June 4, 2021—Tucatinib, a highly-selective HER2-directed tyrosine kinase inhibitor, in combination with trastuzumab and capecitabine offered maintained overall survival (OS) and progression-free survival (PFS) benefits with longer follow-up in patients with HER2-positive metastatic breast cancer, according to updated results of the HER2CLIMB trial, presented at the annual meeting of the American Society of Clinical Oncology, which took place online from June 4 to 8.
Tucatinib an approved treatment in multiple regions of the world in combination with trastuzumab and capecitabine for patients with HER2-positive breast cancer. “The HER2CLIMB trial evaluated tucatinib versus placebo, both in combination with trastuzumab and capecitabine, for HER2-positive metastatic breast cancer after progression on trastuzumab, pertuzumab, and ado-trastuzumab emtansine in any setting (neoadjuvant, adjuvant, and metastatic),” said study lead author Giuseppe Curigliano, MD, PhD, of the University of Milano in Italy, during his presentation of the data. The trial met all primary and secondary endpoints at the primary analysis, with clinically meaningful prolongation of PFS and OS. Dr. Curigliano presented updated efficacy and safety data approximately 2 years after randomization of the last patient.
For the global, randomized, double-blind, placebo-controlled HER2CLIMB trial, 612 patients with HER2-positive metastatic breast cancer were randomized 2:1 to either 300 mg tucatinib twice daily (n = 410) or to placebo (n = 202). In both arms, patients also received 6 mg/kg trastuzumab every 3 weeks, with a loading dose of 8 mg/kg on day 1 of cycle 1, and 1000 mg/m2 capecitabine twice daily from days 1 to 14 in a 21-day cycle. Since the primary analysis, the protocol was amended for unblinding of sites to treatment assignment, to allow for crossover from the placebo arm to tucatinib.
At the time of data cut-off in February 2021, 35 patients taking tucatinib and 1 patient taking placebo were still on their respective treatments, while the others had completed treatment. Of the placebo patients, 26 (12.9%) had crossed over to the other arm, with the first crossover being in February 2020. Nine patients who crossed over remain on tucatinib.
The median overall study follow-up was 29.6 months, including 15.6 months since the primary analysis. A 27% reduction in the risk of death was observed in the tucatinib arm, with a median OS of 24.7 months, compared with 19.2 months in the placebo arm (95% confidence interval 0.59–0.90, P = .004). The OS benefit with tucatinib was consistent across prespecified patient subgroups. Sensitivity analyses accounting for crossover patients also revealed similar OS benefits.
The benefit in PFS was similarly maintained with longer follow-up, at 7.6 months in the tucatinib arm versus 4.9 months in the placebo arm (hazard ratio 0.57, P < .00001).
Tucatinib was well-tolerated, and its safety profile was consistent with previous reports. Treatment-emergent adverse events of any grade were experienced by 99.3% of tucatinib patients and 97.0% of placebo patients. Grade 3 or greater adverse events were reported by 60.6% and 51.3%, respectively. Eight (2%) and 6 (3%) patients, respectively, died due to treatment-emergent adverse events. Study treatment discontinuation due to treated-emergent adverse events remained low, similar to the primary analysis, at 12.9% and 11.7%, respectively. The most common adverse events with tucatinib included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting.
“[The] OS benefit with tucatinib was maintained with an additional 15.6 months of follow-up, including [in the patients who crossed over from placebo],” concluded Dr. Curigliano. “Similarly, PFS benefit was also consistent with the primary analysis.”
The HER2CLIMB trial was funded by Seattle Genetics.