Tumor Mutation Burden in 'Cisplatin-Unfit' Patients With Metastatic Urothelial Cancer

Tumor mutational burden (TMB) could be useful for identifying "cisplatin-unfit" patients with metastatic urothelial carcinoma (mUC) who would have better outcomes with a first-line immune checkpoint inhibitor rather than carboplatin chemotherapy, said authors of a study in JCO Precision Oncology.

Shilpa Gupta, MD, of the Cleveland Clinic Taussig Cancer Institute, and colleagues retrospectively analyzed data on 401 patients who received either a first-line single-agent immune checkpoint inhibitor (n=245) or carboplatin regimen (n=156).

Patients with a higher TMB (cutoff ≥ 10) had improved outcomes with an immune checkpoint inhibitor compared with carboplatin, including better progression-free survival and overall survival, the team reported. There was no significant difference, however, for patients with TMB <10.

"In real-world settings, mUC patients with TMB ≥ 10 have more favorable outcomes on first-line single-agent immune checkpoint inhibitor than carboplatin, adding clinical validity to TMB assessed by an existing U.S. Food and Drug Administration–approved platform," the researchers concluded.

Gupta elaborated on the details of the study in the following interview.

How do the patients in your study reflect more real-world situations than patients in clinical trials?

Gupta: If you look at the clinical trials, typically patients have ECOG performance status 0 or 1. In phase III trials, no one has ECOG 3. So the real-world population is not as robust as what we see in the clinical trials. We have to tailor treatments accordingly, and that is why this study is very meaningful.

What would you most like oncologists to understand about your study?

Gupta: In cisplatin-ineligible patients it is well established that chemotherapy should be offered, not immunotherapy. However, when patients don't want chemo, but we know that chemo is better than immunotherapy, this can help as a clinical tool, in addition to the clinical criteria. When we look at tumor mutational-high patients, immunotherapy is actually better.

So this can be useful to clinical decision-making, if you're on the fence about whether you should offer immunotherapy or not. That's the whole idea of this study.

What other emerging biomarkers may have the potential to improve on prediction of immune checkpoint inhibitor versus chemotherapy benefit?

Gupta: Regarding other potential biomarkers, there is tGE3, F-TBRS, and other angiogenesis gene expression signatures. I think those are all hypothesis generating. In this study, the focus was tumor mutational burden. We are going to look at those separately, as another project.

What other research do you have planned?

Gupta: We are doing a similar study with patients who have FGFR (fibroblast growth factor receptors) mutations or alterations, and looking at outcomes with the treatments they received. That is another real-world study. There are several other trials I'm leading, including one with the NCI, which is a maintenance immunotherapy intensification trial, called the MAIN-CAV trial, which is building on maintenance immunotherapy with cabozantinib.

Read the study here.