Revisiting Gefitinib Discloses Continuing Citations and Persistent Debate

Revisiting Gefitinib Discloses Continuing Citations and Persistent Debate

by David W. Sharp

WHAT'S HOT IN MEDICINE
Rank	Paper	Cites This Period (Mar-Apr 06)	Rank Last Period (Jan-Feb 06)
1	T.J. Lynch, et al., "Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib," New Engl. J. Med., 350(21): 2129-39, 20 May 2004. [Harvard Med. Sch., Boston, MA; Harvard Sch. Public Health, Boston, MA] *821XM	87	1
2	H.H. Hurwitz, et al., "Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer," New Engl. J. Med., 350(23): 2335-42, 3 June 2004. [9 U.S. institutions] *825JY	75	3
3	J.G. Paez, et al., *"EGFR* mutations in lung cancer: Correlation with clinical response to gefitinib therapy,"** Science, 304(5676): 1497-1500, 4 June 2004. [7 U.S. and Japanese institutions] *825YR	70	2
4	G.L. Anderson, et al. (Women’s Health Initiative Steering Comm.), "Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative randomized controlled trial," JAMA-J. Amer. Med. Assoc., 291(14): 1701-12, 14 April 2004. [Program office: NHLBI, Bethesda, MD] *811RJ	63	4
5	A.A. Hedley, et al., "Prevalence of overweight and obesity among US children, adolescents, and adults, 1999-2002," JAMA-J. Am. Med. Assoc., 291(23): 2847-50, 16 June 2004. [Ctrs. Dis. Control & Prevent., Atlanta, GA and Hyattsville, MD; U. Calif., Berkeley] *828GT	58	7
6	D. Cunningham, et al., "Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer," New Engl. J. Med., 351(4): 337-45, 22 July 2004. [9 institutions worldwide] *839RC	45	9
7	M.R. Bristow, et al. (for the COMPANION Investigators), "Cardiac-resynchronization therapy with or without an implantable defribrillator in advanced chronic heart failure," New Engl. J. Med., 350(21): 2140-50, 20 May 2004. [12 U.S. institutions] *821XM	42	5
8	G.H. Bardy, et al. (for the SCD-HeFT Investigators), "Amiodarone or an implantable cardioverter-defribrillator for congestive heart failure," New Engl. J. Med., 352(3): 225-37, 20 January 2005. [7 U.S. institutions] *888JP	42	10
9	R.S. Bresalier, et al., "Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial," 352(11): 1092-1102, 17 March 2005. [8 institutions worldwide] *906PU	42	†
10	C.P. Cannon, et al., "Intensive versus moderate lipid lowering with statins after acute coronary syndromes," New Engl. J. Med., 350(15): 1495-504, 8 April 2004. [5 institutions worldwide] *810CI	41	5
SOURCE: Thomson Scientific's Hot Papers Database. Read the Legend.

ne expectation from molecular medicine is that research at the subcellular, and especially genetic, level will identify targets for more precise pharmacological attack and thus lead to real breakthroughs in drug treatment. The anticancer drug gefitinib illustrates both the excitement that the research community feels about this approach and some of the frustration that clinicians and patients may experience. When this column first touched on gefitinib early last year (see Science Watch, 16[1]: 5, January/February 2005), clinical trials in patients with lung cancer of the non-small-cell type (NSCLC) were starting to appear and there was a hint that testing for mutations in the epidermal growth factor receptor gene (EGFR) might allow more selective prescription of this drug. It is the latter point that has been dominating the Top Ten listings for some time now. Papers #1, #3, and #11 were, respectively, #1, #2, and #8 last time out but they are by no means the only studies of this sort to have been published.

In brief, Lynch et al. (#1) found EGFR mutations in 8 out of 9 gefitinib responders but in none of the 7 patients with no response to the drug. A comparison of Japanese and U.S. tissue samples (#3) was also supportive of a role for such mutations. The third paper, just off the list at #11 (W. Pao, et al., PNAS, 101[36]: 13306-11, 2004; latest citation count 41, total cites 289), had results similar to those in #1 but has the added interest of having data on another synthetic anilinoquinazoline called erlotinib. In June and July, 2006, three more papers were published, all confirming that tumors showing positive for EGFR mutations indicate that a clinical response to gefitinib is more likely. It must be stressed that "response" is a long way short of "cure" and the studies have been done in patients with previously treated advanced lung cancer. A year ago, gefitinib’s prospects took a blow with publication of the Iressa [gefitinib] Survival Evaluation in Lung Cancer trial, which indicated no significant survival advantage (5.6 months for those on gefitinib and 5.1 months for the placebo group; see N. Thatcher, et al., Lancet, 366[9496]: 1527-37, 2005).

Other agents with a target or targets similar to that of gefitinib are in the pipeline but the one attracting most clinical attention is erlotinib, in part because it already has full Food and Drug Administration approval. A recent review from the Christie Hospital, Manchester, U.K., covers the gefitinib story and looks at the future of both drugs (F. Blackhall, et al., Lancet Oncol., 7[6]: 499-506, 2006). The two agents have not yet been compared head to head but, official approval status apart, toxicity profiles may influence decisions. When cure is not in immediate prospect, as here, the quality of life in any enhanced survival time is just as important as the increase in life expectancy. In an influential Canadian trial erlotinib did confer a survival advantage over placebo of around eight weeks (F.A. Shepherd et al., New Engl. J. Med., 353[2]: 123-32, 2005), and from the same trial comes evidence that EGFR status is important with this agent too (G.M. Clark, et al., Clin. Lung Cancer, 7[6]: 389-94, 2006).

The makeup of genes controlling target proteins has not been the sole focus of these studies. Lung cancers are diagnosed in non-smokers, and smoking status is a simpler observation that has been analyzed in some studies—indeed, in Clark and colleagues’ paper cited above it appeared that "smoking history might be more predictive of survival benefit than EGFR expression." Histological cancer subtype, a well-established and non-molecular variable, is also being taken into account.

Mr. David W. Sharp, M.A. (Cambridge) is a contributing editor with The Lancet, London, U.K.



	View the top 10 scientists and/or top 3 Hot Papers in Clinical Medicine.

Science Watch^®, September/October 2006, Vol. 17, No. 5
Citing URL: http://www.sciencewatch.com/sept-oct2006/sw_sept-oct2006_page5.htm