Barcelona, Spain (UroToday.com) Antiangiogenetic therapy has long been a hallmark of the treatment paradigm for metastatic renal cell carcinoma. Endoglin is an endothelial cell surface receptor that is required for angiogenesis and is highly expressed on intertumoral endothelial cells.1 TRC105 is an IgG1 class monoclonal antibody to endoglin. In preclinical models, TRC105 was capable of potentiating anti-VEGF therapy. A recently completed phase Ib trial combining TRC105 with axitinib demonstrated a promising 29% objective response rate,2 and provided the clinical rationale for the present study.
Dr. Toni Choueiri presented the results of a randomized phase II study of axitinib with or without the endoglin antibody TRC105. Eligible patients had advanced or metastatic clear cell renal cell carcinoma and had progressed on at least one prior line of anti-VEGF therapy. A total of 150 patients were randomized 1:1 to receive axitinib (5 mg twice daily) with or without TRC105 (10 mg/kg weekly). The primary endpoint was progression-free survival.
Patients were evenly distributed, with 75 in each arm. They were well-balanced with respect to age (approximately 65 in both arms), though the combination arm had a slightly lower male predominance (65.3%) compared to the axitinib monotherapy arm (76.0%). Most patients – approximately 60% in both arms – received just one prior line of systemic therapy, and the arms were otherwise well-balanced.
At last follow-up, all patients had discontinued treatment in both arms, most commonly for progression of disease although a slightly higher proportion of patients in the combination arm (19.2% versus 13.2%) discontinued due to an adverse event.
Unfortunately, the combination of TRC105 and axitinib did not achieve a statistically significant improvement in progression-free survival compared to axitinib alone as assessed by independent review. In fact, the calculated hazard ratio favored the axitinib monotherapy arm (HR 1.42, p = 0.15), though no statistically significant difference was observed.
Subgroup analyses failed to identify any group that derived benefit from the combination.
Furthermore, while the combination was generally well-tolerated, TRC105 plus axitinib was associated with a higher rate of all-grade adverse events, most notably headache, epistaxis, and gingival bleeding. The most common grade ≥3 adverse event in the combination arm was anemia (15.1%).
In summary, despite promising phase I data and strong biologic rationale, the endoglin antibody TRC105 did not achieve an improvement in progression-free survival when combined with axitinib for the treatment of metastatic renal cell carcinoma after progression on prior VEGF directed therapy. There was a trend toward harm with combination TRC105 plus axitinib, however, this difference was not statistically significant. Given the failure of TRC105 in a previous trial in combination with the VEGF antibody bevacizumab,3 future work attempting to combine anti-endoglin therapy with other antiangiogenic agents should seek to more fully characterize the underlying biologic processes that may be contributing to these clinical trial outcomes.
Presented by: Toni K. Choueiri, MD, Jerome and Nancy Kohlberg Professor of Medicine, Harvard Medical School, Attending Physician, Solid Tumor Oncology, Dana-Farber Cancer Institute, Director, Genitourinary (GU) Oncology Disease, Center, Dana-Farber Cancer Institute, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA
Written by: Michael Lattanzi, MD, Medical Oncology Fellow, Memorial Sloan Kettering Cancer Center, Twitter: @MikeLattanzi at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept – 1 Oct 2019 in Barcelona, Spain
1. K Seon B, Haba A, Matsuno F, Takahashi N, Tsujie M, She X, Harada N, Uneda S, Tsujie T, Toi H, Tsai H. Endoglin-targeted cancer therapy. Current drug delivery. 2011 Jan 1;8(1):135-43.
2. Choueiri TK, Michaelson MD, Posadas EM, Sonpavde GP, McDermott DF, Nixon AB, Liu Y, Yuan Z, Seon BK, Walsh M, Jivani MA. An Open Label Phase Ib Dose Escalation Study of TRC105 (Anti‐Endoglin Antibody) with Axitinib in Patients with Metastatic Renal Cell Carcinoma. The oncologist. 2019 Feb 1;24(2):202-10.
3. Dorff TB, Longmate JA, Pal SK, Stadler WM, Fishman MN, Vaishampayan UN, Rao A, Pinksi JK, Hu JS, Quinn DI, Lara Jr PN. Bevacizumab alone or in combination with TRC105 for patients with refractory metastatic renal cell cancer. Cancer. 2017 Dec 1;123(23):4566-73.