Dalantercept monotherapy fails in refractory, metastatic SCCHN
medwireNews: A phase II trial of single-agent dalantercept in patients with platinum-refractory, recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) has failed to meet its primary efficacy endpoint, a US research team reports.
Of 40 evaluable participants who received subcutaneous dalantercept at a dose of either 0.6 or 1.2 mg/kg every 3 weeks, only two patients given the higher dose achieved a partial response. This equated to an objective response rate (ORR) of 5%, which was lower than the anticipated ORR of interest of 30%.
Editorialists Nicole Chau and Robert Haddad, both from Dana-Farber Cancer Institute in Boston, Massachusetts, USA, say the findings are “quite disappointing but not surprising, because many other antiangiogenic therapies as single agents have also failed to demonstrate significant antitumor activity or clinical efficacy in heavily pretreated, unselected populations with [recurrent or metastatic SCCHN].”
They believe that “[a]ngiogenesis inhibitors are tired of going solo”, and add that “it is imperative to consider rational combination strategies of antiangiogenic agents combined with other systemic therapies or radiotherapy in SCCHN to move the field forward.”
Dalantercept is a soluble receptor fusion protein that blocks the activation of activin receptor-like kinase-1 (ALK1), which is known to be involved in vascular remodelling and tumour angiogenesis, explain the researchers. In preclinical and early clinical studies, dalantercept has shown promising antitumour activity, they write in Cancer.
The current trial included 46 SCCHN patients with incurable or platinum-refractory disease who had received a median of two previous therapies. The majority (78.3%) had SCCHN of the oropharynx or oral cavity.
Progression-free survival was a median of 1.4 months, while median overall survival was 7.1 months, with 22.7% of participants alive at 1 year.
Thirty-five percent of evaluable study participants attained stable disease following dalantercept treatment, of whom five remained stable for a minimum of 3 months.
The overall disease control rate was 40.0%, with rates of 44.4% for the 27 patients given the higher dose and 30.8% for the 13 given the lower dose, indicating “modest dose-dependent anticancer activity”, remark Antonio Jimeno (University of Colorado Denver School of Medicine, Aurora, USA) and fellow investigators.
Seven (15.2%) patients experienced treatment-related adverse events of grade 3 or worse, with hyponatremia the most common. Other frequent drug-related toxicities of any grade were anaemia, peripheral oedema, fatigue, headache and pleural effusion.
“It is noteworthy that the safety profile of dalantercept remains unique among the class of antiangiogenic agents, because the anti-VEGF [vascular endothelial growth factor]– based therapies are more commonly associated with bleeding and other dose-limiting adverse events, such as diarrhea, hypertension, proteinuria, and hand-foot syndrome”, the team comments.
Chau and Haddad agree that the “nonoverlapping toxicities of dalantercept could permit potential future combination with VEGF inhibitors.”
They also suggest combining angiogenesis inhibitors with immunotherapy. “Antiangiogenic agents have the potential to normalize abnormal tumor vasculature and reprogram the tumor immune microenvironment from an immunosuppressive profile toward a more immunosupportive profile, which may enhance the efficacy of anticancer immunotherapies”, the editorialists conclude.
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