4 april 2009: Erbitux - Cetuximab naast chemo werkt alleen bij patienten met uitgezaaide darmkanker die het KRAS wild type gen bezitten. In alle andere gevallen (40%) werkt Erbitux absoluut niet. Het werkt dan zelfs klinisch negatief. Zie artikelen hiernaast in linerkkolom

d.d. 23 juni 2003: Op de afgelopen conferentie van ASCO 2003 werd het middel Erbitux als een van de grotere successen genoemd, o.a. bij uitgezaaide darmkanker. Ook wij hebben Erbitux opgenomen als goed nieuws, ook omdat o.i. op Asco toch de betere studies vanuit de hele wereld worden gepresenteerd. Toch maakt Ralph Moss in zijn afgelopen nieuwsbrieven nogal wat kanttekeningen bij de euforie rondom Erbitux die o.i. zinvol zijn te lezen. Hier het Engelstalige artikel uit de nieuwsbrieven van Ralph Moss. 

Bron: www.cancerdecisions.com 

ERBITUX REDUX

One of the big stories from this year's American Society of Clinical Oncology (ASCO) meeting concerned ImClone Systems' drug Erbitux (cetuximab). There are currently at least 2,500 news stories circulating about this agent. Much of this intense interest stems from a
controversy over alleged insider trading. However, a lot of favorable publicity also arose as a result of several papers presented at ASCO.

On July 30, 2001, Erbitux was hailed in a Business Week cover story, "The Birth of a Cancer Drug." The drug, then called IMC-225, was celebrated as a "blockbuster" that "halts the spread of cancer." In an editorial entitled "The Dawn of a New Era", the magazine claimed
that Erbitux "seems effective against cancers of the colon, pancreas, head and neck and lungs." It suggested that victory might be within sight in the war on cancer.

Lest you think Business Week was alone in its enthusiasm, the Associated Press ran a story on Erbitux in May, 2001, calling it "incredibly exciting" and a "breakthrough." CNN's medical correspondent claimed that Erbitux "may shrink tumors" and "extend lives."
The operative word here was "may" but the media was in a typical feeding frenzy. So was Wall Street.

Bristol-Myers Squibb became so excited that it paid $2 billion for a 20 percent stake in ImClone. According to Forbes, Bristol-Myers "already has the best oncology sales force in the US" and would therefore have the muscle to market the drug successfully. ImClone's CEO
Sam Waksal said that Erbitux "is going to be one of the biggest drugs in the history of oncology." Now, as you may have heard, Waksal is heading to prison for more than seven years for his attempts to unload the stock before it took a nose-dive last year. The same scandal has embroiled his good friend, Martha Stewart.

Now, presumably, Erbitux has been vindicated and stocks of both ImClone and Bristol-Myers are once again soaring. But in reality, for all its conceptual elegance, Erbitux has failed to live up to its promise and publicity. 

A Targeted Therapy

Erbitux does not just randomly kill dividing cells, as conventional chemotherapy does. Instead, it was designed on the 'smart bomb' principle, to target a particular molecule that appears on the surface of cancer cells. This molecule is called Epidermal Growth Factor Receptor (EGFR) and is 'expressed,' by many solid tumors. It is most often seen in head-and-neck cancers, but is also found in other common solid tumors, such as colorectal cancer, and in 40 to 80 percent of the non-small cell form of lung cancer (NSCLC). Thus, a successful test in any commonly occurring form of cancer would have vast implications for the treatment of solid tumors as a whole.

There were a dozen abstracts presented at ASCO 2003 that discussed various aspects of Erbitux, but two of these presented data on response rates, and it is these studies that have generated most of the public comment and stock market activity.

The M.D. Anderson Study on NSCLC

The best publicized of these (Abstract #2581) had as its first author Dr. E.S. Kim of Houston's M.D. Anderson Cancer Center (whose president, John Mendelsohn, MD, invented Erbitux). There, Erbitux was combined with the standard chemotherapeutic drug Taxotere (docetaxel). Taxotere, one of a class of compounds called taxanes, is the only drug approved by the FDA as a second-line treatment for NSCLC patients who have not been helped by prior chemotherapy. All of the patients in this study had advanced lung cancer, which had progressed during prior chemotherapy or else had recurred within three months following initial drug treatment. These patients were all chosen because their tumors had a significant overexpression of the EGFR molecule.

Forty-seven such patients could be evaluated for their response to the drugs as well as for toxicity. Their average age was 60 and their performance status was reasonably good (an average Karnofsky performance scale score of 80). Of these, 13 patients (28 percent)
achieved a partial response (PR), while 8 patients (17 percent) maintained stable disease for a while. The time to disease progression was 89 days (ranging from 17 to 411 days; still ongoing in at least one case). This regimen was said to be "very well tolerated with minimal toxicities." But drug toxicity is often in the eye of the beholder: there were, in
fact, serious grade III infections in 21 percent of the patients, fatigue in 21 percent, and acne-like rash in 19 percent. Four patients (8 percent) had an allergic reaction that required discontinuation of the treatment.

The authors conclude that Erbitux "in combination with docetaxel is well tolerated and the response rate suggests clinical activity in the second-line setting." A final analysis regarding the duration of response and survival data is ongoing.


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 -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, PhD

=======================

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 


 


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