today's big news includes tykerb as well as avastin

[Lani]

Lapatinib Effective in Advanced Breast Cancer


December 28, 2006 — The experimental drug lapatinib (Tykerb, GlaxoSmithKline) doubled the median time to progression when added to capecitabine (Xeloda, Roche) in women with advanced HER2-positive breast cancer that had progressed after chemotherapy and trastuzumab (Herceptin, Genentech/Roche).

The results, from a trial involving 324 patients, are published in the December 28 issue of the New England Journal of Medicine. Preliminary findings were presented at the 2006 American Society of Clinical Oncology meeting and reported at that time by Medscape. The company-sponsored trial was stopped early by an independent data monitoring committee because of the positive results.

The patient population in this study — with advanced or metastatic HER2-positive breast cancer that has progressed despite chemotherapy and trastuzumab — represents the indication for which lapatinib is awaiting approval in the United States, the European Union, Switzerland, Australia, Canada, and New Zealand.

These patients have limited options, commented lead investigator Charles Geyer, MD, director of breast medical oncology at Allegheny General Hospital, in Pittsburgh, Pennsylvania. "Lapatinib combined with capecitabine has demonstrated superior efficacy over capecitabine alone in this group of patients, and we look forward to it being made available to women suffering from this devastating disease," he said in a news release.

Another of the trialists, David Cameron, MD, from the Western General Hospital in Edinburgh, Scotland, told Medscape that once lapatinib is approved, the combination of lapatinib plus capecitabine should be considered "standard of care" for this patient population. Capecitabine is already one of the standard treatments offered to these patients, he explained, and this trial shows adding lapatinib gave superior results.

Lapatinib is also considered to have potential in the treatment of earlier breast cancer, because of its novel mechanism of action, its oral administration, and also its penetration of the central nervous system (CNS). A huge study, aiming to recruit more than 3000 patients with early-stage HER2-positive breast cancer, has just begun to evaluate lapatinib as an adjuvant therapy. Known as the Tykerb Evaluation After Chemotherapy (TEACH), this study is also sponsored by the manufacturer. Dr. Cameron explained that this study would explore whether lapatinib fits into a similar therapeutic niche to that already occupied by trastuzumab, which very quickly became the standard of care.

Separately, lapatinib has also shown efficacy in inflammatory breast cancer, as previously reported by Medscape.

Study Terminated Early as Lapatinib Treatment Was Superior

The advanced breast cancer trial was terminated after an interim analysis showed superiority of the lapatinib group; the analysis was triggered by prespecified events and conducted for 2 years after enrollment started. The median time to progression was 8.4 months in the group taking lapatinib with capecitabine, compared with 4.4 months in the group treated with capecitabine alone (hazard ratio, 0.49; P < .001).

However, there was no difference in survival between the 2 groups, an accompanying editorial points out. There were 36 deaths in the combination-therapy group and 35 in the monotherapy group (hazard ratio, 0.92; P = .72).

The combination-therapy group had a higher tumor response rate (22% vs 14%; P = .09), and fewer patients had CNS metastases, although this difference was not statistically significant (4 vs 10 patients; P = .10).

The editorial notes that lapatinib has also shown activity as a single agent in patients with HER2-positive breast cancer with CNS metastases that are refractory to trastuzumab, adding: "This finding is important because HER2-positive tumors frequently spread to the CNS, where the tumor is sheltered from trastuzumab and most chemotherapeutic agents."

Adverse effects were similar in the 2 groups, except for diarrhea, rash, and dyspepsia, which were more common in the combination group. Less than 15% patients in both groups discontinued because of adverse effects.

Cardiac toxicity was minimal in both groups, the editorial notes, adding that this is a major adverse effect of trastuzumab. However, the trialists point out that there was a bias, as they had selected women who had normal cardiac function after having received various other therapies (including anthracyclines and taxanes) as well as trastuzumab. Also, since the duration of observation was limited, the possibility of late events cannot be excluded. "Nevertheless, the low incidence of adverse cardiac events is reassuring," they comment.

Dr. Cameron presented additional data from the same trial recently at the San Antonio Breast Cancer Symposium. This trial shows that women with advanced HER2-positive breast cancer as a group respond to lapatinib, he explained, but numerically only about half of the patients respond. Pressing questions include defining which ones respond and whether there is a way to identify them. As lapatinib is active against both HER1 and HER2, his team tested tumor samples for the HER1 protein to see whether there was any correlation between levels of this protein and response to treatment. "We found that there wasn't any, and so this protein is not useful for predicting response to therapy," he told Medscape. Further work is now under way to look at activated proteins and also to identify tumors that are resistant to trastuzumab. Finding a way to identify which patients will respond to lapatinib is important, he commented, as it will further refine the patient population that benefits.

Bevacizumab Also Shows Promise

In addition to lapatinib, the editorial highlights bevacizumab (Avastin, Genentech) as another targeted therapy that also shows "great promise in the treatment of breast cancer." However, while the development of lapatinib is directed at breast cancer, bevacizumab was first explored in, and has been approved for, the treatment of colorectal cancer. The 2 drugs also have very different mechanisms of action: lapatinib is targeted at HER1 and HER2, while bevacizumab acts on vascular endothelial growth factor and was the first approved angiogenesis inhibitor.

The editorial cites 2 studies in metastatic breast cancer in which bevacizumab, added to either paclitaxel or capecitabine, produced better results than either chemotherapy alone, However, there was no effect on overall survival in 1 study, and survival data from the other are incomplete.

This may eventually cause problems with patient access to these new therapies, the editorial suggests. All of the targeted therapies available to date are added onto conventional treatment, thus adding costs to the healthcare system. "When the goal is to improve the chance for a cure, these new treatments seem to be well worth the expenditure," comments editorialist Hyman Muss, MD, from the Vermont Cancer Center, in Burlington. "However, when the goal is to improve the quality of life or delay the time to progression by several months, as it is with many treatments for metastatic breast cancer, it is less clear whether the health system can and should bear these expenses."

N Engl J Med. 2006;355:2733-2743, 2783-2785.