Chemotherapy-Sparing Regimen Suggested For HR-Positive, HER2-Positive Advanced Breast Cancer

Author: By Laura Cowen, medwireNews Reporter 

medwireNews: The endocrine combination of abemaciclib plus fulvestrant and trastuzumab significantly improves progression-free survival (PFS) relative to chemotherapy plus trastuzumab in patients with previously treated hormone receptor (HR)-positive, HER2-positive advanced breast cancer, phase II study data show.  

Sara Tolaney (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) and co-investigators say their “results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option” in patients with unresectable, locally advanced, recurrent or metastatic disease who have received at least two HER2-targeted therapies.  

The 237 women participating in the monarcHER trial were randomly assigned to receive the cyclin-dependent kinase 4 and 6 inhibitor abemaciclib in a triplet regimen with trastuzumab and fulvestrant (n=79) or in a doublet regimen with trastuzumab only (n=79), or to receive standard-of-care chemotherapy plus trastuzumab (n=79). 

The doses for each drug were: oral abemaciclib 150 mg every 12 hours on days 1–21 of a 21-day cycle; intravenous trastuzumab 8 mg/kg on day 1 of cycle 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle; and intramuscular fulvestrant 500 mg on days 1, 15 and 29 followed by once every 4 weeks thereafter. 

After a median 19.0 months of follow-up, patients who received the triplet combination had significantly longer median PFS than those who received chemotherapy plus trastuzumab, at 8.3 versus 5.7 months, whereas individuals who received abemaciclib plus trastuzumab did not (median 5.7 months). 

The researchers found that the overall response rate was also significantly higher with the triplet combination than with chemotherapy plus trastuzumab in both the intention-to-treat population (33 vs 14%) and in a post-hoc analysis that only included patients with measurable disease (36 vs 16%). 

Grade 3 or 4 treatment-emergent adverse events (TEAEs) were reported by 68% of 78 patients who received the triplet combination, 50% of those who received abemaciclib plus trastuzumab and 48% of those who received chemotherapy plus trastuzumab. 

The most common grade 3–4 TEAE in all groups was neutropenia, occurring in 27%, 22% and 26%, respectively. However, as Nicolò Battisti and Alistair Ring, both from The Royal Marsden NHS Foundation Trust in Sutton, UK,  point out in an comment that accompanies The Lancet Oncology study, more than 70% of patients receiving abemaciclib experienced grade 1 or 2 diarrhoea, which they say could “represent a substantial challenge in patients who are more frail or in those on therapy for many months”. 

There were two treatment-related deaths, one due to pulmonary fibrosis in a patient who received abemaciclib plus trastuzumab and one due to febrile neutropenia in someone who received chemotherapy plus trastuzumab. 

Sara Tolaney and co-authors conclude that their findings provide “clinical validation of the preclinical hypothesis suggesting that treatment with a CDK4 and CDK6 inhibitor might overcome acquired resistance to trastuzumab”. 

They add: “A chemotherapy-free treatment option in an advanced and heavily pretreated patient population would probably be of interest to both patients and their physicians.” 

Nicolò Battisti and Alistair Ring agree with this conclusion but add that “the key question for the practising oncologist is whether this regimen can fit into the landscape of emerging therapies in HER2-positive breast cancer”.  

They say: “Approvals of neratinib and trastuzumab dexrutecan, and randomised phase 3 data for tucatinib and margetuximab, in addition to the already well established anti-HER2 therapies, mean that multiple questions regarding optimal sequencing, comparative toxicity, and patient preference will arise.” 

References 

Tolaney SM, Wardley AM, Zambelli S, et al. Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial. Lancet Oncol; Advance online publication 27 April 2020. doi:10.1016/S1470-2045(20)30112-1 

Battisti NML, Ring A. CDK4/6 inhibition in HER2-positive breast cancer. Lancet Oncol; Advance online publication 27 April 2020. doi: 10.1016/S1470-2045(20)30164-9