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Published on 18 January 2012

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Lapatinib ‘not suitable’ outside clinical trials

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Lapatinib should not be used outside of clinical trials as single anti-HER2 treatment in combination with neoadjuvant chemotherapy, according to two studies published by The Lancet.

In one study, lapatinib was shown to be less effective than trastuzumab in patients with HER2-positive breast cancer, while in another it was concluded that both were twice as effective than single-agent therapy.

In the first study, Professor Gunter von Minckwitz (German Breast Group, Neu-Isenburg, Germany), Prof. Michael Untch (AGO-Breast Study Group, Berlin, Germany), and colleagues did a randomised trial of lapatinib versus trastuzumab in 620 patients in Germany.

All patients received a standard chemotherapy regimen plus either trastuzumab (309) or lapatinib (311).

The primary outcome of the study was the proportion of patients achieving pathological complete response (pCR—the absence of any residual invasive cancer in the breast and absence of any metastatic cells in the regional lymph nodes).

The researchers found that 30% of the trastuzumab group achieved a pathological complete response compared with 23% in the lapatinib group.

Side-effects were common in both groups. Chemotherapy with trastuzumab was associated with more swelling of legs (39% vs 29%) and shortness of breath (30% vs 21%), and lapatinib with more diarrhoea (75% vs 47%) and skin rash (55% vs 32%).

Many more patients discontinued therapy due to toxic effects in the lapatinib group (33%) than in the trastuzumab group (14%).

Seventy serious adverse events were reported in the trastuzumab group and 87 in the lapatinib group.

“This direct comparison of trastuzumab and lapatinib showed that pathological complete response rate with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab,” concluded von Minckwitz et al.

“Unless long-term outcome data show different results, lapatinib should not be used outside of clinical trials as single anti-HER2 treatment in combination with neoadjuvant chemotherapy.”

In the second study, Dr José Baselga (Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA) and colleagues from the SOLTI group and Breast International Group did a randomised trial involving more than 400 women from 23 countries with HER2-postive breast cancer and tumours greater than 2cm in diameter.

One hundred and fifty four women received lapatinib, 149 trastuzumab, and 152 a combination of both treatments, all pre-surgery, with standard paclitaxel therapy added to each of these anti-HER2 regimens after six weeks.

Following a further 12 weeks of treatment, patients underwent surgery and then received the same anti-HER2 therapy for one year.

The new aspect in this study is that patients received the same anti-HER2 therapy post-surgery as in the pre-surgery component, so eventually data will be available to study the correlation between pCR, the primary study endpoint, and disease free survival and overall survival.

“Dual targeting of HER2-positive tumours with trastuzumab and lapatinib is undertaken because of primary and acquired resistance to both agents, their partly non-overlapping mechanisms of action, and the well characterised synergistic interaction between them in HER2 breast-cancer models,” wrote Baselga et al.

The research team found that the pCR rate was significantly higher in the group given combination treatment (51%) than in the group given trastuzumab alone (30%), a difference of 21%.

No statistically significant difference in pCR between the lapatinib (25%) and the trastuzumab (30%) groups was recorded.

No major cardiac dysfunctions occurred across the treatment groups (anti-HER2 therapy can cause cardiac toxicity).

Frequency of grade 3 diarrhoea was far higher with lapatinib (23%) and lapatinib plus trastuzumab (21%) than with trastuzumab (2%).

Similarly, grade 3 liver-enzyme alterations were more frequent with lapatinib (18%) and lapatinib plus trastuzumab (10%) than with trastuzumab (7%).

“Overall, dual HER2 blockade could be an improved approach to treatment of patients with HER2-positive tumours,” concluded Baselga et al.

“Our study shows that dual inhibition of HER2 by lapatinib and trastuzumab in combination with paclitaxel is better than single-agent targeting of HER2 in the neoadjuvant (pre-surgical) setting.

“Dual HER2 blockade might be a valid approach in patients with early HER2-positive disease.

“Our study also supports investigation of novel targeted agents for breast cancer in the neoadjuvant (pre-surgical) setting, when tumours have not yet acquired resistance to therapy and when chances of clinical benefit are highest.”

The Lancet

 



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