Targeting HER2 with two agents — lapatinib (Tykerb) and trastuzumab (Herceptin) — and adding an aromatase inhibitor (AI) significantly improved progression-free survival (PFS) compared to trastuzumab/AI in patients with HER2-positive and hormone receptor-positive metastatic breast cancer, researchers found.
Results from the large, randomized, phase III ALTERNATIVE trial demonstrated that the combination of lapatinib/trastuzumab/AI provided a clinically meaningful prolongation of PFS compared with trastuzumab/AI with a median PFS of 11.0 versus 5.7 months, respectively, according to Stephen R.D. Johnston, MA, PhD, of The Royal Marsden NHS Foundation Trust in London, and colleagues.
This represented a statistically significant 38% reduction in the risk of disease progression (hazard ratio [HR] 0.62; P=0.0064) in patients not suitable for chemotherapy, the study authors reported online in the Journal of Clinical Oncology. Lapatinib/trastuzumab/AI was also relatively well tolerated compared with trastuzumab/AI.
These findings indicate that patients with HER2-positive/HR-positive MBC who are not candidates for chemotherapy can be adequately treated with dual HER2 blockade plus an AI, Johnston and colleagues emphasized. “Although survival data were immature, there was also a trend in favor of the dual-blockade treatment (median 46.0 versus 40.0 months),” they wrote.
The PFS benefit of lapatinib/trastuzumab/AI compared with trastuzumab/AI was consistent across patient subgroups. The overall response rate (ORR) and clinical benefit rate (CBR) also favored the lapatinib/trastuzumab/AI combination over trastuzumab/AI (ORR 31.7% versus 13.7%, and CBR 41% versus 31%, respectively).
“Dual HER2 blockade enhances clinical benefit versus single HER2 blockade,” the study authors noted. “The use of dual anti-HER2 blockade represents a potential strategy to further improve the outcome of these patients,” Johnston and colleagues added.
The ALTERNATIVE trial enrolled 355 postmenopausal women from 112 sites in 29 countries. All patients had received prior endocrine therapy and experienced disease progression after prior neo(adjuvant)/first-line trastuzumab plus chemotherapy. Patients were randomly assigned 1:1:1 to lapatinib/trastuzumab/AI, trastuzumab/AI, or lapatinib/AI.
In the lapatinib/trastuzumab/AI arm, patients took 1,000 mg/day oral lapatinib. In the lapatinib/AI arm, patients took 1,500 mg/day. In both trastuzumab arms, patients received an IV loading dose of 8 mg/kg trastuzumab followed by a maintenance dose of 6 mg/kg every 3 weeks. Oral AIs included letrozole (Femara; 2.5 mg/day), antinuclear antibodies (1 mg/day), or exemestane (Aromasin; 25 mg/day).
The median PFS with lapatinib/AI versus trastuzumab/AI was 8.3 versus 5.7 months (HR 0.71; P=0.0361).
Common adverse events were seen in lapatinib/trastuzumab/AI; trastuzumab/AI; and lapatinib/AI, respectively, and included:
- Diarrhea (69%, 9%, and 51%)
- Rash (36%, 2%, and 28%)
- Nausea (22%, 9%, and 22%)
- Paronychia (30%, 0%, and 15%)
Frequency of adverse events, mostly grade 1 or 2, was 92% in the two lapatinib arms and 74% in the trastuzumab arm. Serious AEs were reported across the three study groups, with discontinuation lowest in the lapatinib/trastuzumab/AI arm (3%) compared to the trastuzumab/AI (6%) and lapatinib/AI (9%) arms.
Other studies looking at HER2 blockade have been conducted in different patient populations, so “cross-trial comparisons need to be interpreted with caution,” the study authors warned. Although the PFS outcome in ALTERNATIVE lines up with results from other studies, there are a limited number of trials designed for patients with HER2-positive/HR-positive metastatic breast cancer, they pointed out.
In the phase II PERTAIN study of locally advanced or metastatic hormone receptor-positive HER2-positive breast cancer patients, the addition of pertuzumab (Perjeta) to a regimen of trastuzumab and an AI in the first-line setting significantly improved PFS by 3 months. The median PFS was 18.9 months with pertuzumab, trastuzumab and endocrine therapy compared to 15.80 months with trastuzumab plus endocrine therapy.
However, only 77% of patients were trastuzumab-naive and 55% of patients had received induction chemotherapy in this first-line setting, the ALTERNATIVE study authors noted.
The rationale for PERTAIN came from the TAnDEM study, which showed that adding trastuzumab to anastrozole (Arimidex) significantly improved PFS over anastrozole alone. The CLEOPATRA study also demonstrated improved PFS and OS with the addition of pertuzumab to trastuzumab plus docetaxel.
These findings contrast the lack of benefit observed with lapatinib in the adjuvant setting in the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial, Johnston and colleagues pointed out. In addition, the APHINITY trial demonstrated only a modest benefit with pertuzumab.
“This discrepancy may be the result, at least in part, of the excellent outcome with adjuvant single HER2 blockade with TRAS, making the demonstration of additional benefit with dual blockade harder. Dual HER2 blockade may benefit only a small subset of high-risk patients,” they suggested.
Similarly, results from an earlier international trial showed that adjuvant therapy with two HER2-targeted drugs failed to improve disease-free survival in early breast cancer compared with trastuzumab monotherapy. Concurrent administration of lapatinib and trastuzumab resulted in a nonsignificant 16% reduction in DFS compared with trastuzumab alone.
However, in a nonrandomized phase II study, the combination of lapatinib and trastuzumab was effective and well-tolerated in patients with HER2+ breast cancer who had received up to two lines of therapy for advanced disease. The study also showed that metabolic imaging appeared to be helpful for selecting poor responders in advance, thus sparing them the toxicity of chemotherapy.
Original funding for the ALTERNATIVE study was provided by GlaxoSmithKline. As of March 2, 2015, lapatinib was acquired by Novartis, the current sponsor of this study. Johnston reported relationships with Novartis, Eli Lilly, AstraZeneca, OBI Pharma, Puma Biotechnology, and Pfizer. A number of study co-authors also reported relationships with industry, including GlaxoSmithKline and Novartis.