No new safety signals were observed with fam-trastuzumab deruxtecan-nxki (Enhertu) for patients with HER2-positive unresectable or metastatic breast cancer, reinforcing the established risk-benefit profile of the agent, according to a safety follow-up analysis of the randomized phase 3 DESTINY-Breast03 study (NCT03529110) presented at the 2022 ASCO Annual Meeting.1
The label for trastuzumab deruxtecan was updated by the FDA in May 2022, based on superiority for the agent compared with ado-trastuzumab emtansine (Kadcyla) in the DESTINY-Breast03 study.two In the primary analysis, the median progression-free survival (PFS) was not yet reached with trastuzumab deruxtecan compared with 6.8 months for trastuzumab emtansine, which equated to a 72% reduction in the risk of progression or death with the novel antibody-drug conjugate (HR, 0.28; 95% CI, 0.22-0.37; P <.0001). The 12-month PFS rate was 75.8% with trastuzumab deruxtecan vs 34.1% with trastuzumab emtansine.
“Most treatment-emergent adverse events [TEAEs] were grade 1 or 2, and exposure-adjusted incidence rates of grade 3 or greater, TEAEs, and serious TEAEs were lower with trastuzumab deruxtecan than trastuzumab emtansine,” lead investigator Erika P. Hamilton, MD, from the Sarah Cannon Research Institute/Tennessee Oncology, said during a presentation of the safety results. “The risk of nausea, vomiting, fatigue, and alopecia was higher for trastuzumab deruxtecan and occurred in initial treatment cycles.”
In the DESTINY-Breast03 study, patients were randomized 1:1 to receive either trastuzumab deruxtecan (n = 257) or trastuzumab emtansine (n = 261). Efficacy data from the study was from a primary data cutoff of May 21, 2021, while the updated safety findings were from a cutoff of September 7, 2021. At this update, the median treatment duration was 16.1 months for trastuzumab deruxtecan vs 6.9 months for trastuzumab emtansine. Findings from the initial analysis were published in the New England Journal of Medicine.3
Patient characteristics were balanced between arms in the study. In the trastuzumab deruxtecan arm, the median age of patients was 54.3 years and the majority were Asian (58.2%). HER2 status was most commonly 3+ (89.7%) and the ECOG performance status was split between 0 (59%) and 1 (40.6%). The hormone receptor status was evenly positive (50.2%) and negative (49.8%) among patients in the trial. A quarter of patients (23.8%) had stable brain metastases and more than two-thirds had visceral disease (70.5%). The median number of prior lines of therapy was 1 (range, 0-16) for trastuzumab deruxtecan and 2 (range, 0-14) for trastuzumab emtansine.
At the safety update, 54.9% of patients had discontinued trastuzumab deruxtecan and 85.1% had discontinued trastuzumab emtansine. Any-grade TEAEs were experienced by 99.6% of those in the trastuzumab deruxtecan arm and by 95.4% treated with trastuzumab emtansine, with grade 3 or greater TEAEs experienced by 53.3% and 49.8% for each treatment, respectively. Serious TEAEs of any grade were experienced by 21% of patients treated with trastuzumab deruxtecan and for 19.2% of those receiving trastuzumab emtansine, with grade 3 or greater serious TEAEs seen in 15.2% and 14.6% of patients for each treatment, respectively.
TEAEs associated with drug discontinuation were experienced by 14.8% of those treated with trastuzumab deruxtecan and for 7.3% of those in the trastuzumab emtansine arm. TEAEs led to a dose reduction for 23.0% and 13.8% of patients in the trastuzumab deruxtecan and the trastuzumab emtansine arms, respectively.
“Rates of TEAEs both any grade, grade 3 or higher, or serious TEAEs were similar between arms,” said Hamilton. “The most common TEAE associated with drug discontinuation for trastuzumab deruxtecan was interstitial lung disease [ILD]/pneumonitis in approximately 8% of patients, and the most common TEAE associated with discontinuation for trastuzumab emtansine was thrombocytopenia.”
The safety update analyzed exposure-adjusted incidence rates (EAIRs) for TEAEs. The treatment duration in each arm equated to 327.2 patient-years of exposure for trastuzumab deruxtecan and 186.3 patient-years of exposure for trastuzumab emtansine. The EAIRs for trastuzumab deruxtecan and trastuzumab emtansine arms, respectively, were 0.42 and 0.70 for grade 3 or greater TEAEs, 0.17 and 0.27 for serious TEAEs of any grade, 0.12 and 0.20 for grade 3 or more serious TEAEs, 0.12 and 0.10 for TEAEs associated with drug discontinuation, and 0.18 and 0.19 for TEAEs associated with dose reduction.
