1. Goodwin, Peter M.

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COPENHAGEN, Denmark-In a phase Ib study, patients with previously untreated stage 4 pancreatic cancer responded or derived "clinical benefit" from a regimen in which a Wnt signaling inhibitor-the humanized monoclonal antibody vantictumab-was added to nab-paclitaxel and gemcitabine chemotherapy. Colin Weekes, MD, PhD, Associate Professor at the University of Colorado in Denver, reported findings at the European Society for Medical Oncology (ESMO) 2016 Congress.

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"We see early signs of benefit for patients-the length of time the patients are on the study as well as some responses. We have initial early data looking at survival, which seems to also demonstrate that this is an active regimen," said Weekes speaking to Oncology Times at a poster session at ESMO.


"The preliminary results show that this is an active combination, and the biomarker profiles suggest that hopefully we could be looking in the future at a stratified therapy for pancreas cancer," said Debashis Sarker, MD, FRCP, Senior Lecturer and Consultant in Medical Oncology, at Guy's, St Thomas' and King's College Hospitals, London, who was not involved with the study.


Manageable Toxicity

Twenty-four patients were treated with the new combination in the trial with the primary endpoint of investigating tolerability. No grade 4 or 5 vantictumab-related adverse events were observed, the drug did not enhance chemotherapy-related toxicities, it had a "low rate of immunogenicity," and the overall regimen toxicity was described as "manageable."


Weekes said the drug had been relatively safe. "Initially, there was evidence of bone toxicity. But we then applied a bone safety program and, since doing that, we've not seen any additional bone toxicity." Most of the reported toxicity was typical of the standard chemotherapy the patients were receiving, he said. "So it really is pretty well-tolerated."


Stem Cells

Because vantictumab influences stem cell signaling, it was expected to reduce tumor resistance to chemotherapy. The study found that 10 out of 21 evaluable patients responded to the combination and all but two of the remaining patients were also assessed as having derived "clinical benefit." The overall anti-tumor effect was described as "encouraging," and an interim biomarker analysis of baseline tumors suggested a significant association between overall response and a three-gene predictive biomarker (TGFB3, IGF2, SMO).


Two Mechanisms

Weekes said the main aim of the study had been to establish whether adding Wnt pathway inhibition to standard chemotherapy could ultimately improve the outcome for patients by using two agents targeting two different mechanisms simultaneously-Wnt pathway inhibition to mediate stem cells and chemotherapy directed at somatic cells.


"We're trying to target two populations in the tumor to improve outcomes," he said, adding that, in a patient-derived xenograft model, vantictumab had already been shown to augment the efficacy of chemotherapy.


"We see early signs of benefit for patients that consist of the length of time the patients are on study as well as responses. We have some initial early data looking at survival that seems to also demonstrate that this is an active regimen. And a biomarker analysis showed that a three-gene profile does predict for those patients who respond versus those who do not," he said.


The hope was that research could now move forward to phase II studies and beyond to demonstrate evidence of efficacy and show that the biomarker could be helpful in planning regimens. "Maybe we can stratify patients who are going to respond versus not respond," Weekes noted, adding that biomarker stratification could then be included in any future phase III trial.


He said that, because the study had been in the first-line setting, it had opened up the possibility of looking at this dual approach to pancreatic cancer treatment for earlier stages of the disease. "One could also think that if this all works out it could be used in patients who have resectable disease," he said. And he suggested that if stem cells are responsible for recurrence this could impact metastasis. "If we are truly inhibiting stem cell function, it may be that it makes sense to use this type of compound in the adjuvant or even neoadjuvant setting."


After the ESMO Congress, Sarker commented that Wnt signaling was important in pancreatic cancer because it was regarded as one of the key signaling pathways. "We think it has a particular role with regard to pancreatic cancer stem cells," he said, adding that resistance to systemic chemotherapy for advanced pancreatic cancer potentially implicates Wnt signaling. "So if we can inhibit Wnt signaling, we might be able to alleviate some of the resistance that occurs with standard chemotherapy for pancreas cancer."


Sarker noted that the vantictumab trial was one of a whole range of combination studies currently being explored in pancreas cancer using gemcitabine plus nab-paclitaxel as the chemotherapy backbone.


"It does look as though this is a tolerable combination," he said, acknowledging that the early bone toxicity had apparently been managed successfully and other toxicities seemed to be associated with the chemotherapy rather than Wnt signaling inhibition.


Predictive Biomarker

Sarker added that the biomarker analysis was very interesting. "In pancreas cancer, we have no predictive biomarkers that enable us to choose a particular systemic therapy for a patient. This particular study incorporates the use of a three-gene biomarker which has been previously validated in the xenograft model and seems to suggest that patients who have particularly high levels of this biomarker profile potentially will benefit from the treatment," he said. "So, hopefully this can be validated in subsequent phase II and phase III trials that leads us to being able to identify subsets of populations that will particularly benefit from this and ultimately lead to a true stratified therapy for pancreas cancer."


Peter M. Goodwin is a contributing writer.