[OT] Ralph Moss: DOES TYKERB REALLY WORK? - PART I

[Guest guest]

DOES TYKERB REALLY WORK? - PART I

Earlier this year, the US Food and Drug Administration (FDA) approved the drug

Tykerb (lapatinib) to treat advanced breast cancer. Tykerb is what is known as a

dual tyrosine kinase inhibitor. It inhibits both the erbB-2 receptor (usually

abbreviated as HER2 or HER2/neu), and also the epidermal growth factor receptor

(EGFR). It is similar to the drug Herceptin (trastuzumab), but differs from it

in that the Tykerb molecule is smaller, and, unlike Herceptin, can enter the

cell and directly target the gene that produces HER2, while Herceptin is only

able to target the cell surface receptor that activates the HER2 gene. There is

also some evidence to suggest that Tykerb may be able to cross the " blood-brain

barrier " in sufficient quantities to exert a therapeutic effect on cancer that

has spread (metastasized) to the brain.

The drug was approved by the FDA for the treatment of advanced or metastatic

breast cancer in women whose tumors over-express the HER2 protein. Tykerb is

used in combination with the chemotherapeutic drug Xeloda (capecitabine) and is

typically given to those women who have been previously treated with other forms

of chemotherapy, including an anthracycline drug (most commonly Adriamycin), a

taxane (such as Taxol or Taxotere) and Herceptin. Over time, a significant

proportion of women taking Herceptin become resistant to it. Tykerb offers these

women a further option.

An additional advantage for patients is that both Tykerb and Xeloda are oral

medications: they do not have to be given by intravenous infusion in a doctor's

office. Tykerb comes in tablets of 250 mg. A dose is taken once daily for 21

days and in combination with Xeloda on days 1-14 of this 21 day cycle.

According to the manufacturer, GlaxoKline of Research Triangle, NC,

clinical trials of Tykerb " demonstrated that the growth of breast cancer was

delayed significantly in those patients receiving the combination compared to

those taking Xeloda alone. " We shall examine these and other claims for this new

medication.

There are over 140 scientific articles about Tykerb in the medical database

PubMed, but few of these are reports of clinical trials. In fact, most of what

is known or stated about the effectiveness of Tykerb comes from a single

randomized controlled trial (RCT) performed at the Allegheny Cancer Center in

Pittsburgh. In this trial, researchers randomly assigned women with

HER2-positive, locally advanced or metastatic breast cancer that had progressed

after standard treatment, to receive either Tykerb plus Xeloda or Xeloda alone.

The trial was designed to measure " time to progression " - i.e., how long the

women's disease remained stable before it inexorably started to progress again.

The trial found that the median time till progression of the disease was 8.4

months in the Tykerb plus Xeloda group vs. 4.4 months in the Xeloda-alone group.

In addition, the tumor shrinkage ( " response " ) rate was higher in the Tykerb plus

Xeloda group (23.7 percent) vs.13.9 percent in the Xeloda alone group. There did

not appear to be an increase in the most serious toxic effects including

symptomatic cardiac events. The authors concluded that Tykerb plus Xeloda was

superior to Xeloda alone in these women.

However, the question of whether Tykerb prolongs survival is still open. At the

time of approval the FDA said simply that " the survival data are not yet

mature. " In fact, in the Allegheny Cancer Center study there was no

statistically significant survival difference between the two groups. At

follow-up, fifty five (28 percent) of the patients in the Tykerb plus Xeloda

group had died as compared to 64 of the patients (32 percent) in the group given

Xeloda alone.

However, there were reports in the media that a subsequent analysis of the data

by GlaxoKline showed that the delay in progression of the disease was

actually closer to 7 months (rather than the 8.4 months quoted in the approval

data) for the group that received both drugs, as compared to 5 months for those

on Xeloda alone (CBS News, March 13, 2007).

Similar Results in Kidney Cancer

Tykerb performed similarly in patients with advanced kidney cancer, according to

a report presented at the 2006 meeting of the American Society of Clinical

Oncology (ASCO). The drug produced no difference in overall survival nor did it

halt disease progression in a group of 416 patients with advanced renal cell

carcinoma. The median time to progression was 15.3 weeks for patients given

Tykerb vs. 15.4 weeks for those given standard hormone therapy - basically the

same. A subset of patients whose tumors expressed EGFR (one of the drug's

specific targets) did experience a modestly prolonged progression-free interval

when given Tykerb (15.1 weeks for Tykerb vs. 10.9 weeks for hormone therapy).

The median overall survival for this subset was 46 weeks for those given Tykerb

versus 37.9 weeks for those given hormone therapy. This amounted to a two-month

survival advantage in a selected group of patients.

The most commonly reported adverse effects with Tykerb include diarrhea, nausea,

vomiting, rash and hand-foot syndrome (which may include numbness, tingling,

redness, swelling and discomfort of hands and feet). According to the FDA,

generally reversible decreases in heart function (that can lead to shortness of

breath) have also been reported in a small percentage of patients.

In August 2007, however, the FDA amended the Tykerb label to add interstitial

lung disease and pneumonitis to the adverse effects of the drug. These

lung-related effects were seen in clinical trials with both Tykerb alone and

when it was given in combination with other drugs. The FDA recommended

discontinuation of the drug in patients who exhibited such symptoms.

TO BE CONCLUDED, WITH REFERENCES, NEXT WEEK

--Ralph W. Moss, Ph.D.