Ipilimumab and Nivolumab Treatment in Patients With Stage III Urothelial Cancer - Expert Commentary
The first phase of the study included 24 patients (cohort 1). The trial met its primary endpoint of surgical resection within 12 weeks of treatment initiation. A complete pathological response (pCR) was observed in 46% of patients, with no residual muscle-invasive disease in 58% of patients. However, 25% of patients missed the third treatment cycle due to the occurrence of immunotherapy-related adverse events. In the second phase, van Dorp et al. aimed to optimize treatment efficacy and tolerability. Cohort 2 consisted of 30 patients who were equally randomized into a cohort that received two cycles of higher-dose ipilimumab and lower-dose nivolumab (cohort 2A) or two cycles of lower-dose ipilimumab and higher-dose nivolumab (cohort 2B). Both cohorts subsequently received a third cycle with higher dose nivolumab. The primary endpoint of the trial was feasibility, while the secondary endpoint was efficacy, as reflected by the pCR rate. Most patients received all treatment cycles (87%), with the remaining patients missing cycles due to immunotherapy-related adverse events. Out of 30 patients, 26 underwent radical surgery, three refused surgery, and one progressed on treatment and was therefore ineligible for surgery. In cohort 2A, 43% of patients exhibited pCR, while this was only 7% (one patient) in cohort 2B. Moreover, 57% of patients in cohort 2A and 29% in cohort 2B had no residual muscle-invasive disease after surgery. Immunotherapy-related adverse events led to postponing surgery in one patient. The proportion of patients with a grade 3 or higher event was significantly lower in cohort 2B than in cohort 1.
Next, the authors aimed to determine whether a bladder-sparing approach was possible in responders by evaluating urine and plasma circulating tumor DNA (ctDNA), which has been correlated with patient outcomes. Analysis of mean estimated variant allele frequency (eVAF%) in cohort 1 patients indicated no difference between responders and non-responders at baseline. However, there was a correlation between the absence of ctDNA before surgery and response when comparing patients with and without pCR in the bladder. In contrast, responders had a significantly lower mean plasma eVAF% before surgery than non-responders. ctDNA was undetectable in the last plasma sample obtained before surgery in 93% of responders and 40% of non-responders (p<0.01). Plasma ctDNA was subsequently validated in cohort 2A patients, which revealed that it was undetectable in 100% of responders and 18% of non-responders. Moreover, there was a strong association between the absence of plasma ctDNA and progression-free survival.
The findings of this important trial establish dosing for ipilimumab and nivolumab in the perioperative setting for bladder. The combination of high-dose ipilimumab and low-dose nivolumab appears to be necessary and adequate in patients with localized urothelial carcinoma. Notably, plasma ctDNA, but not urinary ctDNA, was a strong prognostic biomarker and may be used to guide treatment decisions. However, whether a bladder-sparing approach can be pursued solely on this biomarker remains to be investigated in further studies. This is particularly important as the sample sizes were small.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
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