PITTSBURGH -- For women with HER2-positive, advanced-stage breast cancer, the time to disease progression may be doubled by adding Tykerb (lapatinib) to Xeloda (capecitabine) chemotherapy, according to a study that was halted early.
PITTSBURGH, Dec. 28 -- For women with HER2-positive, advanced-stage breast cancer, the time to disease progression may be doubled by adding Tykerb (lapatinib) to Xeloda (capecitabine) chemotherapy, according to a study that was halted early.
Progression-free disease was significantly longer with the combination than Xeloda monotherapy (median 8.4 versus 4.4 months), said Charles E. Geyer, M.D., of the Allegheny Cancer Center here, and colleagues in the Dec. 28 issue of the New England Journal of Medicine.
Yet by the end of the study there was no survival advantage with the addition of Tykerb, and a potentially high financial price for a relatively short respite, pointed out Hyman B. Muss, M.D., of the Vermont Cancer Center and University of Vermont in Burlington in an accompanying editorial.
Tykerb, an investigational tyrosine kinase inhibitor of human epidermal growth factor receptor type 2, is getting a priority review by the FDA.
The open-label phase III study included 324 women with HER2-positive locally advanced or metastatic breast cancer that had progressed after treatment with at least an anthracycline, a taxane, and Herceptin (trastuzumab). These women were randomized to the combination of 1,250 mg of Tykerb per day continuously plus 2,000 mg/m2 of Xeloda on days one through 14 of a 21-day cycle or monotherapy with 2,500 mg/m2 of Xeloda on the same schedule.
Women were assessed every six weeks for the first six months then every three months during treatment and afterward until other treatment was started, disease progression or death. Baseline characteristics were similar between groups. Most women had metastatic disease (96%).
The study was ended early when prespecified endpoints were met after 49 disease progression events occurred in the combination therapy group and 72 occurred in the monotherapy group. At that point, data were available for 274 patients.
The hazard ratio for time to progression, based on an evaluation by independent reviewers under blinded conditions, was significantly lower for the combination group (0.49, 95% confidence interval 0.34 to 0.71, P<0.001).
Disease progression was the most common event (101 of 121) though there were 20 breast cancer-related deaths. In a statistical analysis, the only significant effect on time to progression was which treatment group patients were in. Combination therapy was statistically superior as well (one-sided P=0.00004).
Overall, the response rate was 22% (95% CI 16 to 29) for the combination versus 14% (95% CI 9 to 21, P=0.09) for monotherapy. Investigator-assessed response rates were 29% (95% CI 23 to 37) and 17% (95% CI 11 to 24, P=0.01), respectively.
However, the hazard ratio for death was not significantly better for combination therapy (0.92, 95% CI 0.58 to 1.46, P=0.72).
While the central nervous system metastases have occurred in about one-third of women with metastatic breast cancer who receive Herceptin, it appeared to affect fewer women who received Tykerb combination therapy (four versus 11) though the difference was not statistically significant.
Also, serious toxic effects and treatment discontinuation were similar between groups.
The researchers evaluated cardiac function using left-ventricular ejection fraction. They found that no patient had stopped treatment because of a decline in left-ventricular ejection fraction, Also, there were no cases of congestive heart failure or decreases in mean left- ventricular ejection fraction in the combination group. Four women in the combination group and one in the monotherapy group had an asymptomatic cardiac event, but all subsequently had left-ventricular ejection fraction values in the normal range.
Although the cardiac results may have been biased by selecting women who had normal cardiac function despite prior Herceptin treatment and the follow-up may not have been long enough to catch late events, "the low incidence of adverse cardiac effects of lapatinib is reassuring," the authors wrote.
Common adverse events included diarrhea, hand-foot syndrome, nausea, vomiting, fatigue, and rash unrelated to hand-foot syndrome. Most were less than grade 4. Diarrhea, dyspepsia, and rash occurred more often in the combination group. Treatment was stopped because of adverse events among 13% of the combination group and 12% of the Xeloda-monotherapy group.
The researchers said Tykerb plus Xeloda combination therapy by be beneficial particularly among women with metastatic breast cancer resistant to Herceptin or that recurs after adjuvant therapy.
On the other hand, Dr. Muss said in his editorial, the expense of adding new targeted therapies to chemotherapy may not be worth merely improving quality of life or delaying disease progression for a few months without improving the chance for a cure.
"Government leaders and the public, with guidance from health-care professionals, now face hard decisions regarding the use of innovative and expensive treatments for metastatic disease," he wrote. "Before we celebrate the advent of new ways of treating cancer, we must ensure that all who might benefit from these treatments have a chance to receive them."
Both Dr. Muss and Dr. Geyer and colleagues noted that it may be beneficial to try Tykerb earlier in the treatment of HER2-positive breast cancer. Several randomized trials in progress or planning will soon answer whether targeted therapies like Tykerb will be effective as adjuvant therapy.