Confirmed: 2 Anti-HER2 Agents Better Than 1
Confirmed: 2 Anti-HER2 Agents Better Than 1
Baselga J, Bradbury I, Eidtmann H, et al
Lancet. 2012 Jan 16 [Epub ahead of print]
Because trastuzumab and lapatinib have complementary mechanisms of action and synergistic antitumor activity in HER2-positive breast cancer, the investigators postulated that 2 anti-HER2 agents given together would be better than single-agent therapy. To examine this question, a randomized, open-label, phase 3 study enrolled 455 women with HER-positive breast cancer from 23 countries from 2008 to 2010. Tumor size had to be > 2 cm in diameter.
Patients were randomly assigned to receive oral lapatinib at a dose of 1500 mg, intravenous trastuzumab with a loading dose of 4 mg/m, and subsequent doses of 2 mg/kg, or the combination of lapatinib (at a dose of 1000 mg) and trastuzumab. Anti-HER2 therapy alone was first given for 6 weeks and was followed by the addition of low-dose weekly paclitaxel (at a standard dose of 80 mg/m) for 12 weeks prior to definitive surgery. After surgery, patients received adjuvant chemotherapy and the same anti-HER2 treatment as in the neoadjuvant phase to complete 52 weeks of treatment.
The primary endpoint was the rate of pathologic complete response (pCR) analyzed by intention to treat. They found a significantly higher rate of pCR in the group given dual anti-HER2 therapy and no significant difference between the groups receiving either monotherapy. Patients with hormone receptor-negative breast cancer had overall higher pCR rates.
Of the patients who were not candidates for lumpectomy at the time of randomization, 31% in the lapatinib group, 28% in the trastuzumab group, and 26% in the combination group were successfully downstaged by treatment and underwent breast-conserving surgery. At the completion of the 6-week window before chemotherapy was added, there was a higher objective clinical response for the group receiving lapatinib and combination therapy than for those randomly assigned to trastuzumab alone. This difference was not observed at the time of surgery.
There was no major cardiac toxicity. As expected, there was more grade 3 diarrhea and elevation of liver enzymes in the group receiving lapatinib either alone or in combination, and this required a protocol amendment with reduction of the dose of lapatinib for these 2 arms to 750 mg. Trastuzumab alone was more tolerable, and more patients completed treatment as planned.
The investigators concluded that dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer preoperatively. Overall pCR was higher in patients with hormone receptor-negative tumors than in those with -positive tumors.
Of all patients who were randomly assigned, between 26% and 30% were successfully downstaged by treatment and thus were able to receive breast-conserving surgery.
The NeoALTTO study provides proof of concept that dual anti-HER2 therapy is better than single-agent therapy for women with HER2-positive breast cancer. In other HER2 studies, pCR has been shown to correlate with disease-free survival. Overall, there was more toxicity as manifested by diarrhea and abnormal liver function tests in patients exposed to lapatinib, and this worsened during the chemotherapy phase of the study. We need further research to identify groups of patients who may do well with maximal anti-HER2 treatment alone, which would spare them the toxicity of chemotherapy. In addition, for those patients with HER2-positive disease that is also hormonally sensitive, the benefit of hormonal therapy needs to be considered.
Abstract
Lapatinib With Trastuzumab for HER2-Positive Early Breast Cancer (NeoALTTO): A Randomised, Open-Label, Multicentre, Phase 3 Trial
Baselga J, Bradbury I, Eidtmann H, et al
Lancet. 2012 Jan 16 [Epub ahead of print]
Study Summary
Because trastuzumab and lapatinib have complementary mechanisms of action and synergistic antitumor activity in HER2-positive breast cancer, the investigators postulated that 2 anti-HER2 agents given together would be better than single-agent therapy. To examine this question, a randomized, open-label, phase 3 study enrolled 455 women with HER-positive breast cancer from 23 countries from 2008 to 2010. Tumor size had to be > 2 cm in diameter.
Patients were randomly assigned to receive oral lapatinib at a dose of 1500 mg, intravenous trastuzumab with a loading dose of 4 mg/m, and subsequent doses of 2 mg/kg, or the combination of lapatinib (at a dose of 1000 mg) and trastuzumab. Anti-HER2 therapy alone was first given for 6 weeks and was followed by the addition of low-dose weekly paclitaxel (at a standard dose of 80 mg/m) for 12 weeks prior to definitive surgery. After surgery, patients received adjuvant chemotherapy and the same anti-HER2 treatment as in the neoadjuvant phase to complete 52 weeks of treatment.
The primary endpoint was the rate of pathologic complete response (pCR) analyzed by intention to treat. They found a significantly higher rate of pCR in the group given dual anti-HER2 therapy and no significant difference between the groups receiving either monotherapy. Patients with hormone receptor-negative breast cancer had overall higher pCR rates.
Of the patients who were not candidates for lumpectomy at the time of randomization, 31% in the lapatinib group, 28% in the trastuzumab group, and 26% in the combination group were successfully downstaged by treatment and underwent breast-conserving surgery. At the completion of the 6-week window before chemotherapy was added, there was a higher objective clinical response for the group receiving lapatinib and combination therapy than for those randomly assigned to trastuzumab alone. This difference was not observed at the time of surgery.
There was no major cardiac toxicity. As expected, there was more grade 3 diarrhea and elevation of liver enzymes in the group receiving lapatinib either alone or in combination, and this required a protocol amendment with reduction of the dose of lapatinib for these 2 arms to 750 mg. Trastuzumab alone was more tolerable, and more patients completed treatment as planned.
The investigators concluded that dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer preoperatively. Overall pCR was higher in patients with hormone receptor-negative tumors than in those with -positive tumors.
Of all patients who were randomly assigned, between 26% and 30% were successfully downstaged by treatment and thus were able to receive breast-conserving surgery.
Viewpoint
The NeoALTTO study provides proof of concept that dual anti-HER2 therapy is better than single-agent therapy for women with HER2-positive breast cancer. In other HER2 studies, pCR has been shown to correlate with disease-free survival. Overall, there was more toxicity as manifested by diarrhea and abnormal liver function tests in patients exposed to lapatinib, and this worsened during the chemotherapy phase of the study. We need further research to identify groups of patients who may do well with maximal anti-HER2 treatment alone, which would spare them the toxicity of chemotherapy. In addition, for those patients with HER2-positive disease that is also hormonally sensitive, the benefit of hormonal therapy needs to be considered.
Abstract
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