Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin

Figures & data

Figure 1 Enrollment, randomization and follow-up of patients in the study.

Figure 2 Comparison of progression free survival of nimotuzumab + CT + RT and CT + RT arm.

Figure 3 Comparison of disease free survival of nimotuzumab + CT + RT and CT + RT arm.

Figure 4 Comparison of overall survival of nimotuzumab + CT + RT and CT + RT arm.

Figure 5 Comparison of progression free survival of nimotuzumab + RT and RT arm.

Figure 6 Comparison of disease free survival of nimotuzumab + RT and RT arm.

Figure 7 Comparison of overall survival of nimotuzumab + RT and RT arm.

Table 1 Values of Kd for human recombinant EGF, cetuximab and nimotuzumab in EGF receptors from human and green monkey placentas

	EGF (×10^−8 M)	Cetuximab (×10^−8 M)	Nimotuzumab (×10^−8 M)
Human	0.63 +/− 0.06	0.85 +/− 0.05	4.53 +/− 0.01
Green Monkeys	1.23 +/− 0.03	7.12 +/− 0.1	9.13 +/− 0.01

(Adapted from ref. 9). The results are average ± standard deviation of three experiments with three replicates in each one.

Table 2 Relationship between receptor affinities and incidence of acneiform rash for anti-EGFR monoclonal antibodies

Monoclonal antibody description	Kd (M)	% of skin reaction	References
Panitumumab (ABX-EGF/E7.6.3)	5 × 10^−11	100	4, 16
Fully human IgG2
Cetuximab (C225) chimeric IgG1	1 × 10^−10	90	4, 18
Matuzumab (EMD72000) humanized IgG1	3.4 × 10^−10	64	17
Nimotuzumab (h-R3) humanized IgG1	∼1 × 10^−9	2.9	12, 15

(Adapted from ref. 9).

Table 3 EGFR expression across treatment arms for nimotuzumab + RT and RT arm

	Expression	Nimotuzumab + RT (N = 23)		RT (N = 21)		p value*
		N	%	N	%
EGFR	+ (26–69%)	6	26.09	5	23.81	0.5242
	++ (70–89%)	8	34.78	4	19.05
	+++ (>90%)	7	30.43	11	52.38
	Negative	0	0.00	0	0.00
	(0–25%)
	NA	2	8.70	1	4.76

* p value calculated using Fisher's Exact Test; NA-no data on expression available due to exhaustion of tissue.

Table 4 EGFR expression across treatment arms for nimotuzumab + CT + RT and CT + RT arm

	Expression	Nimotuzumab + CT + RT (N = 23)		CT + RT (N = 23)		p value*
		N	%	N	%
EGFR	+ (26–69%)	9	39.13	4	17.39	0.3961
	++ (70–89%)	7	30.43	10	43.48
	+++ (>90%)	4	17.39	6	26.09
	Negative	1	4.35	0	0.00
	(0–25%)
	NA	2	8.70	3	13.04

* p value calculated using Fisher's Exact Test: NA-no data on expression available due to exhaustion of tissue.

Table 5 Clinical study results: summary

Efficacy variable	Group 1				Group 2
	Nimotuzumab + CT + RT	CT + RT	p-value	Hazard ratio	Nimotuzumab + RT	RT	p value	Hazard ratio
Overall Response Rate (at 24 weeks)	100% (20)	70% (14)	0.020		76% (13)	40% (7)	0.023
Median Progression Free survival (at 30 months)	NA	12.66	0.0132	0.373	10.09	6.9	0.2429	0.666
	(24.42, NA)	(6.44, 25.12)			(4.31, NA)	(5.39, 8.97)
Progression Free Survival Rate (%) (at 30 months)	56.52	21.74	0.0157		34.78	13.04	0.0839
Median Disease Free survival (at 30 months)	NA	25.02	0.0251	0.311	NA	8.33	0.1639	0.489
		(12.66, NA)			(16.17, NA)	(6.18, NA)
Disease Free Survival Rate (%) (at 30 months)	56.52	21.74	0.0157		34.78	13.04	0.0839
Median Overall Survival (at 30 months)	NA	21.96	0.0036	0.266	14.37	12.79	0.7079	0.868
		(6.77, 29.95)			(4.83, NA)	(6.18, 23.31)
Overall Survival Rate (%) (at 30 months)	69.57	21.74	0.0011		39.13	21.74	0.1999

Note: The 95% CI are mentioned in brackets. The 95% confidence intervals for the median survival were computed using 25^th percentile as a lower confidence limit and 75^th percentile as an upper confidence limit. NA, Not Available. In the Overall Response Rate, the number in brackets is the number of evaluable patients.

Table 6 Completed and ongoing clinical trials with nimotuzumab

Study number (Country)	Indication	Phase	Study agent(s)	Publication
COMPLETED
IIC RD EC035 (Cuba)	Epithelial tumors	I	nimotuzumab	Journal of Immunotherapy 2003; 26:139–48
IIC RD EC040 (Cuba)	Head and neck cancer	I/II	nimotuzumab + RT	Journal of Clinical Oncology 2004; 22:1646–54
IIC RD EC046 (Cuba)	Head and neck cancer	I/II	nimotuzumab + RT
YMB1000-004 (Canada)	Head and neck cancer	I	nimotuzumab + RT	Abstract · 926, ASCO Meeting 2002
Nimotuzumab/SCCHN/001/IND (India)	Head and neck cancer	II	RT ± CT ± nimotuzumab	Poster · 2446, ASTRO Meeting 2007
IIC RD EC053 (Cuba)	Adult GBM or AA	I/II	nimotuzumab + RT	Cancer Biology & Therapy 2006; 5:375–9
2002SL0008 (China)	NPC	II	RT ± nimotuzumab	Journal Chinese Oncology 2007; 29:197–201
BN-001 PED-04 (Germany)	Refractory, relapsed, pediatric glioma	II	nimotuzumab	Abstract-Poster · 1522, ASCO Meeting 2006
				Abstract-Poster · 2006, ASCO Meeting 2007
ONGOING
IIC RD EC070 (Cuba)	Breast cancer	I	nimotuzumab + CT	Poster, ECCO, 2007
OSAG-101-BSC-05 (Germany)	Glioma-pediatric	III	nimotuzumab + RT	Abstract/Poster 2058, ASCO Meeting 2008
YMB1000-010 (Canada/Korea)	Non-small cell lung cancer	I/II	nimotuzumab + RT	Abstract/Poster 3037, ASCO Meeting 2008
HH-2004/2 (Germany)	Pancreatic cancer	II	nimotuzumab	Abstract/Poster 12504, ASCO Meeting 2006
YMB1000-007 (Canada)	Solid tumors	I	nimotuzumab	Abstract/Poster 13054, ASCO Meeting 2006

Abbreviations: CT, chemotherapy; RT, radiotherapy; NPC, nasopharyngeal cancer; GBM, glioblastomamultiforme; AA, anaplastic astrocytoma.

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