Efficacy, Tolerability, and Biomarker Analyses of Once-Every-2-Weeks Cetuximab Plus First-Line FOLFOX or FOLFIRI in Patients With KRAS or All RAS Wild-Type Metastatic Colorectal Cancer: The Phase 2 APEC Study

Cheng, Ann‐Lii; Cornelio, Gerardo H.; Shen, Lin; Price, Timothy; Yang, Tsung‐Ming; Chung, Ik Joo; Dai, Guang; Lin, Jen Kou; Sharma, Atul; Yeh, Kun‐Huei; Ma, Brigette; Zaatar, Adel; Guan, Zhi‐Zhong; Masood, Nehal; Srimuninnimit, Vichien; Yau, Thomas; Gibbs, Peter; Wang, Xiuwen; Doval, Dinesh Chandra; Oh, Seung Taek; Shim, Byoung Yong; Gorospe, Charity; Wang, Hwei Ming; Sirachainan, Ekaphop; Hill, Andrew; Suh, Kwang Wook; Beier, Frank; Chatterjee, Sudipto; Lim, Robert

doi:10.1016/j.clcc.2016.08.005

Cited by 20 publications

(23 citation statements)

References 25 publications

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“…The APEC study revealed no new safety findings for first‐line, every‐2‐weeks cetuximab plus doublet chemotherapy, mirroring the results from previous (including phase III) studies; no safety analysis was performed for this tumor‐location subgroup analysis because, per data from the CRYSTAL (unpublished) and TAILOR trials, there is no evidence that the safety profile differs meaningfully between right‐ and left‐sided mCRC.…”

Section: Resultsmentioning

confidence: 71%

“…Detailed design and methodology for the nonrandomized, phase II APEC study (NCT00778830) were previously described . The trial was conducted in accordance with the Declaration of Helsinki.…”

Section: Methodsmentioning

confidence: 99%

“…Secondary endpoints included progression‐free survival (PFS), overall survival (OS) and safety. Statistical analysis was performed as previously described …”

Section: Methodsmentioning

confidence: 99%

“…The open‐label, nonrandomized, multicenter, phase II APEC trial demonstrated that first‐line cetuximab administered once every 2 weeks in combination with investigator's choice of either FOLFOX or FOLFIRI yielded good response and survival outcomes in an Asian patient population with RAS wt mCRC, with no new or unexpected safety findings . Furthermore, the APEC trial found no evidence for differences in efficacy between FOLFIRI and FOLFOX chemotherapy when combined with cetuximab in patients with RAS wt mCRC .…”

Section: Introductionmentioning

confidence: 99%

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Phase II APEC trial: The impact of primary tumor side on outcomes of first‐line cetuximab plus FOLFOX or FOLFIRI in patients with RAS wild‐type metastatic colorectal cancer

Price

Shen

B.Y.

et al. 2019

Asia-Pac J Clncl Oncology

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AimThe open‐label, nonrandomized, phase II APEC study enrolled 167 patients with RAS wild‐type (wt) metastatic colorectal cancer (mCRC) to investigate the safety and efficacy of first‐line, every‐2‐weeks cetuximab plus investigator's choice of FOLFIRI or FOLFOX in this patient population.MethodsA subgroup analysis of the APEC study population by primary tumor location was performed.ResultsA total of 130 patients (81.8%) had left‐sided and 29 (18.2%) had right‐sided mCRC. Median progression‐free survival (PFS), overall survival (OS) and overall response rate (ORR) were 14.0 months, 30.6 months and 68.5% for patients with left‐sided tumors and 8.9 months, 24.6 months and 51.7% for patients with right‐sided mCRC, concurring with pivotal phase III trial results. In patients with right‐sided tumors, median PFS was 15.4 months vs 8.3 months with cetuximab plus FOLFIRI vs cetuximab plus FOLFOX, respectively; median OS was 32.1 months vs 21.8 months with cetuximab plus FOLFIRI vs cetuximab plus FOLFOX, respectively.ConclusionThe APEC tumor‐location subgroup analysis results were largely consistent with available literature regarding the equivalent efficacy of cetuximab plus FOLFIRI/FOLFOX in patients with left‐sided RAS wt mCRC. A trend toward improved efficacy with cetuximab plus FOLFIRI compared with cetuximab plus FOLFOX was observed in patients with right‐sided tumors; however, a direct comparison between groups cannot be made due to the nonrandomized study design. Nevertheless, the similar ORR observed with either chemotherapy backbone in patients with right‐sided RAS wt mCRC suggests a potential role for both regimens in this patient population when cytoreduction is a treatment goal.

