Significant Delay in CNS Progression Achieved With Tucatinib Triplet in HER2+ Metastatic Breast Cancer

Nancy U. Lin, MD

The addition of tucatinib (Tukysa) to treatment with trastuzumab (Herceptin) and capecitabine resulted in more than a 60% reduction in the risk of central nervous system (CNS) progression or death in both patients with previously treated HER2-positive metastatic breast cancer who have active or stable brain metastases. Findings from the subgroup of patients with brain metastases from the HER2CLIMB trial were presented as part of the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.¹

“Tucatinib is the first tyrosine kinase inhibitor to demonstrate prolongation of overall survival in patients with HER2-positive metastatic breast cancer with brain metastases in a randomized, controlled trial,” said investigator Nancy U. Lin, MD, associate chief, Division of Breast Oncology, Susan F. Smith Center for Women's Cancers, and director, Metastatic Breast Cancer Program, Dana-Farber Cancer Institute in Boston, Massachusetts.

A report of findings from the subset of patients with brain metastases was also published simultaneously in the Journal of Clinical Oncology.²

Pivotal Initial Findings

In April 2020, the FDA approved the use of tucatinib in combination with trastuzumab and capecitabine for the treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti–HER2-based regimens in the metastatic setting. The approval was based on findings from the primary HER2CLIMB analysis.³

Tucatinib is an oral tyrosine kinase inhibitor that is highly selective for the HER2 kinase domain and also provides minimal inhibition of EGFR.

The pivotal randomized, double-blind phase 2 trial explored the safety and efficacy of the triplet regimen in patients with HER2-positive metastatic breast cancer who had previously been treated with trastuzumab, pertuzumab (Perjeta), and T-DM1 (trastuzumab emtansine; Kadcyla). Eligible patients had an ECOG performance status of 0 or 1 and had to have a brain MRI completed at baseline. Stratification was based on the presence of brain metastases, ECOG performance status, and geographic region.

Patients were randomized 2:1 to receive either 300 mg of tucatinib twice daily (n = 410) or matching placebo (n = 202) in combination with 6 mg/kg trastuzumab every 3 weeks plus a loading dose of 8 mg/kg C1D1 and 1000 mg/m2 of capecitabine twice daily for days 1 to 14 of each 21-day cycle.

In the primary analysis, HER2CLIMB met all primary and alpha-controlled secondary end points. According to blinded independent central review (BICR), the progression-free survival (PFS) rate at 1 year was 33.1% in the tucatinib triplet arm compared with 12.3% in the placebo arm, resulting in a 46% reduction in the risk of disease progression or death (HR, 0.54; 95% CI, 0.42-0.71; P <.001). The median PFS was 7.8 months and 5.6 months with the triplet and doublet regimens, respectively.⁴

Among all patients in the trial, with or without brain metastases, the overall survival (OS) rate at 2 years was 44.9% with added tucatinib and 26.6% without, amounting to a 34% reduction in the risk of death with tucatinib (HR, 0.66; 95% CI, 0.50-0.88; P = .005). The median OS was 21.9 months with the tucatinib regimen and 17.4 months with the placebo regimen.

In patients with brain metastases (n = 291), the PFS rate by BICR at 1 year was 24.9% with the tucatinib combination versus 0% with the placebo combination, which led to a 52% reduction in the risk of progression or death in these patients (HR, 0.48; 95% CI, 0.34-0.69; P <.001). The median PFS in this patient population was 7.6 months in those treated with tucatinib and 5.4 months in those who received placebo.

Updated Findings Focus on Patients With Brain Lesions

The analysis presented at ASCO focused on a subset of patients from the HER2CLIMB study who had brain metastases who did not require immediate local therapy for their CNS lesions. If they did require local therapy, they could be treated and then be eligible after the washout period. Brain MRI was required every 6 weeks in the first 24 weeks of treatment and then every 9 weeks afterwards.

Of 291 patients with brain metastases in the trial, 108 had active metastases that were progressing at baseline, 66 had untreated active metastases, and 117 had treated brain metastases that were stable and showing no signs of progression. A total of 198 patients with brain metastases were treated in the tucatinib arm and 93 were in the control arm.

In the analysis, investigators looked to response and progression by RECIST 1.1 criteria in brain lesions only for signs of efficacy.

The median age was just over 50 years in both arms and 99% of patients were women. More patients had estrogen receptor–positive disease and an ECOG performance status of 1 in both arms. For local therapy for brain metastases, 70.7% of patients in the tucatinib arm received prior radiotherapy and 16.7% underwent surgery compared with 68.8% and 14.0%, respectively, in the placebo arm.

