First-line dual immune checkpoint inhibitor therapies versus combination therapies comprising immune checkpoint inhibitors and tyrosine kinase inhibitors for advanced renal cell carcinoma: a comparative analysis of the effectiveness using real-world data.

BACKGROUND: There are few comparative studies on dual immune checkpoint inhibitors (ICIs) (i.e., IO-IO) and combination therapies comprising ICIs plus tyrosine kinase inhibitors (TKIs) (i.e., IO-TKI) for advanced renal cell carcinoma (RCC), especially in real-world settings. METHODS: We retrospectively evaluated data of 175 patients with IMDC intermediate-risk or poor-risk RCC; as first-line therapy, 103 received IO-IO, and 72 received IO-TKI. An inverse probability of treatment weighting (IPTW) analysis was conducted to balance patients' backgrounds in the IO-IO and IO-TKI groups. RESULTS: Based on the IPTW analysis, progression-free survival (PFS) was longer in the IO-TKI group than in the IO-IO group (median: 15.6 vs. 8.3 months; p = 0.0386). In contrast, overall survival was not different between groups (median: 46.7 vs. 49.0 months; p = 0.465). Although the IPTW-adjusted objective response rate was not significantly different (51.2% vs. 43.9%; p = 0.359), the progressive disease rate as the best overall response was lower in the IO-TKI group than in the IO-IO group (3.3% vs. 27.4%; p < 0.0001). Regarding the safety profile, the treatment interruption rate was higher in the IO-TKI group than in the IO-IO group (70.3% vs. 49.2%; p = 0.005). In contrast, the IO-IO group had a higher corticosteroid administration rate (43.3% vs. 20.3%; p = 0.001). CONCLUSION: IO-TKI therapy exhibited superior effectiveness over IO-IO therapy in terms of PFS improvement and immediate disease progression prevention and was associated with a higher risk of treatment interruption and a lower risk of needing corticosteroids.

Association Between Kidney Function and Outcomes Following Immune Checkpoint Inhibitor-Based Combination Therapy in Patients With Advanced Renal Cell Carcinoma.

BACKGROUND: It remains unclear whether kidney function affects outcomes following immune checkpoint inhibitor (ICI)-based combination therapy for advanced renal cell carcinoma (RCC). METHODS: We retrospectively evaluated data of 167 patients with advanced RCC, including 98 who received ICI dual combination therapy (ie, immunotherapy [IO]-IO) and 69 who received ICI combined with tyrosine kinase inhibitor (TKI) (ie, IO-TKI). In each regimen, treatment profiles were assessed according to the grade of chronic kidney disease (CKD) as defined by the KDIGO 2012 criteria. RESULTS: Of the 98 patients who received IO-IO, 31 (32%), 30 (31%), 15 (15%), and 22 (22%) had CKD G1/2, G3a, G3b, and G4/5, respectively. Of the 69 patients who received IO-TKI, 18 (26%), 25 (36%), and 26 (38%) had G1/2, G3a, and G3b/4/5, respectively. Regarding efficacy, progression-free survival, overall survival, or objective response rate was not different according to the CKD grade in both treatment groups (P > .05). Regarding safety, the rate of adverse events, treatment interruption, or corticosteroid administration was not different according to the CKD grade in the IO-IO group (P > .05), whereas in the IO-TKI group, the incidence of grade ≥ 3 adverse events were significantly higher (P = .0292), and the rates of ICI interruption (P = .0353) and corticosteroid administration (P = .0685) increased, according to the CKD grade. CONCLUSION: There is a differential safety but comparable efficacy profile between the IO-IO and IO-TKI regimens in patients with CKD. Further prospective studies are required to confirm these findings.

Real-world outcomes of nivolumab plus ipilimumab combination therapy for advanced renal cell carcinoma in Japanese patients: data with a minimum of 3 years of follow-up.

