A randomized phase II/III study of the anti-IGF-1R antibody MK-0646 (dalotuzumab) in combination with cetuximab (Cx) and irinotecan (Ir) in the treatment of chemorefractory metastatic colorectal cancer (mCRC) with wild-type (wt) KRAS status.

Watkins, David; Tabernero, Josep; Schmoll, H.-J.; Trarbach, Tanja; Ramos, Francisco Javier; Howe, James R.; Brown, Holly; Clark, Justice; Hsu, Kai‐Cheng; Lu, Brian; Cunningham, David

doi:10.1200/jco.2011.29.15_suppl.3501

Cited by 27 publications

(26 citation statements)

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“…[22][23][24]. However, efficacy of anti-IGF-IR antibodies has been disappointing in clinical trials to date (25)(26)(27)(28)(29)(30). One possible explanation for these results is that in clinical use, drugs studied to date do not adequately inhibit IGF signaling, especially in the context of the need to block autocrine loops in IGF-dependent cancers (31)(32)(33), particularly those driven by IGF-II, which can also signal via IR-A (34).…”

Section: Igf-i Signals By Binding To the Igf-i Receptor (Igf-ir) Or Tmentioning

confidence: 74%

Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin

Friedbichler

Hofmann

Kroez

et al. 2014

Molecular Cancer Therapeutics

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Insulin-like growth factor (IGF) signaling is thought to play a role in the development and progression of multiple cancer types. To date, therapeutic strategies aimed at disrupting IGF signaling have largely focused on antibodies that target the IGF-I receptor (IGF-IR). Here, we describe the pharmacologic profile of BI 836845, a fully human monoclonal antibody that utilizes an alternative approach to IGF signaling inhibition by selectively neutralizing the bioactivity of IGF ligands. Biochemical analyses of BI 836845 demonstrated high affinity to human IGF-I and IGF-II, resulting in effective inhibition of IGF-induced activation of both IGF-IR and IR-A in vitro. Cross-reactivity to rodent IGFs has enabled rigorous assessment of the pharmacologic activity of BI 836845 in preclinical models. Pharmacodynamic studies in rats showed potent reduction of serum IGF bioactivity in the absence of metabolic adverse effects, leading to growth inhibition as evidenced by reduced body weight gain and tail length. Moreover, BI 836845 reduced the proliferation of human cell lines derived from different cancer types and enhanced the antitumor efficacy of rapamycin by blocking a rapamycininduced increase in upstream signaling in vitro as well as in human tumor xenograft models in nude mice. Our data suggest that BI 836845 represents a potentially more effective and tolerable approach to the inhibition of IGF signaling compared with agents that target the IGF-I receptor directly, with potential for rational combinations with other targeted agents in clinical studies. Mol Cancer Ther; 13(2); 399-409. Ó2013 AACR.

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Section: Igf-i Signals By Binding To the Igf-i Receptor (Igf-ir) Or Tmentioning

confidence: 74%

Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin

Friedbichler

Hofmann

Kroez

et al. 2014

Molecular Cancer Therapeutics

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“…The phase II study of figitumumab plus paclitaxel plus carboplatin versus paclitaxel plus carboplatin alone yielded improved objective response rates in the figitumumab plus paclitaxel plus carboplatin versus paclitaxel plus carboplatin alone treatment arm (54% vs. 42%), and subset analysis suggested that the addition of figitumumab (20 mg/kg) to the paclitaxel plus carboplatin regimen might boost progression-free survival (PFS; hazard ratio of 0.56, P ¼ 0.0153) as well as response rate (62% compared with 33%, P ¼ 0.0578) in patients with adenocarcinoma or squamous cell histology (14). The phase II to III randomized, double-blind, placebo-controlled trial of dalotuzumab (MK-0646) with cetuximab and irinotecan in patients with KRAS wild-type stage IV colorectal cancer was stopped prematurely owing to worsened PFS and overall survival in patients randomized to the dalotuzumab arm (35). A phase III randomized, double-blind, placebo-controlled trial of ganitumab (AMG-479) was recently initiated to test the mAb coadministered with gemcitabine in 825 patients with stage IV pancreatic cancer.…”

