BOTHELL, Wash.—In light of October being breast cancer awareness month, here's some good news out of Seattle Genetics for those suffering from this disease. The company reported positive top-line results this week from its HER2CLIMB trial—a randomized, double-blind, placebo-controlled, active comparator pivotal trial—of tucatinib. The trial evaluated tucatinib in combination with trastuzumab and capecitabine compared to trastuzumab and capecitabine alone in patients with locally advanced unresectable or metastatic HER2-positive breast cancer who had previously received trastuzumab, pertuzumab and ado-trastuzumab emtansine (T-DM1).
Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 but doesn't significantly inhibit EGFR, the inhibition of which has been linked to significant toxicities. The compound has demonstrated activity as both a single agent and part of a combination regimen with either chemotherapy or HER2-targeted agents. The FDA has granted tucatinib orphan drug designation for the treatment of breast cancer patients with brain metastases.
The primary endpoint of HER2CLIMB was progression-free survival, which tucatinib met handily: the trial showed that adding tucatinib to the regimen of trastuzumab and capecitabine led to a 46-percent reduction in the risk of disease progression or death. Key secondary endpoints—including overall survival and progression-free survival in patients with brain metastases at baseline—were also met. In terms of overall survival, the addition of tucatinib demonstrated a 34-percent reduction in the risk of death compared to trastuzumab and capecitabine alone. Additionally, of the patients enrolled in the trial, 47 percent had brain metastases when they enrolled. Of those, the patients who received tucatinib saw a 52-percent reduction in their risk of disease progression or death compared to those who received just trastuzumab and capecitabine.
“There is significant unmet medical need following treatment with trastuzumab, pertuzumab and T-DM1 in patients with metastatic HER2-positive breast cancer,” said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. “The addition of tucatinib to the commonly used doublet of trastuzumab and capecitabine represents a potential significant clinical advance for patients with metastatic HER2-positive breast cancer, importantly, including those with brain metastases. Based on these findings, we plan to unblind the trial and offer tucatinib to patients on the control arm. We also plan to submit a New Drug Application to the FDA in the first quarter of 2020, with the goal of bringing a much-needed new medicine to patients.”
The combination of all three drugs was generally well tolerated, Seattle Genetics reported, with “a manageable safety profile.” The most frequent adverse events (AEs) in the tucatinib arm were diarrhea, palmar-plantar erythrodysaesthesia syndrome, nausea, fatigue, and vomiting. AEs of Grade 3 or greater in the tucatinib arm vs. those in the control arm included diarrhea (12.9 vs. 8.6 percent), increased aspartate aminotransferase (4.5 vs. 0.5 percent), increased alanine aminotransferase (5.4 vs. 0.5 percent), and increased bilirubin (0.7 vs. 2.5 percent). Adverse events led to discontinuations in both the tucatinib and control arm, which were reported at 5.7 percent and 3.0 percent, respectively.
Motley Fool's Brian Orelli reported that Seattle Genetics' shares were up 15 percent just before noon after this news was announced. Orelli added that “Tucatinib certainly isn't a cure, but the improvements over the control treatment are quite impressive and suggest the drug will be quickly adopted by doctors for late-stage patients once it's approved. More importantly, the solid efficacy data indicate tucatinib is likely to help earlier-stage patients, which would substantially increase the drug's potential market … While HER2CLIMB is only a Phase 2 clinical trial, the study should be enough to gain an accelerated approval from the Food and Drug Administration given the unmet need for the late-stage patients. Seattle Genetics plans to submit a marketing application in the first quarter of next year, which should result in an approval toward the end of the year.”
Just over a week before the HER2CLIMB results were shared, Seattle Genetics announced that it had dosed the first patient in its HER2CLIMB-02 trial, a randomized Phase 3 clinical trial assessing tucatinib vs. placebo, in combination with ado-trastuzumab emtansine (T-DM1, or Kadcyla) for patients with locally advanced or metastatic HER2-positive breast cancer. HER2CLIMB-02 is intended to support tucatinib's registration in the United States.
Seattle Genetics is also evaluating the efficacy of tucatinib beyond breast cancer. The Phase 2 MOUNTAINEER trial is underway to assess tucatinib in combination with trastuzumab in patients with HER2-positive, RAS wildtype metastatic or unresectable colorectal cancer.