SABCS Coverage: Trastuzumab Superior to Lapatinib in HER2-Positive Breast Cancer, But Combination Is Best

Bonnie Gillis
Published: Wednesday, Mar 02, 2011
Two trials explored the role of lapatinib (Tykerb) as neoadjuvant therapy in early-stage HER2-positive breast cancer and concluded that its effectiveness is statistically no better than standard trastuzumab (Herceptin) therapy. Investigators said that the adverse events many patients experience while taking lapatinib--in particular, severe diarrhea-- might limit its usefulness in this setting. The Neo-ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation), phase III study did find significant improvement in the rate of pathological complete remission (pCR) when using lapatinib and trastuzumab as a combination regimen versus either drug alone (Figure). In the GeparQuinto study, lapatinib combined with epirubicin and cyclophosphamide proved less effective at producing a pCR prior to surgery than trastuzumab administered with the same chemotherapy regimen.

Neo-ALTTO

Neo-ALTTO enrolled 450 women with invasive, operable, HER2-positive breast cancer tumors >2 cm who had adequate cardiac function. Patients were randomized to 1 of 3 regimens for 6 weeks: 1500 mg of lapatinib per day; intravenous trastuzumab, with a 4 mg/kg loading dose followed by 2 mg/kg weekly; or 1000 mg of lapatinib daily with the same trastuzumab regimen that was given in the trastuzumab-only arm. Paclitaxel was introduced in all groups at week 6, and patients continued on neoadjuvant therapy for an additional 6 weeks.

Following surgery, patients were assigned to 34 weeks of adjuvant therapy, with drug selection based on the neoadjuvant regimen received. Women who took single-agent lapatinib or trastuzumab with paclitaxel in the trial's neoadjuvant phase received the same drug as adjuvant therapy. Those who took lapatinib and trastuzumab together received the doublet again. Overall, the women completed 1 year of HER2- targeting treatment.

Trial protocol required the collection of tumor tissue samples after 2 weeks of therapy. Investigators said they obtained >11,000 tissue samples through biopsy to analyze for biomarkers predictive of response or resistance to the regimens used. At the symposium, Jose Baselga, MD, chief of the Division of Hematology/Oncology and associate director of Massachusetts General Hospital Cancer Center in Boston, presented preliminary data only from the neoadjuvant phase of the Neo-ALTTO trial. The primary endpoint for this portion of the study was pCR, defined as an absence of invasive cells in the breast or noninvasive in situ cancer in the breast at surgery.

The pCR rate in the combination arm was 51.3% compared with 24.7% in the trastuzumabonly arm (P = .0001) and 19.5% in the lapatinibonly group. The pCR rate did not differ significantly when comparing the lapatinibonly and trastuzumab-only groups. Assessing pCR as the absence of cancer cells in the breast and lymph nodes produced a rate of 46.9% in the combination arm, compared with 27.6% in the trastuzumab arm (P = .001) and 20% in the lapatinib arm. The difference was again statistically insignificant between the lapatinibonly and trastuzumab-only groups.

Looking at pCR by hormone receptor (HR) status, the combination of lapatinib and trastuzumab provided a more robust benefit for HR-negative patients than it did for HRpositive patients (61.3% vs 41.6%, respectively). Comparing pCR rates in each arm by HR status significantly favored the combination regimen over trastuzumab alone in HR-negative patients (P = .005) and HR-positive patients (P = .03).

"This study shows that dual anti-HER2 blockade with lapatinib plus trastuzumab is valuable in this group of patients with breast cancer," Baselga said. In the lapatinib-only arm, 23% of patients developed grade 3 diarrhea versus 2% of patients receiving trastuzumab and 21% of patients given both drugs together. Diarrhea in the lapatinibonly group increased over time, and the rate of grade 3 diarrhea went from 11% to 22% by the end of the neoadjuvant phase of the trial. The lapatinib arm also experienced a higher rate of grade 3 neutropenia (16%) than the trastuzumab arm (3%) and the combination group (9%). The rate of grade 3 hepatic abnormalities was 13% in the lapatinib arm, with 2 patients experiencing "serious hepatic dysfunction," according to Baselga. The rate of grade 3 hepatic abnormalities only reached 1% in the trastuzumab arm and 9% in the combination arm. Both the lapatinib-only arm and the combination arm had a 7% rate of grade 3 skin disorders compared with 2% of patients taking trastuzumab alone. None of the groups demonstrated any evidence of cardiac dysfunction. Baselga said that although the increased toxicities (particularly diarrhea and liver enzyme abnormalities) were manageable in the lapatinib arm, nearly one-third of patients in this group were unable to complete treatment as planned. Abstract S3-3.

GeparQuinto


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