Efficacy and Safety of an Avelumab and Chemotherapy Combination Treatment Regimen in Cisplatin Ineligible Patients with Metastatic Urothelial Carcinoma - Expert Commentary
However, studies have shown relatively low response rates to first-line ICIs in patients ineligible for platinum-based chemotherapy. The aim of the INDUCOMAIN study was to test the safety and efficacy of induction with avelumab ICI, combination treatment with carboplatin-gemcitabine plus avelumab, and maintenance with avelumab.
A total of 85 patients with mUC were randomized into the experimental arm (n = 42) or the control arm of carboplatin-gemcitabine alone (n = 43). The median age was 74 years and 64.7% of patients had visceral metastasis. Most patients were ineligible for cisplatin due to impaired renal function (61.2%). PD-L1 expression was positive in 42.4% of patients, negative in 34.1% of patients, and unknown in the remaining patients. In the experimental arm, 42.9% of patients discontinued treatment due to disease progression compared to 14% of patients in the control arm. Adverse events (AEs) led to treatment discontinuation in 14.3% of patients in the experimental arm and 7% in the control arm. The median follow up was 40.8 months (95% CI, 37.7 - 43.4). The median treatment duration was 6.21 months in the experimental arm and 4.3 months in the control arm. The median number of cisplatin-based chemotherapy cycles was five in both arms, while the median number of avelumab cycles in the experimental arm was eight.
At the time of database lock, 97.6% of patients in the experimental arm and 100% of patients in the control arm had died. Early progression or death at or prior to first response assessment occurred in 33% of patients in the experimental arm compared to 7% of patients who progressed in the control arm. Among these patients in the avelumab arm, 28.5% never started carboplatin-based chemotherapy. PD-L1 expression was found to be positive in 66.7% of the six patients who died before first response assessment in the experimental arm. The objective response rate (ORR) was 59.5% in the avelumab arm and 53.5% in the control arm (p = 0.57). The median duration of response was 7.1 months in the avelumab arm (95% CI, 5.3 - 13) and 8.7 months in the control arm (95% CI, 5.8 - 12.1) (HR, 1.14; 95% CI, 0.61 - 2.1; p = 0.67). In the avelumab arm, ORR was higher in patients who were positive for PD-L1 expression while ORR was similar in patients in the control arm independent of PD-L1 status. There were no significant differences in progression-free survival or overall survival between the experimental and control arms (p > 0.5). Grade 3 or worse were observed in in 97.6% of patients in the avelumab arm and 79.1% of patients in the control arm. Treatment-related AEs (TRAEs) occurred in 70.7% of patients in the avelumab arm and 72.1% of patients in the control arm. The most common TRAEs were anemia, neutropenia, asthenia, and nausea. The addition of avelumab to platinum-based chemotherapy was associated with a greater risk of specific AEs such as pyrexia and infusion-related reactions.
First-line avelumab induction followed by combination treatment with carboplatin-based chemotherapy did not lead to clinical benefits in patients with mUC. This finding is consistent with other comparable clinical trials. The main limitation of this trial was the small sample size that was further reduced due to patients exhibiting early progression and becoming ineligible for the rest of the treatment regimen.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
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