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With multiple ADCs available, an emerging sequencing strategy is to alternate between different mechanisms of action, such as following a microtubule toxin-based ADC with a topoisomerase-1 inhibitor payload. This approach aims to avoid compounding specific toxicities, like neuropathy, and potentially circumvent resistance, though it is a strategy born from logic rather than clinical trial data.
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Early clinical trial data suggests that topoisomerase-1 payload ADCs retain efficacy in patients previously treated with mirvetuximab. Because mirvetuximab has a different cytotoxic payload, this indicates that targeting the same receptor (FR-alpha) with a different type of toxin is a viable sequencing strategy.
Data from a novel Nectin-4 ADC trial showed zero responses in patients with prior topoisomerase therapy. This strongly suggests that payload resistance, not just the ADC target, is a critical mechanism that will dictate future treatment sequencing.
The modern pipeline of antibody-drug conjugates in solid tumors has largely moved away from older microtubule toxin payloads (like DM4 or MMAE). The majority of ADCs currently in development, and the focus of clinical excitement, utilize camptothecin-based payloads, specifically topoisomerase-1 inhibitors like deruxtecan, reflecting a major technological evolution in the field.
When sequencing antibody-drug conjugates, clinical experience suggests that resistance to the chemotherapy payload is a primary driver of failure. Therefore, oncologists tend to avoid using another ADC with the same payload consecutively, preferring to switch both target and payload if possible.
When planning treatment for patients who will receive multiple antibody-drug conjugates (ADCs), the prevailing clinical strategy is to focus on alternating the drug's payload (e.g., a tubulin inhibitor vs. a topoisomerase I inhibitor). This approach is believed to be more effective at overcoming resistance than alternating the cell-surface target.
A significant clinical challenge is the sequencing of antibody-drug conjugates (ADCs). Retrospective data from large databases indicates that using a second TROP2-targeted ADC after a first one provides very limited efficacy, highlighting an urgent need for prospective trials to define optimal sequencing strategies and overcome resistance.
Rather than moving through distinct lines of therapy, a future strategy could involve an "ADC switch." When a patient progresses on an ADC-IO combination, the IO backbone would remain while the ADC is swapped for one with a different, non-cross-resistant mechanism, adapting the treatment in real-time.
Contrary to concerns about cross-resistance between HER2 antibody-drug conjugates (ADCs), retrospective data shows TDM-1 remains effective after progression on TDXD. This suggests the different cytotoxic payloads are key, allowing for effective sequencing and challenging the assumption that progression on one ADC class member precludes using another.
As multiple effective Antibody-Drug Conjugates (ADCs) become available, the primary clinical challenge is no longer *if* they work, but *how* to use them best. Key unanswered questions involve optimal sequencing, dosing for treatment versus maintenance, and overall length of therapy, mirroring issues already seen in breast cancer.
Historically, therapies for platinum-resistant ovarian cancer were so ineffective that the order of administration was irrelevant. With the advent of multiple active ADCs, the concept of treatment sequencing and potential cross-resistance based on payloads or targets has become a critical, and entirely new, clinical consideration for this disease.