ASCO 2018: Evaluating the Efficacy and Safety of the Oral CXCR4 Inhibitor X4P-001 in Combination with Axitinib in Patients with Advanced Renal Cell Carcinoma
Dr. Vaishampayan and colleagues now present on the updated data on preliminary phase I dose escalation cohorts (n=10) as well as the phase II expansion cohorts (n=41) treated at the recommended phase II dosing. This was a heavily pre-treated population. Most patients had received at two or more lines of therapy (71%), including previous checkpoint inhibitor therapy (46%), TKI (91%), and nephrectomy (91%). Eight patients had to discontinue therapy due to adverse events such as hypertension, acute kidney injury, diarrhea, fatigue, hyperkalemia, retinal vein occlusion, and sepsis. At this time, only 22 patients were clinically evaluable. Of these 22 patients, the combination of X4P-001 and axitinib achieved an objective response rate of 31.8% (1 complete response and 6 partial responses) and a disease control rate of 86.4%.
The main treatment related adverse events were diarrhea, fatigue, hypertension, decreased appetite, dysphonia, and nausea. This is similar to the side effect profile reported to single agent axitinib in AXIS3. Grade 3 hypertension occurred in 9.8% of patients in this study, compared with 16% in AXIS. No other grade 3 adverse events occurred in more than 5% of patients in this study, which is lower than in AXIS, where diarrhea (11%), hypertension (16%), and fatigue (11%) were all reported >5% of the time4.
In prior studies melanoma patient biopsies, treatment with CXCR4 antagonists have been shown to increase both tumor inflammation signature scores and CD8:FoxP3 ratios5. Future studies could leverage this and combine CXCR4 inhibitors with checkpoint inhibitors to further improve clinical efficacy. During the poster discussion session, Dr. Laurence Albiges did not recommend that this combination move forward given the low post-IO response rate and high progressive disease rate of 19% and recommended that a PD-1 inhibitor backbone may be a better partner for the CXCR4 inhibitor.
At the end of her poster discussion talk, Dr. Albiges recommended that we focus on five pre-requisites that we should think about before we develop new combination therapies for mRCC (single agent activity known, rationale for combination, preclinical validation of rationale, which backbone to use, pharmacodynamic biomarker to be validated, biomarker based patient selection/enrichment) as well as four goals for new combinations (achieve major ORR and ultimately CR, be more active then available combinations, be active after CPI failure, and be compatible with doublets like ipi-nivo).
Presented By: Laurence Albiges, MD, PhD
Poster By: Ulka N. Vaishampayan, MD Karmanos Cancer Institute
Written by: Jason Zhu, MD Fellow, Division of Hematology and Oncology Duke University Medical Center, Twitter: @TheRealdJasonZhu at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA
References
1.Atkins M, Joseph R, Ho T, et al. Abstract B201: A phase 1 dose-finding study of X4P-001 (an oral CXCR4 inhibitor) and axitinib in patients with advanced renal cell carcinoma (RCC). Molecular Cancer Therapeutics 2018;17:B201-B.
2.Du Y, Long Q, Guan B, Mu L. Prognostic Value of High CXCR4 Expression in Renal Cell Carcinoma: A System Review and Meta-Analysis. Disease Markers 2015;2015:568980.
3.Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. The Lancet 2011;378:1931-9.
4.Ilie M, Hofman V, Dietel M, Soria J-C, Hofman P. Assessment of the PD-L1 status by immunohistochemistry: challenges and perspectives for therapeutic strategies in lung cancer patients. Virchows Archiv 2016;468:511-25.
5. http://www.x4pharma.com/wp-content/uploads/2017/11/MELA_SITC_Poster_Final.pdf