Clinical Summary:

• Design/Population: Subgroup analyses from the phase 3 HER2CLIMB-05 trial evaluated tucatinib added to trastuzumab and pertuzumab maintenance therapy in patients with previously untreated HER2-positive metastatic breast cancer. Analyses examined outcomes according to hormone receptor status, presence of brain metastases, and de novo versus recurrent metastatic disease.
• Key Outcomes: Tucatinib improved progression-free survival, objective response rate, and duration of response across all major subgroups evaluated. Clinical benefit was observed regardless of hormone receptor status, brain metastasis status, or whether metastatic disease was de novo or recurrent.
• Clinical Relevance: These findings support broad use of tucatinib in the first-line maintenance setting for HER2-positive metastatic breast cancer and reinforce its activity across clinically important patient subgroups.

Erika Hamilton, MD, Sarah Cannon Research Institute, Nashville, Tennessee, discusses updated subgroup analyses from the phase 3 HER2CLIMB-05 trial evaluating the addition of tucatinib to trastuzumab and pertuzumab maintenance therapy in HER2-positive metastatic breast cancer. Previous analyses demonstrated a clinically meaningful progression-free survival benefit with tucatinib, and the current presentation explored whether that benefit was maintained across key patient populations.

The analyses demonstrated consistent efficacy regardless of hormone receptor status, baseline brain metastases, or metastatic disease presentation. The findings also highlighted the importance of endocrine therapy in patients with hormone receptor–positive disease and provide additional support for tucatinib-based maintenance strategies as treatment paradigms continue to evolve with emerging data from studies such as PATINA and DESTINY-Breast09.

Dr Hamilton presented these results at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

Transcript: 

Hello, I'm Dr Erika Hamilton, chief development fficer, late phase, and director of the breast cancer research program at Sarah Cannon Research Institute in Nashville, Tennessee. At ASCO 2026, we had the opportunity to present updated safety and efficacy findings from the HER2CLIMB-05 clinical trial.

As you may recall, this trial evaluated the addition of tucatinib to first-line trastuzumab and pertuzumab, or HP maintenance, for patients with HER2-positive metastatic breast cancer. We had previously reported a progression-free survival benefit of just under 9 months with the addition of tucatinib. In this analysis, we wanted to explore several key subgroups.

Specifically, we looked at hormone receptor–positive versus hormone receptor–negative disease, the presence or absence of brain metastases, and whether metastatic disease presented as de novo metastatic disease or recurrent metastatic disease. We also evaluated objective response rate and duration of response.

Looking first at the overall population, among patients evaluable for response, the objective response rate improved from 15.2% with HP alone to 22.6% with HP plus tucatinib. Duration of response was also prolonged, increasing from 16.9 months to 20.9 months. 

For the first subgroup analysis, hormone receptor–positive disease, progression-free survival improved from 18.1 months to 25.0 months, representing a benefit of approximately seven months. In hormone receptor–negative disease, progression-free survival improved from 12.6 months to approximately 25 months, representing a benefit of more than one year.

We also looked specifically at the hormone receptor–positive population and evaluated outcomes according to endocrine therapy use. Endocrine therapy was permitted on the study but not mandated. About 45% of patients received endocrine therapy, while approximately 55% did not. Regardless of endocrine therapy use, patients benefited from the addition of tucatinib. The hazard ratio was 0.724 among patients receiving endocrine therapy and 0.658 among those who did not. However, progression-free survival was substantially longer among patients who received endocrine therapy—approximately 15 months longer. This reinforces the importance of endocrine therapy in patients with HER2-positive, hormone receptor–positive disease and serves as a reminder to continue offering endocrine therapy in the maintenance setting.

The second subgroup analysis focused on patients with baseline brain metastases. Fortunately, brain metastases were relatively uncommon in this first-line population, occurring in approximately 12.4% of enrolled patients. Among these patients, progression-free survival more than doubled with the addition of tucatinib, increasing from 4.2 months to 8.5 months, corresponding to a hazard ratio of 0.64. Even among the much larger group of patients without brain metastases, tucatinib remained beneficial. Progression-free survival increased from 18.1 months to 27.2 months, representing an improvement of 9.1 months.

The third subgroup analysis evaluated patients with de novo versus recurrent metastatic disease. Regardless of whether patients presented with de novo metastatic disease or recurrent disease, tucatinib improved outcomes. The magnitude of benefit was approximately 12.1 months in de novo disease and 8.6 months in recurrent disease.

Taken together, these analyses demonstrate that adding tucatinib to HP maintenance benefited patients regardless of hormone receptor status, the presence or absence of brain metastases, or whether metastatic disease was de novo or recurrent. 

We are also beginning to think about how these data fit into the evolving first-line treatment landscape. Since HER2CLIMB-05, we have had longer follow-up from the PATINA study evaluating palbociclib in the maintenance setting for patients with hormone receptor–positive disease. That trial did not include hormone receptor–negative patients, unlike HER2CLIMB-05, but it provides another maintenance option. 

We have also seen results from DESTINY-Breast09, which evaluated trastuzumab deruxtecan plus pertuzumab in the first-line setting. That study focused more on upfront treatment and did not specifically incorporate a maintenance phase, instead continuing therapy until progression. As a result, many clinicians are now asking whether we should be using taxane plus HP followed by maintenance, or whether we should move toward T-DXd plus pertuzumab in the frontline setting. I think our patients are telling us that maintenance therapy remains important. Regardless of which induction regimen is selected, I anticipate continuing to consider maintenance strategies for many patients.

We also saw emerging data at ASCO 2026 regarding deep partial responses. This is a relatively new concept, but the data suggest that patients who eventually achieve a deep partial response may have outcomes very similar to those who achieve a complete response, and better than those who achieve a less profound partial response. This suggests that we may not want to stop induction therapy after a fixed number of cycles. Instead, we may want to continue treatment until patients achieve their best possible response before transitioning to maintenance therapy alone.

Overall, there were several exciting advances presented at ASCO 2026 in the first-line HER2-positive metastatic breast cancer space.

Source:

Hamilton EP, Curigliano G, Martin M, et al. Efficacy and safety of tucatinib (TUC) vs placebo (PBO) combined with trastuzumab and pertuzumab (HP) as maintenance therapy for HER2+ metastatic breast cancer by stratified subgroups. Presented at the ASCO Annual Meeting. 2026. Abstract 1005