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Phase II trial of everolimus in patients with refractory metastatic adenocarcinoma of the esophagus, gastroesophageal junction and stomach: possible role for predictive biomarkers

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Abstract

Purpose

Our study was designed to evaluate the efficacy and safety of everolimus in patients with pre-treated metastatic gastric and esophagus cancers in a US-based population focusing on biomarker correlation.

Methods

Patients with advanced upper GI adenocarcinomas who progressed after 1–2 prior regimens received everolimus 10 mg PO daily. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression-free survival (PFS), toxicity, overall survival (OS) and biomarker correlatives of the mTOR pathway. Target accrual was 50 patients based on one-sided type I error of 10 % and power of 90 %.

Results

Forty-five patients were evaluable, 21 gastric, 11 esophagus and 13 from the GEJ. The median age was 64 (range 38–73); all patients had an ECOG of 0 or 1; and 18 patients (40 %) had only 1 prior regimen. The most common grade 3–4 adverse events included fatigue (24 %) and thrombocytopenia (22 %). We observed 1 partial response with 39 % of evaluable patients having stable disease. Median OS was 3.4 months (95 % CI 2.7–5.6 months), and PFS was 1.8 months (95 % CI 1.7–2.2 months). There was a strong correlation between ≥2 + IHC staining for p-S6 in tumor samples with better PFS (p < 0.0001) and DCR (p = 0.0001).

Conclusions

Our clinical outcomes were inferior to the Asian studies, which may be explained by disease heterogeneity. However, there was a similar strong correlation between clinical benefit and tumor high pS6. Testing this biomarker in patient samples from the randomized phase III Granite trial may lead to a positive predictive marker.

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Acknowledgments

We gratefully acknowledge Jacqueline Rogerio and Laura Lalloway of Novartis. Paul Choppa and Raaj Trivedi of Clarient for help with valuable technical assistance. We gratefully acknowledge the Dimitri family of Chatsworth, California for their generous support. This work was partially supported by Novartis pharmaceuticals.

Conflict of interest

The authors have no relevant disclosures.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, USA

    Zev A. Wainberg, Heloisa P. Soares, Lisa Yonemoto, Diego Martinez, Isett Laux, Meghan Brennan & J. Randolph Hecht

  2. Translational Research In Oncology - US (TRIO-US), Los Angeles, CA, USA

    Zev A. Wainberg, Ravi Patel, Brian DiCarlo, David J. Park, Andre Liem, Lisa Yonemoto, Diego Martinez, Isett Laux, Meghan Brennan & J. Randolph Hecht

  3. Comprehensive Blood and Cancer Center, Bakersfield, CA, USA

    Ravi Patel

  4. Coastal Integrative Cancer Center, San Luis Obispo, CA, USA

    Brian DiCarlo

  5. St. Jude Crosson Cancer Institute, Fullerton, CA, USA

    David J. Park

  6. Pacific Shores Medical Group, Long Beach, CA, USA

    Andre Liem

  7. Department of Biomathematics, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, USA

    He-jing Wang

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  1. Zev A. Wainberg
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Correspondence to Zev A. Wainberg.

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Wainberg, Z.A., Soares, H.P., Patel, R. et al. Phase II trial of everolimus in patients with refractory metastatic adenocarcinoma of the esophagus, gastroesophageal junction and stomach: possible role for predictive biomarkers. Cancer Chemother Pharmacol 76, 61–67 (2015). https://doi.org/10.1007/s00280-015-2744-5

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