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TPS11628 Background: Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR). Metformin has shown anti-cancer activity through its cellular (e.g., AMPK activation) and systemic effects (e.g., inhibition of IGF-1). We conducted a pilot study to test the hypothesis that metformin may potentiate mTOR inhibition by sirolimus. Methods: An open-label, randomized study was conducted in which eligible patients with advanced solid tumors were started on sirolimus (3mg daily) alone for the first 7 days. On day 8, patients were randomized to either receive metformin XL (500 mg daily) plus sirolimus (Arm A) or sirolimus alone (Arm B) for until day 21. From day 22 onwards, all patients recieved metformin XL plus sirolimus. The pharmacodynamic (PD) biomarkers were collected at baseline, day 8 and day 22 of cycle 1. The primary endpoint was to compare the change in PD biomarker phospho-p70S6K, using a two-sample t test (log ratio D22/D8 in arm A vs. arm B). The phospho-p70S6K was measured in peripheral blood T cells using Western blot. The secondary endpoints were to assess objective response rate (RECIST 1.1), toxicity (CTCAE V4.0) and changes in the serum levels of PD biomarkers: fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, leptin and adiponectin using two-sample t tests. Results: 24 patients were enrolled, at which time an interim futility analysis was conducted. 18 patients were evaluable for the primary endpoint (8 in arm A; 10 in arm B). The mean log ratios D22/D8 in phospho-p70S6K in arms A and B were -0.12 (SD = 0.13) and -0.16 (SD = 0.29), respectively (P = 0.64). Of the 17 pts evaluable for response, the best response was stable disease in 9 patients and progressive disease in 8 patients. There were no dose-limiting or unexpected toxicities. Of the 21 patients evaluable for serum PD biomarkers, there were no significant differences between arms A and B in fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-BP1, IGF-BP3, leptin and adiponectin (P > 0.05 for all). Conclusions: The addition of metformin to sirolimus, although well-tolerated, was not associated with significant changes in phospho-p70S6k and other PD biomarkers. Based on the results of the interim analysis, the trial was terminated. Clinical trial information: NCT02145559.

Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy. Significance: We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profiling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1); 37–48. ©2017 AACR. See related commentary by Sundar and Tan, p. 14. See related article by Janjigian et al., p. 49. This article is highlighted in the In This Issue feature, p. 1