Antibody-Drug Conjugates (ADCs) in Breast Cancer: Real World Analysis of Outcomes

Antibody-Drug Conjugates (ADCs) in Breast Cancer: Real World Analysis of Outcomes

Abstract #PS08-01; Raghavendra et al.

Real world analysis of patients treated with sequential ADC appears to suggest longer PFS and OS for those treated with T-DXd first; However, given the retrospective nature of the data and the disparity in patient characteristics (e.g., HER2-status, ER-status, previous lines of treatment) the conclusion is not definitive 

Key Takeaways/Potential Implications

• • The analysis indicates longer PFS and OS in HER2 low patients who received T-DXd as their first ADC, however, this difference is likely due to differing patient characteristics between the two groups
    • Additionally, while there was numeric difference in survival in patients who received different sequence of ADCs, no clear statistical difference was observed
    • This, along with the other posters highlighted the high unmet need for a well-controlled study to determine optimal sequencing and patient selection
  • ​​​​​​​Study Information
    • Real world analysis of outcomes in breast cancer patients (N=274) treated with ADCs
      • 174 pts received Trodelvy as 1^st ADC and 100 received T-DXd
      • 19pts treated with Trodelvy followed by T-DXd; 14 pts Trodelvy followed by T-DXd
      • mFU: 7.4mo
    • Clinical characteristics (T-DXd, Trodelvy as first ADC)
      • Number of prior treatments
        • 0: 9%, 18%
        • 1: 12%, 31%
        • 2: 22%, 24%
        • ≥3: 57%, 28%
      • PR status (T-DXd, Trodelvy)
        • Negative: 68%, 91%
        • Positive: 31%, 9%
      • ER status (T-DXd, Trodelvy)
        • Negative: 27%, 84%
        • Positive: 73%, 16%
      • HER2 status (T-DXd, Trodelvy)
        • HER2 0: 9%, 34%
        • HER2 +1: 55%, 41%
        • HER2 +2: 28%, 22%
        • HER2 +3: 3%, 0%
        • Pos: 2%, 0%
        • Unknown: 3%, 2%
      • Efficacy
        • mOS (T-DXd vs Trodelvy): 22.9 mo vs 16.4mo (HR: 1.73)
        • mPFS (T-DXd vs Trodelvy):  7.6mo vs 4.6mo (HR:1.57)
        • mOS in patients receiving sequential ADCs (Trodelvy -> T-DXd vs T-DXd -> Trodelvy): NE vs 13.9 mo (HR: 0.78)
        • mPFS in patients receiving sequential ADCs (Trodelvy -> T-DXd vs T-DXd -> Trodelvy): 5.5mo vs 2.4 mo (HR: 1.02)

Efficacy of Sacituzumab-Govitecan (SG) post Trastuzumab-deruxtecan (T-DXd) and vice versa for HER2-low advanced or metastatic breast cancer (MBC): a French multicenter retrospective study 

(Abstract #PS08-02; Poumeaud et al.)

A retrospective analysis from reportedly the largest cohort study evaluating efficacy of ADC sequencing in HER2-low mBC indicated the subsequent use of ADCs was associated with diminished PFS regardless of ADC administration order or HR-status; Acknowledging the limitations of the data, the authors cautiously conclude that use of T-DXd post Trodelvy may be more efficient than Trodelvy post T-DXd

• Key Takeaways/Potential Implications
  • This large, retrospective study (consistent with other studies) shows decreasing efficacy in HER2-low mBC with the 2^nd ADC following treatment with an initial ADC; This was consistent regardless of whether T-DXd or Trodelvy was administered first
    • Whether this is due to ADC-resistance or changes in the tumor due to other treatment modalities in between ADC treatments remains unclear
  • Interestingly, the authors conclude that T-DXd post Trodelvy could be more efficient than Trodelvy after T-DXd (HR:0.57); however, results are not definitive given the lack of statistical power and limited sample
    • Further studies are needed on the resistance mechanisms of both ADCs to guide therapeutic sequencing strategies
  • Study Information
    • Retrospective study in 19 French comprehensive cancer centers with the inclusion of all HER2-low mBC patients treated with Trodelvy followed (immediately or not) by T-DXd or vice versa
    • Primary objective: second ADC (ADC2) PFS
    • Secondary objective: first ADC (ADC1) progression-free interval (PFS) and OS
    • N=179
      • HR+/HER-low: N=71
      • HR-/HER2-low: N=108
      • Trodelvy -> T-DXd: N=115
      • T-DXd -> Trodelvy: N=64
    • Median line of chemo (ADC1, ADC2): 3, 5​​​​​​​
  • Efficacy
    • ADC1 mPFI -> ADC2 mPFS: 4.3mo -> 2.7mo
      • HR- pts treated with Trodelvy -> T-DXd (N=100): 4.9mo -> 3.2mo
      • HR+ pts treated with T-DXd -> Trodelvy (N=56): 2.7mo -> 2.3mo
    • mPFS with T-DXd as ADC2 vs Trodelvy as ADC2: 3.1mo vs 2.2mo
    • Multivariate Analysis
      • HR status (HR+ vs HR-): HR: 0.76
      • Therapeutic sequence (T-DXd -> Trodelvy vs Trodelvy -> T-DXd): HR: 0.57
    • Resistance to ADC:
      • Primary resistance to ADC1: 40%
      • Primary resistance to ADC2: 54% (+15pt)
        • Primary resistance: pts who have PD as best response to ADC
      • Secondary resistance to ADC1: 60%
      • Secondary resistance to ADC2: 46% (-14 pt)
        • Secondary resistance: pts who have SD or OR as best response to ADC

Sequencing Antibody-Drug Conjugate after Antibody-Drug Conjugate in Metastatic Breast Cancer (A3 study): Multi-Institution Experience and Biomarker Analysis

(Abstract #PS08-03; Abelman et al.)

