Maintained OS Improvement in Patients With HER2+ Breast Cancer Treated With HER2CLIMB Regimen

Overall survival (OS) is maintained with tucatinib (Tukysa), a highly selective, HER2-directed tyrosine kinase inhibitor in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) in HER-positive breast cancer patients (TKI) with and without brain metastases compared to placebo, according to results of the phase HER2CLIMB-02 (NCT03975647).

The HER2CLIMB-02 study comes after the HER2CLIMB study, which had an actual enrollment of 612 patients and a primary end point of progression-free survival. The HER2CLIMB-02 study allowed for crossover from the placebo to the experimental group. Secondary end points include OS, objective response rate, duration of response, and clinical benefit rate. Patients were randomized 2:1 to receive the combination of tucatinib, trastuzumab, and capecitabine (n = 410) or placebo, trastuzumab, capecitabine (n = 202).

The study found that in patients with visceral metastases, the median OS in the experimental group was 21.6 months and 16.9 months in the placebo group. For patients without visceral metastases, the median OS was 32.9 months for the experimental arm and 26.9 months for the placebo cohort.

In an interview with Targeted Oncology, Guiseppe Curigliano, MD, an associate professor of Medical Oncology at the University of Milano and the head of the Division of Early Drug Development at the European Institute of Oncology, discussed the HER2Climb study and the impact of tucatinib in HER2-positive breast cancer care.

TARGETED ONCOLOGY: Could you give a brief overview on the presentation you gave at ASCO this year?

CURLIGLIANO: It's really my pleasure to present to you the updated results of tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2-positive metastatic breast cancer with and without brain metastases. During the HER2CLIMB trial, the key eligibility criteria were HER2- positive metastatic breast cancer with prior treatment, including trastuzumab/pertuzumab (Phesgo), and T-DM1. Patients with brain metastases, even if treated or untreated, have been eligible for treatment in the context of the problem. All patients have been randomized 2:1 to receive tucatinib, trastuzumab, capecitabine versus placebo, trastuzumab, capecitabine.

As you know very well, the protocol prespecified analysis has been presented at least 2 years after the last patient was randomized. And in the context of this presentation, we also had crossover from the placebo arm to receive tucatinib, trastuzumab, and capecitabine. The first patient crossover happened in February 2020. And the data cut off of this presentation has been updated to February 2021. A total of 410 patients have been included in tucatinib, trastuzumab, and capecitabine arm versus 202 patients in the placebo, trastuzumab, and capecitabine arm.

The tucatinib/placebo duration of treatment was a mean over 10 months for tucatinib, trastuzumab, and capecitabine versus 6.1 months for placebo trastuzumab, and capecitabine.

Let's go now to define our results. With the longer follow-up, the median OS was 24.7 months in the tucatinib, trastuzumab, and capecitabine arm versus 19.2 months in the placebo, trastuzumab, and capecitabine arm. So, the OS benefit with tucatinib was mandated that with the longer follow-up with a 5.5-month improvement in median OS in the tucatinib arm compared to the placebo arm. The sensitivity analysis accounting for crossover shows with consistent results with intent to treat analysis. So, all the sub-populations derived with exactly the same OS benefit independently of age, less or more than 65 years old, race, white versus nonwhite, or more receptor status, positive versus negative, baseline brain metastases versus no, equal performance status, zero versus one, and region, North America versus the rest of the world.

So, the OS in an exploratory analysis in patients with and without brain metastases, confirm the OS benefit that has been described in the previous analysis and that is confirmed with a longer follow up.

Looking at the progression-free survival by investigator assessment, again, with a longer follow up, there is a confirmed progression-free survival benefit in the tucatinib, trastuzumab, and capecitabine arm versus placebo, trastuzumab, and capecitabine arm, that was confirmed to be 7.6 months in the tucatinib arm versus 4.9 months in the placebo arm.

The rates of the most common adverse events remain stable with the longer follow-up. The most common toxicity was diarrhea, described as grade 3 in 53 patients, 13% of the patient population. And palmar-plantar erythrodysesthesia syndrome in 14% of the patients. In conclusion, the data of HER2CLIMB presented with the longer follow-up confirmed the OS benefit with tucatinib that was maintained with an additional 15.6 months of follow-up. With 5.5 months improvement in the median OS, the benefit was maintained at the crossover prespecified subgroup, and then improvement in OS was observed in patients with and without brain metastases. Tucatinib in combination with trastuzumab and capecitabine was well tolerated with the low rate of discontinuation and the safety profile was consistent with the primary safety analysis.

What was the data and rationale behind the HER2Climb study?

The rationale behind this study was to provide a duel blockade with tucatinib in combination with trastuzumab and capecitabine in patients that were progressing on the duel blockade with pertuzumab/trastuzumab and T-DM1. The rationale of the study, of course, was related to the capability of tucatinib, very highly selective HER2 directed tyrosine kinase inhibitor, to have major activity in combination to trastuzumab, and potentially to be active also in patients with brain metastases. In fact, this is the only study in the population of metastatic HER2 positive breast cancer population to include also patients with untreated and active brain metastases. And the confirmation of OS benefit can suggest that there is the strong rationale to use to tucatinib in combination with trastuzumab and capecitabine.

Is there anything you found particularly intriguing or exciting so far?

Some of the most important data here are, first, there was also survival benefit in the third-line setting. Up to now, HER2CLIMB is the only study to demonstrate an OS benefit in this setting. And the second intriguing result is the progression-free survival benefiting the patients with brain metastases.

What are the next steps for this research?

I believe the most important next step in the context of metastatic breast cancer is the HER2CLIMB-02 (NCT03975647) study. That is a prospective randomized trial, comparing the tucatinib versus placebo in combination with T-DM1 for patients with advanced metastatic HER2-positive breast cancer. So, this study has been designed to compare T-DM1 plus tucatinib versus T-DM1 plus placebo in patients progressing after dual blockade with pertuzumab/trastuzumab. The primary end point of this study is progression-free survival. In the eligibility criteria, of course, we have also patients with metastatic HER2-positive breast cancer and also patients with brain metastases including untreated brain metastases and previously treated brain metastases. So, if this study is positive, we will have a new standard of care in the second-line setting that will come behind T-DM1 plus tucatinib.

_REFERENCE:

_{Curigliano G, Mueller V, Borges V, et al. Updated results of tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB). J Clin Oncol 2021; 39 (15). DOI: 10.1200/JCO.2021.39.15_suppl.1043}