Angiogenesis-Targeted Combination Active in Advanced RCC

Treatment with 2 angiogenesis-targeting drugs led to objective responses in a fourth of patients with advanced renal cell carcinoma (RCC), results of a dose-finding study showed.

Martin H. Voss, MD

Treatment with 2 angiogenesis-targeting drugs led to objective responses in a fourth of patients with advanced renal cell carcinoma (RCC), results of a dose-finding study showed.

Seven of 28 evaluable patients responded to the combination of dalantercept and axitinib, and 17 patients had stable disease. The median progression-free survival across 3 dose-defined dalantercept groups was 8.3 months.

Responses and disease stability occurred across all 3 dalantercept dose groups, as reported at the Genitourinary Cancers Symposium in Orlando, Florida.

“Dalantercept plus axitinib is well tolerated in pretreated, advanced renal cell carcinoma patients,” reported Martin H. Voss, MD, an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York City. “Dalantercept plus axitinib is associated with clinically meaningful activity.”

The first part of the trial evaluated dalantercept doses of 0.6, 0.9, and 1.2 mg/kg, and the middle dose was selected to carry forward in continued investigation of dalantercept, Voss added.

Dalantercept is the first of a new class of angiogenesis inhibitors that target activin receptor-like kinase 1 (ALK1), a receptor of the transforming growth factor-beta family that is selectively expressed on activated endothelial cells. ALK1 promotes vascular maturation and stabilization, steps in angiogenesis that occur later than those regulated by vascular endothelial growth factor (VEGF), Voss said.

Dalantercept is an ALK1 receptor-Fc fusion protein that binds to BMP9 and BMP10 metalloproteinases to inhibit maturation of vascular cells. In vitro and in vivo studies showed that dalantercept impairs angiogenesis stimulated by VEGF-A and basic fibroblast growth factor. Dalantercept demonstrated antitumor activity associated with decreased tumor vascularity in a variety of preclinical tumor models, including RCC.

In a phase I clinical study, dalantercept demonstrated single-agent activity in 37 patients with various solid tumors that had proven refractory to standard therapies. At doses of 1.6 mg/kg and higher, principal toxicities were noncardiogenic edema and anemia, the former of which responded to treatment with diuretics. Moreover, the study showed no overlapping toxicity with those associated with VEGF therapy, such as hypertension, proteinuria, hand-foot syndrome, and thromboembolic events (Clin Cancer Res. 2014;20:480-489).

The accumulation of evidence provided a rationale to evaluate dalantercept in combination with a VEGF inhibitor.

“Concurrent inhibition of angiogenesis in its different stages may increase the antitumor effect,” said Voss. “Based on in vivo data, dalantercept may enhance and prolong the activity of agents that target the VEGF pathway in advanced RCC.”

Moreover, concurrent treatment with dalantercept and a VEGF inhibitor led to enhanced efficacy in RCC xenograft models, he said.

Investigators designed a 2-part, phase II trial to evaluate the dalantercept-axitinib combination in patients with advanced RCC. In the first part of the trial, 19 patients were enrolled to 3 dalantercept dose groups and also received axitinib 5 mg twice a day. An additional 14 patients were enrolled at the 2 highest dalantercept doses in an expansion clinical evaluation of the combination.

Eligible patients had predominantly clear-cell histology, had progressed on at least 1 prior VEGF receptor tyrosine kinase inhibitor (including adjuvant therapy), had received no more than 3 prior lines of therapy, and had Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Patients with treated, stable, central nervous system disease were eligible.

The safety data showed no grade 4/5 drug-related adverse events (AEs). Patients treated with the 1.2-mg/kg dose in the expansion cohort had more edema when compared with patients treated at the 2 lower doses, contributing to the decision to select the 0.9-mg/kg dose for further evaluation.

The most common AEs with the 0.9-mg/kg dose were fatigue and diarrhea (6 of 9 patients). Grade 3 treatment-related toxicity at that dose consisted of a single case of diarrhea. No grade 3 laboratory AEs occurred in patients who received 0.9 mg/kg of dalantercept. All grades considered, 1 patient each developed anemia and increased creatinine, and 2 patients developed thrombocytopenia.

Activity data showed partial responses in 2 of 6 patients who received 0.6 mg/kg of dalantercept, 3 of 9 who received the 0.9 mg/kg dose, and 2 of 13 who received 1.2 mg/kg. Stable disease was observed in 2, 6, and 9 patients treated with 0.6, 0.9, and 1.2 mg/kg of dalantercept, respectively.