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

Abstract

PURPOSE Human epidermal growth factor receptor 2 (HER2) targeting plus endocrine therapy (ET) improved clinical benefit in HER2-positive, hormone receptor (HR)–positive metastatic breast cancer (MBC) versus ET alone. Dual HER2 blockade enhances clinical benefit versus single HER2 blockade. The ALTERNATIVE study evaluated the efficacy and safety of dual HER2 blockade plus aromatase inhibitor (AI) in postmenopausal women with HER2-positive/HR-positive MBC who received prior ET and prior neo(adjuvant)/first-line trastuzumab (TRAS) plus chemotherapy. This updated article reflects minor numerical corrections in some secondary efficacy analyses that resulted from programming errors and that do not change the major conclusions of the study. METHODS Patients were randomly assigned (1:1:1) to receive lapatinib (LAP) plus TRAS plus AI, TRAS plus AI, or LAP plus AI. Patients for whom chemotherapy was intended were excluded. The primary end point was progression-free survival (PFS; investigator assessed) with LAP plus TRAS plus AI versus TRAS plus AI. Secondary end points were PFS (comparison of other arms), overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. RESULTS Three hundred fifty-five patients were included in this analysis: LAP plus TRAS plus AI (n = 120), TRAS plus AI (n = 117), and LAP plus AI (n = 118). Baseline characteristics were balanced. The study met its primary end point; superior PFS was observed with LAP plus TRAS plus AI versus TRAS plus AI (median PFS, 11 v 5.6 months; hazard ratio, 0.62 [95% CI, 0.45 to 0.88]; P = .0063). A consistent PFS benefit was observed in predefined subgroups. ORR, CBR, and OS also favored LAP plus TRAS plus AI. The median PFS with LAP plus AI versus TRAS plus AI was 8.3 versus 5.6 months (hazard ratio, 0.85 [95% CI, 0.62 to 1.17]; P = .3159). Common adverse events (AEs; ≥ 15%) with LAP plus TRAS plus AI, TRAS plus AI, and LAP plus AI were diarrhea (69%, 9%, and 51%, respectively), rash (36%, 2%, and 28%, respectively), nausea (22%, 9%, and 22%, respectively), and paronychia (30%, 0%, and 15%, respectively), mostly grade 1 or 2. Serious AEs were reported similarly across the 3 groups, and AEs leading to discontinuation were lower with LAP plus TRAS plus AI. CONCLUSION Dual HER2 blockade with LAP plus TRAS plus AI showed superior PFS benefit versus TRAS plus AI in patients with HER2-positive/HR-positive MBC. This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population.

Fulvestrant and trastuzumab in patients with luminal HER2-positive advanced breast cancer (ABC): an Italian real-world experience (HERMIONE 9)

“…While showing less responsiveness to the combination of chemotherapy plus anti-HER2 agents as compared to the HR negative counterpart, results with the combination of anti-HER2 agents and non-steroidal aromatase inhibitors (NSAI) have been quite disappointing with a mPFS not exceeding 4.8 months with trastuzumab and anastrozole and 8.2 months with lapatinib and letrozole as first-line treatment [6,7]. The recently updated ALTERNATIVE trial, which investigated the addition of lapatinib, trastuzumab, or both agents to a NSAI, showed a significant improvement in mPFS for the double HER2 blockade vs trastuzumab plus NSAI (11 vs 5.6 months) [15]. On the other hand the PERTAIN trial reported a mPFS of 21.7 months in the arm with the double HER2 blockade with pertuzumab and trastuzumab plus a NSAI, which was not only significantly higher than that reported by the trastuzumab plus NSAI combination but, more importantly, was similar to that reported in patients who had received chemotherapy before endocrine therapy (mPFS = 18.9 months) [16].…”

Dual HER2 blockade with lapatinib and trastuzumab in combination with chemotherapy in metastatic gastroesophageal adenocarcinoma

“…The principle of dual HER2 blockade, which utilizes different HER2‐targeted agents with complementary mechanisms to overcome drug resistance, has been researched and put into clinical practice in HER2‐amplified breast cancer 10,11 . In the NeoALTTO trial, the combination of trastuzumab and lapatinib plus chemotherapy as neoadjuvant therapy significantly improved rates of pathological complete response in early breast cancer 10 .…”

“…In the NeoALTTO trial, the combination of trastuzumab and lapatinib plus chemotherapy as neoadjuvant therapy significantly improved rates of pathological complete response in early breast cancer 10 . The ALTERNATIVE trial showed that dual HER2 blockade with lapatinib and trastuzumab plus an aromatase inhibitor had superior PFS benefit vs trastuzumab plus aromatase inhibitor (11 vs 5.6 months, HR 0.62 (0.45 to 0.88), P =.0063) in metastatic breast cancer 11 . The authors concluded that this combination offered a safe treatment regime for patients; its adverse events mainly Grade 1‐2 diarrhea, rashes, nausea, and paronychia 11 …”

Assessment of HER2 Protein Overexpression and Gene Amplification in Renal Collecting Duct Carcinoma: Therapeutic Implication

“…With the exception of one single case report [ 22 ], there are no clinical studies that used anti-HER2 compounds in a single or multiple-agent approach in CDC. A large plethora of data indicates that solid tumors with HER2 gene amplification respond to an anti-HER2-targeted therapy [ 26 , 27 , 28 , 29 ], with an improvement in clinical outcomes. Based on this principle, our study provides preliminary evidence in support of testing anti-HER2 therapy in CDC.…”