DESTINY-Breast04 Subgroup Analysis Confirms Trastuzumab Deruxtecan Benefit in HER2-low Metastatic Breast Cancer

Patient history and disease characteristics did not affect outcomes for patients with metastatic HER2-low breast cancer who received fam-trastuzumab deruxtecan-nxki (Enhertu) in the DESTINY-Breast04 study (NCT03734029), according to a subgroup analysis presented at the 2022 San Antonio Breast Cancer Symposium.¹

Benefit was observed with trastuzumab deruxtecan across all prespecified subgroups included in the analysis for progression-free survival (PFS) and overall survival (OS). The included HER2 status by immunohistochemistry (IHC), prior lines of chemotherapy, prior CDK4/6 inhibitor treatment, age, and baseline central nervous system (CNS) metastases. PFS, objective response rate (ORR), and safety findings were included in the poster presentation.¹

A total of 373 patients received trastuzumab deruxtecan 5.4 mg/kg every 3 weeks and 184 were treated with treatment of physician’s choice (TPC). Outcomes for the overall population of DESTINY-Breast04 have been previously reported.²

Among patients with hormone receptor–positive disease who received prior treatment with a CDK4/6 inhibitor the HR for disease progression was 0.55 (95% CI, 0.42-0.74) and 0.42 (95% CI, 0.28-0.64) for those who did not have prior CDK4/6 treatment. The median PFS for trastuzumab deruxtecan vs TPC in the CDK4/6 inhibitor group was 10.0 months vs 5.4 months and 11.7 months vs 5.9 months for those without prior CDK4/6 inhibition.¹

Among those with low disease burden, the median PFS was 11.4 months with trastuzumab deruxtecan vs 5.1 months with TPC (HR, 0.41; 95% CI, 0.30-0.58). For those with high disease burden the median PFS was 9.5 months vs 4.8 months (HR, 0.58; 95% CI, 0.43-0.78).

Twenty-two patients had rapid progression defined as disease progression within 6 months of concluding prior chemotherapy in early breast cancer. The median PFS among patients who received trastuzumab deruxtecan (n = 14) was 8.2 months vs 2.2 months for those who received TPC (n = 8; HR, 0.38; 95% CI, 0.12-1.21). The benefit was also observed among those who did not have rapid progression with a 49% reduction in the risk of disease progression for those who received trastuzumab deruxtecan vs TPC (HR, 0.51; 95% CI, 0.41-0.64). The median PFS for these patients was 9.9 months vs 5.3 months, respectively.

Those with IHC 1+ disease who received trastuzumab deruxtecan had a median PFS of 10.0 months vs 4.8 months with TPC (HR, 0.48; 95% CI, 0.36-0.63). For those with IHC 2+/in situ hybridization-negative disease the median PFS was 9.9 months vs 5.1 months, respectively (HR, 0.55; 95% CI, 0.39-0.76).¹

Patients age 65 years or older had a median PFS of 11.4 months with trastuzumab deruxtecan vs 6.2 months with TPC (HR, 0.57; 95% CI, 0.36-0.89) and those younger than 65 years had a median PFS of 9.8 months vs 4.6 months, respectively (HR, 0.47; 95% CI, 0.37-0.61). Patients receiving 1 prior line of chemotherapy saw a 48% reduction in the risk of death with trastuzumab deruxtecan (HR, 0.52; 95% CI, 0.39-0.70). The median PFS for trastuzumab deruxtecan vs TPC for these patients was 10.1 months vs 6.4 months, respectively. For those who received 2 prior lines of chemotherapy the median PFS with trastuzumab deruxtecan was 9.7 months vs 4.2 months (HR, 0.49; 95% CI, 0.35-0.68).

A 29% reduction in the risk of disease progression or death was observed with trastuzumab deruxtecan compared with TPC among patients who had baseline CNS metastases (n = 32; HR, 0.71; 95% CI, 0.28-1.80). The median PFS for patients who received trastuzumab deruxtecan was 8.1 months vs 4.8 months with TPC. For those without baseline CNS metastases, a 51% reduction in the risk of disease progression or death was observed (HR, 0.49; 95% CI, 0.39-0.62). The median PFS was 10.1 months vs 5.1 months with trastuzumab deruxtecan and TPC, respectively.¹

Finally, for those who did and did not receive prior anthracycline treatment the HRs also favored trastuzumab deruxtecan vs TPC at 0.53 (95% CI, 0.40-0.70) and 0.46 (95% CI, 0.32-0.66).

Objective response rate data were also reported across subgroups for trastuzumab deruxtecan vs TPC as follows¹:

CDK4/6 inhibitor use
Yes: 50.6% vs 13.0%
No: 58.3% vs 25.5%

Disease burden
Low: 54.0% vs 15.3%
High: 51.1% vs 17.2%

Rapid progression
Yes: 50.0% vs 0%
No: 52.4% vs 17.0%

HER2 IHC status
IHC 1+: 49.1% vs 16.8%
IHC 2+/ISH–: 56.6% vs 15.6%

Prior lines of chemotherapy
1: 51.1% vs 19.0%
2: 56.6% vs 13.3%

Age
< 65 years: 53.8% vs 14.7%
≥ 65 years: 47.0% vs 20.8%

Baseline CNS metastases
Yes: 55.0% vs 25.0%
No: 51.1% vs 15.9%

Prior anthracycline treatment
Yes: 51.9% vs 16.6%
No: 53.0% vs 12.7%

Safety profiles for patients who did and did not receive CDK4/6 inhibitors and for patients with low and high disease burden were reported and were consistent across patients. For patients who received prior CDK4/6 inhibitors, the rate of grade 3 or higher adverse effects (AEs) was 49.8% with trastuzumab deruxtecan vs 66.1% with TPC. For those who did not receive prior CDK4/6 inhibition, these rates were 57.1% vs 67.4%, respectively.¹

The rates of ILD were 12.4% and 11.2% with trastuzumab deruxtecan for those who received and did not receive CDK4/6 inhibitors, respectively.

For patients with low disease burden the rate of grade 3 or higher treatment-emergent AEs was 55.0% vs 67.9% with trastuzumab deruxtecan and TPC, respectively. Among those with high disease burden these rates were 50.9% vs 67.0%, respectively. Rates of ILD with trastuzumab deruxtecan in the low tumor burden and high tumor burden subgroups was 12.8% and 12.2%, respectively.¹

Investigators noted that a safety analysis for those with rapid progression was not conducted due to small sample size.¹

References

1. Harbeck N, Modi S, Jacot W, et al. Trastuzumab deruxtecan vs treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: subgroup analyses from DESTINY-Breast04. Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.
2. Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690