ER-low Expressors Experience Benefit With Trastuzumab Deruxtecan in DESTINY-Breast04 Subgroup Analysis

Fam-trastuzumab deruxtecan-nxki was associated with better efficacy outcomes compared with treatment of physician’s choice in patients with HER2-low, estrogen receptor-low metastatic breast cancer, according to findings from a subgroup analysis of the phase 3 DESTINY-Breast04 study.

Fam-trastuzumab deruxtecan-nxki (Enhertu) was associated with better efficacy outcomes compared with treatment of physician’s choice (TPC) in patients with HER2-low, estrogen receptor (ER)–low metastatic breast cancer, according to findings from a subgroup analysis of the phase 3 DESTINY-Breast04 study (NCT03734029). The data, which were presented at the 2023 ESMO Breast Cancer Congress, also showed that these results were comparable with those reported among patients with ER-negative disease.1

Patients were stratified in each treatment arm as ER-negative (immunohistochemistry [IHC] expression 0%) or ER-low (IHC 1%-10%). The median progression-free survival (PFS) for patients with ER-negative disease was 8.5 months (95% CI, 4.3-11.7) in the trastuzumab deruxtecan arm (n = 40) vs 2.9 months (95% CI, 1.4-5.1) in the TPC arm (n = 18; HR, 0.46; 95% CI, 0.24-0.89). For patients with ER-low disease the median PFS was 8.4 months (95% CI, 5.6-12.2) in the investigative arm (n = 35) vs 2.6 months (95% CI, 1.2-4.6) in the control arm (n = 17; HR, 0.24; 95% CI, 0.12-0.48).1

“We know that there is a small proportion of breast cancer that expression ER but at low levels, IHC between 1% and 10% is the threshold we’ve taken for this subanalysis, but we recognize that ER expression is not black or white it is a continuum,” David A. Cameron, MD, said in a presentation of the data. “Up until now we’ve taken the FDA/ASCO-CAP guideline cutoff of 1% to define ER-positive disease, though it is interesting that in recent endocrine adjuvant trials many of the sponsors are shifting the cutoff to 10%. These tumors with ER levels between 1% and 10% have a tendency to behave more like triple-negative breast cancer than those cancers which have high levels of ER expression. this gives us the potential to have 3 levels of ER—negative, low 1% to 10% by IHC, and positive—in just the same way that DESTINY-Breast04 has shown that we can do the same for HER2.”

Cameron, who is a professor of medical oncology at the University of Edinburgh in Scotland, explained that investigators went back into the published data set to look at the outcomes of cancers with ER-low disease.

The median overall survival (OS) for patients with ER-negative disease was 18.2 months (95% CI, 13.6-not estimable [NE]) vs 8.3 months (95% CI, 5.6-20.6) in the trastuzumab deruxtecan and TPC arms, respectively (HR, 0.48; 95% CI, 0.24-0.95). The median OS in those with ER-low disease was 20.0 months (95% CI, 13.5-NE) vs 10.2 (95% CI, 7.8-14.5), respectively (HR, 0.35; 95% CI, 0.16-0.75).1

Response rates were also assessed in the subgroup analysis. Among patients with ER-negative disease who received trastuzumab deruxtecan the objective response rate (ORR) was 50% (95% CI, 33.8%-66.2%) compared with 16.7% (95% CI, 3.6%-41.4%) with TPC. For those with ER-low disease, the ORR rates were 57.1% (95% CI, 39.4%-73.7%) vs 5.9% (95% CI, 0.1%-28.7%) in the investigative and control arms, respectively.1

Eligible patients had received prior chemotherapy and were randomly assigned to receive treatment trastuzumab deruxtecan or TPC (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). Findings from the study were published in the New England Journal of Medicine and included the ER-negative cohort analysis in the supplemental material, Cameron explained.2 Trastuzumab deruxtecan was subsequently approved based on the original data for patients with HER2-low disease metastatic breast cancer.3

Once stratified for ER expression, baseline characteristics differed in prior therapies and metastases. In the ER-negative cohort, 2 patients (5%) in the trastuzumab deruxtecan arm and no patients in the TPC arm received prior CDK4/6 inhibitors compared with 22 patients (62.9%) and 9 patients (52.9%) of patients with ER-low disease in the investigative and control arms, respectively.1

“There some differences as you might expect,” Cameron explained of the baseline characteristics for the subgroup analysis. “These patients express ER, so many of us will use CDK4/6 and they had slightly less prior chemotherapy at 1 line in the majority rather than 2 for the truly triple negative.”

