Research ArticleClinical Studies

Organ-specific Tumor Response to Avelumab Maintenance Therapy for Advanced Urothelial Carcinoma: A Multicenter Retrospective Study

NOBUKI FURUBAYASHI, AKINORI MINATO, TOSHIHISA TOMODA, YOSHIFUMI HORI, KEIJIRO KIYOSHIMA, TAKAHITO NEGISHI, YUSUKE HARAGUCHI, TOSHIKI KOGA, KENTARO KUROIWA, NAOHIRO FUJIMOTO and MOTONOBU NAKAMURA
Anticancer Research December 2023, 43 (12) 5689-5698; DOI: https://doi.org/10.21873/anticanres.16774

Abstract

Background/Aim: The organ-specific therapeutic effects of avelumab for the maintenance treatment of advanced urothelial carcinoma (UC) are unclear. Patients and Methods: Patients who received avelumab for advanced UC that had not progressed with first-line platinum-based chemotherapy and who had measurable disease were retrospectively analyzed. The organ-specific response was evaluated, and progression-free survival (PFS) and overall survival (OS) were estimated. Results: We analyzed 42 patients (male, n=31; median age, 72 years). The overall response rate [complete response (CR)+ partial response (PR)] and disease control rate (CR+PR+stable disease) were 2.4% and 47.6%, respectively. In total, 27, 11, 8 and 5 patients had measurable lymph node [organ-specific response rate (OSRR) 7.4%, organ-specific disease control rate (OSDCR) 59.3%], lung (OSRR 18.2%, OSDCR 36.4%), primary tumor organ (OSRR 0%, OSDCR 100%) and liver (OSRR 0%, OSDCR 100%) disease, respectively. The median PFS and OS was 3.8 months and 20.2 months, respectively. Regarding organ-specific PFS, a log-rank test confirmed significant differences between patients with and without primary tumor organ disease (p=0.009) and patients with and without liver metastasis (p=0.015). Regarding organ-specific OS, a log-rank test revealed no significant differences between patients with and without metastatic disease for all organs (lung: p=0.835; lymph node: p=0.914; bone: p=0.257; primary tumor: p=0.057; liver: p=0.893). Conclusion: In patients receiving avelumab maintenance therapy, no significant differences in OS were observed between patients with and without metastasis to any organ, including the primary organ, although metastases and the primary tumor organ disease showed different responses.

Key Words:

Advanced urothelial carcinoma (UC), which is defined as locally advanced/unresectable, or metastatic (mUC), is associated with a poor prognosis (1). Treatment for advanced UC is mainly palliative, not curative. The first-line standard of care treatment for advanced UC has been platinum-based chemotherapy. Although disease control is achieved in 75-80% of patients after first-line chemotherapy, chemotherapy responses are rarely durable and the median OS is only 9-15 months (2-6).

The role of maintenance therapy has already been well established in other solid tumors (7-13). Avelumab, an anti-programmed cell death ligand 1 (PD-L1) antibody, has been approved as a switch maintenance strategy for advanced UC based on the JAVELIN Bladder 100 trial (14). This clinical study showed that maintenance avelumab plus best supportive care significantly prolonged overall survival in comparison to best supportive care alone among patients with UC whose disease had not progressed with first-line chemotherapy [median overall survival (OS) 21.4 months vs. 14.3 months; p=0.001].

Since tumors in different human organs may have different microenvironments and are composed of different cell types, OS may differ according to the metastatic organ, especially in patients treated with immune checkpoint inhibitors. Moreover, among patients with advanced UC in whom platinum-based chemotherapy had failed, the treatment responses were reported to differ according to the affected organ in patients treated with pembrolizumab, an anti-PD-1 antibody (15-17). However, it remains unclear whether the clinical outcomes in patients treated with avelumab maintenance therapy depends on the metastatic organ, including the primary tumor, as their outcomes may also be influenced by the results of first-line chemotherapy.

In this study, we retrospectively evaluated the clinical outcomes of avelumab maintenance therapy in advanced UC patients without progression on platinum-based first-line chemotherapy in order to clarify the organ-specific therapeutic effects of avelumab, including the outcomes of first-line platinum-based chemotherapy.

