Contrary to its role in lung cancer, PD-L1 expression does not predict benefit from immunotherapy in mesothelioma. Data from major trials shows similar outcomes regardless of PD-L1 status, leading clinicians to omit this test entirely and streamline treatment decisions.

Some experts advocate for using immunotherapy in PD-L1 negative (CPS 0) gastric adenocarcinoma, arguing the biomarker test itself is unreliable. Factors like stromal sampling variability mean a "zero" score might not be truly negative, justifying treatment in a patient who would otherwise be excluded.

Clinicians must weigh the immediate benefits of adding a PD-1 inhibitor for non-muscle-invasive bladder cancer against the potential loss of efficacy for crucial systemic therapies like EV-pembro if the disease later becomes metastatic. This introduces a new layer of long-term treatment strategy from the first diagnosis.

In adjuvant bladder cancer trials, ctDNA status is both prognostic and predictive. Patients with positive ctDNA after surgery are at high risk of relapse but benefit from immune checkpoint inhibitors. Conversely, ctDNA-negative patients have a lower risk and derive no benefit, making ctDNA a critical tool to avoid unnecessary, toxic therapy.

Using a PD-1 inhibitor upfront with BCG for non-muscle-invasive bladder cancer is not an isolated decision. It creates a significant strategic challenge: this early exposure may compromise the efficacy of crucial systemic immunotherapies, like EV-Pembro, if the disease later progresses to a metastatic stage, forcing difficult long-term planning.

Despite major advances in immunotherapy, patient selection remains crude compared to targeted therapies. PD-L1 is still the primary, yet imperfect, biomarker used. Dr. Carbone highlights an urgent need to develop better predictive biomarkers to customize immunotherapy regimens, as is standard for targeted agents.

Current bladder cancer trials often fail to differentiate between patients with primary resistance (never responded) versus acquired resistance (responded, then progressed). Adopting this distinction, common in lung cancer research, could help identify patient subgroups more likely to benefit from immunotherapy re-challenge and refine trial eligibility criteria.

An expert argues forcefully that the PD-L1 biomarker should be "ditched" in bladder cancer. Citing its repeated failure to predict overall survival benefit across multiple major trials, it is deemed an oversimplified and unreliable tool that leads to both over- and under-treatment of patients.

Despite stratifying patients by PD-L1 status, the AGO-OV-229 trial found it was not a predictive marker. Hazard ratios for survival were similar for both PD-L1 positive and negative tumors, challenging its utility for patient selection.