Abstract
Background
In metastatic colorectal cancer (mCRC), regorafenib (RGF), a multi-kinase inhibitor with angiogenic inhibition has modest effects on survival. We reported that autophagy modulation using hydroxychloroquine (HCQ), enhances the anticancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in mCRC, is well tolerated, and has comparable activity to RGF. Thus, we conducted a prospective study of VOR/HCQ versus RGF in mCRC.
Methods
This is a randomised, controlled trial of VOR 400 mg and HCQ 600 mg orally daily versus RGF 160 mg orally daily (3 weeks on/1 week off), every 4 weeks, in patients with mCRC. Primary endpoint: median progression-free survival (mPFS). Secondary endpoints: median overall survival (mOS); adverse events; pharmacodynamic analyses.
Results
From 2/2015-10/2017, 42 patients were randomised to VOR/HCQ and RGF. Median age was 58.4 years. mPFS on VOR/HCQ was 1.9 months versus 4.35 months with RGF (P = 0.032). There was no difference in mOS (P = 0.9). Treatment was tolerated in both arms. In both arms, there was improved anti-tumour immunity.
Conclusions
VOR/HCQ had an inferior PFS when compared to RGF, although there was an increase in anti-tumour immunity in mCRC. VOR/HCQ has a favourable safety profile, and immune or tumour biomarkers may be used to identify clinical benefit of autophagy modulation in mCRC.
Clinical trial registration
NCT02316340.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 24 print issues and online access
$259.00 per year
only $10.79 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The datasets generated and/or analysed during this study are available from the corresponding author on reasonable request
References
Package Insert: STIVARGA (regorafenib) tablets, oral [Internet]. Wayne, New Jersey: Bayer HealthCare Pharmaceuticals 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203085lbl.pdf.
Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303–12.
Patel SR, Karnad AB, Ketchum NS, Pollock BH, Sarantopoulos J, Weitman S, et al. Should we move beyond VEGF inhibition in metastatic colorectal cancer? Lessons from early phase clinical trials. J Gastrointest Oncol. 2014;5:99–103.
Carew JS, Nawrocki ST, Cleveland JL. Modulating autophagy for therapeutic benefit. Autophagy. 2007;3:464–7.
Carew JS, Nawrocki ST, Kahue CN, Zhang H, Yang C, Chung L, et al. Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. Blood. 2007;110:313–22.
Carew JS, Medina EC, Esquivel JA 2nd, Mahalingam D, Swords R, Kelly K, et al. Autophagy inhibition enhances vorinostat-induced apoptosis via ubiquitinated protein accumulation. J Cell Mol Med. 2010;14:2448–59.
Mahalingam D, Mita M, Sarantopoulos J, Wood L, Amaravadi R, Davis LE, et al. Combined autophagy and HDAC inhibition: A phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy. 2014;10:1403–14.
Patel S, Hurez V, Nawrocki ST, Goros M, Michalek J, Sarantopoulos J, et al. Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer. Oncotarget. 2016;7:59087–97.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.
Riechelmann RP, Leite LS, Bariani GM, Glasberg J, Rivelli TG, da Fonseca LG, et al. Regorafenib in patients with antiangiogenic-naive and chemotherapy-refractory advanced colorectal cancer: results from a phase IIb trial. Oncologist. 2019;24:1180–7.
Petrioli R, Chirra M, Messuti L, Fiaschi AI, Savelli V, Martellucci I, et al. Efficacy and safety of regorafenib with 2/1 schedule for patients >/= 75 years with metastatic colorectal cancer (mCRC) after failure of 2 lines of chemotherapy. Clin Colorectal Cancer. 2018;17:307–12.
Bekaii-Saab TS, Ou FS, Ahn DH, Boland PM, Ciombor KK, Heying EN, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20:1070–82.
Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16:619–29.
Van Cutsem E, Martinelli E, Cascinu S, Sobrero A, Banzi M, Seitz JF, et al. Regorafenib for patients with metastatic colorectal cancer who progressed after standard therapy: results of the large, single-arm, open-label phase IIIb CONSIGN study. Oncologist. 2019;24:185–92.
Schulz H, Janssen J, Strauss UP, Langen M, Frey M, Fiala-Buskies S, et al. Clinical efficacy and safety of regorafenib (REG) in the treatment of metastatic colorectal cancer (mCRC) in daily practice in Germany: interim results of the prospective multicentre noninterventional RECORA study. J Clin Oncol. 2017;35(4_suppl):769.
Ferrara N, Adamis AP. Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov. 2016;15:385–403.
Lucas JL, Mirshahpanah P, Haas-Stapleton E, Asadullah K, Zollner TM, Numerof RP. Induction of Foxp3+ regulatory T cells with histone deacetylase inhibitors. Cell Immunol. 2009;257:97–104.
Akimova T, Ge G, Golovina T, Mikheeva T, Wang L, Riley JL, et al. Histone/protein deacetylase inhibitors increase suppressive functions of human FOXP3+ Tregs. Clin Immunol. 2010;136:348–63.
