A Randomized Phase II/III Study of Dalotuzumab in Combination With Cetuximab and Irinotecan in Chemorefractory,<i>KRAS</i>Wild-Type, Metastatic Colorectal Cancer

Sclafani, Francesco; Kim, Tae Y.; Cunningham, David; Kim, Tae W.; Tabernero, Josep; Schmoll, Hans Joachim; Roh, Jae Hoon; Kim, Sun Y.; Park, Young S.; Guren, Tormod Kyrre; Hawkes, Eliza A; Clarke, S.; Ferry, David; Frödin, Jan Erik; Ayers, Mark; Nebozhyn, Michael; Peckitt, Clare; Loboda, Andrey; Mauro, David; Watkins, David

doi:10.1093/jnci/djv258

Cited by 80 publications

(88 citation statements)

References 35 publications

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“…Of the enrolled studies, there were three of them with data exhibited in Clinicaltrials.gov but without formal article published (NCT00372996, 2015; NCT00887159, 2015; NCT00684983, 2016), while the other 14 with full articles. 3 studies contained two sets of data [15, 16, 23]. Three datas from two studies presented their confidental interval (CI) in proportion of 80% and 90%.…”

Section: Resultsmentioning

confidence: 99%

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Update of IGF-1 receptor inhibitor (ganitumab, dalotuzumab, cixutumumab, teprotumumab and figitumumab) effects on cancer therapy

Wang

et al. 2017

Oncotarget

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BackgroundPrognostic studies of insulin-like growth factor-1 receptor(IGF-1R) inhibitors in cancer therapy had promising results in infratests, which exhibited that IGF-1R signalling was crucial in cancer cells growth. However, the conclusion of later clinical trials revealed a dim future for IGF-1R inhibitors to treat cancer. We conducted this analysis to figure out how IGF-1R inhibitors acted in clinical cancer therapy.Material and MethodsWe searched up-to-date studies about the single agent of IGF-1R inhibitors or combination with other therapies in solid tumor. Five IGF-1R anti-agents were involved. The primary endpoint was progression-free survival (PFS). The secondary endpoint was overall survival (OS).Result17studies were enrolled. The results was not significant in overall survival (I2=37.1%, P=0.080, HR=1.08, 95% CI=0.97-1.21) and in progression-free survival (I2=0.0%, P=0.637, HR=1.05, 95% CI=0.98-1.12). OS for dalotuzumab, breast cancer, colorectal cancer, and PFS for prostate cancer even indicated harmful effects.ConclusionSo far, anti-IGF-1R mono-antibodies did not make significant differences in solid tumor prognosis. On the contrary, pessimistic effects were shown in the dalotuzumab, breast cancer, colorectal cancer and prostate cancer subgroups. Further studies of IGF-1R anti-agents were needed, but unwarranted in unselected patients by predictive biomarkers.

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Section: Resultsmentioning

confidence: 99%

“…We found only one study [12] seemed to have the active trend that IGF-1R inhibitors (AMG-479) improved the PFS or OS in advanced solid tumors. Some studies [13–15] revealed IGF-1R inhibitors could shorten OS and PFS. However, more studies [16–25] showed IGF-1R mono-antibodies had no significant value in cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Update of IGF-1 receptor inhibitor (ganitumab, dalotuzumab, cixutumumab, teprotumumab and figitumumab) effects on cancer therapy

Wang

et al. 2017

Oncotarget

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“…Preclinical data have demonstrated that combined inhibition of IGF-1R and EGFR resulted in an enhanced anti-tumor effect in xenograft models [95]. Although in numerous early clinical analyses neither IGFR inhibitors alone nor the combination with anti-EGFR moAbs showed any promising anti-tumor activity in patients with anti-EGFR moAb-refractory mCRC [96], in a more recent randomized phase II/III study, a response to the IGF-1R inhibitor was identified by further exploratory biomarker analyses [97]. In this study, 344 eligible patients with KRAS wild-type tumors were randomly assigned to dalotuzumab (IGF1R inhibitor) or placebo in combination with cetuximab and irinotecan.…”

