MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study

Hickish, Tamas; Thewis, André; Wyrwicz, Lucjan; Saunders, Mark; Sarosiek, Tomasz; Kocsis, Judit; Němeček, Radim; Rogowski, Wojciech; Leśniewski-Kmak, Krzysztof; Petruželka, Luboš; Apte, Ron N.; Mohanty, Prasant; Stecher, Michael; Simard, John; Gramont, Aimery de

doi:10.1016/s1470-2045(17)30006-2

Cited by 135 publications

(108 citation statements)

References 26 publications

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“…In an exploratory analysis in a subgroup of patients, the median survival was 6.1 months (95% CI 4.4–7.2) in the MABp1 group compared with only 2.4 months (95% CI 1.9–3.2) in the placebo group, which reinforces the idea that targeting IL-1 pathways is relevant for the treatment of mCRC. 8 …”

Section: Discussionmentioning

confidence: 99%

“…5,6 Recent clinical data has shown that IL-1 β inhibition using canakinumab could prevent lung cancer growth, 7 and another recent trial has underlined that MAbP1, a monoclonal antibody which targets IL1α, improves quality of life and survival in mCRC. 8 Recently we observed that fluorouracil (5-FU) could activate the NOD-like receptor family, the pyrin domain containing 3-protein (NLRP3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to IL-1β production, which curtails anticancer immunity. IL-1β was also shown to induce the generation and expansion of T H 17 cells, which could promote tumor growth by favoring proangiogenesis and immunosuppression in a IL-17A dependent manner.…”

Section: Introductionmentioning

confidence: 99%

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Fluorouracil and bevacizumab plus anakinra for patients with metastatic colorectal cancer refractory to standard therapies (IRAFU): a single-arm phase 2 study

et al. 2018

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In preclinical models, IL-1β inhibition could enhance the efficacy of fluorouracil (5-FU). In this phase 2 study, we assessed the activity and safety of 5-FU plus bevacizumab and anakinra (an IL-1β and α inhibitor) in patients with metastatic colorectal (mCRC) refractory to chemotherapy and anti-angiogenic therapy.Eligible patients had unresectable mCRC; were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type KRAS). Patients were treated with a simplified acid folinic plus 5-FU regimen and bevacizumab (5 mg/kg) both administered by intravenous infusion for 30 min every 2 weeks. Anakinra (100 mg) was injected subcutaneously once daily. The primary endpoint was the 2-month response rate determined upon CHOI criteria.Thirty two patients with metastatic colorectal cancer were enrolled. Five patients demonstrated response (Choi criteria) and 22 patients had stable disease as the best 2-month overall response. Median progression-free and overall survival were 5.4 (95% CI, 3.6–6.6) and 14.5 months (95% CI, 9–20.6) respectively. Twenty patients experienced grade 3 toxicity. No grade 4 or 5 toxicity related to therapy occurred. The most common grade 3 adverse events were neutropenia in 8 (25%) patients, digestive side effects in 7 (21.9%) patients and hypertension in 6 (18.75%) patients. No treatment-related deaths or serious adverse events were reported.5-FU plus bevacizumab and anakinra has promising activity and a manageable safety profile, suggesting that this combination might become a potential treatment option for patients with refractory mCRC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fluorouracil and bevacizumab plus anakinra for patients with metastatic colorectal cancer refractory to standard therapies (IRAFU): a single-arm phase 2 study

et al. 2018

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“…Directly targeting the cachexia pathway may prove to be a more successful treatment option [17]. Recently, drugs in newly emerging categories such as MABp1, an IL-1a -specific antibody, and BYM338, an anti-ACVR2B antibody, have been tested in clinical trials [18,19].…”

Section: Discussionmentioning

confidence: 99%

Low Skeletal Muscle Mass before Salvage-Line Chemotherapy Is a Poor Prognostic Factor in Patients with Refractory Metastatic Colorectal Cancer

et al. 2018

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Background: Regorafenib and TAS-102 are standard salvage-line treatment options for patients with chemorefractory metastatic colorectal cancer (mCRC). We aimed to evaluate the prognostic significance of skeletal muscle mass in mCRC patients receiving these salvage-line therapies. Methods: We conducted a retrospective analysis of 52 patients with mCRC who received regorafenib or TAS-102 as salvage-line treatment. Skeletal muscle cross-sectional area was measured by pretreatment CT to obtain the skeletal muscle index (SMI, cm²/m²). We divided patients into 2 groups (low-SM/high-SMI) based on the median value of SMI. Result: The median SMI was 51.8 cm²/m² in males and 39.2 cm²/m² in females. In Kaplan-Meier analysis, patients in the low-SMI group showed significantly shorter overall survival (3.7 vs. 7.3 months, log-rank p = 0.002) and progression-free survival (1.9 vs. 2.8 months, log-rank test p = 0.009) than those in the high-SMI group. Subsequent multivariate analysis revealed that the SMI was an independent prognostic factor (hazard ratio = 2.381, 95% CI 1.189–4.944, p = 0.014). Patients in the low-SMI group had significantly more grade 3 or 4 adverse events than those in the high-SMI group (46 vs.12%, p = 0.013). Conclusion: Low skeletal muscle mass is a negative factor for survival outcomes in mCRC patients treated with salvage-line chemotherapy.

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“…There is no dearth of preclinical data to support a role for IL1α in human cancer. Increased survival was reported in a randomized, placebo controlled trial of a neutralizing natural antibody to IL1α in patients with advanced, metastatic colorectal cancer (9). The IL1a precursor is constitutively present in healthy breast cells, and several studies have identified polymorphisms in the IL1α promoter as risk factors in breast cancer.…”

mentioning

confidence: 99%

“…10) and TSLP then contributes to the survival of the tumor cells by increasing Bcl-2 that restricts apoptosis in tumor cells. In that regard, compared with placebo-treated patients, anti-IL1α improved quality of life as well as increased survival (9). …”

mentioning

confidence: 99%

An Interleukin-1 Signature in Breast Cancer Treated with Interleukin-1 Receptor Blockade: Implications for Treating Cytokine Release Syndrome of Checkpoint Inhibitors

Dinarello

2018

Cancer Research

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MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study

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Cited by 135 publications

References 26 publications

Fluorouracil and bevacizumab plus anakinra for patients with metastatic colorectal cancer refractory to standard therapies (IRAFU): a single-arm phase 2 study

Fluorouracil and bevacizumab plus anakinra for patients with metastatic colorectal cancer refractory to standard therapies (IRAFU): a single-arm phase 2 study

Low Skeletal Muscle Mass before Salvage-Line Chemotherapy Is a Poor Prognostic Factor in Patients with Refractory Metastatic Colorectal Cancer

An Interleukin-1 Signature in Breast Cancer Treated with Interleukin-1 Receptor Blockade: Implications for Treating Cytokine Release Syndrome of Checkpoint Inhibitors

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