Rashmi K. Murthy, MD, MBE
In a retrospective pooled analysis of tucatinib in phase Ib studies in HER2-positive breast cancer presented at the 2018 Annual ASCO Meeting, Rashmi K. Murthy, MD, reported that patients with isolated brain metastasis progression benefited from CNS-directed therapy and continuation of systemic treatment.1
Tucatinib is both a novel and potent HER2-specific tyrosine kinase inhibitor (TKI) that has been tested in combination with trastuzumab (Herceptin) and capecitabine,2
as well as in combination with ado-trastuzumab emtansine (T-DM1; Kadcyla).
The agent has “considerable preliminary clinical activity at this point in time in patients with and without brain metastases,” said Murthy, an assistant professor, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.
In the 2 pooled phase Ib studies, 57 patients had received tucatinib and T-DM1 and 60 had received tucatinib/trastuzumab plus capecitabine. Twenty-five patients with isolated brain metastasis were identified and further subdivided into a group of 14 patients who discontinued study treatment and a group of 11 patients who continued systemic therapy on protocol following CNS-directed therapy.
The median time to isolated brain progression was 6.3 months for those who discontinued treatment and 12.3 months for those who continued post-progression treatment, respectively. Additionally, the 11 patients who proceeded to CNS-directed therapy experienced additional time on study to their second progression-free survival event of 8.3 months.
“Although the study is small and retrospective in nature, it is hypothesis generating,” explained Murthy, adding the agent will be further explored in the ongoing randomized HER2CLIMB trial (NCT02614794).
In an interview with OncLive
at the 2018 Annual ASCO Meeting, Murthy discussed the clinical benefit of tucatinib after isolated brain progression in patients with HER2-positive breast cancer.
OncLive: What was the background to this analysis and what prior data were available with tucatinib?
: Tucatinib is a novel potent HER2-specific TKI that is being developed for the treatment of patients with metastatic HER2-positive breast cancer. It has been studied in combination studies, both with T-DM1 as well as trastuzumab and capecitabine. In the phase Ib study of tucatinib, trastuzumab, and capecitabine that was published online in The Lancet Oncology
, the response systemically was 61% and the response in the CNS was 42%.
Why is this a unique agent for patients with HER2-positive breast cancer?
Tucatinib selectively and potently inhibits HER2. Unlike other TKIs in its class, it has less inhibition of EGFR. Therefore, we don't generally see significant EGFR-like toxicities that we see with other TKIs, such as diarrhea and rash. Additionally, in preclinical models, it has been shown to be synergistic with trastuzumab as well as with other agents. It has also shown preclinical CNS activity in patient-derived intracranial xenograft models.
You mentioned its tolerability. What toxicities are associated with tucatinib?
The drug is relatively well tolerated in both the initial monotherapy study, as well as in the more recent combination studies. The main adverse events have been limited to low-grade toxicities—diarrhea, gastrointestinal toxicities like nausea and vomiting, hand-foot syndrome, and fatigue.
What did you find in the retrospective pooled analysis?
In the retrospective analysis presented at the 2018 ASCO Annual Meeting, we pooled 2 phase Ib studies of tucatinib. One was in combination with T-DM1 and the other was in combination with capecitabine and trastuzumab. We identified a subgroup of patients who experienced isolated progression in the brain. Among those patients, we further subdivided them into those who continued on CNS-directed therapy and study treatment and those who discontinued therapy.
Among the 11 patients who received CNS-directed therapy and then continued on study treatment, we noted that they experienced clinical benefit. The median overall duration on study treatment was 20.3 months and the median time to second progression in the CNS was around 8 months.