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

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