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.

Renal cell carcinoma outcomes in end-stage renal disease: A 40-year study from two Japanese institutions.

OBJECTIVES: The objective of the study was to analyze the outcomes of patients with renal cell carcinoma (RCC) arising in end-stage renal disease (ESRD) over a 40-year span. METHODS: We retrospectively evaluated data of patients with ESRD-RCC diagnosed between 1979 and 2020 at two institutions. We assessed changes in stage, surgical approaches, and cancer-specific survival (CSS) following nephrectomy according to era between ESRD-RCC and sporadic RCC. Furthermore, perioperative outcomes in patients with ESRD-RCC were compared between laparoscopic and open surgery. RESULTS: Patients with ESRD-RCC (n = 549) were diagnosed at an earlier stage (p = 0.0276), and the ratio of laparoscopic nephrectomy was increased (p < 0.0001) according to eras. Since 2000 (i.e., after implementation of laparoscopic nephrectomy), patients with ESRD-RCC (n = 305) had significantly shorter CSS (p = 0.0063) after nephrectomy than sporadic RCC (n = 2732). After adjustment by multivariate analysis and propensity score matching, ESRD status was independently associated with shorter CSS (p = 0.0055 and p = 0.0473, respectively). Improved CSS in sporadic RCC (p < 0.0001), but not ESRD-RCC (p = 0.904), according to era contributed to this difference. Laparoscopic nephrectomy showed favorable outcomes, including shorter surgery time, lower estimated bleeding volumes, transfusion rates, and readmission rates, and shorter postoperative hospitalization than open nephrectomy (p < 0.05). CONCLUSIONS: Advances in diagnostic and treatment modalities potentially enable early diagnosis and minimally invasive surgery for patients with ESRD-RCC. As ESRD-RCC may not present indolently, careful post-operative monitoring is needed.

Predictive factors and oncological outcomes of pathological T3a upstaging in patients with clinical T1 renal cell carcinoma undergoing partial nephrectomy.

OBJECTIVES: To investigate predictive factors and oncological outcomes of pathological T3a upstaging in renal cell carcinoma patients who were initially diagnosed as clinical T1 and treated with partial nephrectomy. METHODS AND MATERIALS: The clinical records and survival data of 1617 patients, who had undergone partial nephrectomy for clinical T1 renal cell carcinoma at Tokyo Women's Medical University, Tokyo, Japan between January 2011 and December 2020, were analyzed retrospectively. RESULTS: Of 1617 clinical T1 renal cell carcinoma patients who underwent partial nephrectomy, 28 (1.73%) had pathological T3a upstaging. In the multivariable analysis for pathological T3a upstaging using logistic regression models, male sex and clinical T1b were significant factors associated with pathological T3a upstaging (male sex: odds ratio = 5.07, 95% confidence interval: 1.18-21.8, clinical T1b: odds ratio = 8.36, 95% confidence interval: 3.56-19.6). The Kaplan-Meier method of the recurrence-free survival showed shorter recurrence-free survival in patients with pathological T3a upstaging than in those with pathological T1 (P < 0.0001). In the multivariable analysis using Cox proportional hazards regression models, pathological T3a upstaging was no longer significantly associated with recurrence-free survival after adjustment for other pathological factors (hazard ratio = 1.59, 95% confidence interval: 0.58-4.36). In a sensitivity analysis that analyzed its components individually instead of whole pathological T3a, neither perinephric fat invasion, sinus fat invasion, nor renal vein invasion was associated with recurrence-free survival. CONCLUSIONS: Male sex and clinical T1b were significant predictors for pathological T3a upstaging after partial nephrectomy in clinical T1 renal cell carcinoma patients. Although patients with pathological T3a upstaging had worse recurrence-free survival compared with those without upstaging, multivariable analyses revealed that pathological T3a upstaging was not an independent predictor for poor recurrence-free survival.

Surgical and functional outcomes of repeat robot-assisted laparoscopic partial nephrectomy compared with repeat open partial nephrectomy.

OBJECTIVES: To examine the surgical and functional outcomes of patients who have undergone repeat open partial nephrectomy (reOPN) or robot-assisted laparoscopic partial nephrectomy (reRAPN). METHODS: Until May 2022, 3310 patients with renal tumors underwent nephron-sparing surgery (NSS) at affiliated institutions. Of these, 22 and 17 patients who underwent reOPN and reRAPN, respectively, were included in this study. RESULTS: No significant differences were found between the groups in terms of sex, age, comorbidities, recurrent tumor size at repeat NSS, interval from recurrence to initial NSS, and nephrometry score. ReRAPN had a shorter operative time (median: 138.0 vs. 214.0 min; p = 0.0023) and less estimated blood loss (median: 50.0 vs. 255.0 mL; p = 0.0261) than reOPN. The incidence of complications with Clavien-Dindo grade ≥ 2 was higher in the reOPN group than in the reRAPN group (31.8 vs. 5.9%; p = 0.0467). The mean decrease in the estimated glomerular filtration rate at 3 months postoperatively was not significantly different between the groups. The trifecta achievement rates in the reRAPN (64.7%) and reOPN (27.3%) groups were significantly different (p = 0.0194). On multivariate analysis, age and surgical method were significant predictors of trifecta achievement after partial nephrectomy. CONCLUSIONS: There were no differences in postoperative renal functional outcomes between reOPN and reRAPN. ReRAPN is superior to reOPN in terms of surgical burden. Therefore, ReRAPN is an important minimally invasive surgery for recurrent renal cell carcinoma.

