Cancer Decisions - Free Newsletter

ERBITUX REDUX, Part Two

The Cunningham-Merck Study on Colorectal Cancer

Another clinical study on the new drug Erbitux was presented at this year's meeting of the American Society of Clinical Oncology (ASCO), this one focusing on the use of Erbitux in the treatment of advanced colorectal cancer (Abstract #1012). The German pharmaceutical company, Merck, which owns the European rights to Erbitux, sponsored the study. Dr. David Cunningham of the Royal Marsden Hospital, Sutton, England, was lead investigator. The study concluded that Erbitux, when combined with the cytotoxic drug irinotecan (CPT-11), shrank tumors in 17.9 percent of patients who had previously failed to respond to chemotherapy. By itself, Erbitux shrank tumors in just 9.9 percent, according to the abstract. The median time to progression was 126 days with the combined treatment compared to just 45 days with Erbitux alone.

In a Reuters Health story, Dr. Cunningham gave slightly better figures. "Tumors shrank in 22.9% of patients in the two-drug arm and in 10.8% of patients in the single-drug arm," he said. "Median time to progression was 4.1 months in the combination arm and 1.5 months in the cetuximab [Erbitux]-only arm. Disease stabilized in 55% of patients in the two-drug arm and 32% in the one-drug arm."

At its website, ASCO reprints this Reuters Health story, which characterizes this treatment as "effective". Dr. Cunningham said that this study independently confirmed the "significant activity" of Erbitux in colorectal cancer. He said that the study "may help set new paradigms in the management of patients with metastatic colorectal cancer that has progressed after standard chemotherapy."

"Cetuximab [Erbitux, ed.] seems to modify resistance to conventional cytotoxic drugs," said Dr. Cunningham. He also described Erbitux as "clearly a valuable agent on its own." But exactly how valuable is "clearly valuable on its own?" In this case, it means a time to progression that averages just 45 days and an overall response rate of around 10 percent!

Similarly, oncologists routinely describe the side effects of new agents such as Erbitux as "acceptable." But in this study, "acceptable" meant that roughly 65 percent of patients in the combination arm had serious side effects such as neutropenia (depletion of a certain type of white blood cells), diarrhea, weakness, rash or vomiting. Approximately 50 percent of the Erbitux-only arm experienced "severe side effects including difficulty breathing, weakness and abdominal pain."

Several important warnings need to be sounded about the Erbitux studies:

First, these are small studies, involving just dozens of patients. By contrast, a randomized controlled trial (RCT) generally needs to recruit hundreds of patients. For example, a recent RCT comparing four chemotherapy regimens for NSCLC (non-small cell lung cancer) involved 1,207 patients (Schiller 2002). Large, randomized, multi-center studies would be needed in order to draw any firm conclusions about the actual effectiveness of Erbitux, and these have not yet been done.

Second, we are interpreting abstracts here, not full-scale scientific papers. In abstracts, key information is often omitted. For instance, the M.D. Anderson analysis was limited to "evaluable" patients. That raises a red flag. The paper doesn't mention how many patients were eliminated from consideration for being "unevaluable," i.e., they began the treatment, but later dropped out. Biostatisticians usually insist that all patients who begin a trial be included in the final analysis, on a so-called "intention-to-treat" basis. (Otherwise, one could inflate statistics by systematically excluding non-responders from the evaluation). This "intention-to-treat" criterion often diminishes the perceived benefit of a treatment.

The Cunningham study authors also state that their "preliminary evaluation is based on investigator assessment." This acknowledgement of the intrinsic subjectivity of their interpretation is especially unsettling given that the paper was sponsored by a pharmaceutical company, an interested party, to say the least.

Third, in the lung cancer study there were no complete responses in the treated group; the activity of Erbitux and Taxol resulted only in partial responses and stabilizations. (Nor is there any mention of complete responses in the colorectal study abstract). It is important to keep one's eye on the terminology. A "partial response" is defined as the shrinkage of measurable tumor by 50 percent or more for one month or more. But such 'responses' are of dubious therapeutic value and do not necessarily correlate with increased survival. (See my book, Questioning Chemotherapy, for a fuller treatment of this topic.) When all is said and done, we have no evidence of increased survival with Erbitux.

