ignificantly more women with HER2-positive breast cancer achieved
complete tumor resolution when they received two targeted agents before
surgery instead of one, results of a large European study showed.
Neoadjuvant therapy with trastuzumab (Herceptin) and lapatinib (Tykerb), in addition to chemotherapy, led to pathologic complete response (pCR) in more than half of patients, Jose Baselga, MD, of Massachusetts General Hospital in Boston, and co-authors reported online in The Lancet.
That compared with the 25% to 30% of patients who achieved complete response on trastuzumab or lapatinib alone.
Although the study did not evaluate the effect of treatment on survival, prior studies have shown that pCR correlates with improved disease outcomes in patients treated with trastuzumab and chemotherapy.
"This open-label, multicenter, phase III study showed that dual inhibition of HER2 with lapatinib and trastuzumab in combination with paclitaxel is better than single-agent HER2 targeting," the researchers wrote in conclusion.
"Our study also supports investigation of novel targeted agents for breast cancer in the neoadjuvant setting, when tumors have not yet acquired resistance to therapy and when chances of clinical benefit are highest."
The published results updated and affirmed findings from an initial report more than a year ago.
Results of another study, published simultaneously in The Lancet Oncology, showed that neoadjuvant therapy with trastuzumab plus chemotherapy resulted in a significantly higher rate of pathologic complete response compared with lapatinib and chemotherapy.
Both targeted agents inhibit HER2 but have different mechanisms of action, providing a rationale for evaluating them in combination. Preclinical and clinical evidence had suggested that combining lapatinib and trastuzumab would result in more potent inhibition of HER2 compared with either drug alone.
Baselga and colleagues reported final results from a trial called NeoALTTO, which compared lapatinib, trastuzumab, and the combination for women with HER2-positive breast cancer.
All patients started treatment with the assigned targeted therapy. Paclitaxel was added after six weeks, and neoadjuvant therapy continued for a total of 18 weeks. Surgery followed completion of neoadjuvant therapy, and patients received adjuvant treatment with paclitaxel and the same anti-HER2 regimen as in the neoadjuvant.
The final analysis involved 455 with HER2-positive primary breast cancer larger than 2 cm in diameter. The primary endpoint was pCR, as defined by National Surgical Adjuvant Breast and Bowel Project criteria.
The targeted combination plus paclitaxel resulted in a pCR rate of 51.3% compared with 29.5% in patients who received trastuzumab plus paclitaxel and 24.7% for the lapatinib-paclitaxel arm (P=0.0001). The pCR rate did not differ between the trastuzumab and lapatinib arms.
No major cardiac dysfunction occurred during the trial. Patients treated with lapatinib had higher rates of grade 3 diarrhea (23.4%, 21.1%, respectively) and grade 3 liver-enzyme alterations (17.5%, 9.9%) compared with trastuzumab (2%, 7.4%). Otherwise, adverse events were similar among treatment groups.
Authors of a related commentary said that trials of targeted therapies could change the clinical evaluation process.
Rigorous investigation of a biologic agent in the neoadjuvant setting might obviate the need to begin evaluation of a drug in advanced disease before moving to the neoadjuvant and adjuvant settings, wrote Michael Gnant, MD, and Guenther G. Steger, MD, of the Medical University of Vienna in Austria.
Such an approach to clinical investigation could substantially reduce development costs and bring promising new drugs to patients more quickly, they wrote.
However, they also pointed to NeoALTTO as an illustration of unresolved issues in clinical use of targeted agents. Optimal treatment duration, selection and use of biomarkers, and the expense of combining two costly drugs must be rigorously examined, wrote Gnant and Steger.
The article in The Lancet Oncology provided details of another European trial, called GeparQuinto, a phase III randomized study involving 620 women with previously untreated operable or locally advanced HER2-positive breast cancer.
Patients with clinical stages T1 through T4 were eligible, depending on nodal and hormone-receptor status. All patients received neoadjuvant chemotherapy with the combination of epirubicin, cyclophosphamide, and docetaxel. They were randomized to neoadjuvant trastuzumab or lapatinib.
The primary endpoint was pCR. When the trial ended, 30.3% of patients in the trastuzumab arm and 22.7% of those in the lapatinib arm had achieved pCR, which translated into an odds ratio of 0.68 in favor of trastuzumab (P=0.04).
