Afatinib alone and in combination with vinorelbine or paclitaxel, in patients with HER2-positive breast cancer who failed or progressed on prior trastuzumab and/or lapatinib (LUX-Breast 2): an open-label, multicenter, phase II trial

Abstract

Purpose Resistance to HER2 (ErbB2)-targeted therapy may be mediated by other members of the ErbB family. We investigated the efficacy and safety of the irreversible ErbB family blocker, afatinib, alone as first-line therapy in the advanced setting and in combination with vinorelbine or paclitaxel for those who progressed on afatinib monotherapy, in female patients with metastatic breast cancer who had failed or progressed on prior HER2-targeted therapy in the early disease setting. Methods In this phase II, single-arm, two-part study (ClinicalTrials.gov: NCT01271725), patients in part A received afatinib 40 mg/day in 21-day cycles until disease progression or intolerable adverse events (AEs). Patients with progressive disease could then receive afatinib plus weekly vinorelbine 25 mg/m2 or paclitaxel 80 mg/m2 until disease progression or intolerable AEs (part B). The primary endpoint was confirmed objective response rate (RECIST v1.1). Results Eighty-seven patients were enrolled and 74 were treated in part A (median age: 51 years [range 27–76]; 31 [42%] estrogen receptor-positive, 26 [35%] progesterone receptor-positive). Of these, 39 (53%) patients went on to receive afatinib plus vinorelbine (13 patients) or paclitaxel (26 patients) in part B. Thirteen (18%) and 12 (31%) patients achieved an objective response in parts A and B, respectively. The most common treatment-related AEs with afatinib monotherapy (any/grade ≥ 3) were diarrhea (68%/8%) and rash (49%/4%). Combination therapy was generally well tolerated, with no additive toxicity observed. Conclusion Afatinib treatment, alone or in combination with vinorelbine or paclitaxel, was associated with objective responses in ≥ 18% of patients with metastatic breast cancer for whom prior HER2-targeted therapy has failed. Treatment-related AEs were generally manageable, with few grade ≥ 3 AEs reported. Trial registration ClinicalTrials.gov, NCT01271725, registered 1 July 2011.

CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer

“…The investigations of AFT treatment in BRCA are undergoing. In an open-label, multicenter, and phase II clinical trial, Hickish et al (74) reported that for metastatic BRCA patients whose prior HER2-targeted therapy had undesirably failed, AFT alone and combined with paclitaxel or vinorelbine could enhance the objective response. Our data demonstrated AFT may have a good therapeutic effect on TNBC.…”

Clinical updates on tyrosine kinase inhibitors in HER2-positive breast cancer

“…Afatinib is a pan-HER TKI that is irreversible and has a strong affinity for EGFR, A phase III trial using afatinib to treat HER2 was proposed to early stop recruiting by an independent data tracking group ( Hurvitz et al, 2014 ; Wind et al, 2017 ). In the initial analysis of open-label, phase III LUX-Breast 1 trial the median PFS for the afatinib and trastuzumab groups was 5 months and 6 months, respectively (HR Z 1.10; 95% CI: 0.86–1.41; PZ 0.43) ( Hurvitz et al, 2014 ; Wind et al, 2017 ; Hickish et al, 2022 ). Five percent of afatinib patients and 3% of trastuzumab patients had dosage decreases because of AEs.…”

“…Five percent of afatinib patients and 3% of trastuzumab patients had dosage decreases because of AEs. Treatment was required for 15% of patients in the afatinib arm and 7% of participants in the trastuzumab arm ( Hurvitz et al, 2014 ; Wind et al, 2017 ; Hickish et al, 2022 ). One-quarter of patients in the afatinib group had their dose reduced because of diarrhea, rash, nausea, tiredness, and stomatitis were the most common AEs of any grade.…”

“…As compared to the trastuzumab group, the afatinib group saw greater incidences of PPE syndrome (12% as opposed to 1%). Diarrhea, rash, fatigue, stomatitis, mucosal infection, and hypokalemia were the most commonly reported grade III–IV adverse events (AEs Hurvitz et al, 2014 ; Wind et al, 2017 ; Hickish et al, 2022 ).…”

Aspirin boosts the synergistic effect of EGFR/p53 inhibitors on lung cancer cells by regulating AKT/mTOR and p53 pathways

“…Afatinib is a promising backbone combination partner for a variety of novel regimens with multiple indications. Among these regimens, afatinib is being used in combination with vinorelbine in patients with breast or lung cancer 6,7 . Although we previously reported that afatinib plus vinorelbine had synergistic effect on various lung cancer cells, 8 clinical trials of the two drugs in NSCLC have not been conducted, possibly due to the availability of other more tolerable therapies 5 .…”