Seattle Genetics announced Monday that a pivotal trial of the experimental drug tucatinib in patients with locally advanced unresectable or metastatic HER2-positive breast cancer met its primary endpoint of progression-free survival (PFS), as well as both key secondary goals. The company, whose shares jumped as much as 15% on the news, indicated that it plans to file a marketing application to the FDA for the oral, small molecule tyrosine kinase inhibitor in the first quarter of 2020.
The HER2CLIMB study enrolled 612 patients with locally advanced or metastatic HER2-positive breast cancer who were previously treated with Roche drugs Herceptin (trastuzumab), Perjeta (pertuzumab) and Kadcyla (ado-trastuzumab emtansine). Participants were randomised to receive tucatinib in combination with Herceptin plus capecitabine, or Herceptin plus capecitabine alone. Seattle Genetics noted that 47% of patients in the trial had brain metastases at the time of enrollment.
Top-line results showed that the addition of tucatinib was superior to Herceptin and capecitabine alone, with a 46% reduction in the risk of disease progression or death. In regards to secondary endpoints, an interim analysis showed that tucatinib was also associated with a 34% reduction in the risk of death. In addition, for patients with brain metastases at baseline, the drug demonstrated superior PFS, with a 52% reduction in the risk of disease progression or death versus Herceptin and capecitabine alone.
The company said tucatinib was "generally well tolerated with a manageable safety profile," although it noted that patients who were given the drug had elevated levels of certain liver enzymes. Specifically, 4.5% of patients in the tucatinib group had increased aspartate aminotransferase, versus 0.5% for the comparator arm, while increased alanine aminotransferase was seen in 5.4% and 0.5% of patients in the two groups, respectively. However, increased bilirubin levels were less frequent among tucatinib-treated patients at 0.7%, versus 2.5% for Herceptin plus capecitabine alone. Adverse events leading to discontinuations were "infrequent" in both the tucatinib and control arms, the company added.
Roger Dansey, chief medical officer at Seattle Genetics, remarked "based on these findings, we plan to unblind the trial and offer tucatinib to patients on the control arm." Further results will be presented at the San Antonio Breast Cancer Symposium (SABCS) in December, with analysts at Leerink analysts calling the findings a "near best-case scenario" for the company.
According to Seattle Genetics, tucatinib, which was gained via the purchase of Cascadian Therapeutics in 2018, is highly selective for HER2, but without significant inhibition of EGFR, which "has been associated with significant toxicities." The company recently initiated the Phase III HER2CLIMB-02 trial, which will evaluate tucatinib versus placebo, both in combination with Kadcyla, in approximately 460 patients with unresectable locally-advanced or metastatic HER2-positive breast cancer, including those with brain metastases, who have had prior treatment with a taxane and Herceptin in any setting.
Meanwhile, tucatinib is also being assessed in combination with Herceptin for use in patients with HER2-positive, RAS wild-type metastatic or unresectable colorectal cancer in the mid-stage MOUNTAINEER study. Initial results from 26 patients were recently presented at the European Society for Medical Oncology (ESMO) conference. For related analysis, see ViewPoints: Seattle Genetics rides its ESMO update into strategic partnering position.
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