A retrospective cohort study of the impact of peripheral blood gamma- delta T cells to prognosis of nonmetastatic renal cell cancer after curative resection.

AIM: Gamma-delta-T cells (γδT) have potential antitumor roles and have recently been applied in adoptive immunotherapy. In the present study, we focused on the proportion of γδT cells in the peripheral blood just before surgery for renal cell cancer (RCC) and investigated whether their proportion affected recurrence-free survival (RFS) and overall survival (OS) retrospectively. PATIENTS AND METHODS: A total of 137 patients with localized, non-metastatic RCC who received surgery at our institutes were analyzed retrospectively. The patients were divided into 2 groups: normal and low γδT cell groups based on the proportion of peripheral blood γδT cells. Kaplan-Meier curves were constructed to access the association of the proportion of peripheral blood γδT cells to RFS and OS. Cox regression were also constructed to access the risks to prognosis. Uni- and multivariate logistic regressions were performed to access associations between risk factors and, RFS and OS. RESULTS: Among 137 patients, 40 had a proportion of γδT cells in peripheral blood of less than 1%, which was below the normal range. The remaining 97 patients had these cells in peripheral blood at 1% or higher. In the groups with low γδT cells, 13 patients had recurrences, and 9 patients dies during the observation period. In the groups with normal γδT cells, 16 patients had recurrences, and 8 patients died. The normal γδT cell group demonstrated significantly better prognosis in terms of RFS and OS. Multivariate analysis revealed that a low hemoglobin level, a low proportion of γδT cells, and a high pathological T stage (pT) were statistically independent risk factors for RFS. Age, albumin, C-reactive protein (CRP), % γδT cells, and pT were statistically significant factors affecting OS and only pT was an independent risk factor by multivariate analysis. CONCLUSION: A low proportion of γδT cells was identified as one of the risk factors for RFS. Our findings will provide clues to develop strategies for early intervention in preventing recurrence even after complete resection of RCC and, such as adoptive immunotherapy using autologous γδT cells in patients with a low proportion of γδT cells.

Clinical Trial on the Safety and Tolerability of Personalized Cancer Vaccines Using Human Platelet Lysate-Induced Antigen-Presenting Cells.

Research and development of personalized cancer vaccines as precision medicine are ongoing. We predicted human leukocyte antigen (HLA)-compatible cancer antigen candidate peptides based on patient-specific cancer genomic profiles and performed a Phase I clinical trial for the safety and tolerability of cancer vaccines with human platelet lysate-induced antigen-presenting cells (HPL-APCs) from peripheral monocytes. Among the five enrolled patients, two patients completed six doses per course (2-3 × 107 cells per dose), and an interim analysis was performed based on the immune response. An immune response was detected by enzyme-linked immunosorbent spot (ELISpot) assays to HLA-A*33:03-matched KRASWT, HLA-DRB1*09:01-compliant KRASWT or G12D, or HLA-A*31:01-matched SMAD4WT, and HLA-DRB1*04:01-matched SMAD4G365D peptides in two completed cases, respectively. Moreover, SMAD4WT-specific CD8+ effector memory T cells were amplified. However, an attenuation of the acquired immune response was observed 6 months after one course of cancer vaccination as the disease progressed. This study confirmed the safety and tolerability of HPL-APCs in advanced and recurrent cancers refractory to standard therapy and is the first clinical report to demonstrate the immunoinducibility of personalized cancer vaccines using HPL-APCs. Phase II clinical trials to determine immune responses with optimized adjuvant drugs and continued administration are expected to demonstrate efficacy.

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.

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.

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 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.

Surgical and functional outcomes of robot-assisted laparoscopic partial nephrectomy for renal cell carcinoma in adolescents and young adults: a propensity score matching study.

