Across several previously unreported subgroups of patients with advanced urothelial cancer who have progressed on first-line platinum-containing chemotherapy avelumab as frontline maintenance plus best supportive care demonstrated a survival benefit compared with BSC alone.
Across several previously unreported subgroups of patients with advanced urothelial cancer who have progressed on first-line platinum-containing chemotherapy avelumab (Bavencio) as frontline maintenance plus best supportive care (BSC) demonstrated a survival benefit compared with BSC alone, according to data from post-hoc analyses of the phase 3 JAVELIN Bladder 100 trial (NCT02603432) that were presented during the 2021 ASCO Annual Meeting.1
The progression-free survival (PFS) and overall survival (OS) improvements were seen in patients with upper tract or lower tract disease; metastatic disease, unresectable locally advanced disease, or lymph node–only disease; PD-L1–positive tumors who received frontline gemcitabine/carboplatin; and The Cancer Genome Atlas (TCGA)–defined tumor genomic subtypes, with the exception of those with the luminal subtype (HR, 1.01; 95% CI, 0.403-2.509).
Additionally, an analysis of key immune biomarkers by TCGA subtype did not predict benefit with avelumab in the frontline maintenance setting.
“Overall, it doesn’t appear that this molecular TCGA analysis is able to identify the ‘winners and the losers’ associated with maintenance avelumab. This is important because it means we need to move to different types of biomarkers in the future,” Thomas Powles, MBBS, MRCP, MD, lead study author, professor of genitourinary oncology, and director of Barts Cancer Centre, said in a presentation during the meeting. “We’ve added something to the field today. I believe that biomarker-positive [and] carboplatin subgroups of patients are relevant, and I also think that the molecular analysis builds on what we know and points us in a different direction of biomarker development in the future.”
In the phase 3 JAVELIN Bladder 100 study, first-line maintenance with avelumab plus BSC was found to significantly improve survival vs BSC alone in patients with advanced urothelial cancer that did not progress on frontline platinum-based chemotherapy. Overall, the median OS was 21.4 months with the addition of avelumab and 14.3 months with BSC alone, leading to a 31% reduction in the risk of death (HR, 0.69; 95% CI; 0.56-0.86; 1-sided P = .0005).2
Based on these findings, the FDA approved frontline maintenance with avelumab plus BSC in June 2020 for use in this patient population.
Another analysis on JAVELIN Bladder 100 showed that the survival benefit achieved with this approach was seen in all analyzed subgroups, including those who received cisplatin/gemcitabine or carboplatin/gemcitabine as frontline chemotherapy.3
In the trial, patients with locally advanced or metastatic urothelial cancer that had not progressed on frontline chemotherapy were randomized 1:1 to receive frontline maintenance with avelumab plus BSC (n = 350) or BSC alone (n = 350) until disease progression, unacceptable toxicity, or withdrawal. The data cutoff date was October 21, 2019.
The primary end point of the trial was OS in the overall study population and in those with PD-L1–positive tumors. The post-hoc analyses were conducted in exploratory subgroups, which were defined as: primary tumor site (upper vs lower urinary tract), type of advanced disease (metastatic or unresectable locally advanced disease prior to chemotherapy, or lymph node–only disease following chemotherapy), and TCGA subtype (basal squamous, luminal, luminal infiltrated, or luminal papillary).
The breakdown of the site of primary tumor and type of advanced disease was as follows: upper urinary tract (avelumab/BSC, n = 106; BSC, n = 81), lower urinary tract (avelumab/BSC, n = 244; BSC, n = 269), metastatic disease (avelumab/BSC, n = 216; BSC, n = 215), unresectable locally advanced disease prior to chemotherapy (n = 133 in both arms), and lymph node–only disease after chemotherapy (avelumab/BSC, n = 48; BSC, n = 39).
Additionally, patients with PD-L1–positive tumors who received frontline gemcitabine/carboplatin were analyzed as a specific population of interest. Seventy-four of these patients received avelumab plus BSC vs 54 who received BSC alone.
The baseline characteristics were well balanced between the arms of the subgroups of interest.
The PFS and OS benefits were observed irrespective of primary tumor site or type of advanced disease. There was, however, a greater difference of OS outcomes in those with lower tract primary tumors (HR, 0.62; 95% CI, 0.477-0.802), unresectable locally advanced disease (HR, 0.40; 95% CI, 0.265-0.617), or lymph node–only disease following chemotherapy (HR, 0.55; 95% CI, 0.259-1.152), but the investigators noted that the number of patients and events were small.
The PFS outcomes were similar with avelumab/BSC vs BSC alone in these exploratory subgroups: lower tract (HR, 0.54; 95% CI, 0.434-0.673), locally advanced and unresectable disease (HR, 0.44; 95% CI, 0.315-0.606), and lymph node–only disease (HR, 0.37; 95% CI, 0.205-0.669). Similar to the OS data, the luminal subtype showed the least benefit of the other TCGA subtypes (HR, 0.73; 95% CI, 0.355-1.500).
In the basal squamous subgroup, the median OS was 24.0 months (95% CI, 16.0–not evaluable [NE]) and 17.9 months (95% CI, 12.7–NE) with avelumab/BSC (n = 46) and BSC alone (n = 44), respectively (HR, 0.62; 95% CI, 0.326-1.187). In the luminal subgroup, the median OS was 23.8 months (95% CI, 12.5-NE; n = 30) and NE (95% CI, 14.3–NE; n = 26), respectively (HR, 1.01; 95% CI, 0.403-2.509).
In the luminal-infiltrated group, the median OS was 19.9 months (95% CI, 18.2–NE) with avelumab/BSC (n = 143) and 14.3 months (95% CI, 12.8-18.6) with BSC alone (n = 143; HR, 0.68; 95% CI, 0.481-0.968). Finally, in the luminal papillary subgroup, the median OS was 22.5 months (95% CI, 18.2-26.0) with avelumab/BSC (n = 61) compared with 13.4 months (95% CI, 10.1-NE) with BSC alone (n = 63; HR, 0.63; 95% CI, 0.370-1.079).
Further data showed that longer outcomes were seen in the avelumab arm in patients with PD-L1–positive disease who received frontline gemcitabine/carboplatin for PFS (HR, 0.61; 95% CI, 0.390-0.958) and OS (HR, 0.67; 95% CI, 0.393-1.137). These data were consistent with the overall study population.
Specifically, the median OS was 24.0 months (95% CI, 18.6–not estimable [NE]) with avelumab plus BSC and 16.1 months (95% 9.4–NE) with BSC alone; the median PFS was 3.7 months (95% CI, 2.0-12.0) and 2.4 months (95% CI, 1.9-3.7), respectively.
“These data really support further the approach of giving chemotherapy to get control of the disease and then maintaining that control with maintenance avelumab rather than giving frontline immune therapy, in my opinion, and I think this does really add to the field,” Powles said.
The authors also noted that PD-L1 expression on tumor cells and CD8–positive cells in the total tumor area were higher in the basal squamous subtype vs other TCGA subtypes.