ORLANDO – A combination of a multitarget tyrosine kinase inhibitor (TKI) with an experimental angiogenesis inhibitor showed “clinically meaningful” activity in the treatment of patients with advanced renal cell cancers.

Early results from a phase II study showed an overall response rate of 25% and median progression-free survival of 8.3 months with a combination of the TKI axitinib (Inlyta) and the investigational drug dalantercept, reported Dr. Martin H. Voss from the Memorial Sloan Kettering Cancer Center, New York.

Dalantercept is an angiogenesis inhibitor with a mechanism of action distinct from that of currently marketed TKIs that target vascular endothelial growth-factor receptors (VEGFR). Dalantercept works within the activin receptor-like kinase 1 (ALK1) pathway. This pathway is distinct from the anaplastic lymphoma kinase (a.k.a. “ALK”) pathway targeted by drugs such as crizotinib (Xalkori) and ceritinib (Zykadia).

ALK1 is selectively expressed on activated endothelial cells, and is activated by its ligands, bone morphogenetic proteins (BMP) 9 and 10. It promotes vascular maturation and stabilization. The processes with which ALK1 is involved occur later in angiogenesis than do the processes targeted by VEGF inhibitors.

Dalantercept “is designed as a soluble decoy receptor that has high affinity for BMP 9 and 10 and thus acts as an ALK1 ligand trap,” Dr. Voss explained at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

In preclinical studies, dalantercept was shown to inhibit the maturation of vascular cells and impair angiogenesis stimulated by both VEGF-A and basic fibroblast growth factor.

Modest single-agent activity

In a phase I study of dalantercept monotherapy in 37 patients with a variety of solid tumors that were refractory to standard therapies, there was modest activity of the drug with acceptable toxicities (primarily edema that was noncardiogenic and could be treated with diuretics).

Dr. Voss presented results of the first part of the phase II DART trial, a randomized, double-blind study of dalantercept and axitinib, compared with placebo and axitinib in patients with advanced renal cell cancers (RCC).

Patients with advanced RCC and at least one prior VEFGR-targeted TKI but no more than three prior lines of therapy were randomized to one of three open-label dose-escalation cohorts, consisting of axitinib 5 mg twice daily plus dalantercept in doses of either 0.6, 0.9. or 1.2 mg/kg subcutaneously every 3 weeks. There were also two dose escalation cohorts added later, one at the 0.9 mg/kg dalantercept level, and one at the 1.2 mg/kg dose. A total of 29 patients were enrolled in all cohorts.

Originally, nine patients were enrolled in the 1.2 mg/kg expansion cohort, but when these patients developed more fluid retention than was seen in the lower dose groups, the safety review team recommended expansion of the 0.9 mg/kg cohort, with an additional five patients. The patients appeared to tolerate this dose level well, and the 0.9 mg/kg dose was chose for part 2 of the study, results of which will be presented at a later date.

“Overall, the toxicity profile of the combination was in keeping with the single-agent experience of both of the medications,” Dr. Voss said.

Among the 28 patients available for an efficacy analysis, there were seven partial responses, 17 cases of stable disease, and four cases of progressive disease. The overall disease control rate after at least eight cycles of therapy (approximately 6 months) was 57.1% (16 patients); more than 20% of the population maintained disease control for 1 year, The median PFS, as noted before, was 8.3 months, with the upper limit of the 95% confidence interval not being reached yet.

“Along the same lines, I would say that the recommended phase II dose level has not reached its median progression-free survival in this analysis,” Dr. Voss noted.

Among the 17 patients with two or more prior lines of therapy, the response rate was 29%.

“Part 2 of the study is justified by these very encouraging results and is actively accruing patients.

The investigators plan to enroll 130 patients in the second phase, which will have a primary endpoint of PFS, with secondary endpoints of overall response rate, overall survival, safety, pharmacokinetics, and exploratory biomarkers for disease progression.

Dr. Ulka Vaishampayan, the invited discussant, commented that ALK1 “is an interesting and intriguing target, especially in combination with VEGF. This target does seem to be relevant in kidney cancer, at least in the preclinical testing that has been conducted.”

She noted that although the study has a small sample size, “preliminary results appear to be promising. The rationale is interesting and appears to be robust: of overcoming the mechanism of resistance to VEGF inhibition. However, so far we have no preselection based on target, and I worry will that be a problem moving forward, as the study moves into the randomized setting,”

She said that the investigators should attempt, even in retrospect, to identify a target for selecting patients who might benefit from the combination.

Dr. Vaishampayan is chair of genitourinary oncology at the Karmanos Cancer Institute at Wayne State University in Detroit.

Dual angiogenesis inhibition shows promise in advanced RCC