December 12, 2008 (San Antonio, Texas) — Lapatinib (Tykerb, GlaxoSmithKline) has shown benefit when used as first-line treatment in metastatic breast cancer. A large phase 3 trial, presented here at the 31st Annual San Antonio Breast Cancer Symposium, opens up a potential new use for the drug, which so far has only been approved for use after other drugs have failed.
The results come from a trial of 1286 postmenopausal women with hormone-receptor-positive metastatic breast cancer who had not received any previous treatment. In such patients, endocrine treatment is a standard and accepted first-line therapy, commented lead investigator Stephen Johnston, PhD, from the Royal Marsden NHS Foundation Trusts and Institute of Cancer Research, in London, United Kingdom. In this trial, all the patients were treated with the aromatase inhibitor letrozole (Femara, Novartis), and then half were randomized to also receive lapatinib. The study was funded by GlaxoSmithKline.
In the overall patient population, the addition of lapatinib increased progression-free survival up to 11.9 months, from 10.8 months for letrozole alone (hazard ratio [HR], 0.86; P = .026).
Large Benefit in Subgroup of Patients
The benefit was much larger in a subset of 219 patients whose cancer was also HER2 positive. In this subset of patients, the combination of lapatinib plus letrozole increased progression-free survival to 8.2 months, a 29% increase over the 3 months seen with letrozole alone (HR, 0.71; P = .019).
Also in this subgroup, the overall response rate with the combination was 28%, compared with 15% with letrozole alone (P =.021), and the clinical benefit rate was 48% and 29%, respectively (P = .003). Side effects were manageable, and no new ones emerged, Dr. Johnston commented.
For this particular group of patients — postmenopausal women with metastatic breast cancer that is hormone-receptor positive and HER2 positive, and who have been deemed suitable for endocrine therapy by their physicians — these new results suggest that the addition of lapatinib is beneficial.
"Previously, these women would have been offered an aromatase inhibitor; now the suggestion is that they would do better on an aromatase inhibitor plus lapatinib," Dr. Johnston said.
"There was a much better chance of getting tumor control and holding it for longer," he told Medscape Oncology.
Asked to comment on the finding, Carlos Arteaga, MD, from Vanderbilt University, in Nashville, Tennessee, said the addition of lapatinib to an aromatase inhibitor is a reasonable alternative in these patients. Dr. Arteaga, who moderated the press conference at which these results were highlighted, is the director of the Breast Cancer Research Program and Breast Cancer Specialized Program of Research Excellence (SPORE) of the National Cancer Institute (NCI)-designated Vanderbilt–Ingram Comprehensive Cancer Center.
There have been some previous data in this area from the TANDEM study, in which trastuzumab (Herceptin, Roche) was added to a different aromatase inhibitor, anastrozole (Aromasin, Pfizer). Dr. Johnston said it is unfair to compare the 2 studies, but the results from that study also showed a benefit for the combination over the aromatase inhibitor alone. However, progression-free survival (4.8 months with the combination vs 2.4 months with the aromatase inhibitor alone) was shorter than in the current study, he pointed out.
"My sense is that physicians may be more persuaded" by these latest data on lapatinib plus letrozole, and also by the fact that lapatinib is an oral drug, Dr. Arteaga told Medscape Oncology. Importantly, these data also confirm that HER2 is a mechanism to overcome resistance to hormonal therapy, he said. "There is a pretty significant alteration in the natural history of the disease."
This was the hypothetical basis behind the study. Recent work has shown that interactions between hormone receptors and HER2 receptors are a primary contributor to the development of resistance to hormonal therapy. Both lapatinib and trastuzumab target the HER2-positive receptor, although they interact with it in different ways.
A spokesperson for GlaxoSmithKline said that the company plans to discuss these new data with regulators in the near future. "The encouraging positive results seen in women who are hormone-receptor positive and HER2 positive show that the lapatinib and letrozole combination has the potential to become a first-line oral treatment option for clinicians and patients in this setting in the future," the spokesperson sai
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