BACKGROUND: Long-term follow-up data regarding treatment outcomes of nivolumab plus ipilimumab combination therapy for advanced renal cell carcinoma as a first-line therapy are limited in real-world Japanese populations. METHODS: We retrospectively evaluated data of 56 advanced renal cell carcinoma patients treated with nivolumab plus ipilimumab, with a follow-up of at least 3 years. Survival, tumour response and adverse event profiles were assessed. RESULTS: A total of 41 patients (73%) were histopathologically diagnosed with clear-cell renal cell carcinoma, and 34 (61%) were categorized into the International Metastatic renal cell carcinoma Database Consortium intermediate-risk group. The median follow-up period was 34.4 months. Regarding an effectiveness profile, median progression-free survival, time to treatment failure and overall survival were 9.01, 12.5 and 49.0 months, respectively. Objective response was observed in 27 patients (48%), including eight patients with complete response (14%), and the median duration of response was 30.8 months. Multivariate analyses showed that clear-cell histology was an independent factor of longer overall survival (hazard ratio: 0.23, P = 0.0013). Regarding safety profiles, adverse events of any grade and those with grade ≥3 developed in 40 (71%) and 25 patients (45%), respectively. Median time to adverse event development was 1.68 months. Treatment was interrupted in 28 patients (50%), and corticosteroid administration was needed in 25 (45%). CONCLUSION: The 3-year follow-up data showed that nivolumab plus ipilimumab combination therapy exhibited a feasible effectiveness in real-world Japanese patients with advanced renal cell carcinoma. Accordingly, the high risk of adverse event development, which often requires treatment withdrawal and corticosteroid administration, should be considered.

Real-world efficacy and safety of cabozantinib following immune checkpoint inhibitor failure in Japanese patients with advanced renal cell carcinoma.

BACKGROUND: Real-world data of cabozantinib after failure of immune checkpoint inhibitors for advanced renal cell carcinoma in Japanese population are limited. Additionally, prognostic factors of cabozantinib in this setting are still unknown. METHODS: We retrospectively evaluated data of 56 patients treated with cabozantinib subsequent to failed immune checkpoint inhibitors at four institutions. Regarding the efficacy profile, progression-free survival, overall survival and objective response rate were assessed. In terms of the safety profile, rate of adverse events, dose reduction and treatment interruption were assessed. Furthermore, risk factors of progression-free survival were analyzed. RESULTS: Twenty-nine patients (52%) were treated with cabozantinib as second-line therapy. Most frequent prior immune checkpoint inhibitor treatment was nivolumab plus ipilimumab combination therapy as first-line therapy (n = 30, 54%). Median progression-free survival and overall survival were 9.76 and 25.5 months, respectively, and objective response rate was 34%. All patients experienced at least one adverse event, and grade ≥ 3 adverse events were observed in 31 patients (55%). Forty-four (79%) and 31 (55%) patients needed dose reduction and treatment interruption, respectively. Multivariate analysis showed that reduced initial dose (i.e. <60 mg) (hazard ratio: 2.50, P = 0.0355) and presence of lymph node metastasis (hazard ratio: 2.50, P = 0.0172) were independent factors of shorter progression-free survival. CONCLUSION: Cabozantinib in Japanese patients with advanced renal cell carcinoma who failed immune checkpoint inhibitors was efficacious and had a manageable safety profile. These results appear to be similar to those of previous clinical trials.

Association between lung immune prognostic index and survival of patients with metastatic urothelial carcinoma treated with pembrolizumab.

INTRODUCTION AND OBJECTIVE: Lung immune prognostic index score (LIPI), calculated using the derived neutrophil-lymphocyte ratio and lactate dehydrogenase level, is reported for use in numerous malignancies, while its role on metastatic urothelial carcinoma (mUC) treated with pembrolizumab remains limited. We aimed to investigate association between LIPI and outcomes in this setting. METHODS: We retrospectively evaluated 90 patients with mUC treated with pembrolizumab at four institutions. The associations between three LIPI groups and progression-free survival (PFS), overall survival (OS), objective response rates (ORRs) or disease control rates (DCRs) were assessed. RESULTS: Based on the LIPI, good, intermediate, and poor groups were observed in 41 (45.6%), 33 (36.7%), and 16 (17.8%) patients, respectively. The PFS and OS were significantly correlated with the LIPI (median PFS: 21.2 vs. 7.0 vs. 4.0 months, p = 0.001; OS: 44.3 vs. 15.0 vs. 4.2 months, p < 0.001 in the LIPI good vs. intermediate vs. poor groups). Multivariable analysis further revealed that LIPI good (vs. intermediate or poor, hazard ratio: 0.44, p = 0.004) and performance status = 0 (p = 0.015) were independent predictors of a longer PFS. In addition, LIPI good (hazard ratio: 0.29, p < 0.001) were shown to be associated with a longer OS together with performance status = 0 (p < 0.001). The ORRs tended to be different among patients with Good LIPI compared with Poor, and DCRs were significantly different among the three groups. CONCLUSIONS: LIPI, a simple and convenient score, could be a significant prognostic biomarker of OS, PFS, and DCRs for mUC treated with pembrolizumab.