The trastuzumab regimen was associated with higher rates of edema (39.1% versus 28.7%) and dyspnea (29.6% versus 21.4%) and the lapatinib regimen with more diarrhea (75.0% versus 47.4%) and skin rash (54.9% versus 31.9%).
Premature discontinuation rates were 14.0% with trastuzumab and 33.1% with lapatinib.
"This direct comparison of trastuzumab and lapatinib showed that pathologic complete response rate with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab," Gunter Von Minckwitz, MD, of German Breast Cancer Group in Neu-Isenburg, and co-authors wrote in conclusion.
"Unless long-term outcome data show different results, lapatinib should not be used outside of clinical trials as a single anti-HER2 treatment in combination with neoadjuvant chemotherapy," they wrote.
The results confirm those from a previous report at the San Antonio Breast Cancer Symposium.
Three important lessons can be learned from the results of GeparQuinto, Stephen K. Chia, MD, of the British Columbia Cancer Agency in Vancouver, B.C., wrote in an accompanying commentary.
Baselga disclosed a relationship with Roche. Coauthors disclosed relationships with GlaxoSmithKline, Roche, Novartis, Amgen, Abbott, AstraZeneca, Pizer, and Bristol-Myers Squibb. Coauthors included employees of GlaxoSmithKline.
Gnant disclosed relationships with AstraZeneca, Novartis, Roche, Schering, Pfizer, Novartis, AstraZeneca, Sanofi-Aventis, GlaxoSmithKline, and Amgen. Steger disclosed relationships with AstraZeneca, Roche, Amgen, Novartis, and GlaxoSmithKline.
Neoadjuvant therapy with trastuzumab (Herceptin) and lapatinib (Tykerb), in addition to chemotherapy, led to pathologic complete response (pCR) in more than half of patients, Jose Baselga, MD, of Massachusetts General Hospital in Boston, and co-authors reported online in The Lancet.
That compared with the 25% to 30% of patients who achieved complete response on trastuzumab or lapatinib alone.
Although the study did not evaluate the effect of treatment on survival, prior studies have shown that pCR correlates with improved disease outcomes in patients treated with trastuzumab and chemotherapy.
"This open-label, multicenter, phase III study showed that dual inhibition of HER2 with lapatinib and trastuzumab in combination with paclitaxel is better than single-agent HER2 targeting," the researchers wrote in conclusion.
"Our study also supports investigation of novel targeted agents for breast cancer in the neoadjuvant setting, when tumors have not yet acquired resistance to therapy and when chances of clinical benefit are highest."
The published results updated and affirmed findings from an initial report more than a year ago.
Results of another study, published simultaneously in The Lancet Oncology, showed that neoadjuvant therapy with trastuzumab plus chemotherapy resulted in a significantly higher rate of pathologic complete response compared with lapatinib and chemotherapy.
Both targeted agents inhibit HER2 but have different mechanisms of action, providing a rationale for evaluating them in combination. Preclinical and clinical evidence had suggested that combining lapatinib and trastuzumab would result in more potent inhibition of HER2 compared with either drug alone.
Baselga and colleagues reported final results from a trial called NeoALTTO, which compared lapatinib, trastuzumab, and the combination for women with HER2-positive breast cancer.
All patients started treatment with the assigned targeted therapy. Paclitaxel was added after six weeks, and neoadjuvant therapy continued for a total of 18 weeks. Surgery followed completion of neoadjuvant therapy, and patients received adjuvant treatment with paclitaxel and the same anti-HER2 regimen as in the neoadjuvant.
The final analysis involved 455 with HER2-positive primary breast cancer larger than 2 cm in diameter. The primary endpoint was pCR, as defined by National Surgical Adjuvant Breast and Bowel Project criteria.
The targeted combination plus paclitaxel resulted in a pCR rate of 51.3% compared with 29.5% in patients who received trastuzumab plus paclitaxel and 24.7% for the lapatinib-paclitaxel arm (P=0.0001). The pCR rate did not differ between the trastuzumab and lapatinib arms.
No major cardiac dysfunction occurred during the trial. Patients treated with lapatinib had higher rates of grade 3 diarrhea (23.4%, 21.1%, respectively) and grade 3 liver-enzyme alterations (17.5%, 9.9%) compared with trastuzumab (2%, 7.4%). Otherwise, adverse events were similar among treatment groups.
Authors of a related commentary said that trials of targeted therapies could change the clinical evaluation process.
