HER2CLIMB: Investigating tucatinib with capecitabine and trastuzumab in HER2-positive metastatic breast cancer

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Published: 23 Jan 2020
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Dr Rashmi Murthy - MD Anderson Cancer Center, Houston, USA

Dr Rashmi Murthy speaks to ecancer at the 2019 San Antonio Breast Cancer Symposium about the recent results from the HER2CLIMB study, which investigated the use of tucatinib in combination with capecitabine and trastuzumab versus placebo, in patients with pretreated HER2-positive metastatic breast cancer with and without brain metastases.

She highlights that there is no single regimen that is considered as the standard of care, and there are very limited treatment options for patients with brain metastases.

Dr Murthy outlines the trial design and results from this study, which found that the combination of tucatinib, capecitabine and trastuzumab reduced the risk of death by a third.

She also discusses the management of patients with brain metastases and their representation in clinical trials.

Read more about the study here


HER2CLIMB: Investigating tucatinib with capecitabine and trastuzumab in HER2-positive metastatic breast cancer

Dr Rashmi Murthy - MD Anderson Cancer Center, Houston, USA

HER2 metastatic breast cancer remains incurable and we have limited treatment options in the third line setting. No single regimen is really considered the standard of care, although there are several different regimens recommended by the national cancer guidelines. Up to half of these patients will develop brain metastases and for this patient population in particular there is really limited treatment options that we know cross the blood-brain barrier.

Tucatinib is a drug, it’s an investigational drug that’s administered orally and it’s highly selective for HER2 with minimal inhibition of EGFR. This lends itself well for a potentially favourable toxicity profile without compromising efficacy. In a prior study, in a phase Ib study, we saw that tucatinib, when added to trastuzumab and capecitabine, showed encouraging anti-tumour activity and showed that it was a safe combination in patients who were heavily pre-treated, including those with brain metastases. So this set the background for the HER2CLIMB study which evaluated in a randomised fashion whether the addition of tucatinib or placebo to trastuzumab and capecitabine would be effective in patients who were heavily pre-treated, including those with brain metastases.

Can you outline the trial design?

Patients were eligible for this trial if they had metastatic disease and if they had centrally confirmed HER2 positivity.

They were also required to have had treatment with trastuzumab, pertuzumab and T-DM1. A brain MRI was required in all patients at study entry. Patients who had a history of brain metastases that were stable were allowed to enrol, as most clinical trials, but unique to this trial patients were also allowed to enrol if they had either untreated or previously treated progressing lesions in the brain. Eligible patients were then randomised in a two to one fashion to tucatinib or placebo in combination with trastuzumab and capecitabine. There were several pre-specified stratification factors including the absence or presence of brain metastases, ECOG performance status as well as region of the world.

What were the results of the trial?

The results showed that tucatinib when added to trastuzumab and capecitabine reduced the risk of death in patients with and without brain metastases by a third and reduced the risk of progression or death by half in all the patients, including those with brain metastases. Notably, there was also a near doubling in the confirmed objective response rate seen as well. Further, it confirmed that this triplet regimen was safe and well tolerated and that there weren’t many drug discontinuations due to adverse events which really tells us that it allows for prolonged treatment of patients in a clinical setting.

How was the toxicity profile?

There were some adverse events noted, they were all mostly low grade and the most common ones were diarrhoea, hand foot syndrome, nausea, vomiting and fatigue.

What is the clinical significance of these results?

In patients who are heavily pre-treated this represents a potential new standard of care treatment. So these results are really practice changing and are going to impact how we treat patients in the clinic once the regimen is approved.

How are patients with CNS metastases managed in the clinic?

That’s a great question. Patients with HER2 positive metastatic breast cancer who develop brain metastases are generally offered local treatments such as surgery, focal radiation with either stereotactic radiosurgery or Gamma Knife or, as indicated, whole brain radiation as well. Usually the systemic treatment that they were previously on is continued in the cases where there’s no systemic progression. In cases where systemic progression is identified at the time of progression in the CNS generally the systemic treatment is also changed.

Are patients with brain metastases well represented in clinical trials?

No, actually patients with brain metastases have typically been excluded from clinical trials so that’s what makes the HER2CLIMB study quite unique in that. It’s really a model for hopefully future trials that we’re going to see that hopefully will allow patients with and without brain metastases, including those who have active disease that has previously been untreated or progressing after prior treatment.

Is there anything you’d like to add?

The main takeaway from this is that this represents a major advance for patients with HER2 positive metastatic breast cancer towards improving their outcomes. Really we have not seen an overall survival benefit in a randomised trial setting to date in patients who have received almost all of the contemporary anti-HER2 targeted therapies that we have – trastuzumab, pertuzumab and T-DM1. So I’m really excited that we have this new potential treatment option for patients.