This is important to point out, since, as I have shown, not long ago Erbitux and similar drugs (such as Iressa, which also targets EGFR) were being touted as 'magic bullets' for cancer. After all the positive publicity, which created a frenzy of public anticipation, Erbitux is now being quietly redefined within the scientific community as an adjuvant to standard chemotherapy, and a relatively weak one at that.

Unfortunately, this subtle but crucial redefinition may not reach everyone whose hopes have been raised by the media's exuberant attention. There are sufficient reasons to be cautious in interpreting the Erbitux data. But some doctors are already saying that the ASCO studies prove the drug's utility. "The results showed that patients who got the combination [of Erbitux and Taxotere, ed.] did much better," according to Dr. Nasser Hanna, an assistant professor of medicine at Indiana University, who attended the sessions.

Did much better…than what? Since the studies in question did not randomly assign patients to a control group receiving no Erbitux, there was by definition no basis for comparison with other treatments. We do not know how well a comparable group, receiving, say, standard chemotherapy alone, or best supportive care alone, would have fared when directly compared with the Erbitux or Erbitux-Taxotere groups.

Some people might argue that we can infer this information from previously reported studies: an often-cited clinical trial from M.D. Anderson, for example, showed that the response rate to Taxotere alone in NSCLC was just 10.8 percent (Fossella 2000). So, does this mean that Erbitux, when added to Taxotere, doubles that drug's response rate? Indeed it does not, but interested parties may well argue in just that manner before the FDA in the months to come.

Salt Lake City Study

Such comparisons are extremely slippery. There are reports that chemotherapy given without benefit of Erbitux may yield results that are comparable to, or even better than, those with Taxotere and Erbitux combined. For instance, in May, 2003, the journal Cancer published the results of a phase II trial from Salt Lake City on the use of high-dose Taxol (paclitaxel, another taxane, similar to docetaxel) in advanced NSCLC. This showed even better results using Taxol alone than was reported at ASCO with the Taxotere-Erbitux combination for NSCLC. Using high-dose Taxol alone, there were 16 partial responses (42%). Compare this to the 28 percent of patients who had partial responses with the Taxotere-Erbitux combination in the NSCLC study. High-dose Taxol seems to work as well without the need to add Erbitux.

Other combinations routinely work as well as Taxotere-Erbitux. "In single institution Phase II studies that evaluated the paclitaxel plus carboplatin regimen," says the NCI's PDQ statement for professionals, "response rates have been in the range of 27% to 53% with 1-year survival rates of 32% to 54%" in stage IV NSCLC. Thus, standard chemotherapy alone routinely achieves the same or better response rate than this new treatment. Of course, critics will quickly point out that there were differences between patients in the various trials. Also, Taxol and Taxotere are slightly different compounds, making a direct comparison questionable.

In addition, patients in the Salt Lake trial cited above were "chemotherapy-naive," (i.e., had not been previously treated with chemotherapy) and might therefore be expected to fare better than those who had been heavily pretreated with cytotoxic drugs. I wouldn't try to push the comparison too far. In fact, it is precisely the difficulty of comparing such disparate studies that makes randomized controlled trials (RCTs) the gold standard when it comes to compiling evidence of effectiveness. Phase III RCTs by their nature randomly assign comparable patients to different treatment arms and then observe how the groups fare, especially in regard to that key indicator of benefit, median overall survival. Such trials could yield meaningful data on the actual contribution of Erbitux towards extending the life span of patients with various kinds of cancer.

Early Approval?

There is presently a Phase III RCT in progress, comparing the use of Erbitux in combination with the drugs Oxaliplatin and 5-FU/LV vs. Oxaliplatin and 5-FU/LV alone in patients with previously treated metastatic colorectal cancer. (Oxaliplatin is similar to cisplatin and carboplatin). Yet Erbitux's sponsors are not waiting for the results of such rigorous trials. If recent history is any judge, RCTs may fail to show that the new drug actually prolongs the overall survival of patients who take it. Why would business-people, who have sunk billions of dollars into this drug, run such a risk, unless a vigilant FDA compels them to do so?

After meeting with its partner, Bristol-Myers Squibb, in early June, ImClone has now announced that it will reapply later this year for FDA approval for Erbitux, and Wall Street has gone wild on the news. This could mean that the drug will reach the market by early 2004, months earlier than some analysts had expected. The companies may now request an expedited six-month review and ask for approval for patients who have failed to respond to conventional treatment for colon cancer. They claim that the FDA seemed willing to consider approval based on the colon cancer results presented at ASCO.

