Personalized Therapy in Lung Cancer: Focused on Molecular Targeted Therapy

Shin Yup Lee; Jae Yong Park

doi:10.6058/jlc.2011.10.1.1

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Lee and Park: Personalized Therapy in Lung Cancer: Focused on Molecular Targeted Therapy

Original Article

J Lung Cancer 2011;10(1):1-12.

Published online: 11 January 2011

DOI: https://doi.org/10.6058/jlc.2011.10.1.1

Personalized Therapy in Lung Cancer: Focused on Molecular Targeted Therapy

Shin Yup Lee, M.D., Jae Yong Park, M.D.

Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea

Address for correspondence Jae Yong Park, M.D., Ph.D. Department of Internal Medicine, Kyungpook National University School of Medicine, 50, Samdeok-dong 2-ga, Jung-gu, Daegu 700-712, Korea Tel: 82-53-420-5536 Fax: 82-53-426-2046 E-mail: jaeyong@kyungpook.ac.kr

Revised 2 June 201113 June 2011 Accepted 14 June 2011

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Lung cancer is the leading cause of cancer death worldwide, with an overall 5 year survival rate of 15%. Most patients present with advanced disease that requires systemic chemotherapy, which merely confers several months of survival benefit. Recent advances in understanding the molecular mechanisms underlying lung cancer have led to molecular targeted therapy in this field. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the first successful personalized therapy for non-small cell lung cancer (NSCLC), with about 30 months of median overall survival in patients with sensitive EGFR mutations. In addition, monoclonal antibodies against vascular endothelial growth factor (VEGF) or EGFR are also in current clinical use. Resistance to EGFR-TKIs has emerged as a major limitation of these agents and become challenge clinically. A number of novel targeted agents have been developed and investigated in clinical trials to overcome the limitation of agents currently available. Recently, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene (EML4-ALK), as a novel molecular target of NSCLC, has been identified, and its inhibitor is under rapid clinical development. We herein review the molecular targeted therapies currently available for NSCLC and discuss the clinical data of novel agents under clinical development. (J Lung Cancer 2011;10(1):1 ? 12)

Keywords: Individualized Medicine, Lung neoplasms, Molecular targeted therapy

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Table 1.

Main Clinical Trials of the First Generation EGFR-TKIs

Study	Phase	Setting	Treatment	PFS (mo)	OS (mo)	RR (%)	Primary end point
IDEAL 1	II	2nd/3rd line	G250	2.7	7.6	18.4
			G500	2.7	8.0	19
IDEAL 2	II	3rd line	G250	N/A	7.0	12
			G500		6.0	9
ISEL	III	2nd/3rd line	G	3.0	5.6	8	OS (Unmet)
			Placebo	2.6	5.1	1
BR.21	III	2nd/3rd line	E	2.2	6.7	9	OS (Met)
			Placebo	1.8	4.7	1
INTEREST	III	2nd line, non-inferiority	G	2.2	7.6	9.1	OS (Met)
			Docetaxel	2.7	8.0	7.6
IPASS	III	1st line, non-inferiority	G	5.7	18.6	43.0	PFS (Met)
		Asian, adenocarcinoma, never/light smokers	Pac/Carb	5.8	17.3	32.2
SATURN	III	Maintenance after platinum	E	12.3 wks	12.0	12	PFS (Met)
		doublet	Placebo	11.1 wks	11.0	5
ATLAS	III	Maintenance after platinum	Bev＋ E	4.8	14.4	N/A	PFS (Met)
		doublet＋ Bev	Bev＋ placebo	3.7	13.3	N/A
INTACT 1	III	1st line	Gem/Cis＋ G250 (cont’ d)	5.8	9.9	50.3	OS (Unmet)
			Gem/Cis＋ G500 (cont’ d)	5.5	9.9	49.7
			Gem/Cis＋ placebo	6.0	10.9	44.8
INTACT 2	III	1st line	Pac/Carb＋ G250 (cont’ d)	N/A	9.8	30.4	OS (Unmet)
			Pac/Carb＋ G500 (cont’ d)		8.7	30.0
			Pac/Carb＋ placebo		9.9	28.7
TRIBUTE	III	1st line	Pac/Carb＋ E (cont’ d)	N/A	10.6	21.5	OS (Unmet)
			Pac/Carb＋ placebo		10.5	19.3
TALENT	III	1st line	Gem/Cis＋ E (cont’ d)	N/A	10.0	31.5	OS (Unmet)
			Gem/Cis＋ placebo		10.3	29.9
BeTA	III	2nd line	E＋ Bev	3.4	9.3	12.6	OS (Unmet)
			E＋ placebo	1.7	9.2	6.2

PFS: progression free survival, OS: overall survival, RR: response ratio, mo: months, G250: gefitinib 250 mg, G500: gefitinib 500 mg, G: gefitinib, E: erlotinib, Pac/Carb: paclitaxel/carboplatin, Bev: bevacizumab, Gem/Cis: gemcitabine/cisplatin, cont’ d: continued, N/A: not assessed.

Table 2.