Patients and Methods

Patient population. This retrospective multi-institutional study was approved by the institutional review board of the Kyushu Cancer Center of the National Hospital Organization (2022-33) followed by the review boards of all five participating institutions. This study conformed to the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from all patients.

A total of 42 consecutive cases who received avelumab for maintenance treatment of advanced UC (metastatic or locally advanced) that had not radiologically progressed with first-line platinum-containing chemotherapy were collected from 5 institutions from November 2015 to July 2023. Clinical data were recovered from the patients’ medical records. The regimen, duration, and number of cycles in the first-line platinum-based chemotherapy were determined by each institution. Avelumab was administered intravenously on day 1 at a dose of 10 mg per kilogram of body weight and the cycle was basically repeated every 2 weeks. The patients continued this treatment until disease progression was observed or until toxic effects reached an unacceptable level.

Tumor measurements were generally performed by computed tomography before and after platinum-based chemotherapy and after every four to six cycles of avelumab; however, evaluations were performed when the clinical symptoms worsened. All metastases that measured 5 mm in the long axis [lymph node (LN) metastases 10 mm in the short axis] on computed tomography before platinum-based chemotherapy were defined as measurable lesions in the present study and were measured before platinum-based chemotherapy and before and during avelumab treatment.

The best response was classified as a complete response (CR) (disappearance or reduction to <10 mm on the short axis for all LN metastases), partial response (PR) (>30% reduction), stable disease (SD) [neither CR, PR, nor progressive disease (PD)], or PD (>20% growth) based on Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (18-20). In particular in the analysis of maintenance avelumab therapy, the best overall response of patients who had a CR to platinum-based chemotherapy (no evidence of disease at the start of avelumab) and who had no evidence of disease after the start of avelumab was noted as ‘could not be evaluated (NE)’ (21).

As the overall evaluation for platinum-based chemotherapy and avelumab, the overall response rate (ORR) and the disease control rate (DCR) were determined according to RECIST in up to five lesions in total and up to two lesions per organ for the target lesions (18). In addition, the DCR for avelumab was defined as CR + PR + SD including NE. Furthermore, for the organ-specific response rate (OSRR) and organ-specific disease control rate (OSDCR), the tumor burden was defined as the sum of the long axis for all non-LN metastases or the short axis of all LN metastases that were measured and evaluated according to RECIST 1.1. ORR and OSRR were defined as the proportion of patients who achieved a CR or PR as the best observed response with platinum-based chemotherapy or avelumab, according to the corresponding evaluation criteria. DCR and OSDCR were defined as the proportion of patients who achieved a CR or PR or SD with platinum-based chemotherapy or a CR or PR or SD or NE with avelumab, according to the corresponding evaluation criteria. Bone metastases were excluded from the measurements, but PFS and OS were analyzed according to the presence or absence of bone metastases.

Statistical analysis. All statistical analyses were performed using the JMP® Pro software package, version 17.0.0 (SAS Institute, Inc., Cary, NC, USA). Percentages may not be equal to 100 due to rounding.

We calculated OS and PFS using the Kaplan–Meier method. OS in patients who received avelumab was calculated from the initiation of maintenance of avelumab until the date of death, and PFS in avelumab was calculated from the date of the initiation of avelumab until the date of investigator-assessed clinical and/or radiographic disease. In addition, we calculated OS from the initiation of platinum-based chemotherapy to the date of death. For both OS and PFS, patients who did not have an event were censored on the date of the last follow-up examination. A log-rank test was used to determine differences in PFS and OS in the presence or absence of disease in the primary organ and metastatic sites. p-Values of <0.05 were considered to indicate statistical significance.

Results

Patient characteristics. The clinical characteristics of the 42 patients are presented in Table I. All patients without progression received platinum-based first-line chemotherapy and all patients with advanced UC received maintenance therapy with avelumab switch. The median follow-up period after receiving platinum-based first-line chemotherapy was 16.9 months [interquartile range (IQR)=12.4-25.8] and the median follow-up period after receiving avelumab was 12.3 months (IQR=7.8-18.2 months).

View this table:
Table I.

Characteristics of the patients at the start of avelumab maintenance therapy.

