Trastuzumab Deruxtecan: New Standard of Care in Pre-Treated Advanced Breast Cancer?

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

At 12 months, the estimated progression-free survival rate (PFS) for trastuzumab deruxtecan (T-DXd) was 75.8% versus 34.1% in the trastuzumab emtansine (T-DM1) arm, with a relative risk 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 to 7.8 x 10-22 was “very highly statistically significant,” he said during a presidential symposium session at the European Society for Medical Oncology (ESMO) virtual meeting.

The median PFS was 6.8 months for patients in the T-DM1 arm, and was not achieved in the T-DXd group.

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

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 of DESTINY03 are absolutely surprising, as is the risk ratio of 0.28 and the P-value of 10-22“she said.” I don’t think I’ve seen such a risk ratio in HER2 breast cancer before. “

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

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

In DESTINY-Breast01, over 60% of patients achieved an objective response, with a median PFS of 19.4 months with T-DXd. Based on these data, DESTINY-Breast03 was designed to assess T-DXd face-to-face with T-DM1, Cortés said. As of May 2021, 524 patients were randomized 1: 1 to receive one of two treatment regimens.

In addition to the aforementioned PFS results assessed by an independent, blinded central review, the investigator’s assessment of PFS showed 25.1 months PFS in the T-DXd group and 7.2 months with the T -DM1, with 12-month PFS rates of 76.3% and 34.9%, respectively (HR 0.26, 95% CI 0.20-0.35).

Improvement in efficacy with T-DXd persisted in all predefined subgroups including hormone receptor status, previous treatment with pertuzumab (Perjeta), visceral disease, number of previous treatment lines and the presence or absence of brain metastases.

The estimated 12-month OS 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 pre-defined threshold of statistical significance, “possibly due to immature follow-up,” Cortés observed.

The majority of patients in the T-DXd arm experienced tumor size reduction, 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%).

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

“Pulmonary toxicity was one of the highly anticipated outcomes of this trial,” observed Modi, given that pulmonary toxicity was observed in approximately 16% of patients in the DESTINY-Breast01 study, and included patients with of symptomatic pneumonitis and some rare but fatal cases. , case of LTD.

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

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

  • Mike Bassett is a writer specializing in oncology and hematology. He is based in Massachusetts.

Disclosures

DESTINY-Breast03 was funded by Daiichi Sankyo and AstraZeneca.

Cortés disclosed relationships with Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, Daiichi Sankyo, Celestial, AstraZeneca, Biothea Pharmaceutical, Merus, Seattle Genetics, Erytech, Athenex, Polyphor, Lilly, Servier , GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Kyowa Kirin, MedSIR, Ariad Pharmaceuticals, Baxalta GMBH / Servier Affaires, Bayer Healthcare, Eisai, F. Hoffmann-La Roche, Guardant Health, Piqur Therapeutics, Puma C and Queen Mary University of London. The co-authors revealed multiple connections with the industry.

Modi disclosed his relationships with Novartis, Genentech, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Eli Lilly, MacroGenics and GlaxoSmithKline.


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