Chinese Drug Shows Benefit in HER2-Low Breast Cancer

An investigational antibody-drug conjugate (ADC) significantly reduced the risk of disease progression or death in patients with HER2-low metastatic breast cancer, a Chinese phase III trial showed.

The drug, trastuzumab rezetecan, improved median progression-free survival (PFS) versus physician’s choice of chemotherapy in both the overall study population (16.4 vs 6.8 months; HR 0.27, 95% CI 0.21-0.34, P<0.001) and in the chemotherapy-naive subset (16.6 vs 6.8 months; HR 0.25, 95% CI 0.19-0.33, P<0.001), reported Ying Fan, MD, of Peking Union Medical College in Beijing.

That PFS benefit was consistent regardless of hormone receptor (HR) status, according to findings from the so-called HORIZON-Breast06 trial presented at the European Society for Medical Oncology (ESMO) congress in Madrid and published concurrently in JAMA.

Overall survival (OS) data were immature at data cutoff but favored the trastuzumab rezetecan-treated group, with 12-month OS rates of 90.6% and 81.4%, respectively (HR 0.67, 95% CI 0.48-0.94, nominal P=0.01).

Trastuzumab rezetecan links a HER2-targeted monoclonal antibody to a highly potent topoisomerase I inhibitor. The ADC is approved in China for non-small cell lung cancer and colorectal cancer and carries an FDA orphan drug designation for gastric cancer.

A similar drug — trastuzumab deruxtecan (T-DXd; Enhertu) — already carries multiple FDA-approved indications in breast cancer, including for HER2-positive tumors and HER2-low and -ultralow disease. But whether trastuzumab rezetecan is any better is unclear, with T-DXd trials showing similar results, said Maria Fernanda Mosele, MD, and Fabrice André, MD, PhD, both of Gustave Roussy in Villejuif, France, writing in an editorial accompanying the publication.

“The current study does not establish superiority of trastuzumab rezetecan over trastuzumab deruxtecan and, in countries where trastuzumab deruxtecan is approved, it is likely to remain the preferred option,” according to Mosele and André.

“Because a head-to-head comparison with trastuzumab deruxtecan is unlikely, defining the role of trastuzumab rezetecan in the treatment landscape is a clinical priority,” they wrote. “One strategy would be sequential use: because trastuzumab deruxtecan could move into early-stage hormone receptor-positive treatment, trastuzumab rezetecan could fill an important gap at metastatic relapse.”

ESMO discussant Barbara Pistilli, MD, also of Gustave Roussy, noted that trastuzumab rezetecan in preclinical models demonstrated greater membrane permeability and potency versus T-DXd, along with faster systemic clearance that potentially could reduce off-target toxicities.

However, whether that adds a meaningful clinical advantage compared with approved ADCs is unknown because of a lack of head-to-head trials for comparison, she said.

“Pivotal trials should generate evidence for regulatory approval by comparing new ADCs with the current standard of care,” which in this case is T-DXd, said Pistilli.

HORIZON-Breast06 included 551 patients (median age 55 years) from 73 hospitals across China who were randomized to receive either trastuzumab rezetecan or physician’s choice of taxanes, eribulin, capecitabine, or gemcitabine chemotherapy. Overall, 81.5% were chemotherapy-naive and the rest had received one prior line of chemotherapy for metastatic disease. Nearly three-fourths (73%) were HR-positive.

The PFS benefit with trastuzumab rezetecan versus chemotherapy was also observed in the chemotherapy-treated patients (13.9 vs 5.6 months; HR 0.32, 95% CI 0.19-0.54) and as noted, was independent of HR status:

• HR-positive: 16.4 vs 6.7 months (HR 0.24, 95% CI 0.18-0.33)
• HR-negative: 16.5 vs. 6.8 months (HR 0.34, 95% CI 0.22-0.54)

The benefit seen in the HR-negative population was particularly notable, according to the investigators, since this is “an aggressive, difficult-to-treat subtype that has historically lacked effective targeted options.”

Regarding safety, grade ≥3 treatment-related adverse events (TRAEs) occurred in 84.1% of patients in the trastuzumab rezetecan arm and 67.9% of those on chemotherapy. Serious TRAEs occurred in 37.7% and 13.7%, respectively.

TRAEs leading to dose reductions occurred in 50.4% of patients in the trastuzumab rezetecan group and in 29.2% of the chemotherapy group, while the rates of TRAEs leading to treatment discontinuation were 8.7% and 6.3%, respectively.

Interstitial lung disease occurred in seven patients (2.5%) in the trastuzumab rezetecan group — including grade 3 cases in two patients and one grade 4 case.