Investigating the Optimal Sequential Strategies for Antibody–Drug Conjugate Treatment in Metastatic Breast Cancer
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
The optimal sequential strategy for antibody-drug conjugates (ADCs) in breast cancer remains uncertain. This study aimed to evaluate the efficacy and potential resistance of second ADC (ADC2) following the first ADC (ADC1) in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low MBC.
METHODS
This retrospective, multicenter, real-world study enrolled patients with MBC who received at least 2 different types of ADCs in 3 hospitals in China between July 1, 2017 and May 1, 2023. Outcomes included the objective response rate (ORR) for ADC1 and ADC2, progression free survival 2 (PFS2), defined as the time from initiation of ADC2 to progression, and overall survival (OS).
RESULTS
Seventy-nine female patients were included, 64 of whom had HER2-positive disease. The ORR for ADC2 with similar payload of ADC1 was found to be 5.3%. When switching to a different payload, the ORR of ADC2 increased to 22.6%. The PFS2 for ADC2 remained similar regardless of whether the payload was similar or different. Switching to different payload showed a higher ORR in patients with rapid progression and a durable response longer than 6 months (41.2% vs 15.0%). Specifically, significantly longer PFS2 and OS were seen in patients treated with trastuzumab deruxtecan (T-Dxd) compared to those treated with disitamab vedotin (RC48) after progression from trastuzumab emtansine (T-DM1; median PFS2 5.37 months vs 3.30 months, HR = 0.40, 95% CI 0.17-0.93, P = .034; median OS 50.6 months vs 20.2 months, HR = 0.27, 95% CI 0.08-0.91, P = .034). For patients who progressed after T-Dxd, the median PFS2 was 6.05 months for those treated with RC48 versus 0.93 months for those treated with T-DM1 (HR = 0.03, 95% CI 0.002-0.353, P = .0093). Genomic analysis revealed that alternation of retinoblastoma1 was significantly associated with superior PFS.
CONCLUSION
The alternation of payload achieves different responses in different settings. T-Dxd followed by RC48 may be a potentially beneficial strategy in HER2-positive disease. Further research is needed to elucidate the mechanism of cross-resistance.
Click on any of these tags to subscribe to Topic Alerts. Once subscribed, you can get a single, daily email any time PracticeUpdate publishes content on the topics that interest you.
Visit your Preferences and Settings section to Manage All Topic Alerts
Additional Info
Disclosure statements are available on the authors' profiles:
Optimal Sequential Strategies for Antibody-Drug Conjugate in Metastatic Breast Cancer: Evaluating Efficacy and Cross-Resistance
Oncologist 2024 Apr 04;[EPub Ahead of Print], M Chen, R Huang, R Chen, F Pan, X Shen, H Li, Q Rong, X An, C Xue, Y ShiFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The introduction of antibody–drug conjugates (ADCs) has revolutionized the treatment of metastatic breast cancer and resulted in impressive improvements in both progression-free survival (PFS) and overall survival outcomes across breast cancer subtypes.1–4 However, the efficacy of ADCs in sequence is not well-understood.
This retrospective, multicenter, real-world study evaluated the efficacy of sequential use of ADCs among 79 patients treated at three hospitals in China who received at least two ADCs between July 2017 and May 2023. Most patients (64/79; 81.0%) had HER2-positive metastatic breast cancer. The authors evaluated the objective response rate, PFS, and overall survival associated with the first ADC (ADC1) and second ADC (ADC2) and specifically looked at the outcomes in cases with the same payload versus a switch in the payload. They found that the objective response rate for ADC2 was 5.3% with the same payload, compared with 22.6% with a switch in the payload; however, PFS2 was similar regardless of whether or not there was a switch in the payload. After progression on trastuzumab emtansine, patients who received trastuzumab deruxtecan (T-DXd) survived longer than those treated with disitamab vedotin. Interestingly, in patients who were first treated with disitamab vedotin, PFS2 was similar for T-DXd and trastuzumab emtansine after progression. Genomic analyses revealed that alterations in RB1 were significantly associated with better PFS outcomes.
This study's findings add to existing retrospective data on the sequential use of ADCs. Other multicenter retrospective data on the sequential use of ADCs have shown that most patients have a longer response to ADC1 than ADC2; however, there are some patients with a longer response to ADC2 than ADC1.5–6 It is critical to identify biomarkers that can better predict response and resistance to ADCs, which can potentially inform optimal sequencing. Prospective trials that include biomarker analyses are planned, including TRADE-DXd, which evaluates T-DXd followed by datopotamab deruxtecan or vice versa (principal investigator [PI], Ana Garrido–Castro); SERIES, which evaluates T-DXd after sacituzumab govitecan (PI, Reshma Mahtani); and a prospective registry study of sacituzumab govitecan followed by T-DXd or vice versa (PI, Laura Huppert).
References