Impact of sex on prognosis in patients with advanced renal cell carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Prognostic impact of sex in patients with malignancies treated with immune checkpoint inhibitors has been intensively discussed but remains unclear, especially in advanced renal cell carcinoma. METHODS: We retrospectively evaluated a total of 184 patients with advanced renal cell carcinoma treated with either nivolumab plus ipilimumab combined treatment as first-line therapy (n = 73) or nivolumab as later-line therapy (n = 111) at our affiliated institutions. Progression-free survival, overall survival and objective response rate as well as adverse event profile were compared between sexes. RESULTS: Of the total 184 patients, 48 (26%) were female. Female patients had a significantly shorter progression-free survival than male patients (median: 3.8 vs. 8.3 months, P = 0.0005), but overall survival (median: 39.2 vs. 45.1 months, P = 0.283) and objective response rate (29% vs. 42%, P = 0.119) were not different between them. Similar findings were observed when analyzing within each treatment; in both patient groups treated with nivolumab plus ipilimumab combined therapy and nivolumab monotherapy, progression-free survival was significantly shorter in female than in male patients (P = 0.007, P = 0.017), but overall survival (P = 0.914, P = 0.117) and objective response rate (P = 0.109, P = 0.465) were comparable between them. Moreover, in a more restricted cohort consisting of patients with clear-cell renal cell carcinoma, a shorter progression-free survival in female patients was also observed (3.8 vs. 11.0 months, P < 0.0001). CONCLUSIONS: This retrospective study showed that immune checkpoint inhibitors-based treatment for renal cell carcinoma exhibited less marked effects in female than in male patients. Thus, sex may be an important factor for decision-making on systemic therapy as renal cell carcinoma treatment, although further studies are required to validate the present findings.

Comparison of Outcomes Between Therapeutic Combinations Based on Immune Checkpoint Inhibitors or Tyrosine Kinase Inhibitor Monotherapy for First-Line Therapy of Patients with Advanced Renal Cell Carcinoma Outside of Clinical Trials: A Real-World Retrospective Multi-Institutional Study.

BACKGROUND: Clinical trials have demonstrated the superior efficacy of immune checkpoint inhibitor (ICI)-based combination therapy over sunitinib, a multi-target tyrosine kinase inhibitor (TKI), in patients with advanced renal cell carcinoma. However, such benefits have not been elucidated in populations outside of clinical trials. METHODS: We retrospectively evaluated data from 467 patients with advanced renal cell carcinoma who received ICI-based combination therapy or TKIs, as first-line therapy. Clinical outcome was compared between ICI-based combination therapy and TKIs in each population divided according to trial eligibility. RESULTS: Among 152 patients treated with ICI-based combination therapy and 315 patients treated with TKIs, 76 (50.0%) and 156 (49.5%) were trial ineligible, respectively. Overall survival (p = 0.0072) and objective response rate (p < 0.0001) were significantly higher in ICI-based combination therapy than in TKIs, but progression-free survival was comparable (p = 0.681). In the trial-eligible population, overall survival was longer (p = 0.0906) and the objective response rate was significantly higher (p = 0.0124) in ICI-based combination therapy than in TKIs. In the trial-ineligible population, overall survival (p = 0.0208) and objective response rate (p = 0.0006) were significantly higher with ICI-based combination therapy than with TKIs. A multivariate analysis also showed that ICI-based combination therapy was independently associated with prolonged overall survival (hazard ratio, 0.47; p = 0.0016). Regardless of trial eligibility, progression-free survival did not differ between ICI-based combination therapy and TKIs (trial eligible: p = 0.287; trial ineligible: p = 0.0708). CONCLUSIONS: The present study, using real-world data, provides evidence indicating the therapeutic benefit of ICI-based combination therapy over TKIs for advanced renal cell carcinoma was more statistically significant in the trial-ineligible population than in the trial-eligible population.

