Multinational phase 3 trial of tucatinib versus placebo in combination with trastuzumab-pertuzumab as first-line maintenance therapy for HER2-positive mBC

The multinational phase 3 HER2CLIMB-05 study evaluated adding tucatinib to trastzuzumab and pertuzumab as first-line maintenance therapy in patients with HER2-positive metastatic breast cancer (HER2+ mBC). Patients with centrally confirmed HER2+ mBC without evidence of progression post-induction therapy and no or asymptomatic brain metastases were randomized 1:1 to tucatinib 300 mg (n=326) or placebo (n=328) twice daily combined with trastuzumab-pertuzumab. Primary endpoint was investigator-assessed progression-free survival. The median PFS was 24.9 months in the tucatinib group versus 16.3 months in the placebo group (HR 0.641; p<0.0001); PFS benefit was seen regardless of presence/absence of brain metastases or hormone receptor status. Overall survival data were immature. The most common treatment-emergent adverse events in the tucatinib group were diarrhea (72.7%), nausea (33.1%), and elevated liver enymes (alanine aminotransferase 28.2%; aspartate aminotransferase 25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1%, respectively, were grade ≥ 3. In the tucatinib group, 13.5% discontinued tucatinib due to TEAEs. The authors conclude that addition of tucatinib to trastuzumab and pertuzumab demonstrated improvement in PFS with no new safety signals identified and may be an option for first-line maintenance therapy in patients with HER2+ mBC.