At 1 year, the rate of CNS-PFS, defined as the time from randomization to disease progression in the brain or death, was 40.2% (95% CI, 29.5%-50.6%) in the tucatinib arm compared with 0% in the control arm for all patients with brain metastases, which amounted to a 68% reduction in the risk of CNS progression or death (HR, 0.32; 95% CI, 0.22-0.48; P <.00001). The median CNS-PFS was 9.9 months (95% CI, 8.0-13.9) with the triplet versus 4.2 months (95% CI, 3.6-5.7) with the doublet.

“The CNS-PFS results represent a statistically significant and clinically meaningful delay in progression in the brain,” Lin said.

OS rate in the overall brain metastases population was 70.1% (95% CI, 62.1%-76.7%) in the tucatinib arm versus 46.7% (95% CI, 33.9%-58.4%) in the placebo arm at 1 year, resulting in a 42% reduction in the risk of death (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months (95% CI, 15.5 to not evaluable [NE]) versus 12.0 months (95% CI, 11.2-15.2) in the tucatinib and placebo groups, respectively.

Among patients with active brain metastases, whether treated or untreated, the risk of CNS progression or death was reduced by 64% with the addition of tucatinib, which showed a CNS-PFS rate of 35.0% (95% CI, 23.2%-47.0%) at 1 year compared with 0% in the placebo arm (HR, 0.36; 95% CI, 0.22-0.57; P <.0001). The median CNS-PFS in those with active brain metastases treated with the tucatinib regimen was 9.5 months (95% CI, 7.5-11.1) compared with 4.1 months (95% CI,2.9-5.6) with the placebo regimen.

The risk of death was reduced by 51% with the addition of tucatinib in patients with active brain metastases (HR, 0.49; 95% CI, 0.30-0.80; P = .004). At 1 year, the OS rate was 71.7% (95% CI, 61.4%-79.7%) in the tucatinib arm compared with 41.1% (95% CI, 25.5%-56.1%) in the placebo arm, and the median OS was 20.7 months (95% CI, 15.1-NE) and 11.6 months (95% CI, 10.5-13.8) in the 2 arms, respectively.

In patients with stable brain metastases, the CNS-PFS rate at 1 year was 53.3% (95% CI, 31.4%-71.0%) with tucatinib compared with 0% without, resulting in a 69% reduction in the risk of CNS progression or death (HR, 0.31; 95% CI, 0.14-0.67; P = .002). The median CNS-PFS was 13.9 months (95% CI, 9.7-32.2) for those treated with the tucatinib regimen and 5.6 months (95% CI, 3.0-9.5) for those who received the control regimen.

The risk of death was reduced by 12% from added tucatinib treatment in those with stable brain metastases (HR, 0.88; 95% CI, 0.45-1.70; P = .70). The OS rate at 1 year was 67.6% (95% CI, 53.8%-78.0%) and 55.6% (95% CI, 34.1%-72.6%) in the tucatinib and placebo arms, respectively, and the median OS was 15.7 months (95% CI, 13.8-NE) and 13.6 months (95% CI, 10.2-22.0).

The confirmed intracranial objective response rate (ORR-IC) in patients with measurable intracranial disease was 47% (95% CI, 33.7%-61.2%) in the tucatinib/trastuzumab/capecitabine arm compared with 20% (95% CI, 5.7%-43.7%) in the placebo/trastuzumab/capecitabine arm (P = .03). The median duration of intracranial response was 6.8 months (95% CI, 5.5-16.4) versus 3.0 months (95% CI, 3.0-10.3) in the tucatinib and placebo arms, respectively.

“For patients in the tucatinib arm, more patients were able to continue on their assigned treatment arm for clinically meaningful periods of time before the next progression event,” Lin noted.

In patients with isolated progression in the brain (first CNS progression) who continued on study treatment after receiving local therapy, the median time from randomization to second progression or death was 15.9 months (95% CI, 11.7-28.2) with the tucatinib arm (n = 21) compared with 9.7 months (95% CI, 4.9-12.0) in the placebo arm (n = 9) (HR, 0.292; 95% CI, 0.11-0.77; P = .009). The median time from first CNS progression to a second progression or death was 7.6 months (95% CI, 3.9-11.3) versus 3.1 months (95% CI, 1.2-4.1) in the tucatinib and placebo arms, respectively (HR, 0.332; 95% CI, 0.13-0.85; P = .02).

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

_References

1. _{Lin NU, Murthy RK, Anders CK, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). J Clin Oncol. 2020;38(suppl):1005. doi:10.1200/JCO.2020.38.15_suppl.1005}
2. _{Lin NU, 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. Published online May 29, 2020. doi:10.1200/JCO.20.00775}
3. _{Seattle Genetics announces U.S. FDA approval of Tukysa™ (tucatinib) for people with advanced unresectable or metastatic her2-positive breast cancer. News release. Seattle Genetics, Inc; April 17, 2020. Accessed May 29, 2020. https://bit.ly/2xtQeBe}
4. _{Murthy RK, Loi S, Okines A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020;382:597-609. doi:10.1056/NEJMoa191460}

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