The median age was 72 years (IQR=65-78) and 31 patients were men (73.8%). In this cohort, 30 patients had an ECOG PS of 0 (71.4%), 21 received surgical treatment for the primary tumor (61.9%), 33 had pure UC according to a histological analysis (78.6%) and 17 had Hb <10 g/dl (40.5%). Regarding the primary tumor site, 21 patients (50.0%) had a tumor located in the upper urinary tracts and 21 (50.0%) had a tumor located in the lower urinary tracts. The platinum-based first-line chemotherapy regimens included gemcitabine and cisplatin (n=25; 59.5%), gemcitabine and carboplatin (n=16; 38.1%), and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (n=1; 2.4%). The number of platinum-based first-line chemotherapy cycles was as follows: ≤3 cycles (n=6; 14.3%), <4-6 cycles (n=33; 78.6%), and ≥7 cycles (n=3; 7.1%).

All patients had metastasis. The metastatic sites included the lymph nodes (n=27; 64.3%), lung (n=11; 26.2%), bone (n=9; 21.4%), liver (n=5; 11.9%) and other tissues (n=5; 11.9%). Eight patients had disease of the primary tumor organ (19.0%). Twelve patients (28.6%) died during follow-up.

ORR/DCR and OSRR/OSDCR in patients treated with platinum-based chemotherapy and avelumab for advanced UC. ORR in patients treated with platinum-based chemotherapy was 52.4% (CR: n=2, PR: n=20, SD: n=20, as best response). The ORR and DCR in patients treated with avelumab were 2.4% and 47.6%, respectively [best response: CR (n=0), PR (n=1), SD (n=18), PD (n=22), NE (n=1)] (Table II).

View this table:
Table II.

Overall response rate and disease control rate in patients treated with platinum-based chemotherapy and avelumab maintenance therapy.

The OSRR and OSDCR of avelumab are shown in Table III. Among the 42 patients, the metastatic target organs before platinum-based chemotherapy were the lymph nodes (cases, n=27; number of tumor sites, 60), the lung (cases, n=11; number of tumor sites, 43), primary tumor organ (cases, n=8; number of tumor sites, 8), and liver (cases, n=5; number of tumor sites, 12). The OSRR for each location in platinum-based chemotherapy was as follows: lymph nodes (77.8%), lung (63.6%), primary tumor organ (37.5%) and liver (80.0%). The OSRR and OSDRR for each location in avelumab were as follows: lymph nodes (7.4%, 59.3%, respectively), lung (18.2%, 36.4%), primary tumor organ (0%, 100%) and liver (0%, 40.0%).

View this table:
Table III.

Organ-specific response rate and organ-specific disease control rate in patients treated with platinum-based chemotherapy and avelumab maintenance therapy.

PFS, OS, organ-Specific PFS and OS in patients treated with avelumab for advanced UC, and OS and organ-specific OS in patients receiving platinum-based chemotherapy. The median PFS and OS in patients treated with avelumab was 3.8 months [95% confidence interval (CI)=2.5-6.2 months] and 20.2 months (95%CI=15.9-35.1 months) (Figure 1).

Figure 1.
Figure 1.

Progression-free survival and overall survival in patients treated with avelumab maintenance therapy.

Regarding organ-specific PFS in avelumab, a log-rank test revealed no significant differences in PFS between patients with and without lymph node metastasis (p=0.666), lung metastasis (p=0.393), or bone metastasis (p=0.317). However, a significant difference in PFS was confirmed between patients with and without primary tumor organ disease (p=0.009) and liver metastasis (p=0.015) (Figure 2). Regarding organ-specific OS in patients treated with avelumab, a log-rank test revealed no significant differences in OS between patients with and without lymph node metastasis (p=0.835), lung metastasis (p=0.914), bone metastasis (p=0.257), primary tumor organ disease (p=0.057), or liver metastasis (p=0.893) (Figure 3).

Figure 2.
Figure 2.

Organ-specific progression-free survival in patients treated with avelumab maintenance therapy.

Figure 3.
Figure 3.

Organ-specific overall survival in patients treated with avelumab maintenance therapy.

Regarding organ-specific OS in patients treated with avelumab, including platinum-based chemotherapy, a log-rank test revealed no significant differences in OS between patients with and without lymph node metastasis (p=0.857), lung metastasis (p=0.387) or liver metastasis (p=0.792). However, a significant difference was confirmed between patients with and without bone metastasis (p=0.031) and primary tumor organ disease (p=0.008) (Figure 4).

