HER2CLIMB-05 was a phase III international, randomised clinical trial looking at the benefit of adding tucatinib to trastuzumab and pertuzumab in the maintenance setting of first-line metastatic HER2+ breast cancer. We all know that tucatinib was initially FDA approved based on the original HER2CLIMB study that showed that adding tucatinib to capecitabine and trastuzumab improved not only PFS but also overall survival. So this study really looked at moving tucatinib up into this first-line setting after taxane induction where trastuzumab and pertuzumab is continued in the maintenance phase.

What was the design of the study?

This was a very simple trial randomised in a 1:1 fashion. Patients all had HER2+ metastatic breast cancer. They had received between four and eight cycles of taxane induction with trastuzumab and pertuzumab and had not had progression in coming onto study. They either received HP maintenance with or without endocrine therapy, that was allowed if they were ER+, or on the other arm received HP with the addition of tucatinib, again allowing endocrine therapy if the patient was hormone receptor positive in their tumour as well.

What were the key results?

The study met its primary endpoint which was investigator assessed progression free survival and lengthened progression free survival from 16.3 months to 24.9 months with the addition of tucatinib. So this was an absolute magnitude of benefit of 8.6 months. We also looked at the subset of patients that had hormone receptor positive as well as hormone receptor negative disease and both of these were statistically significant.

For the patients that had hormone receptor negative disease progression free survival was lengthened by 12.3 months and for those patients that had hormone receptor positive disease only about 45% of them received concurrent endocrine therapy per local standards but we did see a significant lengthening of progression free survival by 6.9 months.

What did you see in terms of safety?

In terms of safety and tolerability, I don’t think there were any large surprises. We saw elevated liver function test and diarrhoea as known side effects of tucatinib. In terms of discontinuation, about 13% of patients discontinued tucatinib and the majority of these discontinued due to hepatic AST/ALT increases – about 7.7%. In terms of diarrhoea we saw only 6% of patients in the tucatinib arm reduce because of diarrhoea and we saw 3% of patients reduce the placebo due to diarrhoea, so not a big difference there. In terms of discontinuation, discontinuations due to diarrhoea were actually very infrequent – 1.5% in the tucatinib arm and 0.9% in the control arm.

So, overall no big surprises, it was tolerable and even these liver function test abnormalities really were manageable with dose reductions, interruptions and modifications.

What is the clinical significance of these results?

The clinical significance, we’ve seen a lot of movement in first-line HER2+ metastatic breast cancer here recently. Last San Antonio, San Antonio 2024, we saw results of the PATINA trial. This was also a trial adding palbociclib in the maintenance setting for first-line HER2+ breast cancer but was restricted just to patients that had ER+ breast cancer as well. So HER2CLIMB-05 had both ER+ as well as ER-.

So we expect palbociclib to be an option in the maintenance setting. HER2CLIMB-05 adds another option in the maintenance setting, not only for the hormone receptor positive patients but also those patients that did not have hormone expression on their tumours.

The other study we’ve seen recently was DESTINY-Breast09 looking at the benefit of trastuzumab deruxtecan in the first-line setting. That trial was not designed with any maintenance so it was a head-to-head trial, trastuzumab deruxtecan versus standard taxane, trastuzumab, pertuzumab. So a lot of people are asking how are we going to integrate this? I suspect that even though trastuzumab deruxtecan and DESTINY-Breast09 did not involve maintenance, that there’s not going to be much of an appetite for continuing a cytotoxic for three, four, who knows how many, years. So I anticipate that even though that trial did not allow maintenance as part of the trial design that people will be looking to maintenance strategies such as HER2CLIMB-05, as well as PATINA, for maintenance in the first-line setting. It really presents quite an attractive option for patients to be able to drop out the cytotoxic and to extend PFS in the maintenance setting.