Article

Trastuzumab Deruxtecan Remains Safe and Effective Option for Metastatic Breast Cancer

Author(s):

Updated data from a safety analysis of the phase 3 DESTINY-Breast03 study confirmed the tolerability of trastuzumab deruxtecan among patients with with HER2-positive unresectable or metastatic breast cancer.

Erika P. Hamilton, MD

Erika P. Hamilton, MD

Updated data from a safety analysis of the phase 3 DESTINY-Breast03 study (NCT03529110) confirmed the tolerability of fam-trastuzumab deruxtecan-nxki (Enhertu) among patients with with HER2-positive unresectable or metastatic breast cancer. The data were presented at the 2022 ASCO Annual Meeting.

At the time of the safety analysis, the median treatment duration was 16.1 months for trastuzumab deruxtecan vs 6.9 months for ado-trastuzumab emtansine (T-DM1; Kadcyla), 54.9% of patients had discontinued trastuzumab deruxtecan (n = 257) and 85.1% had discontinued T-DM1 (n = 261). Any-grade TEAEs were experienced by 99.6% of those in the trastuzumab deruxtecan arm and by 95.4% treated with T-DM1, with grade 3 or greater TEAEs experienced by 53.3% and 49.8% for each treatment, respectively.

No new safety signals were observed with trastuzumab deruxtecan for patients with HER2-positive unresectable or metastatic breast cancer, reinforcing the established risk-benefit profile of the agent.1

“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 T-DM1,” 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.”

The label for trastuzumab deruxtecan was updated by the FDA in May 2022, based on superiority for the agent compared with ado-trastuzumab emtansine (T-DM1; Kadcyla) in the DESTINY-Breast03 study.2 In the primary analysis, the median progression-free survival (PFS) was not yet reached with trastuzumab deruxtecan compared with 6.8 months for T-DM1, 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 T-DM1.

In the DESTINY-Breast03 study, patients were randomized 1:1 to receive either trastuzumab deruxtecan or T-DM1. 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. 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%) amongst 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 T-DM1.

Additional data from the safety update showed that serious TEAEs of any grade were experienced by 21% of patients treated with trastuzumab deruxtecan and for 19.2% of those receiving T-DM1, 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 T-DM1arm. TEAEs led to a dose reduction for 23.0% and 13.8% of patients in the trastuzumab deruxtecan and the T-DM1 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 T-DM1 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 T-DM1. The EAIRs for trastuzumab deruxtecan and T-DM1 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 T-DM1 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 T-DM1, 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 T-DM1. The median time for a TEAE associated with first dose reduction was 96 days with trastuzumab deruxtecan vs 19 days with T-DM1. First event remained consistently later with trastuzumab deruxtecan vs T-DM1, 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 T-DM1 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 T-DM1, 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 T-DM1. There was 1 fatal case of ILD/pneumonitis in the T-DM1arm and none with trastuzumab deruxtecan. There were 8 cases of unresolved ILD/pneumonitis in the trastuzumab deruxtecan arm and none with T-DM1. 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.”

References

  1. Hamilton EP, Bragaia VPH, 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. Cortés J, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):1143-1154. doi:10.1056/NEJMoa2115022
Related Videos
Sheldon M. Feldman, MD
Minoo Battiwalla, MD, MS
In this episode of OncChats: Empowering Community Cancer Care, Dr. Rai emphasizes the importance of community outreach and support for patients with cancer, highlighting the need for holistic care that addresses both physiological and psychological aspects of treatment while reinforcing the value of strong relationships between primary care physicians and specialists.
In this episode of OncChats: Empowering Community Cancer Care, Dr. Woodworth sheds light on the “Road to Recovery” survivorship program at Henry Mayo, which supports cancer survivors by providing them with fitness, education, and mental health resources, and underscores the importance of mentorship programs for community providers to ensure equitable cancer care.
In this episode of OncChats: Empowering Community Cancer Care, Drs Woodworth and Rai, discuss their collaborative approach to cancer screening, emphasizing the importance of community efforts and individual assessments in integrating genetic testing and screenings into routine practice.
In this episode of OncChats: Empowering Community Cancer Care, experts discuss the significance of community-based cancer care, emphasizing that most cancers are diagnosed locally and highlighting the importance of collaboration between primary care physicians and specialists to provide optimal education and treatment.
Sunil Adige, MD
Minoo Battiwalla, MD, MS
Margaret E. Gatti-Mays, MD, MPH, FACP