Ramy Sedhom, Clinical Director of Palliative Care at Penn Medicine Princeton Health, shared a post on X:
“Today in JAMA Oncology, we share new real-world evidence supporting reduced-dose EV + Pembro for 1st-line treatment of advanced urothelial cancer (a dz of older adults) led by Penn Medicine – Abramson Cancer Center fellow Ryan Chow and Ronac Mamtani.
EV+pembro is the preferred 1L therapy for aUC. But in clinic, many older or physiologically vulnerable adults struggle with tolerability
As oncologists, we often ask:
Does reducing the EV dose compromise survival?
Until now—little data existed.
We used the Flatiron Health EHR database to evaluate 496 adults w/ aUC who initiated 1L EV+pembro from April 2023–Dec 2024
117 patients (23.6%) received upfront EV dose reductions (1.0 or 0.75 mg/kg in first 2 doses)
379 received standard dosing (1.25 mg/kg)
Key outcome N1: Treatment Interruption
defined as ≥35-day gap between EV doses—a pragmatic surrogate for real-world tolerability.
We observed a 50% reduction in risk of EV interruption with upfront dose reduction (‘start low, go slow’)
aHR 0.49 (95% CI 0.30–0.82)
Key outcome N2: Overall Survival (OS)
Upfront dose reduction did NOT compromise survival
aHR 1.24 (95% CI 0.88–1.76)
In other words:
Less toxicity.
No signal of worse outcomes.
This pattern held in a prespecified high-risk subgroup:
• Age ≥80
• CrCl <30
• ECOG ≥2
Among these physiologically vulnerable adults (n=213), dose reduction again lowered TI risk and did not worsen OS
Real-world practice patterns support this approach.
EV dose reduction increased from 22% at cycle 1 to 39% by cycle 8, suggesting clinicians are already titrating for tolerability.
Why this matters:
Clinicians caring for older (or younger vulnerable) adults often face a dilemma—start at full dose and risk early toxicity and discontinuation, or start lower and risk undertreatment?
Our findings suggest: ‘Start low, go slow’ may be the preferred approach.
This aligns with broader evidence:
Geriatric oncology trials (like GAP70+), population-based studies, and the growing literature on dose-personalization in older adults all converge on the same theme— tolerability matters and dose-reductions often do not compromise OS
And importantly:
Continuity of therapy is especially critical in aUC, where EV-based regimens drive major survival gains. Minimizing interruptions could enhance real-world effectiveness.
The takeaway:
Upfront EV dose reduction appears safe and may improve real-world continuity for patients who need it most—without compromising survival
What’s next?
We advocate for pragmatic trials to evaluate titrated EV dosing strategies that support QOL, tolerability, and patient-centered goals.”
More posts featuring Ramy Sedhom.