Figure 4.
Figure 4.

Organ-specific overall survival in patients treated with platinum-based chemotherapy and avelumab maintenance therapy.

Discussion

This multicenter retrospective study sought to evaluate the organ-specific response to avelumab maintenance therapy in patients with advanced UC whose disease did not progress with first-line platinum-based chemotherapy, including how the primary location and the location of metastases influence OS. The present study confirmed that OS did not differ to a statistically significant extent according to the presence or absence of metastasis at a specific site, including the primary organ, although the tumor responses differed according to the primary and metastatic sites regarding avelumab maintenance therapy.

Platinum-based chemotherapy remains the standard first-line treatment for advanced UC (22). However, responses to chemotherapy are rarely durable due to the development of resistance to chemotherapy. Accordingly, treatments are mainly palliative, although chemotherapy is actively performed (2-6). Furthermore, until now, new agents such as immune-checkpoint inhibitors and antibody-drug conjugates, have been used as sequence treatments after treatment progression with the aim of prolonging OS based on the results of clinical trials of new agents (23, 24). Switch maintenance therapy refers to sequential treatment with a new agent with a different mechanism of action and a less toxic drug to maintain disease control after a fixed duration of initial systemic therapy (25). However, this maintenance approach with the use of other agents, including immune checkpoint inhibitors other than avelumab, have not prolonged the overall survival of patients with advanced UC until now (26).

In current clinical practice, the PFS and OS are similar to PFS and OS reported in the JAVELIN Bladder 100 clinical trial, although the best response to first-line chemotherapy in the present study (CR+PR, 52.4%) was worse than that of the clinical trial (CR+PR, 72.3%). Across subgroups defined by the response to first-line chemotherapy in the JAVELIN Bladder 100 clinical trial, the hazard ratios (HRs) for OS and PFS in the avelumab maintenance group were reported to be <1.0 (27). Therefore, regardless of the response to the first line chemotherapy, avelumab maintenance therapy was shown to be associated with a clinical benefit in advanced UC patients who had not progressed during first-line platinum-based chemotherapy. This was also observed in clinical practice.

The relationship between metastatic sites, including the primary lesion, and treatment outcomes in patients with advanced UC have already been evaluated in patients treated with chemotherapy and immune-checkpoint inhibitors. In the first-line setting, three risk factors for adverse outcomes have been reported for advanced UC patients who experienced treatment failure with first-line platinum-containing regimens (PS, hemoglobin level, and liver metastasis). In this trial, according to the relationship between the metastatic organ and OS, the presence or absence of visceral (including liver, lung, bone and any non-lymph node or soft tissue), lymph node, bone, and liver metastasis was also analyzed, and liver metastasis was found to be the only independent prognostic factor (28).

In the second-line setting, pembrolizumab, an immune checkpoint inhibitor, was associated with significantly longer overall survival and a lower rate of treatment-related adverse events in comparison to chemotherapy as a second-line therapy for platinum-refractory advanced UC in the phase 3 KEYNOTE-045 trial (23). The systematic review and meta-analysis assessed the value of pretreatment clinical characteristics and hematologic biomarkers for the prognostic response to pembrolizumab in patients with metastatic UC, and reported that patients with poor PS, liver metastasis, higher pretreatment NLR, and/or CRP have worse survival despite receiving pembrolizumab treatment (29). Our group previously investigated the organ-specific therapeutic effect of pembrolizumab after the failure of platinum-based chemotherapy for advanced UC. In our analysis, in terms of organ-specific OS, the log-rank test revealed significant differences in OS between patients with and without primary tumor organ disease (p=0.046) and between patients with and without liver metastasis (p<0.001) (15).

