World GI 2016 Press Release: The Debate on the Phase 3 Trial of MABp1 Presented at the 18th ESMO World Congress on Gastrointestinal Cancer

LUGANO - The lively discussion which followed the presentation of ‘A pivotal phase 3 Trial of MABp1 in advanced colorectal cancer’ (1) by Dr. Tamas Hickish during Session XIX: Colorectal Cancer, on Saturday, 2 July 2016, has highlighted several areas of debate which were not covered in the abstract submitted to the Congress’ Scientific Committee nor its accompanying press release.

Professor Dirk Arnold from Instituto CUF de Oncologia in Lisbon, discussant of the abstract at the session and ESMO Executive Board Member, explains: “The abstract addressed a range of important issues, and therefore it was selected to be presented as an oral abstract. First of all, the study was addressing an unmet need in the treatment of patients with very late stage metastatic colorectal cancer having disease-related symptoms, and secondly, it uses an interesting, patient-relevant endpoint, with a new ‘score’ of symptom improvement parameters (which XBiotech wrote, and was developed together with an EMA working group). This is not entirely new, as a similar approach focusing on improvement of disease-related symptoms was used in the mid-1990s resulting in the registration of gemcitabine (a cancer drug used in pancreatic cancer, Burris et al., J Clin Oncol 1997), but of interest.

“The conduct of the trial with a 2:1 randomization and a remarkable sample size presented was acceptable (although the estimation of the benefit and the consecutive sample size planning were not shown). However, a series of problems with the trial were highlighted at the presentation resulting in a lively discussion. Most importantly, the claim of a “76% increase in improvement….” is misleading (as it represents a relative improvement rate).

“The relevant numbers reported for symptom improvement after eight weeks according to this new scale are 33% of patients being treated with the new compound and 19% of patients in the placebo arm, so the difference of patients with symptom improvement with active treatment was only 14%. Interestingly, 19% of patients had symptom improvement without active treatment (in the trials´ placebo arm), relatively more than with the drug. Furthermore, no reference was made about when the onset of symptom relief during the eight weekly period was noted.”

Continues Professor Arnold: “In my discussion about the abstract, I emphasised that the ‘detailed analysis of clinical responders’ with the new symptom-improvement score included all n=309 patients. However, the ‘correlations with (radiographical?) disease stabilization’ and ‘numbers of patients with SAE´s’ had only been done for ‘responders’ versus ‘non-responders’ – independent from treatment, so that ‘responders’ to placebo were also included in this analysis. The same applies to the ‘overall survival’ curve included – for which, however, only a subset of patients (N=175) was registered.

“In conclusion, 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. It’s not yet clear whether there is any benefit in translating this trial into practice.”  

This follow up statement to the original press release incorporates the views of an ESMO key opinion leader; this would have ideally been shared at the Congress where we fast track news which is reviewed as soon as possible by an ESMO spokesperson.

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Notes to Editors

References

(1) Abstract O-027 - ‘A pivotal phase 3 Trial of MABp1 in advanced colorectal cancer’ was presented by Dr. Tamas Hickish during Session XIX: Colorectal Cancer, on 02.07.2016.

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O-027

A pivotal phase 3 trial of MABp1 in advanced colorectal cancer

Hickish Tamas1, André Thierry2, Wyrwicz Lucjan3, Saunders Mark4, Sarosiek Tomasz5, Nemecek Radim6, Kocsis Judit7, Stecher Mike8, de Gramont Aimery9
1Oncology Department, Royal Bournemouth Hospital NHS Foundation Trust, Bournemouth, United Kingdom, 2Saint Antoine Hospital, Paris, France, 3M Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland, 4Christie Hospital NHS Foundation Trust, Manchester, United Kingdom, 5Magodent, Warsaw, Poland, 6Masaryk Memorial Cancer Institute, Brno, Czech Republic, 7University of Debrecen, Debrecen, Hungary, 8XBiotech USA, Inc., Austin, Texas, 9Oncology Department, Institut Hospitalier Franco-Britannique, Levallois-Perret, France

Introduction: The incidence of colorectal cancer (CRC) is associated with economic development and is the second leading cause of cancer in the industrialized world. At least half of patients diagnosed will progress and succumb to the disease. Consequently, a substantial and growing unmet need exists for a therapy to treat patients with advanced CRC.  We evaluated a novel anti-IL-1 alpha antibody therapy in patients with advanced disease and multiple symptoms known to inversely correlate with overall survival.  OR criteria were developed in collaboration with EMA’s Scientific Advice Working Group to assess anti-tumor benefit of therapy based on control of these symptoms.

Methods: 309 patients were randomized 2:1 to receive MABp1 plus best supportive care (BSC) versus placebo plus BSC.  Patients had metastatic colorectal cancer refractory to standard chemotherapy including oxaliplatin and irinotecan. Inclusion criteria also required a constellation of symptoms/functional impairment (ie. pain, fatigue, anorexia, ECOG 1 or 2), weight loss or elevated systemic inflammation.

Objective response criteria used dual-energy X-ray absorptiometry and EORTC-QLQC30 to assess disease control. Secondary endpoints were pharmacodynamics measures also known to correlate with survival. Data was also reported on incidence of Serious Adverse Events (SAEs) and disease progression. Patients were prohibited from receiving any agents that could affect the outcome, including chemotherapy or steroids.

Results: Primary endpoint analysis was performed on 102 placebo and 207 MABp1 patients using a non-parametric statistical test. A 33% treatment response compared to versus 19% for placebo was significant (p=0.0045).  Secondary endpoints were also significant, with improved control of paraneoplastic thrombocytosis and reduced systemic inflammation (IL-6) in treated patients versus placebo (p=0.003 and p=0.004 respectively). Safety and tolerability was excellent as evidenced by a 26% relative risk reduction in the number of SAEs in the treatment arm compared to placebo (p=0.062).

Conclusion: A novel symptom-based OR a criterion was used successfully to assess efficacy of a new anti-cancer agent. These findings provide unequivocal evidence that anti-IL-1alpha monotherapy can serve as a new treatment for advanced mCRC. [NCT02138422]