Regulatory news / Area Oncology
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
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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
- Median TTNT from ADC1 and ADC2
- ADC 1:
- 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
- This analysis indicates that TTNT (time to next treatment) is similar for the first and second ADC used, irrespective of HR-status
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
- 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
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