Schmudde M, Friebe E, Sonnemann J, Beck JF, Broker BM. Histone deacetylase inhibitors prevent activation of tumour-reactive NK cells and T cells but do not interfere with their cytolytic effector functions. Cancer Lett. 2010;295:173–81.
Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Ruttinger D. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer. 2017;5:53.
Abou-Elkacem L, Arns S, Brix G, Gremse F, Zopf D, Kiessling F, et al. Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model. Mol Cancer Ther. 2013;12:1322–31.
Fukuoka S, Hara H, Takahashi N, Kojima T, Kawazoe A, Asayama M, et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (REGONIVO, EPOC1603). J Clin Oncol. 2020;38:2053–61.
Barzi A, Azad NS, Yang Y, Tsao-Wei D, Rehman R, Fakih M, et al. Phase I/II study of regorafenib (rego) and pembrolizumab (pembro) in refractory microsatellite stable colorectal cancer (MSSCRC). J Clin Oncol. 2022;40(4_suppl):15.
Melnyk N, Xie X, Koh DJY, Rajpal M, Moss RA, Gibbon D, et al. CTEP #8342 autophagy modulation with antiangiogenic therapy: a phase I trial of sunitinib (Su) and hydroxychloroquine (HCQ). J Clin Oncol. 2013;31(15_suppl):2553.
Weng Z, Luo Y, Yang X, Greenhaw JJ, Li H, Xie L, et al. Regorafenib impairs mitochondrial functions, activates AMP-activated protein kinase, induces autophagy, and causes rat hepatocyte necrosis. Toxicology. 2015;327:10–21.
Fondevila F, Méndez-Blanco C, Fernández-Palanca P, González-Gallego J, Mauriz JL. Anti-tumoral activity of single and combined regorafenib treatments in preclinical models of liver and gastrointestinal cancers. Exp Mol Med. 2019;51:1–15.
Shimizu S, Takehara T, Hikita H, Kodama T, Tsunematsu H, Miyagi T, et al. Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma. Int J Cancer J Int du Cancer. 2012;131:548–57.
Shi YH, Ding ZB, Zhou J, Hui B, Shi GM, Ke AW, et al. Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis. Autophagy. 2011;7:1159–72.
Arora SP, Moseley JL, Tenner LL, Arellano L, Salazar M, Liu Q, et al. Phase II study of modulation of sorafenib (SOR)-induced autophagy using hydroxychloroquine (HCQ) in advanced hepatocellular cancer (HCC): planned interim efficacy and safety analysis. J Clin Oncol. 2021;39(3_suppl):305.
Brown TJ, Karasic TB, Schneider CJ, Teitelbaum UR, Reiss KA, Mitchell TC, et al. Phase I trial of regorafenib, hydroxychloroquine, and entinostat in metastatic colorectal cancer. J Clin Oncol. 2021;39(15_suppl):e15580-e.
Roberts J, Smylie M, Walker J, Basappa NS, Chu Q, Kolinsky M, et al. Hydroxychloroquine is a safe and effective steroid-sparing agent for immune checkpoint inhibitor-induced inflammatory arthritis. Clin Rheumatol. 2019;38:1513–9.
O’Hara MH, Karasic TB, Vasilevskaya I, Redlinger M, Loaiza-Bonilla A, Teitelbaum UR, et al. Phase II trial of the autophagy inhibitor hydroxychloroquine with FOLFOX and bevacizumab in front line treatment of metastatic colorectal cancer. J Clin Oncol. 2017;35(15_suppl):3545.
Acknowledgements
We would like to thank Merck for providing vorinostat for the study. We would like to thank the study coordinators, Leslie Wood RN and Lisa Longoria. Preliminary results were presented at ASCO 2019 conference, Chicago, IL (poster).
Funding
All authors: Cancer Prevention Research Institute of Texas (CPRIT RP140685) funded this clinical trial. We thank Merck for providing the vorinostat for the study. SPA: NIH CA054174, NIA AG044271.
Author information
Authors and Affiliations
Contributions
All authors conceived and/or designed the work that led to the submission, acquired data and/or played an important role in interpreting the results, drafted or revised the manuscript, approved the final version, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Ethics approval and consent to participate
All patients provided written informed consent before enrollment. This study followed the ethical principles of the Declaration of Helsinki, the International Conference on Harmonization Guidelines for Good Clinical Practice, and local regulations (European Directive 2001/20/EC and US Code of Federal Regulations Title 21). The Institutional Review Board at the University of Texas Health San Antonio approved the original protocol and all subsequent amendments.
Consent to publish
Not applicable.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Arora, S.P., Tenner, L., Sarantopoulos, J. et al. Modulation of autophagy: a Phase II study of vorinostat plus hydroxychloroquine versus regorafenib in chemotherapy-refractory metastatic colorectal cancer (mCRC). Br J Cancer 127, 1153–1161 (2022). https://doi.org/10.1038/s41416-022-01892-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41416-022-01892-6