The study reviewed here found that women diagnosed with HER2-positive, metastatic breast cancer that grew while being treated with Herceptin (chemical name: tastuzumab) benefited from adding Tykerb (chemical name: lapatanib) to the Herceptin rather than switching from Herceptin to Tykerb. These results were presented at the 2009 San Antonio Breast Cancer Symposium.
HER2-positive cancers make too much of the HER2 protein. The HER2 protein sits on the surface of cancer cells and receives signals that encourage the cancer to grow and spread. About one out of every four breast cancers is HER2-positive. Both Herceptin and Tykerb are targeted therapy medicines that work by blocking the HER2 protein's ability to make HER2-positive breast cancers grow. Herceptin and Tykerb work in different ways. Herceptin blocks the protein on the cancer cell's surface. Tykerb blocks the protein inside the cell.
Herceptin is approved by the U.S. Food and Drug Administration (FDA) to treat advanced-stage, HER2-positive breast cancers and to lower the risk of cancer coming back (recurrence) in women diagnosed with HER2-positive, early-stage breast cancer with a high risk of recurrence.
Tykerb is approved by the FDA to be given in combination with Xeloda (chemical name: capecitabine), a type of chemotherapy, to treat HER2-positive, metastatic breast cancer that has stopped responding to anthracyclines, taxanes, and Herceptin.
Rather than stopping Herceptin and switching to Tykerb when metastatic breast cancer comes back or grows while being treated with Herceptin, many doctors have been adding Tykerb to the treatment plan and continuing Herceptin. The researchers who did this study wanted to know if that approach makes sense. The results suggest it does.
All 296 women in this study were diagnosed with HER2-positive, metastatic breast cancer. All the women were "heavily pretreated" before the study, which means each woman had received four or more courses of various chemotherapy medicines and the cancer had stopped responding to each one. Each woman's last treatment course before this study included Herceptin.
When the breast cancer grew while being treated with Herceptin, about half the women continued to get Herceptin and Tykerb was added to the treatment plan. The other women stopped getting Herceptin and switched to Tykerb.
During the study it became clear that adding Tykerb to Herceptin treatment was better than stopping Herceptin and switching to Tykerb. So more than half of the women (52%) who stopped taking Herceptin when they started on Tykerb "crossed over" and started Herceptin again.
No chemotherapy or hormonal therapy medicines were given to the women during this study.
Women treated with BOTH Tykerb and Herceptin lived an average of 14 months compared to 9.5 months for women who switched from Herceptin to Tykerb -- a 26% improvement in survival. Since many of the women who initially switched from Herceptin to Tykerb chose to cross over and get both Tykerb and Herceptin, it's possible that the survival benefits of the Herceptin-Tykerb combination may be even greater.
Herceptin is given intravenously and may cause side effects such as fever, chills, muscle aches, and nausea. These side effects usually are less severe after the first treatment. Herceptin also may cause heart damage that can be life-threatening in some cases. Herceptin costs about $10,000 per month.
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 of Tykerb 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. Tykerb costs $5,000 to $6,000 per month.
The most common side effect seen in this study was diarrhea. One woman died 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 study. Together you can decide if adding Tykerb to your treatment plan makes sense if the cancer stops responding to Herceptin alone.
Visit the Breastcancer.org Targeted Therapies section to learn more about Herceptin and Tykerb.
SAN ANTONIO (MedPage Today) -- A dual biologic attack on heavily pretreated metastatic breast cancer may substantially prolong survival -- without chemotherapy or endocrine therapy, researchers reported here.
Median overall survival improved by 26% -- 4.5 months -- more with the combination of lapatinib (Tykerb) and trastuzumab (Herceptin) than with trastuzumab alone, according to Kimberly L. Blackwell, MD, of Duke University Medical Center, and colleagues.
Adding the second HER2-targeted agent resulted in 15 more women out of 100 alive at one year, Blackwell reported at the San Antonio Breast Cancer Symposium.
This effect in refractory metastatic breast cancer was "similar to that seen with the addition of single biologic agents to chemotherapy in the first line HER2-positive metastatic breast cancer, without the associated significant side effects of chemotherapy," she told attendees.
Her group had reported similarly positive results for the primary endpoint at the American College of Clinical Oncology last year, with a progression-free survival benefit at six months (28% versus 13%, P=0.008).
At that time, overall survival showed a 2.9-month trend for improvement with the addition of lapatinib to trastuzumab at six months (P=0.106) and a trend at 12 months as well (P=0.0596).