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Section: Resultsmentioning

confidence: 71%

Section: Methodsmentioning

confidence: 99%

“…Secondary endpoints included progression‐free survival (PFS), overall survival (OS) and safety. Statistical analysis was performed as previously described …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Phase II APEC trial: The impact of primary tumor side on outcomes of first‐line cetuximab plus FOLFOX or FOLFIRI in patients with RAS wild‐type metastatic colorectal cancer

Price

Shen

B.Y.

et al. 2019

Asia-Pac J Clncl Oncology

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“…The activity of some anti-angiogenic drugs is based on the normalization of tumor vessels, which prevents the invasion of tumor cells and improves the anti-tumor effect of chemotherapy 37 , 38 . Increasing clinical data have demonstrated that many anti-angiogenic drugs combined with chemotherapy, radiotherapy or immunotherapy show better clinical efficacy than monotherapy 39 , 40 . Now this therapeutic strategy has been widely accepted and used by more and more doctors.…”

Section: Discussionmentioning

confidence: 99%

Identification of bioactive anti-angiogenic components targeting tumor endothelial cells in Shenmai injection using multidimensional pharmacokinetics

Zhong

Jiang

et al. 2020

Acta Pharmaceutica Sinica B

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Shenmai injection (SMI) is a well-defined herbal preparation that is widely and clinically used as an adjuvant therapy for cancer. Previously, we found that SMI synergistically enhanced the activity of chemotherapy on colorectal cancer by promoting the distribution of drugs in xenograft tumors. However, the underlying mechanisms and bioactive constituents remained unknown. In the present work, the regulatory effects of SMI on tumor vasculature were determined, and the potential anti-angiogenic components targeting tumor endothelial cells (TECs) were identified. Multidimensional pharmacokinetic profiles of ginsenosides in plasma, subcutaneous tumors, and TECs were investigated. The results showed that the concentrations of protopanaxadiol-type (PPD) ginsenosides (Rb1, Rb2/Rb3, Rc, and Rd) in both plasma and tumors, were higher than those of protopanaxatriol-type (Rg1 and Re) and oleanane-type (Ro) ginsenosides. Among PPD-type ginsenosides, Rd exhibited the greatest concentrations in tumors and TECs after repeated injection. In vivo bioactivity results showed that Rd suppressed neovascularization in tumors, normalized the structure of tumor vessels, and improved the anti-tumor effect of 5-fluorouracil (5FU) in xenograft mice. Furthermore, Rd inhibited the migration and tube formation capacity of endothelial cells in vitro . In conclusion, Rd may be an important active form to exert the anti-angiogenic effect on tumor after SMI treatment.

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Optimizing the Dosing Regimen of Cetuximab and Ramucirumab Using the Model‐Informed Drug Development Paradigm

Khan

Long

et al. 2023

Clin Pharma and Therapeutics

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Model‐informed drug development (MIDD) is a process that integrates drug exposure‐based, biological, and statistical models to enhance the benefit–risk balance in drug development. The US Food and Drug Administration (FDA) MIDD Paired Meeting Pilot Program provides a platform to apply MIDD approaches to drug development and to seek regulatory feedback in a collaborative and streamlined process prior to submission for approval. Eli Lilly and Company (Lilly) participated in the Pilot Program to seek agency alignment to enhance the initial approved dosing regimens of cetuximab (Erbitux; Eli Lilly and Company, Indianapolis, IN) and ramucirumab (Cyramza; Eli Lilly and Company) without conducting additional clinical trials. Here, we describe the overall MIDD strategy at Lilly, the process with the FDA, and the impact of implementing the approach.

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Efficacy, Tolerability, and Biomarker Analyses of Once-Every-2-Weeks Cetuximab Plus First-Line FOLFOX or FOLFIRI in Patients With KRAS or All RAS Wild-Type Metastatic Colorectal Cancer: The Phase 2 APEC Study

Abstract: The observed activity and safety profile is similar to that reported in prior first-line pivotal studies involving weekly cetuximab, suggesting once-every-2-weeks cetuximab is effective and tolerable as first-line therapy and may represent an alternative to weekly administration.

Cited by 20 publications

References 25 publications

Phase II APEC trial: The impact of primary tumor side on outcomes of first‐line cetuximab plus FOLFOX or FOLFIRI in patients with RAS wild‐type metastatic colorectal cancer

Phase II APEC trial: The impact of primary tumor side on outcomes of first‐line cetuximab plus FOLFOX or FOLFIRI in patients with RAS wild‐type metastatic colorectal cancer

Identification of bioactive anti-angiogenic components targeting tumor endothelial cells in Shenmai injection using multidimensional pharmacokinetics

Optimizing the Dosing Regimen of Cetuximab and Ramucirumab Using the Model‐Informed Drug Development Paradigm

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