Section: Acquired Resistance To Anti-egfr Therapy In Crcmentioning

confidence: 99%

Mechanisms of resistance to anti-EGFR therapy in colorectal cancer

et al. 2016

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Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is effective for patients with RAS wild type metastatic colorectal cancer (mCRC). However, only a small percentage of mCRC patients are sensitive to anti-EGFR therapy and even the best cases finally become refractory to this therapy. It has become apparent that the RAS mutations correlate with resistance to anti-EGFR therapy. However, these resistance mechanisms only account for nearly 35% to 50% of nonresponsive patients, suggesting that there might be additional mechanisms. In fact, several novel pathways leading to escape from anti-EGFR therapy have been reported in recent years. In this review, we provide an overview of known and novel mechanisms that contribute to both primary and acquired anti-EGFR therapy resistance, and enlist possible treatment strategies to overcome or reverse this resistance.

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“…Conversely, dalotuzumab plus irinotecan and cetuximab did not improve survival outcome in KRAS wild-type mCRC 99. Meta-analysis studies showed that anti-EGFR monoclonal antibodies alone or in combination with others (FOLFIRI ± cetuximab; FOLFOX4 ± cetuximab; oxaliplatin or irinotecan-based chemotherapy, bevacizumab ± panitumumab; bevacizumab, capecitabine, oxaliplatin ± cetuximab, and irinotecan ± cetuximab) did not present efficacy in patients with mCRC containing KRAS mutations 100–102…”

Section: Future Perspectivesmentioning

confidence: 96%

Immunotherapy for the treatment of colorectal tumors: focus on approved and in-clinical-trial monoclonal antibodies

Françoso¹,

Simioni²

2017

DDDT

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Colorectal cancer is considered a disease of the elderly population. Since the number of geriatric patients continues to rise, monoclonal antibody therapy is the most promising therapy in the recent research. Presently, the monoclonal antibodies most frequently used in the treatment of colorectal tumors are bevacizumab, cetuximab, panitumumab, and ramucirumab. Bevacizumab is a monoclonal antibody that acts on VEGF. Cetuximab and panitumumab act on EGFR. Ramucirumab binds directly to the ligand-binding pocket of VEGFR-2 to block the binding of VEGF-A, VEGF-C, and VEGF-D. These monoclonal antibodies, alone or in association with radiotherapy or chemotherapy, are presenting good results and are increasing patient survival, despite the side effects. Due to the limited number of molecules available, several studies are trying to develop new monoclonal antibodies for the treatment of colorectal tumors. Among those being studied, some recent molecules are in phase I and/or II trials and are yielding advantageous results, such as anti-DR5, anti-Fn14, anti-IGF-1R, anti-EGFR, anti-NRP1, and anti-A33 antibodies. This has been successful in reducing side effects and in treating nonresponsive patients.

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A Randomized Phase II/III Study of Dalotuzumab in Combination With Cetuximab and Irinotecan in Chemorefractory,KRASWild-Type, Metastatic Colorectal Cancer

Abstract: Adding dalotuzumab to irinotecan and cetuximab was feasible but did not improve survival outcome. IGF-1R ligands are promising biomarkers for differential response to anti-EGFR and anti-IGF-1R therapies.

Cited by 80 publications

References 35 publications

Update of IGF-1 receptor inhibitor (ganitumab, dalotuzumab, cixutumumab, teprotumumab and figitumumab) effects on cancer therapy

Update of IGF-1 receptor inhibitor (ganitumab, dalotuzumab, cixutumumab, teprotumumab and figitumumab) effects on cancer therapy

Mechanisms of resistance to anti-EGFR therapy in colorectal cancer

Immunotherapy for the treatment of colorectal tumors: focus on approved and in-clinical-trial monoclonal antibodies

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