If approved, Erbitux could be worth billions of dollars in sales to both ImClone and Bristol-Myers Squibb. The cost of a similar drug, Iressa, is around $1,900 a month (Hopper 2003). If Erbitux is priced similarly it will be worth a fortune for investors. There are presently 172,000 new US cases of lung cancer each year. If the drug were to become the new standard of care, it would earn its parent companies about $327 million per month. And that is not counting off-label uses or foreign markets. No wonder they are grinning from ear to ear.

"...[W]e are now on a track to get this drug to the cancer patients that are waiting for it," Andrew G. Bodnar, a senior vice president of Bristol-Myers Squibb, said in an interview. According to the New York Times, stock analysts say that the prospects for Erbitux's approval have been growing, not only because of the new data," but also because the FDA has recently become more lenient regarding drugs for cancer and other life-threatening diseases." The Times cited the FDA's recent approval of AstraZeneca's drug Iressa, which works in much the same way as Erbitux. The approval came despite the fact that Iressa has been shown in rigorous studies not to prolong overall survival (See the cancerdecisions.com newsletter 6/6/03).

After ImClone and Bristol-Myers announced plans to refile their application, ImClone shares surged $4.21, or 12 percent, to close at $38.53. The stock is up more than three-fold since the start of the year. Bristol-Myers also saw its shares rise in after-hours trading. As with AstraZeneca and its drug Iressa, the recent excitement over these new agents has more to do with Wall Street speculation than it does with sober scientific analysis. Surely the real bottom line should be whether such drugs actually increase the survival time of patients.

Without that information, we are left reading tea leaves.

--Ralph W. Moss, Ph.D.

References:

Akerley W, et al. Weekly, high-dose paclitaxel in advanced lung carcinoma: a phase II study with pharmacokinetics by the Cancer and Leukemia Group B. Cancer. 2003 May 15;97(10):2480-6.

Cunningham, D. Cetuximab (C225) alone or in combination with irinotecan (CPT-11) in patients with epidermal growth factor receptor (EGFR)-positive, irinotecan-refractory metastatic colorectal cancer (MCRC). ASCO 2003: Abstract 1012.

Cetuximab treats refractory metastatic colorectal cancer [Reuters Health]. June 2, 2003. Posted at ASCO website.
http://www.asco.org/ac/1,1003,_12-002123-00_18-0028187-00_19 -0028188-00_20-001,00.asp

Fossella FV, DeVore R, Kerr RN, et al.: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18 (12): 2354-62, 2000.

Hopper L. Oral medication helping patient with lung cancer, Houston Chronicle, May 28, 2003, At: http://www.chron.com/cs/CDA/ssistory.mpl/health/1927104

Kim ES, et al. A phase II study of cetuximab, an epidermal growth factor receptor (EGFR) blocking antibody, in combination with docetaxel in chemotherapy refractory/resistant patients with advanced non-small cell lung cancer: Final report. ASCO 2003; Abstract 2581.

National Cancer Institute's PDQ statement on treatment of stage IV NSCLC: http://www.cancer.gov/cancerinfo/pdq/treatment/non-small-cell-lung/healthprofessional/#Section_140

Pollack, Andrew. ImClone to Reapply for Drug Approval. New York Times, June 6, 2003. http://www.nytimes.com/2003/06/06/business/06DRUG.html

Robert F, et al. Phase Ib/IIa study of anti-epidermal growth factor receptor (EGFR) antibody, cetuximab, in combination with gemcitabine/carboplatin in patients with advanced non-small cell lung cancer (NSCLC). ASCO 2003; Abstract 2587.

Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8.

Shepherd FA, et al.: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18 (10): 2095-103, 2000.

Thongprasert S, et al. Docetaxel as second-line chemotherapy for advanced non-small cell lung cancer. J Med Assoc Thai. 2002 Dec;85(12):1296-300.

Quotes on Erbitux: http://www.aim.org/publications/media_monitor/2002/07/25.html

**NOTE** To view this page in a more printable format, please CLICK HERE.

IMPORTANT DISCLAIMER

The news and other items in this newsletter are intended for informational purposes only. Nothing in this newsletter is intended to be a substitute for professional medical advice.