“EAIRs are a commonly used measure to express risk in patients for studies with long-term follow-up where treatment duration between arms may differ,” said Hamilton. “EAIRs per patient-year were lower in the trastuzumab deruxtecan arm than the trastuzumab emtansine arm, except for TEAEs associated with drug discontinuation, which were primarily driven by the ILD and pneumonitis in the trastuzumab deruxtecan arm.”
The most common drug-related TEAEs of any grade for trastuzumab deruxtecan and trastuzumab emtansine, respectively, were nausea (73.5% vs 27.6%), fatigue (45.9% vs 29.1%), vomiting (44.4% vs 5.7%), neutropenia (43.2 % vs 11.5%), alopecia (37.7% vs 2.7%), anemia (31.9% vs 14.2%), leukopenia (30.7% vs 8.0%), decreased appetite (26.5% vs 13.0%), thrombocytopenia (25.3% vs 52.5% ), diarrhea (23.7% vs 4.2%), and constipation (23.3% vs 9.6%). The most common grade 3 or greater drug-related TEAEs were neutropenia (19.8% vs 3.1%), thrombocytopenia (7.4% vs 24.9%), leukopenia (6.6% vs 0.8%), nausea (6.6% vs 0.4%), anemia ( 6.2% vs. 4.2%), and fatigue (6.2% vs. 0.8%).
The median time to a TEAE that was associated with treatment discontinuation was 224 days with trastuzumab deruxtecan compared with 147 days for trastuzumab emtansine. The median time for a TEAE associated with first dose reduction was 96 days with trastuzumab deruxtecan vs 19 days with trastuzumab emtansine. First event remained later consistently with trastuzumab deruxtecan vs trastuzumab emtansine, except for fatigue (22 vs 24 days, respectively), leukopenia (74.5 vs 92.0 days), neutropenia (64.0 vs 105.0 days), nausea (2.0 vs 3.0 days), and alopecia (27.0 vs. 43.0 days).
The risk of nausea, vomiting, and alopecia was significantly higher with trastuzumab deruxtecan compared with trastuzumab emtansine while the risk of fatigue was found to be similar between groups. The prevalence of fatigue and alopecia remained consistent in the study. Nausea and vomiting prevalence were both consistently higher with trastuzumab deruxtecan throughout the DESTINY-Breast03 study and were consistent over time. Most of the nausea and vomiting events were grade 1 or 2 in severity and resolved. One patient discontinued due to vomiting.
“At the time of DESTINY-Breast03 opening enrollment, there was no mandatory prophylaxis for nausea or vomiting on the study,” Hamilton said. “Anti-emetic prophylaxis recommendations were updated during the study, based on emerging data supporting the moderately emetogenic potential of trastuzumab deruxtecan. This is also now included in the drug’s label.”
Adjudicated drug-related ILD or pneumonitis of any grade occurred in 10.9% and 1.9% of those treated with trastuzumab deruxtecan or trastuzumab emtansine, respectively. These were primary low grade and there were no cases of grade 4 or 5 ILD/pneumonitis. The time to onset of ILD/pneumonitis was 181 days with trastuzumab deruxtecan and trastuzumab emtansine. There was 1 fatal case of ILD/pneumonitis in the trastuzumab emtansine arm and none with trastuzumab deruxtecan. There were 8 cases of unresolved ILD/pneumonitis in the trastuzumab deruxtecan arm and none with trastuzumab emtansine. The remaining cases were recovering/resolving, resolved/recovered, or resolved/recovered with sequelae.
“There were no new grade 3 events observed in the safety update, with the rate remaining low at 0.8%. The only new case of adjudicated drug-related ILD/pneumonitis was 1 event that was grade 2 in the trastuzumab deruxtecan arm,” said Hamilton. “The majority of these cases resolved with ongoing follow-up.”
1. Hamilton EP, Bragaia HPV, Yeo W, et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive (HER2+) unresectable and/or metastatic breast cancer (mBC): Safety follow-up of the randomized, phase 3 study DESTINY -Breast03. J Clin Oncol. 2022;40(suppl 16):1000. doi:10.1200/JCO.2022.40.16_suppl.1000
2. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. FDA. May 4, 2022. Accessed June 4, 2022. https://bit.ly/3ybhZLL
3. Cortes J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):1143-1154. doi:10.1056/NEJMoa2115022