Tucatinib Combination Demonstrates Multiple Positive Responses in HER2-Positive Metastatic Breast Cancer

Nancy Lin, MD

Multiple positive responses were observed in an exploratory efficacy analysis evaluating tucatinib (Tukysa) in combination with trastuzumab (Herceptin) and capecitabine in patients with previously treated HER2-positive metastatic breast cancer with brain metastases in the previously reported HER2CLIMB (NCT02614794) trial. Lead author Nancy Lin, MD, and colleagues reported that the combination doubled the intracranial objective response rate (ORR-IC) reduced risk of IC progression or death by two-thirds and reduced the risk of death by nearly half, in a presentation during the Society of Neuro-Oncology 2020 Virtual Brain Metastases Conference.¹

In the HER2CLIMB study, 410 patients received the combination tucatinib (300 mg twice a day), trastuzumab (6 mg/kg once every 3 weeks), and capecitabine (1000 mg/m² twice a day) compared with 202 patients in the control group who received placebo, trastuzumab, and capecitabine in similar doses.²

The data presented at the conference evaluated the 291 patients enrolled in HER2CLIMB who had brain metastases at baseline. Of these, 174 patients were classified as having active brain metastases and 117 were classified as having treated stable brain metastases, defined as patients who were previously treated with no evidence of progression at baseline. Baseline characteristics were well balanced between the treatment arms. In the tucatinib arm, 70.7% of patients had prior radiotherapy compared with 68.8% in the placebo arm. In the tucatinib arm, 16.7% of patients had prior surgery compared with 14.0% of patients in the placebo arm. The exploratory analysis examined response and progression according to RECIST 1.1 for brain lesions.

“Among all patients with brain metastases, we calculated central nervous system progression-free survival [CNS-PFS] from randomization to disease progression in the brain or death, and overall survival [OS],” Lin said, who is the associate chief, Division of Breast Oncology at the Susan F. Smith Center for Women’s Cancers, and associate professor of medicine at Harvard Medical School in Boston, Massachusetts. Further, among patients with measurable IC disease, the investigators measured ORR-IC and duration of intracranial response (DOR-IC).

For patients in the tucatinib arm, median CNS-PFS was 9.9 months compared with 4.2 months in the placebo arm (HR, 0.32; 95% CI, 0.22-0.48; P <.00001). “In one year, 40% of patients were still alive in the tucatinib arm versus zero patients in the placebo arm,” Lin said. The median OS also favored patients in the tucatinib arm at 18.1 months compared with 12.0 months (HR, 0.58; 95% CI, 0.40-0.85; P =.005). At one year, 70.1% of patients in the tucatinib arm were still alive compared with 46.7% of patients who received placebo.

In the subset of patients with active brain metastases, Lin said the benefit of tucatinib was maintained both for CNS-PFS and OS. Median CNS-PFS was 9.5 months in the tucatinib arm compared with 4.1 months in the placebo arm (HR, 0.36; 95% CI, 0.22-0.57; P <.0001). Median OS was extended by more than 9 months in the tucatinib arm, which was reported as 20.7 months compared with 11.6 months in the placebo arm (HR, 0.49; 95% CI, 0.30-0.80; P =.004).

Lin said CNS-PFS benefits were maintained in patients who received tucatinib among patients with stable brain metastases. Specifically, patients who received tucatinib had a median CNS-PFS of 13.9 months versus 5.6 months for patients in the placebo arm (HR, 0.31; 95% CI, 0.14-0.67; P =.002).

“The differences in [OS] were attenuated with a hazard ratio of 0.88 and in this small subset did not reach statistical significance,” Lin said. Median OS for the tucatinib arm was 15.7 months compared with 13.6 months for the placebo arm (95% CI, 0.45-1.70; P =.70).

The ORR-IC in patients with active brain metastases and measurable intracranial lesions at baseline was 47% in the tucatinib arm and 20% in the placebo arm. “Most of the responses were partial responses,” Lin said. “The median duration intracranial response was 6.8 months for the tucatinib arm versus 3.0 months for the placebo arm.”

For patients with isolated progression who continued with assigned study treatment, tucatinib was associated with an improvement in median time from randomization to second progression or death of 15.9 months (95% CI, 11.7-28.2) versus 9.7 months for the placebo arm (95% CI, 4.9-12.0). The hazard ratio was reported as 0.292 (95% CI, 0.11-0.77; P =.009).

When the investigators looked at median time from first CNS progression to second progression or death, PFS was 7.6 months for the tucatinib arm (95% CI, 3.9-11.3) compared with 3.1 months in the placebo arm (95% CI, 1.2-4.1). The hazard ratio was 0.332 (95% CI, 0.13-0.85; P =.02).

Among all patients enrolled in HER2CLIMB, irrespective of the presence or absence of brain metastases at study baseline, the investigators calculated the time to new brain lesions or death. “The addition of tucatinib was associated with a 48% reduction in the risk of developing a new CNS lesion or death in this analysis,” Lin said.

Lin said the CNS-PFS results represent a clinical meaningful delay in progression in the brain. The agent also reduced the risk of developing new brain lesions or death by nearly half in patients with or without brain metastases.

“These results together with the HER2CLIMB primary analysis demonstrate that the triplet of tucatinib, trastuzumab, and capecitabine is an active regimen for the treatment of patients with intracranial and extracranial disease in patients with HER2-positive metastatic breast cancer,” Lin concluded.

_References:

_{1. Lin MU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol; 2020;38:(23):2610-261. doi: 10.1200/JCO.20.00775}

_{2. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for her2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609}