Trastuzumab Deruxtecan Data Impresses at ESMO

Antibody–drug conjugates (ADC) are taking center stage as second- and third-line treatments for HER2-positive metastatic breast cancer. However, a dearth of data limits direct comparisons of the safety and efficacy of ADCs—even the original HER2-targeting ADC trastuzumab emtansine (T-DM1; Kadcyla; Roche) and the newer trastuzumab deruxtecan (T-DXd; Enhertu; AstraZeneca, Daiichi Sankyo).

Early results of DESTINY-Breast03, a multinational, randomized, phase III trial comparing T-DM1 with T-DXd as a second-line treatment for patients with inoperable or metastatic HER2-positive breast cancer, were released at the 2021 European Society of Medical Oncology (ESMO) Congress, held September 16–21. The study—the first randomized trial of T-DXd, and the first to compare two ADCs in any malignancy—could change standard of care.

The two ADCs are superficially similar but exhibit several differences. Although both use the HER2 antibody trastuzumab to target malignant cells, T-DXd carries approximately eight drug molecules per antibody, whereas T-DM1 ferries about 3.5 drug molecules per antibody. Each ADC boasts a different drug, with T-DXd toting a topoisomerase I inhibitor not commonly used for breast cancer, and T-DM1 bringing an antimicrotubule agent. Additionally, the linkers connecting the drug to the antibody in T-DXd have been engineered to be cleavable by tumor cells, which can release membrane-permeable drug molecules that may kill neighboring tumor cells. This is the so-called bystander effect, which may be beneficial because HER2 expression even in HER2-positive tumors can be heterogeneous.

Preliminary data from 524 patients, presented by lead investigator Javier Cortés, MD, PhD, of the Ramón y Cajal University Hospital in Madrid, Spain, looked strong for T-DXd, at least with respect to the primary endpoint of progression-free survival (PFS): Median PFS was not reached for the T-DXd cohort after a median follow-up of 16.2 months compared with 6.8 months and 15.3 months, respectively, for the T-DM1 group. Additionally, the 12-month PFS rate was 75.8% with T-DXd and 34.1% with T-DM1, yielding a remarkably low hazard ratio of 0.28 (P = 7.8 × 10⁻²²).

Whether PFS will directly correlate with overall survival (OS), which was not mature at the time of this interim analysis, remains unclear, so continued study will need to ascertain whether the T-DXd's longer PFS translates into an OS benefit. Nevertheless, experts unaffiliated with the trial expressed excitement about the T-DXd data. “The efficacy for T-DXd in this randomized trial is unprecedented,” said Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center in New York, NY.

Safety and toxicity data eased fears about T-DXd's potential to cause lung damage, which was documented in phase II trials. In the DESTINY-Breast03 trial, this adverse event was, as expected, more pronounced with T-DXd than T-DM1. However, no grade 4 or 5 lung toxicity occurred, perhaps due to the selection of a different patient population—or increased awareness of T-DXd–associated lung toxicity and its management.

“If the efficacy is impressive, I would say the safety from DESTINY [-Breast]03 is reassuring,” Modi said. However, the mechanism of lung toxicity remains poorly understood, and whether it's safe to resume T-DXd treatment after the side effect has manifested and been treated is not known. “This implies, of course, that vigilance and early intervention is required to deliver T-DXd safely,” Modi added.

“In my opinion, these data support that T-DXd can be the standard of care for second-line, HER2-positive metastatic breast cancer,” Cortés said. Expanding on these findings, studies of T-DXd are proliferating, with one new trial—DESTINY-Breast09—comparing T-DXd with pertuzumab, and trastuzumab plus docetaxel, the current standard-of-care first-line regimen. –Nicole Haloupek

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