Overall survival (OS) was maintained, and even improved, in patients with pretreated HER2-positive breast cancer receiving tucatinib (Tukysa) plus trastuzumab (Herceptin) and capecitabine versus placebo. The updated HER2CLIMB trial (NCT02614794) findings were presented by Giuseppe Curigliano, MD, PhD, at the 2021 American Society of Clinical Oncology Annual Meeting.
“Tucatinib in combination with trastuzumab and capecitabine continues to improve progression-free and overall survival in patients with HER2-positive breast cancer,” said Curigliano, associate professor of medical oncology at the University of Milano and the head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy. “This combination has the potential to become a new standard of care in this patient population.”
Significantly, OS benefit with tucatinib was maintained with an additional 15.6 months of follow-up (total of 29.6 months), a 5.5-month improvement in median OS was seen in the total population. The median OS in the tucatinib arm was 24.7 months (95% CI, 21.6-28.9) versus 19.2 months (95% CI, 16.4-21.4) in the placebo arm (HR, 0.73; 95% CI, 0.59-0.90; P = .004). Tucatinib also significantly reduced the risk of disease progression or death by 40% in patients with brain metastases and by 30% in patients with visceral metastases.
Curigliano presented the updated findings from the randomized, double-blind, placebo-controlled phase 2 HER2CLIMB trial. A total of 612 patients with unresectable, locally advanced or metastatic HER2-positive breast cancer were enrolled in the study. All had been previously treated with trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadycla); had an ECOG performance status of 0 or 1; and a brain MRI at baseline. Patients with treated stable brain metastases, untreated metastases not needed immediate treatment, previously treated progressing metastases not needed immediate therapy, and patients with no evidence of brain metastases were all eligible.
Patients were divided into 2 arms: tucatinib (n = 410) and placebo (n = 202). Over a 21-day cycle, patients in the tucatinib arm were given 300 mg tucatinib orally twice daily (PO BID), 6 mg trastuzumab every 3 weeks (loading dose 8 mg on day 1 of cycle 1), and 1000 mg capecitabine PO BID (days 1-14). The placebo arm received the same regimen of trastuzumab and capecitabine. As of the post-analysis cut-off date, February 8, 2021, 404 (98.5%) patients had received at least 1 dose of tucatinib, and 35 patients (8.5%) are continuing treatment in the tucatinib arm. In the placebo arm, 197 (97.5%) patients received at least 1 dose of placebo, and 1 patient (0.5%) is continuing treatment in the placebo arm. Twenty-six patients (12.9%) crossed over from the placebo arm to the tucatinib arm, 9 (4.5%) of whom remain on treatment.
The primary end point of the study was progression-free survival according to RECIST v1.1 by blinded independent central review. Secondary end points included OS and PFS in patients with metastases and confirmed overall survival in patients with measurable disease.
PFS in the tucatinib arm was consistent with the primary analysis; its benefit was maintained with longer follow-up (HR, 0.57; 95% CI, 0.47-0.70; P < .00001), with the median PFS being 7.6 months in the tucatinib arm compared with 4.9 months in the placebo arm.
Regarding safety, “the tucatinib regimen continues to be safe and well tolerated with additional follow-up,” Curigliano said. “In the 15.6 months since the primary analysis, only 1 additional patient discontinued tucatinib due to an adverse event.”
The most common adverse events (AEs) in the tucatinib arm included diarrhea (n = 331, 81.9%), palmar-plantar erythodysesthesia syndrome (n = 264, 65.3%), nausea (n = 243, 60.1%) fatigue and vomiting (n = 193, 47.8%). Grade 3 or higher AEs included palmar-plantar erythodysesthesia syndrome (n = 57, 14.1%), diarrhea (n = 53, 13.1%), and fatigue (22, 5.4%), which were more common in the tucatinib arm versus the placebo arm.
Curigliano G, Mueller V, Borges V, et al. Updated results of tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with or without brain metastases, J Clin Oncol. 2021;39(suppl 15; abstr 1043). doi:10.1200/JCO.2021.39.15_suppl.1043