The present study analyzed the relationship between tumor site (lymph node, lung, bone, liver metastasis and primary tumor) and clinical outcome in patients receiving avelumab maintenance therapy, and revealed that there was no significant difference in OS between patients with and without metastasis at each of these sites, although a significant difference in PFS was confirmed between patients with and without primary tumor organ disease and between patients with and without liver metastasis. However, it is worth noting that among visceral metastases, liver metastasis has already been reported be associated with a poor prognosis in patients receiving platinum-based chemotherapy and in patients receiving pembrolizumab (28, 29). These phenomena may be due to the fact that patients without progression on platinum-based chemotherapy were targeted for avelumab maintenance therapy. In summary, the strategy of avelumab maintenance therapy would extend or improve the initial benefit achieved with platinum-based chemotherapy; thus, although it is an immunotherapy similar to pembrolizumab (which is administered platinum-refractory advanced UC as opposed to patients who shown no progression on platinum-based chemotherapy), the metastatic site – including primary tumor – may not have a significant effect on the outcomes of avelumab maintenance therapy. In the subgroup analysis of the JAVELIN bladder 100 Trial, the HRs of liver and lung metastases for PFS and OS were <1.0 in patients receiving avelumab maintenance therapy (27). Furthermore, a retrospective analysis of a real-world cohort of 108 patients treated with avelumab maintenance for advanced UC also reported that liver metastasis at the time of the initiation of platinum-based chemotherapy was significantly associated with PFS (HR=2.32, 95%CI=1.17-4.59), but not OS (HR=1.06, 95%CI=0.35-3.18) (30). These results based on a clinical trial and the retrospective analysis of a large study population are consistent with our findings.

Therefore, we additionally analyzed the tumor site (while investigating for lymph node, lung, bone, liver metastasis, and primary tumor) and the OS from first-line platinum-based chemotherapy including avelumab maintenance therapy, and revealed a significant difference between patients with and without bone metastasis (p=0.031) and between patients with and without primary tumor organ disease (p=0.008), although a log-rank test showed no significant differences in OS between patients with and without lymph node, lung, or liver metastasis. However, in the subgroup analysis of the JAVELIN Bladder 100 trial, the HR of metastatic disease site (stratified as visceral or non-visceral) when initiating 1L chemotherapy was <1.0 (27). This difference between the present results and the subgroup analysis of the JAVELIN bladder 100 Trial may be due to the methods of the present study, in which the results were analyzed for each tumor site.

Study limitations. The present study was retrospective and consisted of a relatively small number of patients, including the fact that the upper urinary tract was the primary tumor site in half of the patients. The present study was a multicenter study; thus, there may have been slight differences between the institutions with regard to clinical practices, the timing of the evaluation of the treatment, the regimen, and the number of platinum-based first-line chemotherapy cycles, and the treatment after avelumab maintenance therapy depended on the protocol of each institution. These background characteristics may have affected the results. Finally, we did not evaluate quality of life or patient reported outcomes.

Conclusion

The present study found that OS did not differ to a statistically significant extent according to presence or absence of metastasis on a specific organ, including the primary organ, in patients receiving avelumab maintenance therapy, although tumor responses in patients treated with avelumab maintenance therapy were different and depended on the primary and metastatic sites.

Acknowledgements

The Authors thank Japan Medical Communication (https://www.japan-mc.co.jp/) for editing the English language of this manuscript.

Footnotes

  • Authors’ Contributions

    Study concept and design: N.F. (Nobuki Furubayashi), A.M. T.N. and M.N.; acquisition of data: A.M., T.T., Y.H., K.K. (Keijiro Kiyoshima), Y.H., and T.K.; statistical analysis: N.F. (Nobuki Furubayashi), and T.N.; analysis and interpretation of data: all Authors; drafting of the original manuscript: N.F (Nobuki Furubayashi), A.M. and M.N.; critical revision of the manuscript for important intellectual content: all Authors; supervision: K.K. (Kentaro Kuroiwa), N.F. (Naohiro Fujimoto) and M.N. All Authors have read and approved the final version of the manuscript.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest in relation to this study.

  • Received October 12, 2023.
  • Revision received November 8, 2023.
  • Accepted November 9, 2023.

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Organ-specific Tumor Response to Avelumab Maintenance Therapy for Advanced Urothelial Carcinoma: A Multicenter Retrospective Study
NOBUKI FURUBAYASHI, AKINORI MINATO, TOSHIHISA TOMODA, YOSHIFUMI HORI, KEIJIRO KIYOSHIMA, TAKAHITO NEGISHI, YUSUKE HARAGUCHI, TOSHIKI KOGA, KENTARO KUROIWA, NAOHIRO FUJIMOTO, MOTONOBU NAKAMURA
Anticancer Research Dec 2023, 43 (12) 5689-5698; DOI: 10.21873/anticanres.16774
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