BACKGROUND: Cancer development in adolescents and young adults (AYAs) has elicited recent interest. We investigated the surgical and functional outcomes of robot-assisted laparoscopic partial nephrectomy (RAPN) for renal cell carcinoma (RCC) in AYAs. METHODS: We retrospectively reviewed the medical records of 1023 patients with clinical stage I RCC who underwent RAPN before January 2021. Patients were divided into two groups: AYAs (aged 18-39 years) and non-AYAs (aged 40-89 years). The trifecta criteria, defined as a negative surgical margin, no perioperative complications (Clavien-Dindo grade > 2), and preserved postoperative renal function (1-year postoperative estimated glomerular filtration rate > 90% of baseline), were used to compare outcomes. We performed 1:1 propensity-score matching on the patient cohort. RESULTS: There were initially 125 and 898 patients in the AYAs and non-AYAs groups, respectively, and 108 patients were included in each group after propensity score matching. There were no significant differences in surgical factors (operation time, clamping ischemia time, estimated blood loss, length of hospital stay, surgical complication rate) or renal function in the early postoperative period. The mean postoperative renal function was better (p = 0.0200) and the decrease in estimated glomerular filtration rate was lower (p = 0.0026) in AYAs than in non-AYAs 12 months postoperatively. The trifecta achievement rates in the AYAs and non-AYAs groups were significantly different (67.6% and 53.7%, respectively, p = 0.0220). CONCLUSION: Although there was no difference in surgical burden between the groups, the estimated glomerular filtration rate was better preserved in AYAs than in non-AYAs at 6 and 12 months post-RAPN.

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.

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.

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.

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.

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.

Prognostic Impact of Trial-Eligibility Criteria in Patients with Metastatic Renal Cell Carcinoma.

OBJECTIVE: The aim of the study was to evaluate the prognostic impact of trial-eligibility criteria on outcome in real-world metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors (TKIs). PATIENTS AND METHODS: mRCC patients treated with TKIs as first-line systemic therapy were retrospectively evaluated. The patients were determined as trial-ineligible when they met at least 1 following trial-ineligible criteria; Karnofsky performance status score <70, hemoglobin <9.0 g/dL, creatinine >2.4 mg/dL (male) or >2.0 mg/dL (female), calcium >12.0 mg/dL, platelet <100,000 /µL, neutrophil <1,500 /µL, nonclear-cell histology, and brain metastasis. RESULTS: Of 238 patients, 101 patients (42%) were determined as trial-ineligible. Progression-free survival (PFS) and overall survival (OS) after the TKI initiation were significantly shorter in the trial-ineligible patients than in the trial-eligible patients (median PFS: 5.53 vs. 15.8 months, p < 0.0001; OS: 13.8 vs. 43.4 months, p < 0.0001). Objective response rate was also significantly lower in the trial-ineligible patients (15% vs. 37%, p = 0.0003). Multivariate analysis further showed that the trial-eligibility was an independent factor for PFS (hazard ratio [HR]: 2.46, p < 0.0001) and OS (HR: 2.39, p < 0.0001). In addition, the number of trial-ineligible factors were negatively correlated with PFS and OS. CONCLUSIONS: In real-word, the substantial number of mRCC patients did not meet the trial-eligibility criteria, and their outcome was worse than that in the trial-eligible patients. Further studies focusing on the outcome in real-world trial-ineligible patients in the immune checkpoint inhibitor era are warranted.

Hypopituitarism in patients with metastatic renal cell carcinoma treated with ipilimumab and nivolumab combination therapy.

OBJECTIVE: We investigated the incidence of hypopituitarism in Japanese patients with metastatic renal cell carcinoma (mRCC) who received ipilimumab and nivolumab (I-P) therapy and compared patient characteristics and survival rates between patients with hypopituitarism and those without. METHODS: Twenty-two patients with mRCC who received I-P therapy as first-line treatment were the subjects of this retrospective study. The diagnosis of hypopituitarism was based on the hormone loading test. RESULTS: Hypopituitarism occurred in 41% (9/22) patients who received I-P therapy. Median time of diagnosis was 12 weeks (IQR: 9.5-20). Clinical symptoms, such as fatigue, weakness or fever, were observed in 7 patients, while 2 patients had no clinical presentation. The following deficiency patterns were observed: isolated ACTH in 4 patients, ACTH and GH in 2 patients, ACTH and TSH in 2 patients and triple deficiency (ACTH, GH and TSH) in 1 patient. All patients with hypopituitarism were in the IMDC intermediate group, while 46% of those without hypopituitarism were in the IMDC intermediate group. Other patient characteristics were not different between the two groups. Object response rate was 33% (3/9) in patients with hypopituitarism and 23% (3/13) in those without (P = 0.5954). Progression free survival (PFS) was significantly longer in those with hypopituitarism than those without (median: 24.7 vs. 4.5 months, P = 0.0008), while overall survival did not differ (P = 0.136). CONCLUSIONS: Compared with the clinical trial, the incidence of hypopituitarism was higher than expected. Patients with hypopituitarism tended to have longer PFS, which may suggest that optimal management of hypopituitarism results in better prognosis.

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.