In a multi-institutional, real-world study, sequential use of ADC after ADC lead to cross-resistance in a subset of patients with resistance being driven by antibody target in some versus payload in others; Additional biomarker analysis revealed candidate resistance mutations that may guide treatment

• Key Takeaways/Potential Implications
  • Updated data from the A3 study (originally presented at ASCO 2023) indicates that ADC resistance may be driven by either antibody target or payload
    • This aligns with previous expressed concerns from clinicians on sequencing ADCs with the same target and/or payload
  • Biomarker analysis using tissue sequencing data indicated that TOP variants may drive resistance to topoisomerase-I inhibitor payloads
    • However, in some cases, and as observed in other studies as well, a subset of patient appeared to also show improved survival in their 2^nd ADC, further highlighting the need for well controlled studies and the role of biomarker analysis for patient selection
  • Study Information
    • Clinicopathological assessment (from chart review) of all patients at three academic institutions treated with multiple ADCs for mBC (HER2-postive mBC excluded)
      • N= 68 (HR+/HER2-: 30, TNBC: 38, HER2-low: 50)
    • “Cross-resistance” to the second ADC: patients with progressive disease on first restaging assessment or progression within 60 days of treatment initiation
      • Every subsequent ADC beyond the first was compared against the prior ADC for presence of identical “antibody target” and “payload”
    • Median lines of treatment in metastatic setting before ADC2: 4
  • Results
    • Cross resistance: 38/64 (59%)
      • Change in Ab target, change in payload: 23/47 (49%)
      • Change in Ab target, same payload: 3/10 (30%)
      • Same Ab target, change in payload: 8/14 (57%)
      • Same Ab target, same payload: 2/3 (67%)
    • PFS
      • Trodelvy -> T-DXd:
        • HR+/HER2- (N=7): 249d -> 168d
        • TNBC (N=14): 231 days -> 84 days
      • T-DXd -> Trodelvy
        • HR+/HER2- (N=11): 147d -> 50day
        • TNBC (N=7): 42d -> 93d
      • Sequencing information was available for 20 patients who received multiple ADCs with 15 unique reports performed at the time of resistance to ADC1, prior to initiation of ADC2, or after ADC2 if presence of cross-resistance
        • Variants in topoisomerase-I associated genes (TOP1, TOP2A, TOP3A, TOP3B) were identified in a subset of patients mediating cross-resistance to the second ADC with a topoisomerase-I inhibitor payload

Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC)

(Abstract #PS08-04; Huppert et al.)

Multicenter, retrospective study data indicated ADC sequencing was associated with diminished therapeutic benefit regardless of ADC order or HR-status; however, there are a subset of patients who had a more durable response to 2^nd ADC compared to 1^st  

• Key Takeaways/Potential Implications
  • Similar to the other studies, this retrospective analysis indicates the sequential administration of ADCs in HER2-low mBC is associated with less therapeutic benefit for the 2^nd ADC
    • However, a subset of patients exhibited a more durable response to the 2^nd ADC they received versus the 1^st
  • Although the data shows a numerically greater survival when Trodelvy is used first, this benefit may be due to the patients receiving T-DXd as their first ADC being more heavily pretreated in this population
    • As ADCs advance into earlier LoT and sequential use of ADC becomes more common, additional data is needed to better understand ADC resistance, as well as optimal ADC administration order
  • Study Information
    • Multicentre, retrospective cohort study of HER2-low mBC patients receiving T-DXd and Trodelvy monotherapy (in either order, with or without intervening therapies)
    • N = 84 (HR+: 56, HR-: 28)
    • Median lines of therapy prior to ADC (HR+, HR-): 4, 2
      • Trodelvy -> T-DXd (HR+, HR-): 3.0, 2.0
      • T-DXd -> Trodelvy (HR+, HR-): 4.5, 3.0
    • Efficacy
      • HR+/HER2-low:
        • T-DXd -> Trodelvy (N=32):
          • ORR: 47% -> 19%
          • rwPFS: 5.5mo -> 2.6 mo
          • rwOS: 19.8mo -> 4.9mo
        • Trodelvy -> T-DXd (N=24):
          • ORR: 77% -> 35%
          • rwPFS: 8.0mo -> 3.7mo
          • rwOS: 22.8mo -> 7.8mo
        • HR-/HER2-low:
          • T-DXd -> Trodelvy (N=3):
            • ORR: 33% -> 0%
            • rwPFS:  undetermined
            • rwOS: undetermined
          • Trodelvy -> T-DXd (N=25):
            • ORR: 68% -> 35%
            • rwPFS: 7.8mo -> 2.8mo
            • rwOS: 16.5mo -> 6.5mo
          • Safety
            • During treatment with Trodelvy:
              • Discontinuations: 8%
              • Dose reductions: 46%
              • Received growth factor support: 61%
            • During treatment with T-DXd:
              • Discontinuations: 11%
              • Dose reductions: 16%
              • ILD diagnosis: 17%
                • Gr1-2: 8%, Gr3/4: 5%, Gr5: 4%