medwireNews: Patients with metastatic or unresectable colorectal cancer (CRC) may benefit from MABp1 antibody therapy targeting interleukin (IL)-1α, suggests a phase III trial using novel criteria for assessing efficacy in palliative care.
“Our findings suggest that development of a new class of agents that selectively target disease pathophysiology is feasible”, say Tamas Hickish, from Poole Hospital NHS Foundation Trust in the UK, and co-authors in The Lancet Oncology.
The team recruited trial participants with advanced CRC refractory to oxaliplatin and irinotecan, an ECOG performance score of 1 or 2, systemic inflammation, weight loss and other markers of poor prognosis. In all, 207 patients were randomly assigned to receive MABp1 7.5 mg/kg every 2 weeks over 8 weeks and 102 were given placebo.
The investigators worked with the European Medicines Agency to design a study using disease symptoms as the 8-week primary endpoint, defined as stable or increased lean body mass, as measured by dual-energy X-ray absorptiometry, and stability or improvement in at least two of fatigue, pain or anorexia, according to the EORTC QLQ-C30 questionnaire.
The composite primary endpoint in the intention-to-treat population was achieved by 33% of MABp1-treated patients and 19% of controls, giving a significant relative risk (RR) of 1.76. The difference was also significant in the per-protocol analysis, with an identical RR of 1.76, at 40% of 169 patients given MABp1 and 23% of 83 controls.
However, at week 8, a similar proportion of patients in the MABp1 and placebo groups had achieved stable disease (17 vs 12%) and there were no RECIST partial or complete responses reported for either treatment.
A comparable 8% and 11% of the MABp1 and placebo group patients had died by week 8; there were no treatment-related deaths.
After a median of 6.1 months, 91% and 93% of patients in the groups had died, respectively. The researchers observe that at this time survival analysis data were available for 57% of 222 patients who had not achieved the primary endpoint and 56% of the 87 patients who had. Among these individuals, median overall survival (OS) was 4.2 and 11.5 months respectively, giving a significant hazard ratio of 0.31.
The author of a linked comment notes that the trial required a protocol amendment and excluded patients who crossed over from placebo to MABp1 in an open-label extension, reducing the number of patients available for analysis.
“This analysis did show a survival benefit for MABp1, but with notable bias because it selects for patients who progress early or who were not well enough to crossover to MABp1, making the results very difficult to interpret”, writes Timothy Price, from Queen Elizabeth Hospital in Woodville, South Australia.
Nevertheless, noting the extended OS among patients who achieved the primary endpoint, he adds: “The interleukin 1 pathway does, therefore, seem to be a potential therapeutic target, whether by the actions of a derived antibody or via an individual's own humoral response, which has led the authors to rightly postulate additional opportunities beyond interleukin 1α.”
Serious adverse events occurred in a comparable 23% of the MABp1 group and 32% of controls; patients given MABp1 had higher rates of grade 3 or 4 elevated alkaline phosphatase (4 vs 2%) and aspartate aminotransferase (3 vs 2%), but lower rates of anaemia (4 vs 5%) and fatigue (3 vs 7%).
The investigators note that patients with refractory CRC and disease-related symptoms “have few treatment options” and available options have “toxic effects that might lead to little or no overall clinical benefit”.
“MABp1, an antibody derived from natural human immunity, is intended to augment endogenous immunoregulatory mechanisms in patients to help antagonise the chronic inflammatory process involved in tumour growth and disease progression”, they summarise.
“A novel endpoint that combined self-reported and objective measures to assess the effects of antibody monotherapy showed significant clinical benefit. MABp1, therefore, might offer a new standard of care in the treatment of advanced colorectal cancer.”
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