Intracranial efficacy of tucatinib in metastatic HER2-positive breast cancer
Previous results of the phase III HER2CLIMB trial indicated that in women with metastatic HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, a combination of tucatinib with trastuzumab and capecitabine resulted in a significantly longer survival than trastuzumab and capecitabine alone. During ASCO 2020, a subgroup analysis of this trial was presented specifically looking into the intracranial efficacy of tucatinib in 291 HER2CLIMB patients with brain metastases at baseline. Interestingly, the addition of tucatinib to trastuzumab and capecitabine doubled the intracranial response rate, reduced the risk of central nervous system (CNS) progression or death by two-thirds and reduced the risk of death by nearly half. In a second HER2CLIMB presentation at ASCO 2020, the combination of tucatinib, trastuzumab and capecitabine was shown to be well tolerated and had a manageable safety profile.
Introduction
Up to half of the patients with HER2-positive metastatic breast cancer may develop brain metastases. Effective and tolerable treatment options for these patients are needed. Tucatinib is an oral tyrosine kinase inhibitor (TKI) that is highly selective for the kinase domain of HER2 with minimal inhibition of EGFR. The HER2CLIMB trial previously showed clinically meaningful and statistically significant improvements in overall survival (OS) and progression-free survival (PFS) in all patients when tucatinib was added to trastuzumab and capecitabine, as well as a PFS prolongation in patients with brain metastases.
HER2CLIMB included a total of 612 patients with HER2+ metastatic breast cancer. All patients received prior treatment with trastuzumab, pertuzumab and T-DM1 and needed to have an ECOG performance status of 0 or 1. A brain MRI at baseline was required for all patients, regardless of the presence or absence of a history of known CNS-disease. Stratification factors included the presence of brain metastases, ECOG performance status, and region of the world. Patients were randomised (2:1) to receive either tucatinib (300 mg, twice daily) in combination with trastuzumab and capecitabine, or placebo in combination with trastuzumab and the same dose of capecitabine. Trastuzumab was given at a loading dose of 8 mg/kg on day 1 of cycle 1 if needed and then at a maintenance dose of 6 mg/kg on day 1 of 21-day cycles thereafter. Capecitabine was given at 1,000 mg/m2 orally, twice daily on days 1 through 14 of every 21-day cycle.1,2
Results
Among the 612 patients enrolled in the study, 291 patients had brain metastases. Of them, 174 patients had active brain metastases (N=108 with previously treated but progressing lesions and N=66 with untreated lesions) and 117 patients had treated stable brain metastases.1
Compared to placebo, tucatinib reduced the risk of CNS progression or death by 68% in patients with brain metastases (HR [95%CI]: 0.32 [0.22-0.48], p< 0.00001). At one year, 40.2% of the patients randomised to tucatinib versus 0% of patients randomised to placebo were alive and free of CNS progression. The median CNS-PFS was 4.2 months in the placebo arm, and extended to 9.9 months in the tucatinib arm, representing an absolute improvement of more than 5 months. Also with respect to OS, a benefit was seen in favour of tucatinib, with a hazard ratio of 0.58 and a p-value of 0.005. At one year, 70.1% of patients randomised to tucatinib were alive as compared to 46.7% of patients in the control arm. The median OS was 12.0 months in the placebo arm and extended to 18.1 months in patients treated with tucatinib-trastuzumab-capecitabine.1
In the tucatinib arm, 5.5% of patients achieved a complete intracranial response (versus 5.0% in the placebo arm) with an additional 41.8% achieving a partial response intracranial (versus 15.0%). Of note, only two patients (3.6%) had progressive CNS disease as best response. The duration of intracranial response was 6.8 months in the tucatinib arm versus 3.0 months in the placebo arm. The median time from randomisation to second progression or death was 15.9 months for patients in the tucatinib arm, as compared to 9.7 months for the placebo arm (HR [95%CI]: 0.292 [0.11-0.77], p= 0.009). Finally, the median time from first CNS progression to second progression or death was 7.6 months in the tucatinib arm versus 3.1 months in the placebo arm (HR [95%CI]: 0.332 [0.13-0.85], p= 0.02).1
In HER2CLIMB, the treatment with the tucatinib-trastuzumab-capecitabine was generally well tolerated and came with a manageable safety profile. Diarrhoea was the most common adverse event (AE) observed in both arms (80.9% in the tucatinib arm versus 53.3% in the placebo arm). Of note, this diarrhoea was mainly of grade 1 and 2 and was manageable with dose modifications. The median time to diarrhoea onset was 12 days in the tucatinib arm, and 22 days in the placebo arm. Antidiarrheal medications were used in 49.7% of cycles in the tucatinib arm and 39.8% of cycles in the placebo arm. Elevated liver enzymes (ALT/AST/bilirubin) were primarily grades 1 and 2, transient, asymptomatic, reversible and manageable with dose modifications. Palmar-plantar erythrodysesthesia was not different when accounting for longer duration of treatment. Treatment discontinuation of tucatinib due to treatment-emergent AEs was infrequent and capecitabine was the most commonly dose modified agent in both arms.2
Conclusions
In HER2CLIMB patients with brain metastases at baseline, the addition of tucatinib to trastuzumab and capecitabine doubled the intracranial response rate, reduced the risk of CNS progression or death by two-thirds and reduced the risk of death by nearly half. In addition, the CNS-PFS results represent a delay in progression in the brain. Tucatinib thereby is the first TKI to demonstrate an OS prolongation in patients with HER2+ metastatic breast cancer with brain metastasis in a randomised, controlled trial.1 Furthermore, the combination of tucatinib, trastuzumab and capecitabine was well tolerated and had a manageable safety profile. Treatment discontinuation due to TEAEs was infrequent and capecitabine was the most commonly dose modified agent in both arms.2 These results, together with the HER2CLIMB primary analysis, demonstrate that this is an active regimen for intracranial and extracranial disease in patients with HER2+ metastatic breast cancer.
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). Presented at ASCO 2020; Abstract 1005.
2. Okines AFC, Paplomata E, Wahl TA, et al. Management of adverse events in patients with HER2+ metastatic breast cancer treated with tucatinib, trastuzumab, and capecitabine (HER2CLIMB). Presented at ASCO 2020; Abstract 1043.
