Regardless of Treatment Sequence, ADCs Deliver Modest Clinical Activity in Metastatic BC

Nicolas Mai, MD

Regardless of treatment sequence, the antibody-drug conjugates (ADCs) sacituzumab govitecan (Trodelvy; SG) and trastuzumab deruxtecan (Enhertu; TDXd), demonstrated modest clinical activity in patients with metastatic breast cancer (MBC), according to findings of a retrospective study in patients who were treated sequentially with both agents. Multivariable analysis showed no significant difference in ADC2 progression-free survival (PFS) by age, which agent was chosen as ADC1, or estrogen receptor (ER) status.

Findings were presented in a poster by lead author Nicholas Mai, MD, during the 2024 ASCO Annual Meeting.¹

All patients with metastatic breast cancer and who received both SG and TDXd, in any sequence, were eligible, according to Mai, a medical oncology fellow at Memorial Sloan Kettering Cancer Center, New York, NY. The objectives of the study were to determine real-world PFS, identify factors affecting longer PFS, and evaluate the effect treatment sequencing had on outcomes.

The medical charts of 85 patients in total were reviewed by investigators. It was determined that 54 patients had ER-positive MBC and 31 had triple negative breast cancer (TNBC). Thirty-three patients received SG followed by TDXd (14 ER+, 19 TNBC), and 52 received TDXd followed by SG (40 ER+, 12 TNBC).

PFS was determined clinically and analyzed using Kaplan-Meier. Univariate and multivariate associations for survival were determined using Cox-proportional hazards models.

Investigators reported longer time to treatment failure for ADC1 and earlier treatment line was significantly associated with longer ADC2 PFS. The HR for treatment lines preceding ADC2 was 1.10 (95% CI, 1.01-1.21; P = .034). The HR for ADC1 time to treatment failure was 0.94 (95% CI, 0.89-1.00; P = .044). In the poster, investigators wrote that ADC2 PFS was not notably affected by ADC sequence.

When SG was administered first, median PFS was 3.5 months (95% CI, 2.67-7.70) and when TDXd was administered first, the median PFS was 2.83 months (95% CI, 2.57-3.73). The HR was 1.69 (95% CI, 0.98-2.94; P = .06).

When differences in PFS between initial and sequential ADC therapy were stratified by individual ADC, 64 patients (75%) had a PFS of ADC2 that was shorter than that of ADC1 by a pseudo median of 2 months, according to Wilcoxon signed rank test (95% CI, –2.85 to –1.13; P ≤ .001).

Comparing SG PFS before vs after TDXd revealed that patients who received SG first had a median PFS of 5.13 months (95% CI, 3.27-7.27) and when patients received TDXd first, the median PFS was 2.83 months (95% CI, 2.57-3.73). The HR for progression or death was 2.17 (95% CI, 1.25-2.77; P = .006).

Conversely, TDXd PFS before vs after SG did not show significant PFS difference (HR, 1.25; 95% CI, 0.76-2.06; P = .038). When comparing TDXd PFS before vs after SG, patients who received SG first had a median PFS of 3.50 months (95% CI, 2.67-7.70) and those who received TDXd first had a median PFS of 4.90 months (95% CI, 3.30-5.60).

The median age of patients who received SG was 62 years (n = 33) as compared with a median age of 58 years in patients who received TDXd (n = 52). Twenty-five patients (76%) were over 50 years of age in the SG-first group compared with 43 patients (83%) in the TDXd-first group.

The majority of patients in both groups were White (SG = 64%; TDXd = 73%) followed by Asian (15%; 9.6%, respectively), and Black (15%; 12%, respectively). Overall, patients were heavily pretreated, with a median of 5 prior therapies at the time of ADC1 and 7 at the time of ADC2.

When treatment lines administered between ADC1 and ADC2 were analyzed, patients who received SG first had zero lines (42%), 1 line (36%), and 2 lines (21%), whereas patients who received TDXd first had 44%, 35%, and 21%, respectively. Among patients who received SG first, 6 patients (18%) had ADC2 treatment ongoing compared with 8 patients (15%) who received TDXd first (P = .7).

Although both SG and TDXd used sequentially after each other have significantly shorter PFS regardless of sequence, a subgroup of patients still demonstrate PFS benefit with these ADCs. The investigators recommended that continuing research should define this group to identify optimal use of these agents, noting that patients who respond well to initial ADC and who are less pretreated may have longer PFS on sequential ADC regimens.

REFERENCE:

1. Mai, N, Klar M, Ferraro E, et al. Real world outcomes of sequential ADC therapy in metastatic breast cancer: Patients treated with sacituzumab govitecan and trastuzumab deruxtecan. J Clin Oncol. 2024;42(suppl 16):1085-1085. doi:10.1200/JCO.2024.42.16_suppl.1085