Summary of EGFR Biomarker Analyses from Randomised Trials

Groups	Treatment	High expression, high copy number, or mutation positivity		Low expression, low copy number, or mutation negativity		p-inter^†
Groups	Treatment	HR∗ (95% CI)	p-value	HR∗ (95% CI)	p-value	p-inter^†
EGFR copy number
BR.21	E vs plac	0.43 (0.23∼0.78)	0.004	0.80 (0.49∼1.29)	0.35	0.12
ISEL	G vs plac	0.61 (0.36∼1.04)	0.07	1.16 (0.81∼1.64)	0.42	0.05
INTEREST	E vs Doc	1.09 (0.78~1.51)	0.62	NR
EGFR protein expression
BR.21	E vs plac	0.68 (0.49∼0.95)	0.02	0.93 (0.63∼1.36)	0.70	0.25
ISEL	G vs plac	0.77 (0.56∼1.08)	0.13	1.57 (0.86∼2.87)	0.14	0.05
EGFR mutation
BR.21	E vs plac	0.55 (0.25∼1.19)	0.12	0.74 (0.52∼1.05)	0.09	0.47
IPASS	G vs PCa	0.48 (0.36∼0.64)^‡	＜0.0001	2.85 (2.05∼3.98)^‡	＜0.0001	＜0.0001
KRAS mutation
BR.21	E vs plac	1.67 (0.62∼4.50)	0.30	0.69 (0.49∼0.97)	0.03	0.09

^∗ HR is for overall survival unless otherwise stated

^† p for interaction

^‡ HR is for progression free survival.

E: erlotinib, G: gefitinib, plac: placebo, Doc: docetaxel, PCa: paclitaxel-carboplatin, HR: hazard ratio, CI: confidence interval, NR: not reported.

Table 3.

Mechanisms of Resistance to EGFR-TKI

Intrinsic resistance	Acquired resistance
Drug-resistant EGFR mutations	Second-site EGFR mutations
- T790M	- T790M, D761Y, T854A
- Exon 20 insertion	Pathways bypassing EGFR signaling
Genomic alterations co-occuring with EGFR mutations	- MET activation
- HER2 TK domain mutations	ㆍ MET gene amplification
- PTEN loss	ㆍ HGF overexpression
- PIK3CA mutation	- IGF 1R overexpression
- IGF 1R overexpression	- Epithelial to mesenchymal transition (EMT)
Resistance in EGFR wild type tumors
- KRAS mutation
- BRAF mutation
- EML4-ALK
- MET activation
ㆍ MET amplification
ㆍ HGF overexpression

Table 4.

Targeted Agents for Lung Cancer in Clinical Development

Class of target	Drug	Target	Phase∗
ErbB family	BIBW2992 (Afatinib)	EGFR, HER2 (irreversible)	III
	HKI-272 (Neratinib)	EGFR, HER2 (irreversible)	II
	Lapatinib	EGFR, HER2 (reversible)	II
	AV-412/MP-412	EGFR, HER2 (reversible)	I
	AZD8931	EGFR, HER2/3 (reversible)	I
	PF-00299804	EGFR, HER2/4 (irreversible)	III
	EKB-569 (Pelitinib)	EGFR, HER2/4 (irreversible)	II
	IMC-11F8 (Necitumumab)	EGFR (monoclonal antibody)	III
	Pertuzumab	HER2 (monoclonal antibody)	II
EGFR/VEGF	ZD-6474 (Vandetanib)	EGFR, VEGFR2, RET	III
	BMS-690514	EGFR, HER2/4, VEGFR1/2/3	II
	XL647	EGFR, HER2, VEGFR2/3, EPHB4	II
MET	PF-02341066 (Crizotinib)	MET, ALK	III
	ARQ197	MET	III
	XL184	MET, VEGFR1/2/3, RET, c-Kit, Flt3	II
	GSK1363089 (Foretinib)	MET, VEGFR1/2/3, PDGFR, c-Kit, Flt3	I/II
	MetMAb	MET (monoclonal antibody)	II
IGF1R	CP-751,871 (Figitumumab)	IGF1R	III
PI3K/AKT/mTOR pathway	Temsirolimus	mTOR	II
	Everolimus	FKBP-12, mTOR	II
	AP23573	mTOR	II
	MK2206	AKT	II
	XL147	PI3K	I
	Enzastaurin	PKC	II
	ISIS3521	PKC	III
RAS/RAF/MAPK/MEK pathway	AZD6244	MEK	II
	PD-0325901	MEK	II
STAT signaling	Dasatinib	Src, PDGFR, c-Kit	II
HSP90	IPI-504 (Retaspimycin)	Hsp90	II
	17-AAG (Tanespimycin)	Hsp90	I
VEGFR	Sorafenib	VEGFR2/3, PDGFR, RAF, c-Kit	III
	Sunitinib	VEGFR1/2/3, PDGFR, c-Kit, RET, Flt3	III
	BIBF-1120	VEGFR, PDGFR, FGFR	III
	Cediranib	VEGFR1/2/3, PDGFR, c-Kit	III
	Motesanib	VEGFR1/2/3	III

^∗ Based on ClinicalTrials.gov.

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