Immune checkpoint inhibitors effective in variant urothelial carcinoma

June 17, 2020

Anti–PD-1/PD-L1 agents were associated with similar efficacy across pure and variant histologies in patients with advanced urothelial carcinoma, with the exception of those with a neuroendocrine variant.

Treatment with anti­–PD-1/PD-L1 immune checkpoint agents showed comparable efficacy, regardless of whether patients had variant urothelial carcinoma (VUC) or pure urothelial carcinoma (PUC), according to a retrospective cohort analysis; however overall survival (OS) and progression-free survival (PFS) were worse for patients with neuroendocrine (NE) VUC.

The objective response rate (ORR) was 28% for the PUC group versus 29% for the VUC group (OR, 1.03; 95% CI, 0.64-1.66; P = .90). There were no significant differences between the PUC group and any of the specific subtypes in the VUC group. There was also no significant different between the ORR in the NE group (25%) and the PUC group (P = .83).

The median PFS was 4.1 months in the PUC group compared with 5.2 months in the VUC group (P = .43). In the NE group, the median PFS was 3.7 months (HR vs PUC, 1.87; 95% CI, 0.92-3.79; P = .09). The median OS was 11 months for the PUC group compared with 10.1 months in the VUC group (P = .60); however, the median OS was only 4.6 months in the NE group (HR vs PUC, 2.75; 95% CI, 1.40-5.40; P = .003).

“There was no significant association between histological variant subtypes and ORR among patients treated with immune checkpoint inhibitors (ICIs) in this retrospective study. PFS and OS were comparable between PUC and VUC, but shorter in patients with tumors harboring NE features. Our data suggest that histology subtype may not be a biomarker of response to ICI, although patients with NE tumors seem to have poor long-term outcomes,” the study investigators wrote.

The analysis included patients with locally advanced unresectable or metastatic UC treated at 18 institutions who started treatment between May 2013 and May 2019. Three patient subsets were assessed: PUC, VUC, and NE. VUC was defined as tumors with both UC plus at least 1 variant histology. The variant histologies for patients in the VUC subgroup included squamous, micropapillary, sarcomatoid, plasmacytoid, adenocarcinoma, neuroendocrine, nested, and other.

After accounting for missing data and applying exclusion criteria, the ORR evaluable population included 395 patients, the OS evaluable population included 406 patients, and the PFS evaluable population included 403 patients. The investigators provided baseline characteristics for the patients in the OS analysis cohort, which included 286 patients with PUC, 120 patients with VUC, and 9 patients with NE.

Overall, patient characteristics were well balanced between the PUC and VUC cohorts. In the PUC group, the mean age was 69 years, 76% were male, 65% were ever smokers, and 80% were White. Fourteen percent had upper tract tumors, 51% had cystectomy or (nephro)ureterectomy, 24% had Hgb <10, and 20% had liver metastasis. Twenty-three percent had an ECOG performance status of 0, 50% had a status of 1, 23% had a status of 2, and 4% had a status of 3. Immune checkpoint inhibitors received included atezolizumab (Tecentriq; 51%), avelumab (Bavencio; 1%), durvalumab (Imfinzi; 3%), nivolumab (Opdivo; 7%), and pembrolizumab (Keytruda; 38%).

In the VUC subgroup, the mean age was 69 years, 71% were male, 69% were ever smokers, and 82% were White. Sixteen percent had upper tract tumors, 60% had cystectomy or (nephro)ureterectomy, 28% had Hgb <10, and 15% had liver metastasis. Twenty-six percent had an ECOG performance status of 0, 53% had a status of 1, 21% had a status of 2, and 1% had a status of 3. Immune checkpoint inhibitors received included atezolizumab (50%), durvalumab (5%), nivolumab (7%), and pembrolizumab (38%).

Patients characteristics for the NE subgroup were, for the most part, comparable with the PUC and VUC subgroups; however, the distribution of Bellmunt risk factors was significantly different for the NE subgroup (P = .03).

In their conclusion, the authors wrote, “In the absence of high-level definitive evidence, retrospective studies can provide real-world information relevant to clinical practice. This study supports routine use and further clinical trial investigation of ICI, including novel combinations, across histological subtypes in advanced UC.”

Reference

Miller NJ, Khaki AR, Diamantopoulos LN, et al. Histological subtypes and response to PD-1/PD-L1 blockade in advanced urothelial cancer: a retrospective study. J Urol. 2020;204(1):63-70. doi: 10.1097/JU.0000000000000761