Comparison of the Impact of Immune-Related Adverse Events Due to Immune Checkpoint Inhibitor Dual Combination Therapy and Immune Checkpoint Inhibitor Plus Tyrosine Kinase Inhibitor Combination Therapy in Patients with Advanced Renal Cell Carcinoma.

BACKGROUND: The prognostic impact of immune-related adverse events during immune checkpoint inhibitor-based combination therapy for advanced renal cell carcinoma remains unclear, especially in terms of differences between regimens. OBJECTIVE: We aimed to clarify the prognostic impact of immune-related adverse events in patients with advanced renal cell carcinoma receiving immune checkpoint inhibitor dual combination therapy (IO-IO) or immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy (IO-TKI). METHODS: We retrospectively evaluated the data of 148 patients who received immune checkpoint inhibitor-based combination therapy as first-line therapy. Patients were divided into two groups based on regimens, namely IO-IO and IO-TKI. The associations between immune-related adverse event development and outcomes, such as progression-free survival, overall survival, and objective response rate, were compared between the two groups. RESULTS: In the IO-IO and IO-TKI groups, 67 of 91 (74%) and 31 of 57 (54%) patients, respectively, experienced at least one immune-related adverse event and the rate was significantly higher in the IO-IO group (p = 0.0204), where immune-related adverse events development was significantly associated with longer progression-free survival (p < 0.0001) and overall survival (p = 0.0102), and a higher objective response rate (p = 0.0028). A multivariate analysis revealed immune-related adverse event development as an independent factor for longer progression-free survival (hazard ratio, 0.25; p < 0.0001) and overall survival (hazard ratio, 0.42; p = 0.0287). There were no significant associations between immune-related adverse events and progression-free survival, overall survival, or objective response rate in the IO-TKI group. CONCLUSIONS: The development of immune-related adverse events was positively associated with the outcome of patients with advanced renal cell carcinoma treated with IO-IO combination therapy; no such correlation was observed for IO-TKI combination therapy.

Impact of Body Mass Index on Outcomes in an Asian population of Advanced Renal Cell Carcinoma and Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors.

OBJECTIVES: To clarify the impact of body mass index (BMI) on treatment outcomes including survival, tumor response, and adverse events (AEs) in patients with advanced renal cell carcinoma (RCC) or urothelial carcinoma (UC) treated with immune checkpoint inhibitors (ICIs) in an Asian population. METHODS: We retrospectively evaluated 309 patients with advanced RCC or UC who received ICIs between September 2016 and July 2021. The patients were divided into high- (i.e., ≥25 kg/m2) and low-BMI (<25 kg/m2) groups according to the BMI at the time of treatment initiation. RESULTS: Overall, 57 patients (18.4%) were classified into the high-BMI group. In RCC patients treated with ICIs as first-line therapy or UC treated with pembrolizumab, progression-free survival (PFS) (p = 0.309; p = 0.842), overall survival (OS) (p = 0.701; p = 0.983), and objective response rate (ORR) (p = 0.163; p = 0.553) were comparable between the high- and low-BMI groups. In RCC patients treated with nivolumab monotherapy as later-line therapy, OS (p = 0.101) and ORR (p = 0.102) were comparable, but PFS was significantly longer in the high-BMI group (p = 0.0272). Further, multivariate analysis showed that BMI was not an independent factor of PFS or OS in all the treatment groups (any, p>0.05). As for AE profiles, in nivolumab monotherapy, the rate was significantly higher in the high-BMI group (p = 0.0203), whereas in the other two treatments, the rate was comparable. CONCLUSIONS: BMI was not associated with survival or response rates of advanced RCC or UC patients treated with ICIs in an Asian population. AEs might frequently develop in high-BMI patients with RCC in nivolumab monotherapy.

Therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

OBJECTIVES: To explore the therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. PATIENTS AND METHODS: Forty-one patients with synchronous metastatic renal cell carcinoma who received nivolumab plus ipilimumab as first-line systemic therapy at our affiliated institutions were retrospectively evaluated. We focused on the prognosis, including tumor responses in primary kidney and metastatic lesions in patients treated with deferred cytoreductive nephrectomy. In addition, the overall survival according to nephrectomy status (i.e. deferred cytoreductive nephrectomy vs. upfront cytoreductive nephrectomy vs. without cytoreductive nephrectomy) was compared. RESULTS: During a median follow-up period of 12.0 months, seven (30%) patients received deferred cytoreductive nephrectomy at a median time of 10.4 months after nivolumab plus ipilimumab initiation. All the patients showed tumor shrinkage in their primary kidney lesions, including six (86%) patients with ≥30% of shrinkage. Metastatic lesions were also shrunk by ≥30% in six (86%) patients, including two (29%) obtaining complete response. At the last time of follow-up, three (43%) patients were disease-free. The overall survival rate after nivolumab plus ipilimumab initiation tended to be higher in patients with deferred cytoreductive nephrectomy compared with those with upfront cytoreductive nephrectomy (1-year survival rate: 100% vs. 72.4%, P = 0.0587) and those without cytoreductive nephrectomy (vs. 58.2%, P = 0.0613). CONCLUSIONS: The present retrospective data showed that deferred cytoreductive nephrectomy had the potential to exert a therapeutic effect in a subset of patients who obtained favorable tumor responses to nivolumab plus ipilimumab for a certain period. Prospective randomized clinical trials are needed to confirm the prognostic impact of deferred cytoreductive nephrectomy after frontline immunotherapy in synchronous metastatic renal cell carcinoma.

Efficacy and Safety of Immunotherapy-Based Combinations as First-Line Therapy for Metastatic Renal Cell Carcinoma in Patients Who Do Not Meet Trial Eligibility Criteria.

BACKGROUND: Data regarding the efficacy and safety profiles of immune checkpoint inhibitors (ICIs) for metastatic renal cell carcinoma (mRCC) trial-ineligible patients in the real world remain unclear. OBJECTIVES: The aim of this study was to clarify the impact of trial eligibility on ICI-based combination therapy for mRCC. PATIENTS AND METHODS: We collected clinical data of mRCC patients receiving ICIs since 2016, and 222 patients were registered. Among these patients, we evaluated 93 patients treated with ICI-based combination therapy, including nivolumab plus ipilimumab, pembrolizumab plus axitinib, or avelumab plus axitinib, as first-line therapy. Patients were classified into the trial-ineligible group when they had at least one of the following factors at the time of treatment initiation: Karnofsky performance status (KPS) < 70%, hemoglobin level < 9.0 g/dL, estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2, platelet count < 100,000/µL, neutrophil count < 1500/µL, non-clear cell histology, or brain metastasis. The remaining patients were classified into the trial-eligible group. RESULTS: Forty-eight patients (52%) were classified into the trial-ineligible group. The frequency of patients with trial-ineligible factors was highest for low eGFR (n = 20, 45%), followed by non-clear cell histology (n = 17, 36%) and low KPS score (n = 12, 25%). There was no significant difference in progression-free survival (median: 24.0 vs. 11.0 months, p = 0.416), overall survival (1-year rate: 87.0% vs. 85.3%, p = 0.634), or objective response rate (52% vs. 42%, p = 0.308) between the trial-eligible and -ineligible patients. The incidence rate of adverse events was higher in the trial-eligible patients than in the trial-ineligible patients (91% vs. 75%, p = 0.0397); however, the rate of grade 3 or higher adverse events was comparable between the two groups (42% vs. 40%, p = 0.796). CONCLUSIONS: There are many trial-ineligible patients in the real world. Nevertheless, the efficacy and safety of ICI-based combination therapy in trial-ineligible patients were non-inferior compared with those of trial-eligible patients.

Efficacy of Cabozantinib for Papillary Compared With Clear-cell Renal Cell Carcinoma Following Immune Checkpoint Inhibitor Treatment.

