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SAN ANTONIO -- Adding tucatinib (Tukysa) to trastuzumab emtansine (T-DM1; Kadcyla) reduced the risk of disease progression or death by 24% in previously treated HER2-positive breast cancer patients with locally advanced unresectable or metastatic disease, a multinational phase III study found.

Median progression-free survival (PFS) reached 9.5 months with the anti-HER2 combination, as compared with 7.4 months with T-DM1 plus placebo (HR 0.76, 95% CI 0.61-0.95, P=0.0163), Sara Hurvitz, MD, of the Fred Hutchinson Cancer Center in Seattle, reported here at the San Antonio Breast Cancer Symposium.

Interim results on overall survival (OS) were currently "unreliable," said Hurvitz, but appeared mixed. With 53% of events recorded for the final analysis, median OS was not reached in the combination arm versus 38 months in the placebo arm (HR 1.23, 95% CI 0.87-1.74).

While PFS among the large subset of patients with brain metastases was not formally tested, there was a strong trend favoring the tucatinib arm: median 7.8 months versus 5.7 months in the placebo arm (HR 0.64, 95% CI 0.46-0.89).

"This is the second randomized study which included patients with brain metastases to demonstrate that a tucatinib-containing regimen delays disease progression in HER2-positive advanced disease," said Hurvitz during a press briefing.

Press briefing moderator Kate Lathrop, MD, of the Mays Cancer Center at UT Health San Antonio, observed that unlike in the current trial, patients in clinical practice do not routinely receive central nervous system imaging unless they have symptoms, meaning those with asymptomatic brain metastases who might benefit from earlier tucatinib are unlikely to be identified.

Hurvitz agreed and called it a "pressing need" to re-examine guidelines on how and when brain imaging is performed.

While current guidelines indicate that patients should only undergo brain imaging if they are symptomatic, "we are getting to a point now that we do have drugs that do have activity intracranially and may help us delay the need for whole brain radiation or even surgery," Hurvitz said.

"We have no randomized studies looking at the optimal timing of brain imaging. Nor do we have studies that compare [starting with] systemic therapies like tucatinib to staring with local-regional therapy, and then adding in tucatinib," she added. "These are studies that are going to be important for us in defining these guidelines."

Explaining the rationale behind the current HER2CLIMB-02 study, Hurvitz pointed out that the incidence of brain metastases in patients with locally advanced unresectable or metastatic HER2-positive breast cancer remains high.

The previous HER2CLIMB trial -- which led to tucatinib's approval -- showed that adding the HER2 tyrosine kinase inhibitor to a regimen containing trastuzumab and capecitabine significantly improved PFS and OS in heavily pretreated patients with metastatic HER2-positive disease, including those with brain metastases.

T-DM1 is a HER2-directed antibody-drug conjugate approved to treat advanced or metastatic HER2-positive breast cancer in patients previously treated with trastuzumab and a taxane. Hurvitz noted that preclinical data and a phase Ib/II study evaluating the combination of tucatinib and T-DM1 demonstrated encouraging antitumor activity as well as a manageable safety profile.

Study discussant Valentina Guarneri, MD, PhD, of the University of Padova in Italy, noted that patients with brain metastases have long been excluded from clinical trials.

"Since optimal therapy for these patients should not be an afterthought, clinical trials taking the risk of including these patients must be valued," she said, and added that the data from this study "further supports studies in the early disease setting aiming at preventing the development of brain metastases."

included 463 HER2-positive breast cancer patients with locally advanced unresectable or metastatic disease who progressed after trastuzumab and a taxane in any setting. The trial allowed patients to enroll if they had previously treated stable, progressing, or untreated brain metastases not requiring immediate local therapy. The primary endpoint was PFS, with OS a secondary endpoint.

Participants were in their mid-50s, nearly all were women, and 43% were enrolled in North America. Roughly 44% had presence or history of brain metastases at baseline (half of which were active metastases), and 60% had hormone-receptor positive cancers. Just under half of the patients (46%) had initially been diagnosed with stage IV disease.

The median number of prior lines of systemic therapy in the metastatic setting was one (range 0-8), and Hurvitz noted that the vast majority of patients were previously treated with pertuzumab (Perjeta) and that prior use of trastuzumab deruxtecan (T-DXd; Enhertu) was an exclusion factor for the trial. At progression, nearly half of the patients in each study arm went on to receive T-DXd.

Regarding safety, the most common treatment-emergent adverse events (TEAEs) included nausea, diarrhea, and fatigue. Common grade ≥3 TEAEs were alanine and aspartate aminotransferase elevations (both 16.5% in the tucatinib arm and 2.6% in the placebo arm). Discontinuations due to TEAEs were more frequent in the tucatinib arm.

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