Tracing Tucatinib's Role in HER2+ Breast Cancer Treatment

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).

OncLive: What was the background to this analysis and what prior data were available with tucatinib?

Why is this a unique agent for patients with HER2-positive breast cancer?

You mentioned its tolerability. What toxicities are associated with tucatinib?

What did you find in the retrospective pooled analysis?

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.Murthy: 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%.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.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.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.

Can you further expand on these next steps with tucatinib?

This will be further studied as an exploratory endpoint in the ongoing HER2CLIMB study. The study provides further support for the ASCO and ESMO guidelines, which currently favor the continuation of HER2-directed therapy in the setting of isolated CNS progression following CNS-directed therapy. Currently, tucatinib is being studied in an ongoing randomized, double-blind, placebo-controlled, phase II registration study, which permits enrollment of patients with or without brain metastases. It randomizes them to receive either trastuzumab and capecitabine plus placebo, or trastuzumab and capecitabine plus tucatinib.

Depending upon the results of that trial, it could lead to the approval of tucatinib in the third-line setting for patients with HER2-positive metastatic breast cancer. The indication would be for patients who have had prior exposure to trastuzumab, pertuzumab (Perjeta), and T-DM1.

What other questions do we still have with tucatinib?

The other feature of this trial is that it allows the continuation of study treatment following CNS-directed therapy in patients who have isolated brain progression. One of the exploratory endpoints would be to look at this further and see whether the results we found are seen in a larger prospective randomized trial. We do not know whether this drug is something that could be brought into earlier lines of therapy in the metastatic setting. Also, we do not know if we could use it even earlier in the neoadjuvant setting as part of a potential de-escalation strategy. We should also consider it in the adjuvant setting for those patients who have higher-risk disease and may benefit from additional HER2-targeted strategies.

We are also interested in developing this drug for patients who have leptomeningeal disease, which is a current unmet clinical need. These patients have a very poor prognosis and generally have this complication as a late-stage event in their breast cancer course. We need new treatments and strategies for those patients. This is a trial that it is in development through the Translational Breast Cancer Research Consortium for leptomeningeal disease.

References

1. Murthy R, Hamilton E, Ferrario C, et al. Clinical benefit of tucatinib after isolated brain progression: a retrospective pooled analysis of tucatinib phase 1b studies in HER2+ breast cancer. J Clin Oncol. 2018;36 (suppl; abstr 1015).
2. Murthy R, Borges V, Conlin A, et al. Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study [published online May 28, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30256-0.