BACKGROUND: The efficacy of combined immunotherapy for papillary renal cell carcinoma (pRCC) based on prolonged progression-free survival (PFS) and overall survival in several clinical trials remains unknown. We aimed to compare the efficacy of cabozantinib in patients with pRCC and those with clear-cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: This retrospective study included 27 patients with metastatic RCC who received cabozantinib as second-line or later therapy between June 2020 and October 2021. Objective response, PFS, and toxicity were compared between the ccRCC and pRCC groups. RESULTS: Out of 27 patients, seven and 20 were diagnosed with pRCC and ccRCC, respectively. Out of the seven patients with pRCC, cabozantinib was used as second-line treatment in four patients and as third-line treatment in three patients, and all seven patients had had prior immunotherapy. One and two patients achieved complete and partial responses, respectively; four patients had stable disease, and none had progressive disease. The rates of objective response (43% vs. 30%, p=0.65) and disease control (100% vs. 85%, p=0.54) were similarly high in patients with pRCC and ccRCC. Changes in the target lesions were -19% and -10% (p=0.11), respectively. With a median follow-up of 7.1 months, the median PFS tended to be longer in patients with pRCC than in those with ccRCC (not reached vs. 10.7 months, p=0.12). Discontinuation due to toxicity was observed in four (57%) patients with pRCC and 10 (50%) patients with ccRCC. CONCLUSION: Cabozantinib is effective for pRCC, similar to ccRCC. This information may help physicians to select treatment options for pRCC.

Changes in Real-World Outcomes in Patients with Metastatic Renal Cell Carcinoma from the Molecular-Targeted Therapy Era to the Immune Checkpoint Inhibitor Era.

BACKGROUND: Knowledge of changes in the outcome in patients with metastatic renal cell carcinoma from the molecular-targeted therapy era to the immune checkpoint inhibitor (ICI) era remains limited in the real-world setting. OBJECTIVES: We aimed to clarify outcome changes from the previous molecular-targeted therapy era to the current ICI era in patients with metastatic renal cell carcinoma using multi-institution real-world data. METHODS: We retrospectively evaluated 415 patients with metastatic renal cell carcinoma who received first-line systemic therapy at five Japanese institutions between January 2008 and August 2021. We divided the patients into two groups based on the treatment era: molecular-targeted therapy era (January 2008-August 2018) and ICI era (September 2018-August 2021). According to the era, progression-free survival, overall survival, and objective response rate from first-line systemic therapy were compared. RESULTS: Overall, 304 (73.3%) and 111 (26.7%) patients were categorized into the molecular-targeted therapy and ICI eras, respectively. The proportion of patients without prior nephrectomy (p = 0.0030) or those with low Karnofsky Performance Status scores [≤ 70] (p = 0.0258) were significantly higher in the ICI era group. The patients in the ICI era group had significantly longer overall survival (median: not reached vs 23.2 months, p = 0.0001) and a higher objective response rate (47.8% vs 24.7%, p < 0.0001) than those in the molecular-targeted therapy era group, and progression-free survival tended to be longer in the ICI era group (median: 13.3 vs 8.75 months, p = 0.0579). Multivariate analysis further showed that the treatment era (ICI vs molecular-targeted therapy) was an independent factor for overall survival and objective response (both, p < 0.0001). CONCLUSIONS: The present multi-institution real-world data showed the improved outcome of previously untreated patients with metastatic renal cell carcinoma in the ICI era group compared with that in the molecular-targeted therapy era group. These findings strongly encourage the use of ICI-based treatment for patients with metastatic renal cell carcinoma in the real-world setting. Further studies with extended follow-up periods are needed to confirm our findings.

Outcomes of nivolumab monotherapy for previously treated metastatic renal cell carcinoma: a real-world multi-institution data with a minimum of 2 years of follow-up.

OBJECTIVES: To investigate the long-term follow-up outcomes of nivolumab monotherapy for previously treated metastatic renal cell carcinoma, using real-world data. METHODS: A total of 121 patients were treated with nivolumab monotherapy as subsequent therapy after the failure of prior tyrosine kinase inhibitor therapy between January 2013 and December 2021 at four affiliated institutions. To evaluate the outcome after 2 years or more, we selected patients in whom nivolumab therapy was started in December 2019 or earlier because data collection was performed until the end of December 2021. RESULTS: Seventy-four patients were evaluated. During the median follow-up period of 25.8 months, 62 (84%) and 40 (54%) patients had disease progression and died, respectively. Nivolumab was administered as second-line therapy in 43 patients (58%). The median progression-free survival and overall survival were 5.52 and 31.1 months, respectively, and objective response rate was 36%. There was no difference in progression-free survival or overall survival based on the treatment line of nivolumab (P = 0.915, P = 0.559). The magnitude of tumor response and development of immune-related adverse events were significantly associated with progression-free survival (P < 0.0001, P < 0.0001, respectively) and overall survival (P < 0.0001, P = 0.0002, respectively). Treatment-related adverse events developed in 38 patients (51%), including 33 (45%) who had immune-related adverse events. Steroid administration was needed in nine patients (12%). CONCLUSIONS: The present real-world multi-institution study with long-term follow-up data demonstrates that nivolumab monotherapy is effective for previously treated metastatic renal cell carcinoma, prolonging survival, improving tumor response and has a manageable safety profile.

