NeoALTTO Trial Shows No Benefit of Lapatinib Plus Trastuzumab in Secondary Survival Endpoints in HER2-Positive Early Breast Cancer
The phase III NeoALTTO trial showed a significantly improved pathologic complete response rate with lapatinib (Tykerb) plus trastuzumab (Herceptin) vs either alone in women with HER2-positive early breast cancer. As reported in The Lancet Oncology by de Azambuja et al, the combination was not associated with any benefit in the secondary endpoints of event-free survival or overall survival, although the investigators noted that the trial was not powered to detect survival differences. Significantly better event-free survival and overall survival were observed in patients with pathologic complete response, with the association in event-free survival being significant in the combination group.
Study Details
In this open-label trial, 455 patients were randomly assigned between January 2008 and May 2010 to receive oral lapatinib at 1,500 mg (n = 154), intravenous (IV) trastuzumab at a 4 mg/kg loading dose followed by 2 mg/kg (n = 149), or lapatinib at 1,000 mg plus trastuzumab (n = 152) for 6 weeks, followed by an additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel 80 mg/m². Definitive surgery was performed at 4 weeks after the last dose of paclitaxel. After surgery, patients received three cycles of FEC (fluorouracil at 500 mg/m², epirubicin at 100 mg/m², cyclophosphamide at 500 mg/m²) given IV every 3 weeks followed by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy.
Pathologic complete response was observed in 51.3% of the combination recipients vs 29.5% of the trastuzumab recipients (P = .0001), and there was no difference in pathologic complete response between the trastuzumab group and the lapatinib group (24.7%, P = .34).
Secondary endpoints included event-free survival and overall survival analyzed in the intention-to-treat population and the association between pathologic complete response and event-free survival and overall survival assessed by landmark analysis at 30 weeks after randomization. Follow-up is ongoing.
Event-Free Survival and Overall Survival
At a median event follow-up of 3.77 years, 3-year event-free survival was 78% in the lapatinib group, 76% in the trastuzumab group, and 84% in the combination group, with no significant differences observed between the lapatinib and trastuzumab groups (hazard ratio [HR] = 1.06, P = .81) or between the combination and trastuzumab groups (HR = 0.78, P = .33).
At a median survival follow-up of 3.84 years, 3-year overall survival was 93% for lapatinib, 90% for trastuzumab, and 95% for combination therapy, with no significant differences between the lapatinib and trastuzumab groups (HR = 0.86, P = .65) or between the combination and trastuzumab groups (HR = 0.62, P = .19).
Association With Pathologic Complete Response
Landmark analyses showed that 3-year event-free survival was significantly better in women who achieved pathological complete response vs those who did not (HR = 0.38, P = .0003). This association was significant in the combination group (HR = 0.32, P = .012), but not in the lapatinib group (HR = 0.43, P = .095) or the trastuzumab group (HR = 0.45, P = .075). Three-year overall survival was also significantly better in women achieving pathologic complete response (HR = 0.35, P = .005), although the association failed to reach significance in the combination group (HR = 0.35, P = .13), lapatinib group (HR = 0.41, P = .24) or trastuzumab group (HR = 0.42, P = .14).
Adverse Events
The most common adverse events were diarrhea, rash/erythema, hepatic adverse events, and neutropenia (not related to FEC administration) and were consistent with the known safety profiles of lapatinib and trastuzumab. Excluding the FEC administration period, patients receiving lapatinib had higher rates of grade 3 or 4 neutropenia (17% in lapatinib group, 3% in trastuzumab group, 13% in combination group). Primary cardiac events occurred in three patients (< 1%). There were more primary or secondary cardiac events in the combination group (5% vs 1% in both the lapatinib and trastuzumab groups), but there were no statistically significant differences between groups. No fatal adverse events considered related to study drugs were observed.
The investigators concluded: “Although event-free survival or overall survival did not differ between treatment groups, findings from our study confirm that patients who achieve pathological complete response after neoadjuvant anti-HER2 therapy have longer event-free and overall survival than do patients without pathological complete response.”
Evandro de Azambuja, MD, of Institut Jules Bordet, is the corresponding author for The Lancet Oncology article.
The study was funded by GlaxoSmithKline. For full disclosures of the study authors, visit www.thelancet.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
