Last week we began a discussion of the targeted drug, Tarceva (erlotinib) in the treatment of non-small cell lung cancer. We conclude, with references, this week.

It is difficult to reconcile the results of the two phase III clinical trials that we described in last week's newsletter. In the 2005 Canadian study, patients who received Tarceva lived approximately two months longer than those who did not receive the drug (Shepherd 2005). In the larger M.D. Anderson study, however, there was no survival advantage whatsoever in the general patient population, although lifelong non-smokers did seem to benefit (Herbst 2005). Each trial featured a somewhat dissimilar drug regimen and a different patient population. So the divergent results were probably due to differences in the way that patients were selected for the two studies.

As scientists get better at choosing which patients are likely to benefit from Tarceva treatment (for example, including or excluding patients based on previous smoking history or on tests for the presence of EGFR mutations) they may be able to make Tarceva work more effectively, even though the number of patients for whom it may truly be useful will be but a diminishing percentage of the total.

On June 1, 2004, Sloan-Kettering Institute filed a patent application entitled "Use of mutations in EGFR kinase as an indicator of therapeutic efficacy of erlotinib in the treatment of NSCLC." They hope to make targeted drugs more effective by treating only those patients whose genetic profile indicates that they are likely to benefit. It is a laudable goal. But whether drug companies, such as Genentech, will take to such a narrowly focused patient base remains to be seen. For obvious reasons their profits are tied to increasing, rather than restricting, the number of people who receive their medications. In fact, it is highly ironic that the better scientists become at pinpointing the recipients who are most likely to benefit from such drugs, the less value those drugs will have for the pharmaceutical industry.

According to an article by Robert L. Comis, MD, of Drexel University, Philadelphia, in the magazine Oncologist, there are no clear cut factors that predict either objective response, time to progression, or survival with Tarceva (or for a similar drug, Iressa) in NSCLC. In particular, patients who are female, lifetime non-smokers, and have adenocarcinoma, particularly if they are of Asian descent, might derive the most benefit. But Comis emphasizes that "the vast majority of lung cancer patients do not fit into the categories of patients that might derive benefit from [Tarceva] erlotinib-based interventions for advanced lung cancer and less advanced disease" (Comis 2005).

Meanwhile, Genentech may run into consumer resistance to its strategy of charging whatever the market will bear for these drugs. A study in Canada showed that lung cancer patients, while accepting the general utility of such treatments, are only willing to pay around $100 per month in Canadian dollars (equal to around US $90) for such a drug. In reality, the cost of Tarceva alone is US $90 per day (not per month!), or over $30,000 per year. Avastin will cost much more still - around $100,000 per year for lung cancer patients.

The economic reality is that many patients will be discouraged when they hear the price (especially if they are paying all or a substantial part of the cost out of pocket) and will avoid these medications because they are so wildly overpriced. In Canada, only a minority of NSCLC patients are still receiving employment income. The rest rely on disability payments, pension income, or social assistance for financial support (Leighl 2006). In the US, the safety net for patients is even less secure. But the fact that patients cannot afford these drugs (without selling or mortgaging their homes) does not mean that they will not agonize over the "your money or your life" choice. Maybe if the evidence of the limited benefit of these drugs were presented in a more objective way, patients and their physicians could make more informed decisions about whether or not to include Tarceva or Avastin in their treatment protocols.

--Ralph W. Moss, Ph.D.

References:

Comis RL. The current situation: Erlotinib (Tarceva) and gefitinib (Iressa) in non-small cell lung cancer. Oncologist. 2005;10:467-470.

Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005;23:5892-9.

Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101:13306-13311.

Shepherd FA, Rodrigues Pereira J, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123-132.

Leighl NB, Tsao WS, Zawisza DL, Nematollahi M, Shepherd FA. A willingness-to-pay study of oral epidermal growth factor tyrosine kinase inhibitors in advanced non-small cell lung cancer. Lung Cancer. 2006;51:115-121.

Susan, David. Analysis: Drugs added to cancer guidelines, March 9, 2006. Available at:
http://www.sciencedaily.com/upi/index.php?
feed=Science&article=UPI-1-20060309-19085300-bc-us-cancer-biologicals-analysis.xml

Dr. David Ettinger's consulting work for Genentech is described at:
http://theoncologist.alphamedpress.org/cgi/content/full/11/4/358

Dr. Mark Kris's consulting work for Genentech is described at:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=545207&rendertype=abstract