Efficacy and safety of immune checkpoint inhibitors in elderly patients with metastatic renal cell carcinoma.

PURPOSE: To clarify the efficacy and safety profile of immune checkpoint inhibitors (ICIs) for elderly patients with metastatic renal cell carcinoma (mRCC). METHODS: We retrospectively evaluated 149 mRCC patients treated with nivolumab monotherapy as subsequent therapy (n = 89) and nivolumab plus ipilimumab as first-line therapy (n = 60) at 5 affiliated institutions. The patients were divided according to age: > 70 (elderly) vs. ≤ 70 years (young). Efficacy was analyzed by comparing progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) between elderly and young patients. Safety was assessed by comparing the incidence rates of immune-related adverse events (irAEs). RESULTS: In the nivolumab monotherapy group, 34/89 patients (38%) were classified as elderly. There was no significant difference in PFS (p = 0.607), OS (p = 0.383), ORR (p = 0.0699), or DCR (p = 0.881) between elderly and young patients. In the nivolumab plus ipilimumab group, 20/60 patients (33%) were classified as elderly. There was no significant difference in PFS (p = 0.995), OS (p = 0.714), ORR (p = 0.763), or DCR (p = 1.000) between the two groups. The incidence rate of irAEs was not significantly different in the nivolumab (any grade: p = 0.121; grade ≥ 3: p = 0.542) or in the nivolumab plus ipilimumab (any grade: p = 0.666; grade ≥ 3: p = 0.576) group; a higher rate of gastrointestinal irAEs was observed in elderly than in young patients (any grade 15% vs. 3%). CONCLUSIONS: The efficacy and safety of nivolumab monotherapy and nivolumab plus ipilimumab were comparable between elderly and young patients. Thus, chronological age alone should not be a contraindication in the use of ICIs for mRCC.

Predictive Impact of Early Changes in Serum C-Reactive Protein Levels in Nivolumab Plus Ipilimumab Therapy for Metastatic Renal Cell Carcinoma.

BACKGROUND: Serum C-reactive protein (CRP) is reportedly associated with metastatic renal cell carcinoma (mRCC) activity. However, in the era of immune checkpoint inhibitors, the predictive value of CRP is unclear. In this study, we investigated the predictive impact of pretreatment CRP levels and early changes in CRP levels for the treatment of mRCC with nivolumab plus ipilimumab (NIVO-IPI) therapy. METHODS: Forty-eight patients with mRCC treated with NIVO-IPI as a first-line therapy were retrospectively analyzed. First, patients were divided into 2 groups: initial CRP ≥ 1.0 mg/dL and < 1.0 mg/dL. Progression-free survival (PFS) was compared between the 2 groups. Second, based on the CRP change within the first 3 months of NIVO-IPI, patients were placed in the normal group (CRP remains < 1.0 mg/dL), normalized group (CRP decreased < 1.0 mg/dL), and non-normalized group (CRP remained or increased to ≥ 1.0 mg/dL). The predictive association between CRP change and PFS was evaluated. RESULTS: PFS was significantly lower in the high initial CRP group (n = 24, 50%) compared to the normal CRP group (n = 24, 50%) (median: 4.3 vs. 28.1 months, P = .03). As for the early CRP change, the normal (2.7 vs. 28.1, P = .0002) and normalized (2.7 vs. 11.0, P = .0094) groups showed significantly higher PFS, compared to the non-normalized group. Meanwhile, there was no significant difference between normal, and normalized groups (P = .51). The objective response rate was higher in the normal (57.1% vs. 18.7%, P = .015) and normalized (81.8 vs. 18.7%, P = .0008) groups, compared to the non-normalized group. Multivariate Cox regression analysis showed that normal [Hazard ratio (HR) = 0.15, 95% Confidence interval (CI) = 0.02-0.70, P = .026] and normalized (HR 0.21, 95% CI = 0.05-0.73, P = .015) CRP showed significant association with PFS. CONCLUSION: In the NIVO-IPI therapy for mRCC, early changes in CRP could predict PFS. This data may be useful for the early detection of ineffective NIVO-IPI therapy and conversion to subsequent therapies.

