Dr Mehta-Shah on the Future of CTCL Novel Drug Development

We thought that adding PD-1 inhibitors like nivolumab to a PI3K inhibitor could synergize — but we learned they also synergized in terms of their toxicity. There’s still some work to be done about rationally developed combinations that could overcome resistance and mitigate toxicity.

The menu of targeted options in cutaneous T-cell lymphoma is growing, but the tools to match the right drug to the right patient have not kept pace. Reliable biomarkers largely are not available to the average physician, and many promising assays are not yet CLIA-certified for use at the bedside.

Neha Mehta-Shah, MD, MSCI, of the Division of Oncology at Washington University School of Medicine, describes how clinicians navigate that gap today, and what the next generation of CTCL drug development will require.

In a second part of her discussion at the 6th World Congress of Cutaneous Lymphoma (WCCL), Mehta-Shah turned from target discovery to the practical questions of patient selection, overcoming resistance, and how the field can develop new drugs more efficiently.

In the absence of standardized predictive biomarkers, treatment selection rests largely on phenotype, Mehta-Shah explained. CD30 expression can steer clinicians toward brentuximab vedotin, the CD30-directed antibody-drug conjugate, but more broadly, prognostic genomic features tend to correlate with the disease’s phenotype. That has produced a compartment-based paradigm: agents that work well in the blood, such as mogamulizumab, for patients with high blood burden; agents like brentuximab vedotin for tumor-stage disease and large-cell transformation.

Because the compartment that matters most to a patient changes over time, treatment is adapted in real time. This is an approach Mehta-Shah expects to grow more sophisticated as newer assays become clinically available.

In a study led by Mehta-Shah’s team through the NCI’s Experimental Therapeutics Clinical Trials Network, the hypothesis that adding the PD-1 inhibitor nivolumab to a PI3K inhibitor (duvelisib) would synergize proved true. But the agents also synergized in toxicity, with immune-mediated adverse events limiting the combination. Rationally developed combinations that overcome resistance while mitigating toxicity, she said, remain a work in progress.

Looking ahead, Mehta-Shah offered cautious optimism. She hopes the field could have 3-4 new options for patients within roughly the next decade. Getting a drug FDA-approved in CTCL through a phase 3 trial typically requires more than 300 patients and the coordinated effort of 10 to 15 nations’ centers, and she framed the meeting itself as evidence of the international collaboration such approvals demand.

The path forward, Mehta-Shah suggested, will depend on novel, more efficient clinical-trial designs that can shorten approval timelines for these rare diseases worldwide.