optimal combinational strategies by conducting mouse co-clinical trials mirroring the ongoing clinical study. Methods: Patients with R/M-SCCHN were eligible if they had progressed on platinum-based chemotherapy, and were treated with BKM120 100mg/day. The primary endpoint was disease control rate (DCR) at 8 weeks. Secondary endpoints included response rate (RR), progression-free survival rate (PFS), overall survival (OS) and safety. Patient-derived xenografts (PDXs) with genomic annotations were established directly from patients for evaluation of novel drug combinations and biomarkers. Based on the integrated clinical and preclinical data, study protocol had been revised to combine BKM120 and erbitux to explore whether erbitux increases the efficacy of BKM120 in R/M-SCCHN. Results: A total of 52 patients were enrolled. Patient characteristics included median age (55 years; range, 31-82); male (84.6%); ECOG performance status 0/1/2 (13.5%/73%/13.5%); locoregional/metastatic/both (30.8%/30.8%/38.4%); oral cavity/oropharynx/larynx primary (36.5%/30.8%/13.5%); prior chemotherapy regimens 1/≥2 (40%/60%). Seven patients were not evaluable due to rapid progression or withdrawal. DCR at 8 weeks was 60% (27/45) and RR was 2.2% (1/45) in BKM120 monotherapy. Median PFS and OS were 8.0 (95% CI, 5.3-9.5) and 30.7 weeks (95% CI, 11.8-26.6). After protocol revision, 11 patients were treated with BKM120 and erbitux after progression to BKM120. In combination phase, PR was observed in 18.1% (2/11) and SD was 45.5% (5/11) in patients who failed to BKM120. Toxicities were not increased in combination phase. In seven established PDXs, we tested BKM120 alone or in combination with erbitux. All PDXs showed strong resistance to single-agent BKM120, whereas three PDXs (3/7, 42.8%) demonstrated strong synergistic inhibition of tumor growth to combined BKM120 and erbitux, compared with single agent (vs. BKM120, P & lt;0.01; vs. Erbitux, P & lt;0.01), which resembled the responses of corresponding patients. We found several genetic alterations in F2 tumors including EGFR fusion, HRAS mutation (G12D), MYC amplification, KRAS mutation (G13D), and EGFR amplification. Interestingly, two PDXs with RAS mutations demonstrated synergistic effect of BKM120 and erbitux. Conclusions: Combining BKM120 and Erbitux would be effective treatment strategies with manageable toxicity in R/M-SCCHN based on strong rationale of co-clinical trial with PDXs (NCT01527877). Citation Format: Han Na Kang, Mi Ran Yun, Kyoung Ho Pyo, Myung-Ju Ahn, Jong-Mu Sun, Sun Min Lim, Soonmyung Paik, Byoung Chul Cho, Hye Ryun Kim. Mouse-human co-clinical trials demonstrate superior efficacy with combinational approach of BKM120 and erbitux over BKM120 monotherapy in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M-SCCHN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5012. doi:10.1158/1538-7445.AM2017-5012
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2017-5012
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2017
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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