Association of tumor burden with outcome in first-line therapy with nivolumab plus ipilimumab for previously untreated metastatic renal cell carcinoma.

OBJECTIVES: To investigate the prognostic impact of tumor burden in patients receiving nivolumab plus ipilimumab as first-line therapy for previously untreated metastatic renal cell carcinoma (mRCC). METHODS: We retrospectively evaluated 62 patients with IMDC intermediate- or poor-risk mRCC, treated with nivolumab plus ipilimumab as first-line therapy at five affiliated institutions. Tumor burden was defined as the sum of diameters of baseline targeted lesions according to the RECIST version.1.1. We categorized the patients into two groups based on the median value of tumor burden (i.e., high vs. low). The association of tumor burden with progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) with nivolumab plus ipilimumab treatment was analyzed. RESULTS: The median tumor burden was 63.0 cm (interquartile range: 34.2-125.8). PFS was significantly shorter in patients with high tumor burden (n = 31) than in those with low tumor burden (n = 31) (median: 6.08 [95% CI: 2.73-9.70] vs. 12.5 [4.77-24.0] months, P = 0.0134). In addition, OS tended to be shorter in patients with high tumor burden; however, there was no statistically significant difference (1-year rate: 77.3 vs. 96.7%, P = 0.166). ORR was not significantly different between patients with high and low tumor burden (35 vs. 55%, P = 0.202). Multivariate analysis of PFS further showed that tumor burden was an independent factor (HR: 2.22 [95% CI: 1.11-4.45], P = 0.0242). CONCLUSIONS: Tumor burden might be a useful factor for outcome prediction, at least for PFS prediction, in patients receiving nivolumab plus ipilimumab for mRCC. Further prospective studies are warranted to confirm our findings.

Antibiotic use and survival of patients receiving pembrolizumab for chemotherapy-resistant metastatic urothelial carcinoma.

OBJECTIVES: The use of antibiotics alters gut microbiota and has been reported to impact outcomes in immune checkpoint inhibitor (ICI) treatment in various types of cancer. We investigated the impact of antibiotics on patients with metastatic urothelial carcinoma (mUC) treated with pembrolizumab. MATERIALS AND METHODS: The data of 67 patients with chemotherapy-resistant mUC who were treated with pembrolizumab were retrospectively evaluated. The patients were classified into groups according to antibiotic status (with-antibiotic and without-antibiotic), and the progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) were compared between the 2 groups. RESULTS: PFS (median: 1.1 vs. 8.9 months; P < 0.001) and OS (median: 2.3 vs. 19.5 months; P < 0.001) were significantly shorter in the with-antibiotic group (n = 15, 22%) than in the without-antibiotic group (n = 52, 78%). Patients in the with-antibiotic group had significantly higher Eastern Cooperative Oncology Group performance status scores (P = 0.042). Multivariable analyses revealed antibiotic use as an independent predictor of PFS (P < 0.001) and OS (P = 0.002). No patients in the with-antibiotic group achieved a complete response to pembrolizumab. The ORR (complete response (CR) + partial response (PR)) was higher among patients not treated with antibiotics than among patients treated with antibiotics, though the difference was not significant (34.6% vs. 13.3%, P = 0.093). The DCR (CR + PR + stable disease) was also higher among patients in the with-antibiotic group than in the without-antibiotic group (57.7% vs. 20.0%, P = 0.008). CONCLUSION: The use of antibiotics was negatively associated with outcomes in patients with mUC who are administered pembrolizumab. Baseline performance status was worse for these patients. Further analyses are required to identify associations between antibiotic use, bacterial infection for which it was indicated or its influence on performance status, on treatment outcomes.