Real world data analysis on ADC sequencing showed that time to next treatment is similar for the first and second ADC used, irrespective of HR-status. However, with limited data, no definitive conclusions can be drawn yet

Sequencing antibody-drug conjugates (ADCs) in patients (pts) with HER2-negative (HER2-) metastatic breast cancer (MBC). - (Abstract #213P; Morganti et al.)

Real world data analysis on ADC sequencing showed that time to next treatment is similar for the first and second ADC used, irrespective of HR-status. However, with limited patient numbers (N=62), no definitive conclusions can be drawn highlighting the need for well controlled, prospective studies on this topic. 

• Assessment
  • This analysis indicates that TTNT (time to next treatment) is similar for the first and second ADC used, irrespective of HR-status
    • Interestingly, in this real-world dataset, TROP2-targeting ADCs were predominately sequenced before HER2-targeting ADCs, potentially due to high number of TNBC patients in the data set
  • These conclusions appear to differ from a series of RWD presented at SABC 2023 which showed efficacy consistently decreased for the 2nd ADC
    • This highlights the heterogeneity of responses increasing the need to better understand ADC resistance and the effect of sequential use of ADCs
  • Study Information 
    • Real world study of patients with HER2- mBC who received ≥2 ADCs and had ≥6mo follow-up at Dana-Farber Cancer Institute between Jun 2014 and Jan 2023
      • N = 62
      • At ADC1 start: 29 were triple negative (12 HER2-low) and 33 HR+ (12 HER2-low)
      • Median 1L of chemotherapy prior to ADC1
    • DNADX: pre- and post-treatment plasma were retrieved from 38 patients; tumor fraction was inferred and the association between DNADX 5-class subtype classification (X0, X1, X2, X3, X4) and outcomes was investigated
    • mFU: 23.1mo
    • ADC Treatment Distribution:
      • ADC 1:
        • Anti-TROP2-TOPi: 65%
        • Anti-HER2-TOPi: 23%
        • nonHER2/nonTROP2-microtublin inhibitor (MI): 13%
      • ADC2:
        • Anti-TROP2-TOPi: 31%
        • Anti-HER2-TOPi: 66%
        • nonHER2/nonTROP2-microtublin inhibitor (MI): 3%
      • 26pts had consecutive ADCs, while 36pts had 1-5 intervening treatments
        • Post ADC1 Regimens: chemotherapy (67%), targeted therapy (11%), IO + chemotherapy (8%), chemotherapy + targeted therapy (6%), other (8%)
      • Outcomes
        • Median TTNT from ADC1 and ADC2
          • Overall Population: 4.3mo and 5.4mo
          • HR+ mBC: 4.7mo and 5.6mo
          • TNBC: 4.1mo and 5.3mo
        • Median TTNT-postADC1: 4.4mo
          • Did not differ if treatment postADC1 was an ADC or other therapy
        • DNADX Analysis
          • Distribution of tumor fraction did not differ across timepoints and across clusters (after excluding X0)
          • DNADX clusters were associated with OS, but neither with TTNT from ADC1 nor with TTNT from ADC2

Special symposium highlighted the complexity of ADC resistance with examples of potential resistance mechanisms for T-DXd and Trodelvy discussed. - (Special Symposium; Lorusso et al.)

• The ADC clinical landscape was noted to be dominated by TOPO1i ADCs with 6 targets (TROP2, HER2, B7H3, HER3, CLDN18.2, and FRα) making up >50% of the programs
  • It was questioned whether these ADCs could be sequenced or if the ADC payload would dictate resistance to subsequent ADCs
• Due to the complexity and multiple components of ADCs, mechanisms of resistance were emphasized to be extremely complicated
  • For example, resistance may be patient/tumor specific with multiple resistance mechanism for the same ADCs
  • ADC resistance is potentially associated with the mechanisms surrounding: binding of ADC to target, receptor-mediated ADC internalization, lysosomal degradation of ADC/payload release, payload escape to cytosol, cytotoxic action of payload as well as cancer cell death by apoptosis
• Published data from the P2 DAISY trial suggests T-DXd resistance may be associated with SLX4 mutations, downregulation of HER2-expression and T-DXd uptake
• In reference to Trodelvy resistance, the speaker discussed data suggesting a connection to TOP1 and TROP2 mutations
  • RWD on Trodelvy and T-DXd sequencing from the A3 study (ASCO 2023, SABCS 2023) were outlined with no hard conclusions drawn as to which ADC to use first   
    • Data from AACR 2024 was highlighted where, in a cohort of 4 patients treated with Trodelvy followed by other TOPO-1i-payload ADCs, patients developed TOP1 mutations at time of Trodelvy progression with little therapeutic benefit from second ADC
  • A research briefing on a case study of a TNBC patient with Trodelvy resistance showed that the patient had a TOP1 and a TROP2 mutation on two separate metastatic sites
    • The speaker emphasized how this case study highlights the complexity of ADC resistance as one patient had two totally different molecular alterations associated with two separate components of an ADC
  • Combination approaches were the main method of overcoming ADC resistance discussed; these include ADC combinations with TKIs, statins, ICIs and DNA-damaging agents