Section: Highlights Of Clinical Trial Resultsmentioning

confidence: 99%

Targeting the Insulin-like Growth Factor Axis for the Development of Novel Therapeutics in Oncology

et al. 2012

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Insulin-like growth factors (IGF) are polypeptide hormones with potent anabolic and mitogenic effects that regulate cell growth and differentiation. Dysregulation of the IGF axis has been well documented in the development and progression of multiple types of cancer. As a result, compounds targeting the IGF axis have become an area of intense preclinical and clinical research for cancer therapeutics. The IGF axis is intimately involved with the insulin-signaling pathway because of their close homologies. This homology may explain hurdles encountered in the clinical development of IGF-targeted therapies, such as less-than-expected antitumor efficacy that may arise from compensatory increases in the activity of insulin receptor isoform A (IR-A), in response to IGF-I receptor (IGF-IR) inhibition and perturbations in glucose homeostasis, arising from the inhibition of insulin receptor isoform B (IR-B) activity. In this brief review, we compare differentiating factors that characterize the 3 major classes of IGF-targeting compounds: therapeutic antibodies that target IGF-IR, small molecule tyrosine kinase inhibitors that inhibit kinase activities of IGF-IR and IR, and antibodies that target IGF ligands. Cancer Res; 72(1); 3-12. Ó2012 AACR.

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“…However, clinical data with the combination of cetuximab or panitumumab with the anti-IGF-1R monoclonal antibodies cixutumumab, dalotuzumab, or ganitumumab have been underwhelming (60)(61)(62). It is possible that a better insight on mechanisms of tumor dependence specific for these 2 pathways could enhance the chances of success for such strategies; in that regard, studies such as these could help improve patient selection strategies for the development of these regimens.…”

Section: Discussionmentioning

confidence: 99%

Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer

Huang

Khambata‐Ford

2012

Clinical Cancer Research

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Purpose: This study examined potential correlations between markers related to the insulin-like growth factor-1 receptor (IGF-1R) pathway and clinical benefit from the anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in metastatic colorectal cancer (mCRC).Experimental Design: Gene expression profiles for 70 pretreatment specimens from metastatic lesions of patients with chemorefractory mCRC receiving cetuximab monotherapy were analyzed using 74 predefined Gene-Chip probesets representing 33 unique IGF-1R pathway markers to determine correlations with progression-free survival (PFS) and disease control rate.Results: Higher IGF-1R, higher GRB 7 , and lower INSIG 2 expression were associated with longer PFS with cetuximab in univariate analyses, particularly in patients with wild-type K-Ras tumors: median, 122 versus 60 days (P ¼ 0.01), 122 versus 57 days (P ¼ 0.011), and 57 versus 156 days (P < 0.0001), favoring higher IGF-1R, higher GRB 7 , and lower INSIG 2 expression, respectively. Lower IGF-1 expression was associated with a PFS benefit with cetuximab, whereas lower IGFBP 3 and INSR expression levels showed trends for a PFS benefit. Lower INSIG 2 expression (vs. higher expression) was associated with greater PFS in the high epiregulin-expressing group (P ¼ 0.001), but not in the low-expressing cohort suggesting an effect independent from the previously reported effect of epiregulin expression. Lower INSIG 2 expression was also associated with higher disease control rate in the overall population (51.4% vs. 11.4%; P ¼ 0.001) and wild-type K-Ras subset (76.2% vs. 18.2%; P < 0.0001).Conclusions: These results suggest that markers of the IGF-1R pathway may play a role in predicting benefit from cetuximab therapy in mCRC. Additional clinical studies are warranted to validate these findings.

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A randomized phase II/III study of the anti-IGF-1R antibody MK-0646 (dalotuzumab) in combination with cetuximab (Cx) and irinotecan (Ir) in the treatment of chemorefractory metastatic colorectal cancer (mCRC) with wild-type (wt) KRAS status.

Cited by 27 publications

References 0 publications

Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin

Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin

Targeting the Insulin-like Growth Factor Axis for the Development of Novel Therapeutics in Oncology

Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer

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