Trastuzumab Deruxtecan: New Standard of Care in Pretreated, Advanced Breast Cancer?

Trastuzumab deruxtecan (Enhertu) demonstrated “unprecedented” efficacy compared with trastuzumab emtansine (Kadcyla) in patients previously treated with trastuzumab and taxane for HER2-positive metastatic breast cancer, according to results from the DESTINY-Breast03 trial.

At 12 months, the estimated progression-free survival (PFS) rate for trastuzumab deruxtecan (T-DXd) was 75.8% compared with 34.1% in the trastuzumab emtansine (T-DM1) arm, with a hazard ratio of 0.2840 (95% CI 0.2165-0.3727), reported Javier Cortés, MD, of the International Breast Cancer Center, Quiron Group, in Barcelona.

The P-value at 7.8 x 10^-22 was “very highly statistically significant,” he said at a presidential symposium session at the European Society for Medical Oncology (ESMO) virtual meeting.

Median PFS was 6.8 months for patients in the T-DM1 arm, and was not reached in the T-DXd group.

“These data support T-DXd becoming the standard of care for second line HER2-positive metastatic breast cancer,” Cortés stated.

ESMO discussant Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center in New York City, called the efficacy reported in the trial “unprecedented.”

These PFS curves from DESTINY03 are absolutely startling, as is the hazard ratio of 0.28 and the P value of 10^-22,” she said. “I don’t believe I’ve seen a hazard ratio like this in HER2 breast cancer before.”

Cortés explained that T-DM1 was established as the second-line standard of care for HER2-positive metastatic breast cancer, based on the EMILIA study, which reported a PFS of 9.6 months. “In the changing treatment landscape, more recent clinical trials and real-world studies have demonstrated median PFS outcomes with T-DM1 in the range of 6 to 7 months,” he stated.

“Trastuzumab deruxtecan is an antibody-drug conjugate with a HER2 antibody, tetrapeptide-based cleavable linker, and a novel topoisomerase I inhibitor payload,” explained Modi, who was an investigator for the phase II DESTINY-Breast01 study, in Cancer Research. The agent received accelerated approval from the FDA in 2019.

In DESTINY-Breast01, more than 60% of patients achieved an objective response, with a median PFS of 19.4 months with T-DXd. Given this data, DESTINY-Breast03 was designed to evaluate T-DXd head-to-head with T-DM1, Cortés said. As of May 2021, 524 patients were randomized 1:1 to received either of the two regimens.

In addition to the aforementioned PFS results as assessed by blinded independent central review, PFS by investigator assessment showed PFS of 25.1 months in the T-DXd group and 7.2 months with T-DM1, with 12-month PFS rates of 76.3% and 34.9%, respectively (HR 0.26, 95% CI 0.20-0.35).

Improved efficacy with T-DXd persisted across all pre-defined subgroups, including hormone receptor status, prior pertuzumab (Perjeta) treatment, visceral disease, number of prior lines of therapy, and the presence or absence of brain metastases.

The estimated overall survival (OS) rate at 12 months was 94.1% in the T-DXd arm and 85.9% in the T-DM1 group (HR 0.56, 95% CI 0.36-0.86). However, OS did not reach the prespecified cutoff for statistical significance, “likely due to immature follow-up,” Cortés observed

The majority of patients in the T-DXd arm experienced a reduction in tumor size, with confirmed overall response rates of 79.7% in the T-DXd arm versus 34.2% in the T-DM1 group. Almost twice as many patients in the T-DXd arm achieved a complete response (16.1% vs 8.7%).

As for safety, the incidence of treatment-emergent adverse events (TEAEs) grade 3 or higher was similar in both groups. Drug-related TEAEs associated with treatment discontinuation or dose reduction were more common in the T-DXd group (12.8% vs 5.0%), the most common of which were interstitial lung disease (ILD)/pneumonitis, nausea, and neutropenia.

“Lung toxicity was one of the highly-anticipated outcomes from this trial,” Modi observed, considering that lung toxicity was seen in approximately 16% of patients in the DESTINY-Breast01 study, and included patients with symptomatic pneumonitis and some rare, but fatal, cases of ILD.

Cortés reported that ILD/pneumonitis was reported in 10.5% of patients treated with T-DXd. However, no grade 4 or 5 cases of ILD/pneumonitis were reported in the study, while just 0.8% of patients had grade 3 cases, he said.

“T-DXd delivered in this early-line setting was associated with less lung toxicity, resetting the risk/benefit analysis in its favor,” Modi noted. “This was a major difference from [DESTINY-Breast01], and a great relief.”