Novel Antibody Offers Hope for Patients With Advanced CRC

Liam Davenport

July 05, 2016

BARCELONA — A novel anti-interleukin (IL)-1α antibody significantly improved clinical response compared with placebo in highly symptomatic patients with advanced colorectal cancer that had not responded to chemotherapy, according to results from a phase 3 trial.

The investigational product, MABp1 (Xilonix, XBiotech Inc), is the first monoclonal antibody immunotherapy to specifically target IL-1α. It is currently under regulatory review in both the United States, where it has received a Fast Track designation, and Europe, where it is under accelerated review, with a decision expected as early as the fourth quarter of 2016.

The results were presented here at the 18th World Congress on Gastrointestinal Cancer by Tamas Hickish, MD, consultant medical oncologist, Dorset Cancer Centre, and visiting professor, Bournemouth University, the United Kingdom.

He explained that the study used a novel criteria based on symptom control and objective measures to assess clinical responses. It showed that the antibody increased the clinical response by 76% compared with placebo, he said, and also led to a nonsignificant reduction in serious adverse events and an increased incidence of stable disease. In addition, responders had a three-fold increase in median overall survival, as well as improvements on several other parameters.

However, discussant for the paper, Dirk Arnold, MD, PhD, from the Instituto CUF de Oncologia in Lisbon, Portugal, raised several questions about the findings.

Dr Arnold, who was not involved in the study, emphasized that the 76% improvement in clinical response rates was a relative difference.

The MABp1 and placebo groups had clinical response rates of 33% and 19%, respectively, he pointed out. "That makes a difference of 14%, not more or less," he said, adding that "the important message" is that 19% of placebo patients showed a clinical response, "even if we don't give them an active treatment."

Dr Arnold also pointed out that the response rate was reported after 8 weeks of treatment, which "can be a long time for a patient who is suffering from symptoms."

He noted that it remains to be shown when the response occurs during treatment and how long the improvement is maintained. He added: "We have to ask whether this clinical response in symptom improvement was really correlated to other outcome parameters."

Dr Arnold also emphasized the difference seen between responders vs nonresponders and noted that some of the responders showed "remarkable improvements." However, he underlined that the responders group also included 19% of the patients given placebo. He said that, therefore, "we are here comparing response vs nonresponse, independent from treatment," adding: "We cannot claim that this is related to the treatment."

The "key question" is whether the "potential clinical benefit" seen in the study will translate into an overall benefit and whether there are any markers of a successful response, Dr Arnold commented. "It would be nice to learn more about that."

Study Details

Dr Hickish explained that IL-1α promotes tumor angiogenesis and can drive the host metabolism to burn muscle and lose weight. Moreover, previous studies have demonstrated that it can have effects in the brain, causing the fatigue, anxiety, and anorexia commonly seen in advanced cancers.

To examine the effect of MABp1 in advanced colorectal cancer with multiple symptoms known to affect survival, the researchers randomly assigned 309 patients who had not responded to standard chemotherapy with oxaliplatin and irinotecan to receive MABp1 or placebo in a 2:1 ratio, alongside best supportive care.

The participants had symptoms and/or functional impairments, such as pain, fatigue, anorexia, Eastern Cooperative Oncology Group performance status of 1 or 2, weight loss, or elevated systemic inflammation. Treatment was given for 8 weeks, after which patients entered an open-label extension, in which those given placebo could cross over to MABp1.

The researchers developed a novel set of criteria for assessing objective response, which were based on the control of symptoms and developed in conjunction with the Scientific Advice Working Group of the European Medicines Agency. The criteria were used alongside dual-energy x-ray absorptiometry and the European Organisation for Research and Treatment of CancerQLQ-C30 quality-of-life questionnaire to assess disease control and the clinical response.

The primary analysis was performed on 207 patients receiving MABp1 and 102 receiving placebo (median age, 64 and 63 years, respectively). The two groups were well balanced in terms of baseline characteristics.

Clinical response at 8 weeks significantly differed between the MABp1 and placebo groups, at 33% vs 19% (P = .0045). The study drug was also associated with a nonsignificant 26% relative risk reduction in serious adverse events (P = .062) and a 53% increased incidence of stable disease (P = .12).

Responders to therapy had a significantly greater median overall survival than nonresponders, at 11.5 months vs 4.2 months and a hazard ratio of 0.31 (P > .001). Responders also had a higher incidence of stable disease at 8 weeks, at 24.1% vs 111.7% (P = .006) and a significant reduction in serious adverse events, at 5.7% vs 29.3% (P < .001).

Responders also reported, compared with nonresponders, significant improvements in global quality of life, role, emotional and social function, pain, fatigue, and anorexia (P < .001 in all cases).

To conclude, Dr Hickish said, "What we propose has been shown here is that, using this novel assessment of clinical response…with just 8 weeks' treatment exposure, it's possible to identify patients who are going to respond and derive an overall survival benefit from treatment."

"In this study, Xilonix anti-interleukin-1α antibody is able to improve clinical responses and therefore improve overall survival," Dr Hickish added.

The study was funded by XBiotech Inc. The researchers have disclosed no relevant financial relationships.

18th World Congress on Gastrointestinal Cancer (WCGC). Abstract O-027. Presented June 29, 2016.

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