Updated ALTERNATIVE Results Favor Dual HER2 Blockade in HER2+/HR+ Metastatic Breast Cancer

Updated results from the phase 3 ALTERNATIVE study showed that dual HER2 blockade plus aromatase inhibition (AI) in post-menopausal women with HER2-positive, hormone receptor (HR)–positive metastatic breast cancer outperformed single HER2 blockade. 

The new results, printed in the Journal of Clinical Oncology,1 include numerical corrections that affected secondary analyses but did not affect the major conclusions of the study; nonetheless, the original ALTERNATIVE study, which was published in 2017, was retracted.

Typically, according to the investigators led by Stephen R. D. Johnston, PhD, of the Royal Marsden NHS Foundation Trust, in England, patients with HER2-positive cancers are given chemotherapy regardless of their HR status. Johnston and colleagues noted that targeted agents such as trastuzumab (Herceptin), lapatinib (Tykerb), pertuzumab (Perjeta), and trastuzumab-emtansine (T-DM1; Kadcyla) have significantly improved outcomes. However, the investigators said not all patients need or can tolerate chemotherapy. In such cases, anti-HER2 therapies paired with endocrine therapy can be a good option. Earlier research has suggested HER2-blockade with endocrine therapy (ET) in the first-line setting can improve outcomes over ET alone. In the ALTERNATIVE study, Johnston and colleagues set out to evaluate the use of a dual HER2-blockade, using a combination of trastuzumab and lapatinib.

“Dual targeting of HER2-positive tumors with [trastuzumab] and [lapatinib] is beneficial because of differing mechanisms of action and because of the well-characterized synergistic interaction between them in HER2 [breast cancer] models,” the investigators wrote. “In the clinic, dual anti-HER2 blockade has been shown to improve outcomes in both the neoadjuvant and the metastatic setting compared with single HER2 blockade.”

The investigators enrolled a group of 355 patients with HER2-positive/HR-positive metastatic breast cancer who were not expected to undergo chemotherapy and who had previously received treatment with ET and had progressed on or after a trastuzumab and chemotherapy–based neoadjuvant/adjuvant regimen and/or in the first-line setting. The enrollees were randomly split into 3 groups: one group received lapatinib plus trastuzumab plus AI (n = 120), one group received trastuzumab plus AI (n = 117), and the final group received lapatinib plus AI (n = 118). Investigators chose whether patients received steroidal or nonsteroidal AI.

The primary end point was to evaluate progression-free survival (PFS) with lapatinib plus trastuzumab and AI versus trastuzumab plus AI.

The data showed that lapatinib plus trastuzumab and AI had a median PFS of 11 months (HR, 0.62; 95% CI, 0.45-0.88; P = .0063) versus 5.6 months on the trastuzumab-plus-AI. Overall response rate (ORR), clinical benefit rate, and overall survival were also superior in the lapatinib plus trastuzumab and AI group.

Comparing lapatinib plus AI to trastuzumab plus AI resulted in a median PFS of 8.3 months versus 5.6 months, respectively (HR, 0.85; 95% CI, 0.62-1.17; P = .3159).

The rates of any-grade adverse events (AEs) were 92% with the triplet regimen, 74% with trastuzumab and AI, and 92% with lapatinib and AI. Most AEs were grade 1 or 2, and the most common were diarrhea, rash, nausea, and paronychia. Rates of serious AEs were similar across the 3 groups, though the group with lapatinib plus trastuzumab and AI had the lowest number of AEs leading to discontinuation.

Johnston and colleagues wrote that although it is too early to report survival data, early indications suggest the dual blockade is similarly superior.

The investigators noted that their results contrast with the lack of benefit shown in the adjuvant setting in the ALTTO2trial, and the minimal benefit shown in the APHINITY3 trial.

“This discrepancy may be the result, at least in part, of the excellent outcome with adjuvant single HER2 blockade with [trastuzumab], making the demonstration of additional benefit with dual blockade challenging,” they wrote. “Dual HER2 blockade may benefit only a small subject of high-risk patients.”

In conclusion, the authors said the results of this trial show a “clinically meaningful and robust” benefit with lapatinib plus trastuzumab and AI in patients previously treated with trastuzumab and ET, as well as a “relatively good” tolerability. Thus, they said, the data suggest patients with HER2-positive/HR-positive metastatic breast cancer who are not candidates for chemotherapy should be considered for this regimen.

“This combination can potentially offer an effective and well-tolerated chemotherapy-sparing alternative treatment regimen for patients for whom chemotherapy is not intended,” Johnston et al concluded.

_References:

1. _{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. Published online August 21, 2020. doi:10.1200/JCO.20.01894}
2. _{Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: Results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial. J Clin Oncol. 2016;34(10):1034-1042. doi:10.1200/JCO.2015.62.1797}
3. _{von Minckwitz G, Procter M, de Azambuja E, et al; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377:122-131. doi:10.1056/NEJMoa1703643}