Pyrotinib Plus Metronomic Vinorelbine Is Active in HER2+ Advanced Breast Cancer After Trastuzumab

Pyrotinib Plus Metronomic Vinorelbine in

HER2+ Advanced Breast Cancer | Image Credit:

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Treatment with the combination of pyrotinib and metronomic vinorelbine was safe and efficacious in patients with HER2-positive advanced breast cancer who received prior treatment with trastuzumab (Herceptin), according to data from a single-center, prospective phase 2 trial (NCT04903652) conducted in China.¹

Findings published in Cancer Research and Treatment showed that at a median follow-up of 35 months, patients treated with pyrotinib plus vinorelbine (n = 36) experienced a median progression-free survival (PFS) of 13.5 months (95% CI, 8.33-18.5). Furthermore, the overall response rate (ORR) was 38.9% (95% CI, 23.1%-56.5%), which was comprised of 14 partial responses. The disease control rate (DCR) was 83.3% (95% CI, 67.2%-93.6%).

“Anti-HER2 antibody-drug conjugates [ADCs] are currently the preferred regimen for patients [with HER2-positive advanced breast cancer] previously treated with trastuzumab…However, their use [is] not yet common practice due to economic factors. As such, exploration of small molecule combination therapies is still necessary,” lead study author Chunfang Hao, MD, PhD, of the Department of Breast Oncology at Tianjin Medical University Cancer Institute and Hospital in China, and colleagues, wrote.

Investigators from Tianjin Medical University Cancer Institute and Hospital who initiated the open-label phase 2 study enrolled patients 18 to 75 years of age with histologically confirmed HER2-positive recurrent or metastatic breast cancer (immunohistochemistry 3+ and/or fluorescence in situ hybridization positive) who experienced disease progression on trastuzumab or within 12 months of completing treatment. Key inclusion criteria consisted of an ECOG performance status of 0 to 2, a life expectancy of at least 12 weeks, at least 1 measurable lesion per RECIST 1.1 criteria, and normal organ function. Patients were excluded if they had visceral crisis; or received prior treatments for advanced/metastatic disease including radiotherapy, endocrine therapy, surgery (except local puncture), or targeted therapy.

All patients received pyrotinib at 400 mg once per day plus vinorelbine at 40 mg thrice weekly during 21-day cycles. Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal.

PFS served as the trial’s primary end point. Based on data from the phase 3 EMILIA trial (NCT00829166), where the control regimen of lapatinib (Tykerb) and capecitabine led to a median PFS of 6.4 months, the goal of this phase 2 study was to extend the median PFS to 12.0 months.^1,2 Secondary end points included ORR, duration of response, DCR, overall survival (OS), and safety.¹

Investigators enrolled 36 patients from October 21, 2019, to January 21, 2022. The median age was 54 years (range, 31-71), and 97.2% of patients were female. Patients had an ECOG performance status of 0 (25.0%) or 1 (75.0%). Metastatic sites at baseline included lung (75.0%); liver (33.3%); bone (50.0%); brain (16.7%); and skin, lymph nodes, and soft tissue (88.9%). Furthermore, 8.3% of patients had 1 metastatic site at screening, 27.8% had 2 sites, 19.4% had 3 sites, and 44.4% had at least 4 sites. Notably, 52.8% of patients had hormone receptor–positive disease.

Additionally, 13.9% of patients were given trastuzumab in the early breast cancer setting, 63.9% received the agent in the advanced setting, and 22.2% of patients were administered trastuzumab in both the early and advanced settings. Primary trastuzumab resistance was reported in 25.0% of patients, and 75.0% had secondary resistance. Lapatinib was previously given to 41.7% of patients. Prior lines of chemotherapy in the metastatic setting included 0 (2.8%), 1 (36.1%), 2 (38.9%), 3 (19.4%), and 4 (2.8%).

Twelve patient deaths were reported; however, OS data were immature at the time of this analysis. At the data cutoff date of December 28, 2023, 29 patients had experienced disease progression or died. Two patients were lost to follow-up, and 5 remained on study treatment.

Findings from a post-hoc subgroup analysis showed that patients with lung metastases (n = 27) experienced a median PFS of 14.2 months compared with 7.6 months for those without lung metastases (n = 9; nominal P = .037). Patients with primary trastuzumab resistance (n = 9) achieved a median PFS of 19.7 months vs 10.9 months for those with secondary resistance (n = 27; nominal P = .207). Those previously treated with lapatinib (n = 15) had a median PFS of 8.3 months compared with 15.3 months for those naive to lapatinib (n = 21; nominal P = .008).

Regarding safety, no new or unexpected adverse effects (AEs) were reported, and AEs did not lead to any patient deaths. Seventeen patients experienced grade 3 AEs, but no grade 4/5 AEs occurred. The most common any-grade AEs included diarrhea (94.4%), nausea (80.6%), vomiting (75.0%), decreased appetite (88.9%), stomachache (27.8%), neutropenia (38.9%), leucopenia (33.3%), anemia (30.6%), increased alanine aminotransferase (8.3%), and increased aspartate aminotransferase (8.3%). Grade 3 AEs consisted of diarrhea (27.8%), vomiting (8.3%), stomachache (5.6%), neutropenia (2.8%), and anemia (2.8%).

“There are several limitations in this study. Given single-arm design and small sample size of this study, all results should be interpreted with caution. Due to limited availability of ado-trastuzumab emtansine [Kadcyla], fam-trastuzumab deruxtecan-nxki [Enhertu], and pertuzumab [Perjeta] during the study period and economic factors, no patients in our study had been treated with these ADCs and pertuzumab, which is quite different from the patient characteristics of global population, impacting the extrapolation and it is also not easy to compare with other global studies,” study authors concluded. “Nonetheless, this dual-oral regimen appears to be a feasible approach in this setting and warrants further study in larger randomized trials.”

References

1. Hao C, Wang X, Shi Y, et al. Combination therapy of pyrotinib and metronomic vinorelbine in HER2+ advanced breast cancer after trastuzumab failure (PROVE): a prospective phase 2 study. Cancer Res Treat. Published online August 9, 2024. doi:10.4143/crt.2024.340
2. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-1791. doi:10.1056/NEJMoa1209124