Cetuximab Every 2 Weeks Versus Standard Weekly Dosing Administration Schedule

Figures & data

Table 1. Mean (SD) pharmacokinetics parameters at week 5 in the EMR 62202-045 study.

Dose, mg/m^2 (n)	Dosing schedule	Cmin, μg/ml^†	AUC0-t, μg/ml/h^†	t1/2, h	CL, l/h
400/250 (n = 13)	Q1W	49.6 (26.1)	17,787 (6739)	100.6 (32.3)	0.027 (0.009)
400 (n = 8)	Q2W	25.6 (11.8)	28,202 (6711)	134.7 (38.6)	0.027 (0.007)
500 (n = 9)	Q2W	34.7 (16.0)	35,794 (8180)	137.0 (44.5)	0.026 (0.008)
600 (n = 10)	Q2W	47.3 (30.8)	44,392 (22,349)	133.2 (20.4)	0.028 (0.011)
700 (n = 6)	Q2W	69.9 (25.4)	60,927 (9340)	156.1 (48.5)	0.19 (0.004)

† C_min and AUC for Q2W schedules reached steady state on week 5, except for 700 mg/m² group when steady state reached around week 11.

AUC: Area under the concentration time curve; CL: Clearance; C_min: Minimum concentration; PK: Pharmacokinetics; Q1W: Weekly; Q2W: Every 2 weeks; SD: Standard deviation; t_1/2: Elimination half-life.

Table 2. Comparable efficacy of first-line cetuximab every 2 weeks dosing schedule plus FOLFOX versus cetuximb weekly plus folinic acid/fluorouracil/oxaliplatin.

Study	Design	n	ORR, %	mPFS, months	mOS, months	Ref.
Studies evaluating Q2W schedule
CECOG-CORE2	Randomized phase II	77	62.0	9.2	23.0	[25]
APEC	Nonrandomized phase II	188	61.2	11.1	27.0	[13]
OPTIMIX-ACROSS	Open-label Single-arm Nonrandomized phase II	99	60.6	10.1	20.8	[29]
FLEET^†	Open-label Single-arm Nonrandomized phase II	37	64.9	13.1	38.1	[14]
CEBIFOX	Single-arm Nonrandomized phase II	57	64.9	10.1	28.7	[28]
CELINE^†	Open-label Nonrandomized phase II	60	70.0	13.7	31.0	[27]
Ji et al.	Nonrandomized phase II	73	72.6	9.8	NR	[30]
Studies evaluating Q1W reference schedule
CECOG-CORE2	Randomized phase II	75	53.0	9.5	25.8	[26]
OPUS	Randomized phase II	82	57.0	8.3	22.8	[53]

† KRAS/BRAF wt.

Outcomes with cetuximab Q2W or Q1W in combination with FOLFOX were consistent with previous data from the cetuximab plus FOLFOX arm of the OPUS study (KRAS wt).

FOLFOX: Folinic acid/fluorouracil/oxaliplatin; mOS: Median overall survival; mPFS: Median progression-free survival; NR: Not reported; ORR: Objective response rate; Q1W: Weekly; Q2W: Every 2 weeks; wt: Wild-type.

Table 3. Comparable efficacy of first-line cetuximab Q2W dosing schedule plus FOLFIRI versus cetuximab Q1W plus FOLFIRI.

Study	Design	Biomarker selection	n	ORR, %	mPFS, months	mOS, months	Ref.
Studies evaluating Q2W schedule
APEC	Nonrandomized phase II	KRAS wt	101	54.5	11.1	26.6	[13]
		RAS wt	57	68.4	12.8	28.7
Personeni	Non-randomized phase II	KRAS wt	168	48.9	8.2	23.3	[31]
Studies evaluating Q1W reference schedule
CRYSTAL	Randomized phase III	KRAS wt	316	57.3	9.9	23.5	[54]
		RAS wt	178	66.3	11.4	28.4

Outcomes with cetuximab Q2W in combination with FOLFIRI were consistent with previous data from the pivotal CRYSTAL study of cetuximab Q1W plus FOLFIRI in RAS wt mCRC.

FOLFIRI: Folinic acid/fluorouracil/irinotecan; mCRC: Metastatic colorectal cancer; mOS: Median overall survival; mPFS: Median progression-free survival; ORR: Overall response rate; Q1W: Weekly; Q2W: Every 2 weeks; wt: Wild-type.

Table 4. Comparable outcomes of ≥third-line cetuximab Q2W plus irinotecan with those from prior studies of cetuximab Q1W plus irinotecan in KRAS-unselected or wild-type chemorefractory mCRC.

Study	Design	Biomarker selection	n	ORR, %	mPFS, months	mOS, months	Ref.
Studies evaluating Q2W schedule
Jensen et al.	Non-randomized phase II	(K)RAS-unselected	174	16.7 (PR)	4.3	10.6	[36]
		KRAS exon 2 wt	104	25.0 (PR)	5.5	12.1
Studies evaluating Q1W reference schedule
BOND	Randomized Open-label phase III	(K)RAS-unselected	218	22.9 (PR)	4.1	8.6	[55]
Di Fiore et al.	Meta-analysis	KRAS exon 2 wt	182	42.3 (CR ± PR)^†	5.5	13.2	[56]

† CR: 1.6%; PR: 40.7%.

CR: Complete response; mCRC: Metastatic colorectal cancer; mOS: Median overall survival; mPFS: Median progression-free survival; ORR: Overall response rate; PR: Partial response; Q1W: Weekly; Q2W: Every 2 weeks; wt: Wild-type.

