Fwd: THE MOSS REPORTS Newsletter (06/21/03)

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Sat, 21 Jun 2003 21:58:01 -0400 (EDT)

 

THE MOSS REPORTS Newsletter (06/21/03)

 

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Ralph W. Moss, Ph.D. Weekly CancerDecisions.com

Newsletter #88 06/21/03

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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, PhD

 

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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/healthprofess\

ional/#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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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.

 

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