The study reviewed here found that women diagnosed with HER2-positive metastatic breast cancer that either came back or progressed while getting Herceptin (chemical name: tastuzumab) benefited from adding Tykerb (chemical name: lapatanib) to the treatment plan instead of switching from Herceptin to Tykerb.
Both Herceptin and Tykerb are targeted therapy medicines.
There were almost 300 women in the study. After the HER2-positive metastatic breast cancer came back during Herceptin treatment, about half the women continued to get Herceptin AND had Tykerb added to their treatment plans. The other half stopped getting Herceptin and switched to Tykerb.
Six months later:
A year after the change in their treatment plans, 45% of the women treated with both Herceptin and Tykerb were alive, compared to 36% of the women who switched to Tykerb.
Both Herceptin and Tykerb work by blocking the ability of the HER-2/neu protein to make HER2-positive breast cancer cells grow. Herceptin and Tykerb do this in different ways. Herceptin blocks the protein on the cancer cell's surface. Tykerb blocks the protein inside the cell.
Tykerb, in combination with the chemotherapy medicine Xeloda (chemical name: capecitabine), is approved by the U.S. Food and Drug Administration to treat HER2-positive, metastatic breast cancer that has stopped responding to Herceptin. But rather than stopping Herceptin and switching to Tykerb when metastatic breast cancer comes back or progresses, many doctors have been adding Tykerb to the treatment plan while continuing Herceptin.
Even though Tykerb isn't approved to be used in combination with Herceptin, the results of this study suggest that this approach might be better than stopping Herceptin and switching to Tykerb. The researchers think that blocking the effect of the HER2/neu protein both outside and inside the cancer cell at the same time might be better than blocking the protein in only one place. This approach is known as "total HER2 blockade."
Herceptin is given intravenously. Herceptin can cause flu-like side effects such as fever, chills, muscle aches, or nausea. These side effects generally become less severe after the first treatment. Herceptin can sometimes cause heart damage and in some cases the heart damage can be life-threatening.
Tykerb is a pill taken by mouth. Tykerb doesn't seem to cause the serious heart problems associated with Herceptin. The most common side effects from Tykerb when given in combination with Xeloda are diarrhea, redness and tingling in the hands and feet, and a rash. These side effects usually aren't severe. Other side effects can include stomach upset, vomiting, and fatigue.
In this study, the most common side effect was diarrhea. About 48% of the women treated with Tykerb alone had diarrhea; 60% of the women treated with Herceptin and Tykerb had diarrhea. One woman did die from a heart problem, but the heart problem wasn't directly related to the Herceptin or Tykerb treatment.
If you're being treated with Herceptin for HER2-positive metastatic breast cancer, you might want to talk to your doctor about the results of this research. Together you and your doctor can decide whether adding Tykerb to your treatment plan might make sense for you if the cancer stops responding to Herceptin alone.
Visit the Breastcancer.org Targeted Therapies section to learn more about Herceptin and Tykerb.
CHICAGO, June 2 -- Combining targeted biologic therapies after progression of metastatic HER2-positive breast cancer may improve response despite prior treatment with multiple trastuzumab (Herceptin) regimens.
Addition of the tyrosine kinase inhibitor lapatinib (Tykerb) to the monoclonal antibody trastuzumab reduced risk of disease progression 27% compared with lapatinib alone, reported Joyce O'Shaughnessy, M.D., of the Baylor-Sammons Cancer Center in Dallas, and colleagues here at the American Society of Clinical Oncology meeting.
Continued use of trastuzumab after recurrence or progression is common in practice, but the study provides some of the first supportive clinical data for the practice, commented Francisco J. Esteva, M.D., Ph.D., of the M.D. Anderson Cancer Center in Houston, who was a discussant for the study.
"Total HER2 blockade with lapatinib and trastuzumab may provide a chemotherapy-free option for HER2-positive metastatic breast cancer patients," Dr. O'Shaughnessy said.
However, Dr. Esteva was more skeptical.
"Biologic therapy without chemotherapy for metastatic breast cancer is an interesting area of investigation but not ready for prime time," he said. "The efficacy of available targeted drugs is higher when they are combined with chemotherapy."
Given the activity of lapatinib as monotherapy in earlier studies of this patient population, the researchers tested it with trastuzumab in a phase III randomized trial to see if total HER2-positive blockade would improve clinical outcomes.
The study randomized 296 HER2-positive metastatic breast cancer patients with progression on their most recent trastuzumab regimen to receive lapatinib at the standard 1,500 mg a day oral dose or the combination of 1,000 mg a day of lapatinib and a loading dose of 4 mg/kg of intravenous trastuzumab then 2 mg/kg per week.
Patients had already had extensive treatment with an average of four or five chemotherapy regimens and three trastuzumab regimens for metastatic breast cancer.
Despite this, the group treated with lapatinib and trastuzumab had an improved rate of clinical benefit -- defined as complete response, partial response, or stable disease for at least six months -- compared with those who had lapatinib alone (24.7% versus 12.4%, odds ratio 2.2, P=0.01).
The rate of confirmed complete or partial response alone was not significant for combination therapy compared with lapatinib alone (10.3% versus 6.9%, OR 1.5, P=0.46).
For the primary endpoint, progression-free survival at six months was significantly greater with combination biologic treatment (28% versus 13%, hazard ratio 0.73, P=0.008).
After adjustment for performance status and extent of disease, the benefit remained significant (HR 0.72, P=0.0095).
Overall survival showed a trend for benefit with lapatinib and trastuzumab compared with lapatinib alone at both six months (80% versus 70%, HR 0.75, P=0.106) and 12 months (45% versus 36%), which was strengthened by adjustment for performance status and baseline disease extent (HR 0.71, P=0.0596).
The study is the first phase III trial to confirm the preclinical synergism seen with these agents, Dr. O'Shaughnessy said.
She also noted that the combination "has a predictable and manageable toxicity profile," with the most common adverse event being diarrhea (48% lapatinib alone versus 60% combination).
There were eight patients with treatment-related cardiac events in the combination therapy arm compared with three in the lapatinib arm. One cardiac event was fatal, a case of cardiac failure for which the cause of death was determined to be pulmonary thromboembolism in the combination therapy group.
"Continuation of trastuzumab is the best option for patients who develop progressive disease on or after trastuzumab-based therapy," Dr. Esteva concluded. He recommended this with sequential administration of endocrine therapy, chemotherapy, or biologic therapy.
The study was conducted and funded by GlaxoSmithKline.
American Society of Clinical Oncology 2008 Annual Meeting; Abstract 1015
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