A review of the HER2CLIMB study using oral the TKI tucatinib as therapy for HER2-positive metastatic breast cancer.
Kevin M. Kalinsky, MD, MS: The HER2CLIMB study is a pivotal study in patients with HER2 [human epidermal growth factor receptor 2]–positive metastatic breast cancer. This was a landscape change for patients with HER2-positive metastatic breast cancer. There are a number of points I want to raise.
The way the study was designed was comparing Herceptin [trastuzumab] plus capecitabine with or without tucatinib. This led to the approval of tucatinib. The other thing that’s important to note in the design is that there was a significant proportion of patients who had CNS [central nervous system] metastases, and that reflects patients who were previously treated with other agents, including progression on trastuzumab.
We saw an overall survival advantage. This is clearly a standard of care for our patients with HER2-positive disease. It’s also important to note that, within that CNS metastases group, there was a range. There were some patients who might have had small asymptomatic brain metastases who were not previously treated. They had a small subgroup of patients who had small CNS metastasis detected who did not receive radiotherapy. They looked at giving tucatinib, and they looked to see whether there was a delay in terms of the need for utilization of radiotherapy compared with placebo, and they saw that.
Because it’s clearly an active drug systemically, and it’s an active drug in terms of getting the CNS, I suspect that this drug will continue to move up in terms of the lines of therapy we use, including in the operable setting. There is an ongoing study that’s looking at patients with residual disease to see whether there’s a benefit of fitting tucatinib in terms of decrease the likelihood of a metastasis, including CNS metastasis.
Sarah Sammons, MD: HER2CLIMB is a phase 3 randomized placebo-controlled clinical trial of tucatinib or placebo added to trastuzumab and capecitabine in patients with HER2-positive metastatic breast cancer. One of the most important things about the trial was that all these patients had received trastuzumab and pertuzumab, and all the patients had had prior T-DM1 [trastuzumab emtansine]. About 50% of patients in the trial population had brain metastases. More important, a large portion of that 50% had either untreated brain metastases—so their brain metastasis had not undergone surgical resection or radiation—or progressive metastases, which means they had undergone surgery or radiation. Despite that, the brain metastasis is growing. We’ve never seen a phase 3 trial include those high-risk patients before, so that was exciting.
The clinical trial showed that the addition of tucatinib to capecitabine and trastuzumab in the intention-to-treat population improved progression-free and overall survival significantly. Most important, the largest impact of this study was on patients with brain metastases. This is the first trial in the third-line setting, and this is the first trial ever to show an overall survival benefit in patients with a history of brain metastases, especially those with treated progressive or untreated brain metastasis.
In the brain metastases population, tucatinib improved their overall survival and progression-free survival substantially. The investigators also required patients to have baseline and standardized MRIs throughout, so they were able to track intracranial efficacy, including intracranial progression-free survival and intracranial overall response rate. Both intracranial progression-free survival improved drastically with the addition of tucatinib in patients with stable treated brain metastases, progressive brain metastases, and untreated brain metastases, which is very exciting. We also saw a substantial improvement in intracranial overall response rate with the addition of tucatinib to trastuzumab and capecitabine.