Figure 1. PADIS study results.

(A) Q2W was noninferior to Q1W for median OS (months) after IPTW (27.9 vs 24.7). (B) Q2W was noninferior to Q1W for median PFS (months) after IPTW (10.1 vs 10.3).

HR: Hazard ratio; IPTW: Inverse probability of treatment weighting; OS: Overall survival; PFS: Progression-free survival; Q1W: Weekly; Q2W: Every 2 weeks.

Figure reproduced (without changes) from Kasper et al. [10], under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Figure 2. QUICK study results: Q2W was noninferior* to Q1W for overall survival in a line-agnostic setting.

*HR (95% CI), 0.94 (0.85–1.03).

HR: Hazard ratio; Q1W: Weekly; Q2W: Every 2 weeks.

Figure reproduced (without changes) from Lamy et al. [11], under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Brodowicz T , CiuleanuTE, RadosavljevicDet al. FOLFOX4 plus cetuximab administered weekly or every second week in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer: a randomized phase II CECOG study. Ann. Oncol.24(7), 1769–1777 (2013).

 PubMed Web of Science ®Google Scholar

Cheng AL , CornelioG, ShenLet al. 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 II APEC Study. Clin. Colorectal Cancer16(2), e73–e88 (2017).

 PubMed Web of Science ®Google Scholar

Fernandez-Plana J , PericayC, QuinteroGet al. Biweekly cetuximab in combination with FOLFOX-4 in the first-line treatment of wild-type KRAS metastatic colorectal cancer: final results of a phase II, open-label, clinical trial (OPTIMIX-ACROSS Study). BMC Cancer14, 865 (2014).

 PubMed Web of Science ®Google Scholar

Soda H , MaedaH, HasegawaJet al. Multicenter Phase II study of FOLFOX or biweekly XELOX and Erbitux (cetuximab) as first-line therapy in patients with wild-type KRAS/BRAF metastatic colorectal cancer: The FLEET study. BMC Cancer15, 695 (2015).

 PubMed Web of Science ®Google Scholar

Kasper S , MeilerJ, KnippHet al. Biweekly Cetuximab Plus FOLFOX6 as First-Line Therapy in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The CEBIFOX Trial. Clin. Colorectal Cancer19 (4), 236–247; e236 (2020).

 PubMed Web of Science ®Google Scholar

Kotake M , AoyamaT, MunemotoYet al. Multicenter phase II study of infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin, plus biweekly cetuximab as first-line treatment in patients with metastatic colorectal cancer (CELINE trial). Oncol. Lett.13(2), 747–753 (2017).

 PubMed Web of Science ®Google Scholar

Ji JH , ParkSH, LeeJet al. Prospective phase II study of neoadjuvant FOLFOX6 plus cetuximab in patients with colorectal cancer and unresectable liver-only metastasis. Cancer Chemother. Pharmacol.72(1), 223–230 (2013).

 PubMed Web of Science ®Google Scholar

Jensen BV , SchouJV, JohannesenHHet al. Cetuximab every second week with irinotecan in patients with metastatic colorectal cancer refractory to 5-FU, oxaliplatin, and irinotecan: KRAS mutation status and efficacy. J. Clin. Oncol.28(Suppl. 15), 3573–3573 (2010).

 Google Scholar

Bokemeyer C , BondarenkoI, HartmannJTet al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann. Oncol.22(7), 1535–1546 (2011).

 PubMed Web of Science ®Google Scholar

Personeni N , RimassaL, VerusioCet al. FOLFIRI and Cetuximab Every Second Week for First-Line Treatment of KRAS Wild-Type Metastatic Colorectal Cancer According to Phosphatase and Tensin Homolog Expression: A Phase II Study. Clin. Colorectal Cancer14(3), 162–169 (2015).

 PubMed Web of Science ®Google Scholar

Van Cutsem E , LenzHJ, KöhneCHet al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J. Clin. Oncol.33(7), 692–700 (2015).

 PubMed Web of Science ®Google Scholar

Jensen BV , SchouJV, YilmazMet al. Cetuximab plus irinotecan administered biweekly with reduced infusion time to heavily pretreated patients with metastatic colorectal cancer and related RAS and BRAF mutation status. Int. J. Cancer doi:10.1002/ijc.33448 (2020). ( Online ahead of print).

 Web of Science ®Google Scholar

Cunningham D , HumbletY, SienaSet al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med.351(4), 337–345 (2004).

 PubMed Web of Science ®Google Scholar

Fiore FD , CutsemEV, Laurent-PuigPet al. Role of KRAS mutation in predicting response, progression-free survival, and overall survival in irinotecan-refractory patients treated with cetuximab plus irinotecan for a metastatic colorectal cancer: analysis of 281 individual data from published series. J. Clin. Oncol.26(Suppl. 15), 4035 (2008).

 PubMedGoogle Scholar

Kasper S , FochC, MessingerDet al. Noninferiority of cetuximab every-2-weeks versus standard once-weekly administration schedule for the first-line treatment of RAS wild-type metastatic colorectal cancer. Eur. J. Cancer144, 291–301 (2021).

 PubMed Web of Science ®Google Scholar

Lamy FX , BatechM, BoutmyEet al. Comparative effectiveness of weekly versus every-2-weeks cetuximab in metastatic colorectal cancer in a US-insured population. J. Comp. Eff. Res.9(16), 1117–1129 (2020).

 PubMed Web of Science ®Google Scholar