More Evidence That Dual Blockade Effective in HER2+ Breast Cancer

Martha Kerr

January 20, 2012

January 20, 2011 — Lapatinib is less effective than trastuzumab for HER2-positive breast cancer, but the combination, known as dual blockade, is nearly twice as effective as monotherapy with either, according to the results of 2 studies published online January 17, one in the Lancet Oncology and the other in the Lancet.

Positive results using dual blockade (pertuzumab plus trastuzumab) were reported last month at the San Antonio Breast Cancer Symposium, and reported at that time by Medscape Medical News.

Editorials accompanying the 2 studies note that perhaps as important as the actual results is how the studies were conducted. Both studies show the value of academic collaborations in such defining trials, and that such trials should not be conducted by pharmaceutical companies alone.

In the first study — a randomized phase 3 trial known as GeparQuinto — eligible patients had untreated HER2-positive operable or locally advanced breast cancer.

In all, 620 eligible women were randomized in a 1:1 ratio to receive neoadjuvant treatment with 4 cycles of intravenous epirubicin 90 mg/m² plus intravenous cyclophosphamide 600 mg/m² every 3 weeks. This was followed by 4 cycles of intravenous docetaxel 100 mg/m² every 3 weeks with either intravenous trastuzumab 6 mg/kg (with a loading dose of 8 mg/kg) for 8 cycles every 3 weeks or oral lapatinib (1000 to 1250 mg/day) throughout all cycles before surgery.

The investigators report that 30.3% of patients in the trastuzumab group and 22.7% of patients in the lapatinib group had a pathological complete response (odds ratio, 0.68; 95% confidence interval [CI], 0.47 to 0.97; P = .04).

Chemotherapy with trastuzumab was associated with more edema (39.1% vs 28.7%) and dyspnea (29.6% vs 21.4%), and with lapatinib was associated with more diarrhea (75.0% vs 47.4%) and skin rash (54.9% vs 31.9%).

Treatment was discontinued in 14% of the trastuzumab group and 33.1% of the lapatinib group. There were 70 serious adverse events in the trastuzumab group and 87 in the lapatinib group.

Because lapatinib was associated with such a high rate of significant adverse effects, lead investigator Michael Untch, MD, from the Helios Klinikum, Berlin-Buch, in Germany, and colleagues advise that "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."

"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," the investigators conclude.

Stephen K. Chia, MD, from the division of medical oncology at the British Columbia Cancer Agency in Vancouver, commends the study design in an accompanying editorial, and notes that "the rapid accrual in GeparQuinto is essential to minimize overall timelines for drug development."

Dr. Chia writes that "no adjuvant trials should be done without an adequate signal from preoperative trials showing safety, efficacy, target modulation, and, ideally, the identification of predictive biomarkers such that we no longer pick a loser to study in larger and more resource-intensive adjuvant trials."

Dual Blockade Is Better

In the second study, José Baselga, MD, from the Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston, and colleagues randomized women from 23 countries with HER2-positive primary breast cancer with tumors more than 2 cm in diameter to oral lapatinib 1500 mg, intravenous trastuzumab (a loading dose of 4 mg/m² and subsequent doses of 2 mg/kg), or lapatinib 1000 mg plus trastuzumab.

The study design called for women to receive anti-HER2 therapy alone for the first 6 weeks; weekly paclitaxel (80 mg/m²) was then added to the regimen for 12 weeks before definitive surgery was undertaken. After surgery, patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks. The primary end point was the rate of pathological complete response.

In all, 154 patients received lapatinib, 149 received trastuzumab, and 152 women received both.

Pathological complete response rate was significantly higher in women receiving dual therapy (51.3%; 95% CI, 43.1 to 59.5) than in those receiving trastuzumab alone (29.5%; 95% CI, 22.4 to 37.5), for a difference of 21.1% (95% CI, 9.1 to 34.2; P = .0001).

Dr. Baselga's team found no significant difference in pathological complete response rates between the lapatinib (24.7%; 95% CI, 18.1 to 32.3) and trastuzumab (–4.8%; 95% CI, –17.6 to 8.2; P = .34) groups.

There were no cases of major cardiac dysfunction. Grade 3 diarrhea was more frequent with lapatinib (23.4%) and lapatinib plus trastuzumab (21.1%) than with trastuzumab (2.0%). Grade 3 liver-enzyme alterations were more frequent with lapatinib (17.5%) and lapatinib plus trastuzumab (9.9%) than with trastuzumab (7.4%).

"The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumor activity in models of HER2-overexpressing breast cancer," Dr. Baselga and colleagues write.

They conclude that "dual inhibition of HER2 with lapatinib and trastuzumab in combination with paclitaxel is better than single-agent HER2 targeting. 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.

Michael Gnant, MD, from the Department of Surgery, and Guenther G. Steger, MD, from the Department of Medical Oncology, both at the Medical University of Vienna, Austria, caution in an accompanying editorial that findings from neoadjuvant and adjuvant treatment trials such as the 2 described here need to be viewed "from a scientific and a regulatory perspective."

"Trials in the neoadjuvant setting based on research-based hypotheses (after establishment of drug safety) could lead to a saving of enormous sums in drug development costs, and promising new drugs for treatment of early breast cancer could become available much more quickly than at present," Drs. Gnant and Steger believe.

Echoing the point that Dr. Chia made in his editorial, the Austrian editorialists note that "questions about duration of treatment and possible differential efficacy in biomarker-selected patient subcohorts need to be incorporated into clinical trials of targeted therapies."

Drs. Gnant and Steger assert that "standard defining trials should not be left to drug manufacturers, with their economic incentive towards protracted treatment durations, alone; such trials are best governed by collaborative academic groups and should be accompanied by translational research enterprises."

Both trials were supported by GlaxoSmithKline, the manufacturer of lapatinib. GeparQuinto also received support from Roche, the manufacturer of trastuzumab and pertuzumab, and sanofi-aventis. Dr. Untch has disclosed no relevant financial relationships. Dr. Chia reports receiving an honorarium from GlaxoSmithKline and an unrestricted research grant from Hoffmann-La Roche. Dr. Baselga reports receiving honoraria from Roche. Dr. Gnant reports serving on advisory boards for and received consulting fees from AstraZeneca and Novartis; and receiving lecture fees or research support from Roche, Schering, Pfizer, Novartis, AstraZeneca, sanofi-aventis, GlaxoSmithKline, and Amgen. Dr. Steger reports serving on advisory boards for and/or receiving consulting fees or support from AstraZeneca, Roche, Amgen, Novartis, and GlaxoSmithKline.

Lancet Oncol. Published online January 17, 2012. Abstract, Editorial
Lancet. Published online January 17, 2012. Abstract, Editorial

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