More patients in the ER-negative cohort had 2 lines of prior chemotherapy (60% in the trastuzumab deruxtecan arm and 72.2% in the TPC arm) compared with the ER-low cohort (40.0% and 52.9%, in the investigative and control arms, respectively).1

Progesterone receptor expression among patients in the ER-low cohort receiving trastuzumab deruxtecan was as follows: 1% to 10% of PR staining positive (57.1%), PR staining greater than 10% (11.4%), negative (31.4%). These rates were 23.5%, 17.6%, and 58.8% in the TPC arm.

Baseline liver and central nervous system (CNS) metastases were in the ER-negative cohort for the trastuzumab deruxtecan arm were 47.5% and 12.5%, respectively. In the TPC arm these rates were 27.8% and 5.6%. In the ER-low cohort, liver metastases and CNS metastases in the trastuzumab deruxtecan arm were reported in 65.7% and 2.9% of patients, respectively. In the TPC arm of this cohort, the rates were 47.1% and 11.8%, respectively.1

Safety outcomes were consistent with the primary analysis and thus a merged dataset for ER-low and ER-negative populations for both arms were presented, Cameron explained.

The median duration of treatment in the trastuzumab deruxtecan arm was 8.2 months (range, 0.2-33.3). Patients in this arm (n = 75), experienced adverse events (AEs) of grade 3 or higher at a rate of 53.3%. The most common any-grade AEs in the trastuzumab deruxtecan arm included nausea (77.3%), vomiting (40.0%), fatigue (37.3%), decreased appetite (34.7%), alopecia (33.3%), constipation (33.3%), diarrhea (29.3%), anemia (30.7%), aspartate aminotransferase (AST) increased (26.7%), alanine aminotransferase (ALT) increased (18.7%), white blood cell count decreased (18.7%), and neutrophil count decreased (14.7%).1

Grade 3 AEs in the trastuzumab deruxtecan arm included nausea (4.0%), vomiting (1.3%), fatigue (8.0%), decreased appetite (1.3%), diarrhea (2.7%), anemia (10.7%), AST increased (5.3%), ALT increased (4.0%), white blood cell count decreased (5.3%), and neutrophil count decreased (2.7%).

The median treatment duration in the TPC arm (n = 32) was 3.5 months (range, 0.3-17.6) and 75.0% of patients had an AE of grade 3 or higher. In the TPC arm these AEs occurred as follows: nausea (34.4%), vomiting (21.9%), fatigue (40.6%), decreased appetite (25.0%), alopecia (31.3%), constipation (21.9%), anemia (34.4%), diarrhea (21.9%), AST increased (28.1%), ALT increased (21.9%), white blood cell count decreased (31.8%), and neutrophil count decreased (38.1%). Grade 3 AEs included fatigue (9.4%), decreased appetite (3.1%), anemia (3.1%), diarrhea (3.1%), white blood cell count decreased (25.0%), and neutrophil count decreased (25.0%).1

References

  1. Cameron DA, Jacot W, Yamashita T, et al; DESTINY-Breast04 Investigators. DESTINY-Breat04 subgroup analyses of trastuzumab deruxtecan vs treatment of physician’s choice in patients with HER2-low, estrogen-receptor expression immunohistochemistry 0-10% metastatic breast cancer. Presented at: 2023 European Society for Medical Oncology Breast Cancer Congress; May 11-13, 2023; Berlin, Germany.
  2. Modi S, Jacot W, Yamashita, et al; DESTINY-Breast04 Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690
  3. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. FDA. August 5, 2022. Accessed May 12, 2023. bit.ly/3zGfOPt