HER2 Blockade Regimen Appears Superior as Treatment of HER2+ HR+ Metastatic Breast Cancer

Frontline trastuzumab in combination with lapatinib (Tykerb) and an aromatase inhibitor (AI) appeared superior to trastuzumab/AI as treatment of patients with HER2-positive, HR-positive metastatic breast cancer, according to the randomized phase 3 ALTERNATIVE study published in the Journal of Clinical Oncology.

The study met its primary end point of superior progression-free survival (PFS) with the triplet regimen compared to either doublet.

“To our knowledge, this is the first large, randomized clinical trial exclusively evaluating this chemotherapy-sparing regimen in a HER2-positive/HR-positive metastatic breast cancer population of patients who had already received prior endocrine therapy and prior trastuzumab plus chemotherapy in the neo(adjuvant) and/or first-line metastatic setting,” wrote Stephen R. D. Johnston, PhD, et al. “Our study demonstrated that the combination of lapatinib plus trastuzumab plus AI provided a clinically meaningful prolongation of PFS compared with trastuzumab plus AI, representing a statistically significant 38% reduction in the risk of disease progression.”

In the study, the median PFS with the triplet was 11.0 versus 5.6 in the trastuzumab/AI arm (HR, 0.62; 95% CI, 0.45-0.88; P =.0063). A similar magnitude of benefit was also observed, favoring the triplet in 2 sensitivity analyses of PFS. One analysis did not censor patients receiving alternative anticancer treatments before a PFS event (HR, 0.65; 95% CI, 0.47-0.91), and the second included non-radiologic progressions as events (HR, 0.64; 95% CI, 0.46-0.89).

The median PFS with the lapatinib/AI regimen was 8.3 months, which was compared with the trastuzumab regimen (HR, 0.85; 95% CI, 0.62-1.17; P =.3159). The PFS benefit for the triplet was consistent in predefined groups of patients, including those with measurable disease, those treated with AIs, and those who had already received trastuzumab in the neoadjuvant, adjuvant, or metastatic setting.

The PFS benefit of the triplet in the primary analysis was also consistent with a Cox regression analysis, including all factors that had a significant effect on PFS in addition to the treatment (HR, 0.56; 95% CI, 0.396-0.796). The benefit was also consistent in the centrally confirmed HER2-positive subpopulation (by FISH or IHC: HR, 0.63; 95% CI, 0.40-1.01 & by FISH only: HR, 0.57; 95% CI, 0.35-0.94). The benefit of the triplet was consistent as well in a centrally confirmed HER2-positive/HR-positive subpopulation (HR, 0.72; 95% CI, 0.43-1.23).

The objective response rate (ORR) with the triplet was 31.7% compared with 13.7% with trastuzumab/AI, and 18.6% for lapatinib/AI. The median duration of response was 14.0 months, 8.4 months, and 11.1 months, respectively.

In the intent-to-treat population for the triplet arm versus trastuzumab/AI and lapatinib/AI, 6 patients (5%) had a complete response versus 1 (<1%) and 8 (7%); 32 patients (27%) had a partial response versus15 (13%) and 14 (12%); 52 patients (43%) had stable disease versus 52 (44%) and 61 (52%); and 18 patients (15%) had progressive disease versus 37 (32%) and 28 (24%), respectively.

The clinical benefit rate was 40% for the triplet versus 30% with trastuzumab/AI and 34% for lapatinib/AI. Overall survival (OS) data were immature at the time of the current analysis for the triplet versus trastuzumab/AI but trended in favor of the triplet with medians of 46.0 months versus 40.0 months, respectively (HR, 0.60; 95% CI, 0.35-1.04). The median OS with lapatinib/AI was 45.1 months compared with trastuzumab/AI (HR, 0.91; 95% CI, 0.55-1.51).

The most common adverse events (AEs) observed with the triplet versus lapatinib/AI and trastuzumab/AI were, respectively, diarrhea (69%, 9%, and 51%, respectively), rash (36%, 2%, and 28%, respectively), nausea (22%, 9%, and 22%), and paronychia (30%, 0%, and 15%), and most events were grades 1/2. Grade 3/4 AEs were low in all 3 treatment arms, occurring in <5% of patients. However, 13% of patients in the triplet and 6% in the lapatinib/AI arm had experienced grade 3 diarrhea. There were no diarrhea events of grade 4 severity.

In the triplet arm versus trastuzumab/AI and lapatinib/AI arms, serious AEs occurred in 14%, 10%, and 17% of patients, while treatment-related AEs occurred in 5%, 2%, and 4% of patients, respectively. Almost all deaths in the study were a result of disease progression, with the exception of 1 death that was a result of cardiogenic shock in the lapatinib/AI arm and 1 as a result of cardiopulmonary arrest in the trastuzumab/AI arm. Cardiac safety-related events occurred in 7% of the triplet arm, 3% in the trastuzumab/AI arm, and 2% in the lapatinib/AI arm.

AEs led to treatment discontinuation in 3% of patients in the triplet arm versus 6% in the trastuzumab/AI arm and 9% in the lapatinib/AI arm. The most common AEs that led to treatment discontinuation included transaminases increase, which occurred in the lapatinib/AI arm when the dose of lapatinib was at its highest. The dose of lapatinib was reduced in 20% of patients in the triplet arm versus 17% in the lapatinib/AI arm. The primary reason for dose reductions were AEs in 71% of the triplet arm, and 37% in the lapatinib/AI arm, as well as patient noncompliance in 25% and 63%, respectively. Dose interruptions of lapatinib were required in 38% of the triplet arm versus 35% in the lapatinib/AI arm, which was mainly because of AEs in 51% versus 50% of patients, respectively.

Trastuzumab dose delays were required in 19% of the triplet arm versus 9% in the trastuzumab/AI arm, and the main reasons for delays were AEs (38% vs. 15%) and noncompliance (28% vs. 15%, respectively). Overall, 75% in the triplet arm, 82% in the trastuzumab/AI arm, and 84% in the lapatinib/AI arm discontinued treatment, which was mostly due to disease progression in 64% versus 72% and 70% or AEs in 4% versus 6% and 9%, respectively.

Overall, 355 patients were enrolled in the study across 112 sites in 29 countries. The baseline characteristics of these patients appeared well balanced across the 3 treatment arms. Patients were randomized 1:1:1 to receive AI therapy with either trastuzumab (n = 117), lapatinib (n = 118), or the combination of trastuzumab and lapatinib (n = 120). The purpose of this study was to evaluate the superiority of the triplet in terms of PFS compared with either of the 2 doublet combinations.

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_Reference

_{Johnston SRD, Hegg R, Im SA, et al. Phase III, randomized study of dual human epidermal growth factor receptor 2 (HER2) blockade with lapatinib plus trastuzumab in combination with an aromatase inhibitor in postmenopausal women with her2-positive, hormone receptor-positive metastatic breast cancer: updated results of ALTERNATIVE. J Clin Oncol. 2020. Published online Aug 21, 2020. doi: 10.1200/JCO.20.01894}