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SAN ANTONIO -- Patients with heavily treated metastatic HER2-positive breast cancer lived significantly longer with the addition of an investigational anti-HER2 drug to trastuzumab (Herceptin) and chemotherapy, a large randomized trial showed.

Almost three times as many patients were alive without disease progression after 1 year when treated with tucatinib, trastuzumab, and capecitabine, as compared with the two drugs (33.1% vs 12.3%). The 2-year overall survival (OS) was 44.9% with tucatinib and 26.6% without it. Among patients with brain metastases, a fourth remained alive without disease progression at 1 year versus none of the patients randomized to placebo in addition to trastuzumab and capecitabine.

Most patients in both treatment groups had one or more adverse events (AEs); the frequency of diarrhea (80.9% vs 53.3%) and increased liver enzymes (AST, 21.3% vs 11.2% and ALT, 20.0% vs 6.6%) was notably higher with tucatinib, as reported at the San Antonio Breast Cancer Symposium (SABCS). The study was published simultaneously in the .

"The tolerability profile and low discontinuation rate allow for continued HER2 inhibition until progression in heavily pretreated patients," said Rashmi Murthy, MD, of MD Anderson Cancer Center in Houston. "[The study] is the first randomized trial completed in patients with HER2-positive metastatic breast cancer that included patients with untreated or previously treated, progressing brain metastases."

"Tucatinib in combination with trastuzumab and capecitabine has the potential to become a new standard of care in this population with and without brain metastases."

The results might have won the day for at least some of the breast cancer specialists attending SABCS.

"This is the most exciting study presented today at San Antonio," Amy Tierstein, MD, of the Icahn School of Medicine at Mount Sinai in New York City, said via email. "This trial is the first trial I am aware of that also included patients with untreated or progressive brain metastases. The benefit for the addition of tucatinib ... was very impressive."

"Overall, tucatinib reduced risk of progression or death by 50%," Tierstein added. "I think this regimen may be considered a new standard of care for pretreated HER2-positive metastatic breast cancer. Very exciting."

Although breast cancer treatment has improved dramatically over the past 2 decades, most patients with metastatic HER2-positive breast cancer ultimately die of the disease. Current standard-of-care treatment for HER2-positive metastatic breast cancer consists of first-line trastuzumab plus pertuzumab (Perjeta) and a taxane, followed by second-line trastuzumab emtansine (Kadcyla) for patients who have progressive disease. Progression after trastuzumab emtansine leaves patients with no single standard-of-care regimen, Murthy noted.

Additionally, improvement in systemic therapy for breast cancer has been accompanied by an increase in brain metastases. As many as half of patients with metastatic disease may develop brain metastases, which have limited treatment options, Murthy continued.

Tucatinib has high selectivity for the kinase domain of HER2 and a minimal inhibitor effect on epidermal growth factor receptor (EGFR), which may alter the toxicity profile as compared with other anti-HER2 therapies. In a , the combination of tucatinib, trastuzumab, and capecitabine had "impressive antitumor activity" in patients with metastatic HER2-positive breast cancer, including patients with brain metastases.

The early results led to the international, randomized, phase III trial to evaluate trastuzumab and capecitabine plus tucatinib or placebo in 612 patients with metastatic HER2-positive breast cancer. Each of the patients had already received trastuzumab, pertuzumab, and trastuzumab emtansine. Patients with brain metastases could participate, including those with brain metastases >2 cm, if approved by the medical monitor.

Investigators randomized patients 2:1 to the tucatinib and placebo arms, respectively. The primary endpoint was PFS, as assessed by a blinded independent review committee. Secondary endpoints included OS, PFS in patients who had brain metastases, objective response, and safety. Almost half the patients (291, 47.5%) had brain metastases at baseline.

After a median follow-up of 14 months, the tucatinib arm had a 46% reduction in the hazard for disease progression or death as compared with the placebo arm (95% CI 0.42-0.71, P<0.001). The median PFS was 7.8 months with tucatinib and 5.6 months with placebo. Subgroup analysis yielded hazard ratios that were consistent with the overall analysis, Murthy reported. A comparison of investigator-assessed PFS showed consistency with the values that emerged from the independent review committee.

A difference in PFS was evident within 6 months (62.9% vs 46.3%), as was OS (75.5% vs 62.4%), and continued to the end of follow-up. Median OS was 21.9 months with tucatinib and 17.4 months with placebo. The addition of tucatinib was associated with a 34% reduction in the survival hazard (95% CI 0.50-0.88, P=0.005), which remained consistent across the subgroup analysis.

Patients with brain metastases had a 1-year PFS of 24.9% with tucatinib versus 0% in the placebo arm, and median PFS also favored the tucatinib arm (7.6 vs 5.4 months), representing a 52% reduction in the hazard for progression or death.

The most common AEs (all grades) in the tucatinib arm were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, and vomiting. Fatal AEs occurred in 1.5% of the tucatinib arm and 2.5% of the placebo group.