MABp1 Improves Symptoms in Phase III CRC Study

Tamas Hickish, MD

MABp1 (Xilonix), a novel anti—interleukin 1-alpha (IL-1α) antibody, was safe, well-tolerated, and demonstrated a significant impact on symptoms compared with placebo for patients with advanced colorectal cancer (CRC), according to findings from a phase III study presented at the 2016 World Congress of Gastrointestinal Cancer.

In the trial, there were no dose-limiting toxicities or immunogenic reactions reported with MABp1. Additionally, there was a 26% reduction in the incidence of serious adverse events with MABp1 compared with placebo (P = .062).

“These data suggest MABp1 is very well tolerated,” said lead investigator Tamas Hickish, MD, FRCP, Medical Oncologist at Bournemouth University in Bournemouth, UK. “MABp1 has the potential to meet the real and urgent need for more effective, less toxic therapies for patients with advanced colorectal cancer. I believe this study of a completely novel drug will give new insight into how to treat advanced bowel cancer.”

The purpose of the trial was twofold: To evaluate MABp1 as an immunotherapy in CRC and to implement new criteria for determining objective response (OR) using the control and decrease of symptoms as a benchmark. Hickish explained that the endpoints used in this trial were based on newly formulated OR criteria.

“The criteria for response were developed in collaboration with the Scientific Advice Working Group of the European Medicines Agency (EMA) to assess anti-tumor benefit of therapy based on control of specific symptoms,” he said. This unique model was based upon observations of MABp1 in patients with advanced CRC that suggested physical recovery strongly correlated with improved survival.

The phase III trial evaluated the utility of MABp1 for interleukin-1α blockade and symptom control-based OR (primary endpoint) in 309 patients with mCRC that were refractory to prior standard oxaliplatin and irinotecan chemotherapy. IL-1α is a potent inflammatory mediator of chronic inflammation that is secreted by cells in response to infection or injury and also by many types of tumors.

Patients in the trial were required to have multiple symptoms known to inversely correlate with a poorer outcome that could include pain, fatigue, ECOG performance status 1 or 2, weight loss, and/or elevated systemic inflammation, or to exhibit functional impairment. Patients were not allowed to use agents that could affect the outcome during the course of the trial, including chemotherapy or steroids.

The trial randomized 207 patients to receive MABp1 plus best supportive care (BSC) and 102 patients to placebo plus BSC. Disease control status was objectively described by lean body mass evaluation using dual-energy X-ray absorptiometry and the EORTC-Quality of Life Questionnaire 30 (QLQC30)

By the newly developed criteria, the response to treatment with MABp1 was 33% versus 19% with placebo (P = .0045). According to the design of the new endpoint, this improvement in response should correlate with overall survival (OS); however, the study was not designed to directly compare OS in the investigational arm with the placebo group. In the study, all patients in the placebo arm crossed over to receive MABp1 after 8 weeks, which confounded this endpoint.

“This study provides the first evidence that health status can actually be used to measure efficacy of antitumor therapy in advanced, refractory colorectal cancer, and that clinical responses based on health status can be a predictor of overall survival benefit,” according to Hickish.

The incidence of adverse events (AEs) was similar in each arm, with the most common AEs being abdominal pain, peripheral edema, fatigue, anemia, constipation, decrease in weight, asthenia, decreased appetite, and nausea. Responses to MABp1 were associated with improvements in lean body mass, fatigue, and pain, which may be inline with the mechanism of action, according to Hickish.

“IL-1α is upregulated in tumors to promote tumor invasiveness, metastases, and angiogenesis by helping to provide crucial blood supply for tumor growth, and it can also send the body’s metabolism out of control, causing it to burn muscle and lose weight; the effects on the brain can cause the fatigue, anxiety, and the cachexia associated with advanced cancer,” he explained.

In a review of results from the study, Dirk Arnold, MD, Instituto CUF de Oncologia in Lisbon, noted that the findings were unreliable due to the methodology used in the study. Moreover, he said that the benefit associated with MABp1 was unclear and that potential clinical consequences could not yet be determined.

"The jury is still out on whether the study made sense but as the results do not bear close inspection, they also cannot be relied upon," said Arnold. "It’s not yet clear whether there is any benefit in translating this trial into practice."

Despite these drawbacks, in March 2016, the EMA validated a marketing authorization application for MABp1 as a treatment for advanced CRC based on the phase III findings. Along with the presentation of the phase III data, the developer of the medication, XBiotech, announced that the application had been granted an accelerated assessment by the EMA. The company believes an approval decision could arrive before the end of 2016.

A separate phase III study is being conducted in the United States to support a regulatory filing. This trial hopes to enroll 800 patients, with recruitment expected to complete by the end of 2016. The primary endpoint for the study is OS, with secondary outcome measures focused on lean body mass, progression-free survival, objective response rate, and safety (NCT01767857).

Hickish T, Andre T, Wyrwicz L, et al. A pivotal phase 3 trial of MABp1 in advanced colorectal cancer. Presented at: 2016 World Congress on GI Cancer; June 28 - July 2, 2016; Barcelona, Spain. Abstract O-027.

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According to Hickish, measures of improved health status correlated with improvement in nearly all self-reported and laboratory-based measures of health, such as reduced systemic inflammation. Patients receiving MABp1 showed improved symptom control (secondary endpoint). Additionally, MABp1-treated patients showed better control of paraneoplastic thrombocytosis (P = .003) and reduced IL-6 mediated systemic inflammation compared with placebo (P = .004).