The updated results further support clinical synergism from using two separate mechanisms to attack HER2, Blackwell said.
"Lapatinib has a potential benefit of working where tumors have become resistant to trastuzumab through a potential resistance mechanism of cleavage of the extracellular domain -- the known binding site for trastuzumab," she said at a press conference here.
Both drugs are approved for use in the metastatic setting, but this is the first evidence for continuing trastuzumab through progression and adding a second type of anti-HER2 therapy, rather than just switching to a different drug, commented press conference moderator Edith Perez, MD, of the Mayo Clinic in Jacksonville, Fla.
But Mark Pegram, MD, of the University of Miami, predicted that "the cost will be staggering, so this is going to have to be a home run."
Currently, the cost of trastuzumab is estimated at around $10,000 per month (about $3,500 wholesale), while lapatinib costs around $5,000 to $6,000 per month.
However, that's likely to go down when trastuzumab goes off patent in the next few years, Pegram told MedPage Today.
The phase III EGF104900 study included 296 women with HER2-positive metastatic breast cancer that had progressed despite prior treatment that included trastuzumab and chemotherapy with an anthracycline and taxane.
The average number of prior chemotherapy regimens was four in the lapatinib group and five in the combination group, with about a quarter to a third of patients having gone through at least six regimens.
These women were randomized to treatment with lapatinib at a dose of 1,500 mg per day alone or at a dose of 1,000 mg per day with 2 to 4 mg of trastuzumab each week.
The updated intent-to-treat survival analysis revealed a median overall survival of 9.5 months in the lapatinib alone group compared with 14 months in the combined group with a hazard ratio for survival of 0.74 (P=0.026).
Six-month survival rates were the same as previously reported, 80% with lapatinib compared with 70% with dual HER2 blockade, but the 12-month survival rates improved with more patients reaching this point of follow-up (56% and 41%, respectively).
The association was strengthened by adjustment for significant baseline factors, including number of metastatic sites, time from diagnosis, and performance status (HR 0.71, P=0.0116).
These benefits were despite the fact that 52% of patients assigned to single-agent lapatinib crossed over to the addition of trastuzumab.
Single agent patients who progressed after at least four weeks on therapy could crossover to the combination arm because of concern over withholding trastuzumab, which at the time was not commercially available.
Blackwell said there were no new safety signals with longer follow-up.
Serious events -- defined as grade 3 or higher left ventricular dysfunction or a drop in ejection fraction at least 20% compared with baseline and to below normal -- occurred in 10% versus 2%, respectively.
One death occurred, a case of cardiac failure in the dual biologic group with pulmonary thromboembolism as the cause of death.
"I'm always impressed when I show the bottom of this slide [on adverse events], because point in fact, when you look at chemotherapy-containing trials of heavily pretreated metastatic breast cancer you usually see a slide full of adverse events," Blackwell said at the press conference.
However, there was only one grade three or four event (diarrhea, "almost certainly attributable to the lapatinib") that occurred in more than 5% of patients.
Grade three or four toxicity of any kind occurred in 2% of patients with the combination compared with less than 1% with single agent lapatinib.
These "exciting" trial results could foreshadow the results of the ongoing ALTTO and Neo-ALTTO trials, both of which are comparing lapatinib plus trastuzumab versus either treatment alone in early stage breast cancer, Pegram said.
Blackwell agreed that the biology probably will be similar despite the different setting.
However, she cautioned that the population in her trial was likely one with highly HER2-driven tumors since they had survived a relatively long time with metastatic cancer on regimens that included trastuzumab.
The study was conducted and funded by GlaxoSmithKline.
Blackwell reported receiving research grants from Genentech, Abraxis, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, Reata, and Celsion and consulting for Novartis, sanofi-aventis, and Abraxis.
Coauthors reported conflicts of interest with GlaxoSmithKline, Merck, Novartis, Roche, and Exelixis. Several coauthors were employees of GlaxoSmithKline.
Perez reported serving on the steering committee for sorafenib (Nexavar) and for a Genetech trial and serving on an independent monitoring committe for Novartis, all without direct funding from the companies.
Pegram reported potential conflicts of interest with Genetech, GlaxoSmithKline, sanofi-aventis, and Amgen.
Primary source: San Antonio Breast Cancer Symposium Source reference: Blackwell KL, et al "Updated Survival Analysis of a Randomized Study of Lapatinib Alone or in Combination with Trastuzumab in Women with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab Therapy" SABCS 2009; Abstract 61.
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