Results of a phase 3 study of an investigational monoclonal antibody, MABp1 (Xilonix; XBiotech), evaluated for cachexia in metastatic colorectal cancer (CRC), revealed a surprising finding: patients in the experimental arm showed a trend toward increased overall survival (an end point difficult to reach in any treatment-refractory cancer), with pharmacodynamics activity consistent with this result, investigators reported at the 2015 Gastrointestinal Cancers Symposium, held in San Francisco, California.
“Interim survival and quality of life, analyzed at the conclusion of enrollment, showed a 39% shorter median overall survival (2.0 vs 2.8 months) for patients receiving megestrol acetate versus Xilonix and a trend in increased risk of death (hazard ratio, 2.17; P=.17),” noted George A. Fisher, MD, Stanford University School of Medicine, California, the author of the study.
The objective of the open-label, multicenter, phase 3 randomized trial was to evaluate the efficacy and safety of MABp1 in CRC complicated with cachexia.
According to an interview with Michael Stecher, MD, medical director at XBiotech, MABp1 is the first drug of its kind—a true human monoclonal antibody that targets interleukin-1αα (IL-1α).
“A true human antibody is different than a fully human antibody,” explained Stecher, “in that it’s cloned directly from a human B cell; it hasn’t been developed in a mouse…. To our knowledge there are no other antibodies in the clinic that have been cloned directly from a human.”
Patients with metastatic CRC who were eligible for this trial had failed 1 cytotoxic line of therapy (either oxaliplatin or irinotecan) and lost greater than 5% of total body weight in the previous 6 months.
“With a cachectic population,” explained Stecher, “we didn’t want to randomize the placebo, so we randomized megestrol. Thus, the trial was Xilonix the antibody (3.75 mg/kg intravenously every 2 weeks) versus megestrol (oral 800 mg daily)—1:1 randomization with a primary end point of overall survival.”
In patients treated with MABp1, physical and role function did not decline during therapy; however, these functions worsened in those patients receiving megestrol (median change, –13.3 and –16.7, respectively; P=.02 vs MABp1). Furthermore, MABp1 patients had a treatment-related reduction in platelet counts compared with those in the megestrol group (median reduction, –60,000/mm3 vs 10,000/mm3, respectively; P=.03).
According to Fisher, platelet count is a key pharmacodynamic measure. Because platelets support tumor growth and metastasis, increasing platelet numbers in advanced cancer are often prognostic of poor survival. “IL-1α on platelets, which may mediate pro-tumor effects, is a target of antibody therapy,” noted Fisher, although the precise mechanics of the drug remain somewhat of a mystery.
“This may be an effect of IL-1α on the surface of platelets that the antibody’s binding to,” Stecher hypothesized regarding platelet reduction, “or it may be through a reduction in IL-6, which we had seen in previous trials.”
While the reasons behind its success continue to be explored, the most important outcome of the drug could not be denied—the trend toward improved survival between the 2 arms. “In the Xilonix group,” iterated Stecher, “we had a median survival of 2.8 months versus 2 months’ survival in the megestrol arm. That didn’t reach significance—it was .17—but it’s a very good trend.”
The study enrolled 40 patients between March 2013 and July 2014, at which time it was halted to revise inclusion criteria to reduce screen failures. Investigators are currently using an amended phase 3 protocol to simplify enrollment for an ongoing study of MABp1 in an advanced CRC population.
“It was a difficult trial to accrue because of the cachexic component,” said Stecher. “Finding colorectal cancer patients who had lost 5% of their total body weight in 6 months was challenging, so we decided to change the criteria. We’ve changed the protocol to be a traditional third-line protocol, double-blind placebo-controlled…so the population is going to be totally different. They’re not going to have weight loss.”
Fisher GA. A phase III study of Xilonix in refractory colorectal cancer patients with weight loss. J Clin Oncol (ASCO Annual Meeting Abstracts). 2015;33(suppl 3):Abstract 685. Poster presented at: 2015 Gastrointestinal Cancers Symposium; January 15-17, 2015; San Francisco, CA. http://meetinglibrary.asco.org/content/140631-158. Accessed January 27, 2015.