Rigorous investigation of a biologic agent in the neoadjuvant setting might obviate the need to begin evaluation of a drug in advanced disease before moving to the neoadjuvant and adjuvant settings, wrote Michael Gnant, MD, and Guenther G. Steger, MD, of the Medical University of Vienna in Austria.
Such an approach to clinical investigation could substantially reduce development costs and bring promising new drugs to patients more quickly, they wrote.
However, they also pointed to NeoALTTO as an illustration of unresolved issues in clinical use of targeted agents. Optimal treatment duration, selection and use of biomarkers, and the expense of combining two costly drugs must be rigorously examined, wrote Gnant and Steger.
The article in The Lancet Oncology provided details of another European trial, called GeparQuinto, a phase III randomized study involving 620 women with previously untreated operable or locally advanced HER2-positive breast cancer.
Patients with clinical stages T1 through T4 were eligible, depending on nodal and hormone-receptor status. All patients received neoadjuvant chemotherapy with the combination of epirubicin, cyclophosphamide, and docetaxel. They were randomized to neoadjuvant trastuzumab or lapatinib.
The primary endpoint was pCR. When the trial ended, 30.3% of patients in the trastuzumab arm and 22.7% of those in the lapatinib arm had achieved pCR, which translated into an odds ratio of 0.68 in favor of trastuzumab (P=0.04).
The trastuzumab regimen was associated with higher rates of edema (39.1% versus 28.7%) and dyspnea (29.6% versus 21.4%) and the lapatinib regimen with more diarrhea (75.0% versus 47.4%) and skin rash (54.9% versus 31.9%).
Premature discontinuation rates were 14.0% with trastuzumab and 33.1% with lapatinib.
"This direct comparison of trastuzumab and lapatinib showed that pathologic complete response rate with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab," Gunter Von Minckwitz, MD, of German Breast Cancer Group in Neu-Isenburg, and co-authors wrote in conclusion.
"Unless long-term outcome data show different results, lapatinib should not be used outside of clinical trials as a single anti-HER2 treatment in combination with neoadjuvant chemotherapy," they wrote.
The results confirm those from a previous report at the San Antonio Breast Cancer Symposium.
Three important lessons can be learned from the results of GeparQuinto, Stephen K. Chia, MD, of the British Columbia Cancer Agency in Vancouver, B.C., wrote in an accompanying commentary.
- Lapatinib plus chemotherapy offers no advantages over chemotherapy plus trastuzumab in the adjuvant setting, a conclusion drawn recently by investigators in a large randomized trial that compared the two agents as adjuvant therapy for patients with early-stage HER2-positive breast cancer.
- The preoperative (neoadjuvant) setting is ideally suited for testing new therapies.
- Clinical researchers and patients have embraced the preoperative model as standard of care and as a strategy for evaluating new therapies.
Baselga disclosed a relationship with Roche. Coauthors disclosed relationships with GlaxoSmithKline, Roche, Novartis, Amgen, Abbott, AstraZeneca, Pizer, and Bristol-Myers Squibb. Coauthors included employees of GlaxoSmithKline.
Gnant disclosed relationships with AstraZeneca, Novartis, Roche, Schering, Pfizer, Novartis, AstraZeneca, Sanofi-Aventis, GlaxoSmithKline, and Amgen. Steger disclosed relationships with AstraZeneca, Roche, Amgen, Novartis, and GlaxoSmithKline.
Primary source:
The Lancet Source reference: Baselga
J, et al "Lapatinib with trastuzumab for HER2-positive early breast
cancer (NeoALTTO): A randomized, open-label, multicenter, phase III
trial" Lancet 2012; DOI:10.1016/S0140-6736(12)61846-3.Additional
source: The Lancet Source reference: Gnant M, Steger GG "Dual
inhibition of HER2 in breast cancer treatment" Lancet 2012;
DOI:10.1016/S0140-6736(12)60068-3.Additional source: Untch M et al.
"Lapatinib versus trastuzumab in combinatioin with neoadjuvant
anthracyclline-taxane-based chemotherapy (GeparQuinto, GBG 44): A
randomized phase III trial." Lancet Oncol.
2012;doi:10.1016/S1470-2045(11)70397-7. Source reference: Untch M et
al. "Lapatinib versus trastuzumab in combinatioin with neoadjuvant
anthracyclline-taxane-based chemotherapy (GeparQuinto, GBG 44): A
randomized phase III trial." Lancet Oncol.
2012;doi:10.1016/S1470-2045(11)70397-7.
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