Data on Enfortumab Vedotin suggests that for modern therapies, maintaining patients on treatment longer via a lower, more tolerable starting dose is more important than administering the maximum labeled dose upfront, a concept inherited from the cytotoxic chemotherapy era.
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Unlike immunotherapy, where re-challenge after progression is dubious, there is an emerging clinical practice of re-challenging patients with the same antibody-drug conjugate (ADC), such as enfortumab vedotin (EV), after a treatment break forced by toxicity. Anecdotally, patients are showing great responses, highlighting a key area for prospective data generation.
After observing deep, MRD-negative responses at their starting dose, Colonia Therapeutics unconventionally tested a lower dose level. This counter-intuitive strategy aims to identify the minimum effective dose, which is crucial for maximizing the safety profile (the therapeutic window) and improving commercial viability through lower manufacturing costs.
The development of PARP-1 selective inhibitors like seriparib signals a shift in drug innovation. Instead of only chasing higher efficacy, these new agents aim for a more favorable toxicity profile (less GI toxicity, fewer dose discontinuations) to improve patient quality of life and treatment adherence.
The next frontier in CSCC isn't just about new drugs, but about optimizing existing ones. A key research area is determining the minimum number of immunotherapy doses required for an optimal response—potentially just one or two—to limit toxicity, reduce treatment burden, and personalize care for high-risk patients.
The Phase 2 TRAIT study suggests starting adjuvant abemaciclib at a lower dose and escalating over several weeks significantly reduces early discontinuations due to side effects like diarrhea. This strategy helps more patients get through the initial high-toxicity period and remain on the effective dose for the full two-year course.
Perioperative enfortumab vedotin-pembrolizumab (EV-Pembro) is surprisingly well-tolerated on a per-cycle basis compared to the traditional GEMSYS chemotherapy regimen. This challenges preconceived notions about the toxicity of this powerful combination, though cumulative toxicity over longer durations remains a key factor.
For the ADC belantamab mafodotin, clinicians should not feel rigidly bound to the initial every-three-week schedule. Data shows that spreading doses out to every 8 or 12 weeks is a viable strategy, as most patients stabilize or even improve their depth of response despite holding the drug, allowing for better toxicity management.
In the DESTINY-CRC02 trial, the lower 5.4 mg/kg dose of trastuzumab deruxtecan (TDXD) resulted in a higher response rate in colorectal cancer compared to the 6.4 mg/kg dose used in gastric cancer. This counter-intuitive finding suggests better tolerability led to longer treatment duration and superior outcomes.
Clinical trial data shows that despite specific toxicities, antibody-drug conjugates (ADCs) can be better tolerated overall than standard chemotherapy. For example, trials for both sacituzumab govitecan and dato-DXd reported fewer patients discontinuing treatment in the ADC arm compared to the chemotherapy arm.
The decision to test Enfortumab Vedotin/Pembrolizumab (EVP) in early-stage muscle-invasive bladder cancer was directly driven by its "flabbergasting" results in the metastatic setting. This highlights a strategy where overwhelming late-stage efficacy signals a therapy should be rapidly moved to earlier, curative-intent settings.
