Colorectal cancer: Pivotal Phase III data for Xilonix presented

XBiotech Inc., developer of next-generation True Human™ antibody therapies, has presented positive results from a pivotal Phase III trial of Xilonix™, the company's lead monoclonal (IgG1k) antibody immunotherapy for the treatment of advanced colorectal cancer (CRC). In the study, Xilonix-treated patients with advanced disease and multiple symptoms known to inversely correlate with overall survival experienced a 76% relative increase in clinical response rate (CRR), a measure of health status, compared to placebo (33% vs. 19%, respectively; p=.0045). In addition, the primary endpoint of CRR was shown to be a predictor of overall survival benefit and improved health outcomes for virtually all other measures. Among all responders (in both the active treatment and placebo arms of the study), clinical response was associated with a 2.7-fold increase in overall survival (11.5 versus 4.2 months in responders vs. non-responders, respectively).

The CRR, a novel composite endpoint developed in collaboration with European Medicines Agency (EMA) Scientific Advice Working Group, measured pain, fatigue, appetite loss, and muscle loss - symptoms associated with disease progression and poor prognosis for survival. Treatment with Xilonix was well tolerated, with an adverse event profile comparable to placebo. The data were presented at the 18th European Society of Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer in Barcelona, Spain.

"This study provides what we believe to be the first evidence that health status can actually be improved in patients with advanced colorectal cancer refractory to further treatment with existing therapies," Dr. Tamas Hickish, Chair of the Xilonix European Phase III Study and Consultant Medical Oncologist, Royal Bournemouth Hospital NHS Foundation Trust, UK. "Since patients with advanced disease have limited treatment options and are often weakened from successive rounds of toxic chemotherapy, an ideal therapy would effectively control disease without doing further harm. In this first-of-its-kind study, not only did treatment with Xilonix demonstrate clinical benefit but it was also very well-tolerated, suggesting Xilonix has the potential to meet the real and urgent need for more effective, less toxic therapies for patients with advanced colorectal cancer."

In addition to increased overall survival, responders gained more lean body mass compared to non-responders (p<0.0007), had reduced fatigue and pain (p<0.001) and improved appetite (p<0.001). Control of thrombocytosis and systemic inflammation (IL-6), which are known prognosticators of overall survival - were also significantly improved in responders vs. non-responders (p<0.0002 and p<0.0007, respectively).

"This study provides evidence that novel endpoints based on symptom recovery may serve as a predictor of overall survival benefit, and thus may be used to evaluate an anti-tumor agent in this disease," said Dr. Hickish. "New clinical endpoints are needed to evaluate anti-cancer agents with the potential to improve health status while prolonging life for patients with advanced cancer."

There was a notable lack of toxicity associated with Xilonix treatment in the study. The most common adverse events (AEs) reported were abdominal pain, peripheral edema, fatigue, anemia, constipation, decrease in weight, asthenia, decreased appetite, and nausea. The majority of these events were characterized as mild to moderate, and appeared to be related to the underlying disease. The prevalence of AEs was similar in both treatment and placebo groups. While the study was not powered to demonstrate a difference in serious adverse events (SAEs) between treatment and placebo groups, there was a 26% reduction in the risk of SAEs in the treatment arm vs. placebo (p=0.062), a unique and notable finding.

"This study was conducted where the unmet need is greatest - among patients with the most debilitating symptoms of advanced disease and poor prognosis for overall survival. We intentionally set a high bar for demonstrating benefit by treating patients suffering from recalcitrant disease accompanied by symptoms that are considered irreversible unless the underlying disease can be effectively controlled," said John Simard, XBiotech Founder, President and Chief Executive Officer. "We believe these findings demonstrate that Xilonix has potential as a breakthrough therapy for treating advanced colorectal cancer patients with improved efficacy and safety."

Study Methodology

In the double-blind placebo-controlled Phase III study, 309 patients were randomized (2:1) to receive Xilonix plus best supportive care (BSC) versus placebo plus BSC. Patients were required to have failed all conventional therapy and had inoperable or metastatic disease with debilitating symptoms that predict poor survival. Study participants also had failed all available chemotherapy and had metastatic disease with one or more symptoms of metabolic dysfunction and functional impairment (i.e., elevated systemic inflammation, unintentional weight loss, pain, fatigue, anorexia). Patients were required to have an Eastern Cooperative Oncology Group (ECOG) function status of only 1 or 2. Elderly patients (>70 years of age) were eligible as well, in contrast to many studies of anti-cancer therapies in advanced disease.

The study's primary endpoint measured CRR after 8 weeks of therapy. This novel endpoint was developed in consultation with the EMA, which has provided a regulatory path to encourage and expedite the development of anti-cancer agents that improve patient health status while prolonging life. These guidelines enable development of anti-cancer agents based on an effect that improves debilitating symptoms in patients, particularly where the effect is the result of an anti-tumor mechanism and the clinical measures are considered prognosticators for overall survival.

CRR was assessed using dual-energy X-ray absorptiometry to determine lean body mass (LBM) and using the standard European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ-C30) to capture patients' own assessment of their fatigue, pain, and anorexia from baseline to week 8. To be classified as responders, patients had to maintain or improve LBM and maintain or improve in at least two of the three categories of pain, fatigue and anorexia. Secondary endpoints evaluated paraneoplastic thrombocytosis and systemic inflammation, both known correlates for survival in colorectal cancer. As specified in the Phase III protocol, investigators also followed up with patients after study completion or discontinuation to track their survival status.

About True Human™ Therapeutic Antibodies

Unlike previous generations of antibody therapies, XBiotech's True Human™ antibodies are 100 percent human, derived from individuals who possess natural immunity to certain diseases. With discovery and clinical programs across multiple disease areas, XBiotech's True Human antibodies have the potential to harness the body's natural immunity to fight disease with increased safety, efficacy and tolerability.

The first of these therapies, Xilonix™, for advanced colorectal cancer, is in Phase III clinical trials in the United States with a Fast Track designation by the U.S. Food and Drug Administration (FDA). In Europe, Xilonix Phase III clinical trials have been completed, and the therapy is under accelerated review following the validation of its Market Authorization Application by the European Medicines Agency (EMA).

Study: A Double-Blind Placebo Controlled Phase III Study of Monoclonal Antibody Targeting Interleukin-1 alpha (IL-1a) in Advanced Colorectal Cancer aCRC.