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

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

This phase III study, led by the German Breast Group, compared outcomes associated with neoadjuvant lapatinib versus trastuzumab in patients who received an anthracyclinebased chemotherapy regimen prior to surgery. Following surgery, the women randomized to lapatinib were given trastuzumab for 12 months, and women initially assigned to trastuzumab continued on the drug for an additional 6 months. Michael Untch, MD, Multidisciplinary Breast Cancer Center, Helios Clinic, Berlin, Germany, presented results from the neoadjuvant phase of the trial for the subset of patients with HER2-positive disease.

The trial enrolled 2500 women with untreated, primary invasive breast cancer, of which 620 were HER2-positive. Looking at disease characteristics, median tumor size was 4 cm. About 17% of patients had locally advanced disease, ~28% had multifocal disease, 69% were node-positive at baseline, 47% had high-grade, aggressive tumors, and 42% were estrogen receptor (ER)- and progesterone receptor (PR)-negative.

Patients were randomized to 4 cycles of epirubicin and cyclophosphamide, administered concurrently with trastuzumab or lapatinib. Women randomized to trastuzumab received a loading dose of 8 mg/kg followed by 6 mg/kg every 3 weeks, and those given lapatinib received 1000 to 1250 mg per day. After the first 4 cycles, all the patients were given 4 cycles of docetaxel 100 mg/m2.

The rate of discontinuation was 10% higher in the lapatinib arm than in the trastuzumab arm (23% vs 13%, respectively), primarily because of severe diarrhea. Partway through the trial, the investigators decided to counter the diarrhea by lowering the dose of lapatinib and administering loperamide, which Untch said reduced the incidence of grade 3 diarrhea, and he recommended giving it to all patients taking lapatinib.

GeparQuinto applied more stringent criteria than the National Surgical Adjuvant Breast and Bowel Project (NSABP) guidelines used in the Neo-ALTTO trial for determining pCR. Untch said his group defined pCR as no microscopic evidence of invasive or noninvasive cancer cells in the breast and lymph nodes at the time of surgery. Using this strict criteria yielded a pCR rate of 31.3% in the trastuzumab arm compared with 21.7% in the lapatinib arm (P <.05). When they reanalyzed pCR data according to NSABP guidelines, the rate of pCR was still better with trastuzumab than with lapatinib (50.4% vs 35.2%, respectively; P <.05). Untch said other studies have suggested that pCR is an independent predictor of long-term outcomes. In addition, Untch noted that the women who took neoadjuvant trastuzumab were more likely to receive breast-conserving surgery than those treated with lapatinib (65.6% vs 56.0%). He said this was likely because of tumor shrinkage and hypothesized that future studies might find HER2 blockade allows some women to forgo surgery altogether. Abstract S3-1.

Comments from Discussant

Eric Winer, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, who served as the formal discussant for the data presentation, pointed out that trastuzumab outperformed lapatinib in both trials. "It is not clear to what extent this is due to the patients who were not able to complete lapatinib treatment as planned," he noted.

Winer added that because lapatinib and trastuzumab attack different targets in HER2-positive breast cancer, evidence leans toward combining them. "There are abundant data to suggest that the combination of trastuzumab plus lapatinib is better than either drug alone."

ER-negative patients were more likely to obtain pCR regardless of the definition used by the trials, he noted. He did not concur with Untch that pCR predicts long-term outcomes. He said that while it is possible that the failure of ER-positive patients to achieve a pCR might not compromise eventual disease-free survival (DFS), longer follow-up is needed. "pCR is variable and associated with hormone receptor subtype. We need further data on anti-HER2 therapies [before using pCR as a surrogate for DFS]," Winer said.

"The combination of lapatinib and trastuzumab plus docetaxel will be studied in the adjuvant setting. It should not be used as neoadjuvant therapy outside the setting of a clinical trial," he cautioned.

_____________________________________

Baselga J, Bradbury I, Eidtmann H, et al. First Results of the NeoALTTO Trial (BIG 01-06 / EGF 106903): a phase III, randomized, open label, neoadjuvant study of lapatinib, trastuzumab, and their combination plus paclitaxel in women with HER2-positive primary breast cancer. Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX.

Untch M, Loibl S, Bischoff J, et al. Lapatinib vs trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy: primary efficacy endpoint analysis of the GeparQuinto study (GBG 44). Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX.

Published in Oncology & Biotech News. January 2011.