Can Dasatinib Improve Trastuzumab Efficacy in HER2+ Breast Cancer?

Combining trastuzumab and paclitaxel with dasatinib is well tolerated and has a high response rate in patients with metastatic HER2-positive breast cancer, according to a phase II study. The combination will likely be more useful as a treatment option beyond the first line.

“Although treatment with trastuzumab has clearly improved the outcome of HER2-positive patients, most patients do progress during the course of their disease,” wrote study authors led by Alberto Ocana, MD, PhD, of the Universidad de Castilla La Mancha in Spain. Other research has linked the activated cytoplasmic kinase SRC to trastuzumab resistance, suggesting that the SRC inhibitor dasatinib could have synergistic effects.

The new study was a phase II open-label trial including 29 patients with metastatic HER2-positive breast cancer, conducted by the Spanish Breast Cancer Group. They were treated with a combination of dasatinib, trastuzumab, and paclitaxel; the median age in the study was 49 years, 59% were postmenopausal, and 76% were hormone receptor positive. Most patients had visceral metastases (83%), and most had not received prior trastuzumab therapy (66%).The results were published in Breast Cancer Research and Treatment.

The objective response rate (ORR) to this regimen was 79.3%, including 3 complete responses (10.3%) and 20 partial responses (69.0%). Three other patients had stable disease (10.3%), while three patients (10.3%) progressed; the clinical benefit rate was 82.8%. The median progression-free survival (PFS) in the trial was 23.9 months.

Six patients (20.7%) discontinued the therapy due to adverse events; those leading to discontinuation included neutropenia, fatigue, angor pectoris, and neurotoxicity. Most adverse events in the trial were grade 1 or 2, with the most common including alopecia, fatigue, AST and ALT increases, anemia, and neutropenia. Other reasons for treatment discontinuation included progressive disease (37.9%), investigator/sponsor criteria (24.1%), and withdrawal of consent (6.9%); one patient died while on study treatment.

The researchers confirmed the suspected mechanism of action for dasatinib by measuring phosphorylated SRC and AKT in peripheral blood mononuclear cells. In both cases, there was a reduction in levels, suggesting that dasatinib was reaching its targets and improving the regimen’s efficacy. There was no significant association between expression levels of those proteins and with any efficacy endpoints.

“The efficacy observed in this study in terms of ORR and PFS is high and in line with that observed with the combination of trastuzumab, pertuzumab, and taxanes as first-line therapy for HER2-positive metastatic breast cancer,” the authors wrote. The study was limited, though, by its single-arm design and small sample size.

The authors also noted that the efficacy with this combination does not appear superior to the combination of trastuzumab and pertuzumab, so further research should likely focus on its use in later lines of therapy, rather than as a first-line option. Also, future research could look into the combination of dasatinib with dual HER2 blockade with trastuzumab and pertuzumab. Still, the authors concluded that “the high efficacy observed and the good toxicity profile pave the way for the future of development of this combination in metastatic breast cancer.”