A NOVEL COMBINATION FOR RENAL CANCER

ORLANDO, Florida ― The results are early, but an investigational agent targeting a novel pathway has shown "encouraging" evidence of safety and activity in advanced renal cell carcinoma (RCC), say investigators.

Dalantercept, under development by Acceleron Pharma, is a novel antiangiogenic inhibitor of the activin receptor–like kinase 1 (ALK1) pathway and may complement the activity of vascular endothelial growth factor (VEGF) pathway inhibitors in RCC.

Preliminary data from part 1 of the DART study, which was presented here at Genitourinary Cancers Symposium (GUCS) 2015, showed that the combination of dalantercept and axitinib (Inlyta, Pfizer Inc), a VEGF tyrosine kinase inhibitor, was associated with clinically meaningful activity, including partial responses and prolonged disease control, in patients with advanced RCC, according to lead investigator Martin H. Voss, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, in New York City.

"The preliminary median progression-free survival of 8.3 months in all dose levels combined is encouraging," said Dr Voss.

Another key finding from this small phase 2 randomized trial (n = 29) was the objective response rate of 25.0% (7 partial responses of 28 patients), and stable disease was observed in 17 of 28 patients (60.7%). The disease control rate at 6 months was 57.1% (16 of 28 patients).

Novel Pathway

ALK1 is a type 1 receptor of the TGFβ superfamily that is selectively expressed on endothelial cells, explained Dr Voss. It binds to the ligand bone morphogenetic proteins 9 (BMP9) and 10 (BMP10), and ALK1/BMP9 signaling promotes vascular stabilization and maturation, which are downstream events from the proliferative stages of angiogenesis that are driven primarily by VEGF.

"Dalantercept is an ALK1 receptor–Fc fusion protein that binds with high affinity to BMP9 and BMP10 and thereby acts as a ligand trap," said Dr Voss. "It inhibits the maturation of vascular cells and impairs VEGF-A and basic fibroblast growth factor–stimulated angiogenesis both in vivo and in vitro."

Early Data Encouraging

In preclinical models, dalantercept showed potent antitumor activity that was accompanied by decreased tumor vascularity in a variety of types, including RCC.

A first-in-human phase 1 trial also evaluated dalantercept as monotherapy, in a cohort that included 37 patients with variety of solid tumors that were all refractory to standard therapies (Clin Cancer Res.2014;20:480).

Fluid overload and anemia were seen at dose levels ≥1.6 mg/kg. "There was noncardiogenic edema that was responsive to diuretics," explained Dr Voss. "And there were nonoverlapping toxicities with VEGF-targeted drugs."

There was also a partial response in 3% of patients, and 45% experienced stable disease.

On the basis of preclinical and phase 1 results, Dr Voss and his team moved ahead with the DART study. Preliminary findings from part 1, which assessed safety and tolerability of the combination in patients with advanced RCC who were treated with at least one prior VEGFR tyrosine kinase inhibitor but three or fewer prior lines of therapy, were presented at the meeting. The goal was to determine the recommended phase 2 dose level for part 2.

As of January 16, 2015, a total of 29 patients were enrolled; 15 patients were initially enrolled in three dose escalation arms (six at 0.6 mg/kg, four at 0.9 mg/kg, and five at 1.2 mg/kg). Additional patients were subsequently enrolled in expansion cohorts at 0.9 (n = 5) and 1.2 mg/kg (n = 9) to further characterize safety and pharmacokinetics.

Axitinib was added to the investigational drug at 5 mg twice a day for a 21-day cycle at all dose levels.

Table. Preliminary Responses to Dalantercept (Given in Combination With Axitinib)

Response	0.6 mg/kg (n = 6)	0.9 mg/kg (n = 9)	1.2 mg/kg (n = 13)	Overall (n = 28) n/%
Partial response	2	3	2	7 (25)
Stable disease	2	6	9	17 (60.7)
Progressive disease	2	0	2	4 (14.3)
Disease control rate ≥ 8 cycles (~6 months)	3	6	7	16 (57.1)
Median progression-free survival (months)	5.5	NR	6.9	8.3 (4.1, NR)
One patient was not evaluable.

Overall, the combination of dalantercept and axitinib were well tolerated with a generally nonoverlapping safety profile.

The most common treatment-emergent adverse events were fatigue, diarrhea, dysphonia, and peripheral edema. "The adverse event profile of both agents was consistent with single-agent experience," said Dr Voss. "There were also no grade 4/5 drug-related adverse events."

More edema events were observed at the 1.2-mg/kg dose level, as compared with the other two doses. On the basis of preliminary activity and safety data at the 0.9-mg/kg dose level, dalantercept 0.9 mg/kg was selected as the recommended phase 2 dose level for part 2 of this study.

"Part 2 of the DART study will randomize patients to dalantercept plus axitinib or placebo plus axitinib and is currently enrolling at approximately 50 centers in the US," concluded Dr Voss. The cohort will include 130 patients.

Preselection Needed

In a discussion of the paper, Ulka N. Vaishampayan, MD, from the Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, noted that ALK1 is a novel target in kidney cancer, and this presentation was both interesting and intriguing.

"This target does seem to be relevant in kidney cancer, at least in preclinical testing," she said. "The current study does have a small sample size, but the preliminary results are promising."

But although the results are robust, Dr Vaishampayan cautions that thus far, there is "no preselection based on target, and I worry if that will be a problem moving forward, as this study moves into the randomized setting."

"That will be something that can hamper positive results," she said. "Attempts should be made to identify patients ― even retrospectively — to identify a target to select patients."

The study was sponsored by Acceleron Pharma. Dr Henner reports relationships with Bayer, Novartis, BMS, and Pfizer. Several coauthors also report relationships with industry, including Acceleronas, noted in the abstract.

2015 Genitourinary Cancers Symposium (GUCS) 2015. Abstract 407. Presented February 28, 2015.