Durable Response to Enfortumab Vedotin Compared to Re-challenging Chemotherapy in Metastatic Urothelial Carcinoma After Checkpoint Inhibitors.

BACKGROUND: Enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, has been used for patients with metastatic urothelial carcinoma (mUC) after progressing on checkpoint inhibitors (CPIs). Re-challenging chemotherapy with platinum agents and continuing CPIs beyond progressive disease (PD) have often been chosen following PD on CPIs, and several studies indicate favorable treatment effects of re-challenging chemotherapy. There is little evidence for comparing EV and re-challenging chemotherapy in real-world clinical practice. OBJECTIVE: The aim was to reveal the real-world treatment outcomes of EV, re-challenging chemotherapy, and continuing CPIs beyond PD in mUC patients. PATIENTS AND METHODS: A multi-institutional dataset of 350 mUC patients treated with CPIs was utilized. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) were evaluated to compare the treatment arms. RESULTS: One hundred and nine mUC patients were treated with EV with a median follow-up of 6.4 months. The ORR and disease control rate (DCR) were 48% and 70%, respectively. The OS from PD on pembrolizumab exhibited significant differences among the three groups, with a median OS of 8, 14, and 29 months in continuing pembrolizumab beyond PD, re-challenging chemotherapy, and EV, respectively. When comparing the survival outcomes from the initiation of the treatment, there is neither a difference in OS (p = 0.124), PFS (p = 0.936), nor ORR (p = 0.816) between EV and re-challenging chemotherapy. Notably, the DOR in patients who achieved an objective response was significantly longer in the EV group than the re-challenging chemotherapy group (a median of 11 and 5 months, p = 0.049). For OS, the difference was not statistically significant (27 and 11 months in EV and re-challenging chemotherapy, respectively: p = 0.05). CONCLUSIONS: A superior effect of EV on patient survival compared to re-challenging chemotherapy and continuing pembrolizumab beyond PD was observed in our real-world analysis, which is attributed to the durable DOR in EV treatment despite the similar ORR to re-challenging chemotherapy.

Enfortumab vedotin (EV) is an antibody­drug conjugate targeting Nectin-4 and is now utilized for patients with metastatic urothelial carcinoma following treatment with checkpoint inhibitors (CPIs). Until recently, repeating chemotherapy using platinum drugs or continuing CPIs were often the treatments used for these patients. In the present study, we reported real-world treatment outcomes, mainly focusing on EV and repeating chemotherapy. Although the objective responses to the treatments were comparable, the duration of response for patients responding to the treatment was significantly longer in patients treated with EV than in those repeating chemotherapy, resulting in extended survival time with EV treatment.

Prognostic Impact of Immune-Related Adverse Events as First-Line Therapy for Metastatic Renal Cell Carcinoma Treated With Nivolumab Plus Ipilimumab: A Multicenter Retrospective Study.

BACKGROUND: Immune checkpoint inhibitors can cause various immune-related adverse events (irAEs). This study aimed to evaluate the association between the incidence of irAEs and oncological outcomes of metastatic renal cell carcinoma (mRCC) treated with nivolumab plus ipilimumab as first-line therapy. PATIENTS AND METHODS: We retrospectively analyzed data from 69 patients with mRCC treated with nivolumab plus ipilimumab as first-line therapy between September 2018 and September 2021 at 4 institutions. Cox regression analyses were performed to investigate the important factors affecting overall survival (OS) in patients with mRCC treated with nivolumab plus ipilimumab as first-line therapy. RESULTS: During observation with a median follow-up of 9.1 months, the median OS was not reached, while the median progression-free survival was 6.0 months. Patients with irAEs had significantly prolonged OS and progression-free survival than those without irAEs (p = .012 and .002, respectively). Multivariate analysis showed that 3 independent factors, including C-reactive protein (CRP), irAEs, and performance status (PS), were significantly associated with OS (p = .04, .02, and .01, respectively). The patients were subsequently divided into 3 groups as follows: group 1, 20 patients with all 3 independent OS predictors; group 2, 18 patients with irAE predictors alone or 2 positive independent OS predictors (irAEs + CRP or irAEs + PS); group 3, 31 patients with 3 negative independent S predictors. OS varied significantly among the 3 groups (p = .004). CONCLUSION: The appearance of irAEs could predict OS in patients with mRCC treated with nivolumab plus ipilimumab as the first-line therapy.

Predicting Objective Response of Pembrolizumab in Platinum-Refractory Urothelial Carcinoma Based on NLR Fluctuation and Liver Metastases.

BACKGROUND AND PURPOSE: It is well known that patients with objective response to pembrolizumab have a durable duration of response leading to favorable survival outcomes. We investigated the possibility of predicting the objective response with concise indicators obtained from daily clinical practice. Methods In our multi-institutional cohort, 220 platinum-refractory metastatic urothelial carcinomas (mUC) treated with pembrolizumab for at least six weeks with complete information of objective response were investigated. Results The median follow-up was 7.3 months, and 119 patients deceased during the follow-up. A multivariate logistic regression analysis exhibited two independent variables predicting the objective response, including the neutrophil-lymphocyte ratio (NLR) change at six weeks of treatment and liver metastasis. We proposed a risk group using these two indicators. Patients with no predictive indicators / one of those were assigned to favorable (42%) / intermittent (47%) risk groups. Patients with both indicators were assigned to poor risk (11%). Notably, the objective response rate was well delineated in 41%, 25%, and 0% for favorable, intermediate, and poor risk groups, respectively (p<0.001). Distinct overall survival (OS) between the risk groups was also confirmed with the median OS of 14.1, 11.7, and 4.2 months in favorable, intermediate, and poor risk groups, respectively. CONCLUSIONS: At the six weeks of the pembrolizumab treatment, our risk model predicts the objective response rate precisely. Notably, those classified as 'poor risk'-marked by liver metastasis and a heightened NLR-should be considered for alternative therapy with a different mode of action, highlighting a critical decision point in treatment optimization.

Real-world survival outcome comparing abiraterone acetate plus prednisone and enzalutamide for nonmetastatic castration-resistant prostate cancer.

BACKGROUND: There is little evidence of abiraterone acetate (AA) plus prednisone for patients with non-metastatic castration-resistant prostate cancer (nmCRPC). In this study, we conducted a comparative analysis of real-world survival outcomes between AA plus prednisone and enzalutamide (Enz) in patients with nmCRPC, utilizing our consortium dataset. MATERIALS AND METHODS: The clinical records of 133 nmCRPC patients treated with first-line Enz or AA plus prednisone were analyzed. The primary endpoints of the study were overall survival (OS) and cancer-specific survival (CSS). Cumulative incidence function (CIF) using Fine and Gray models was also utilized to assess non-cancer-caused death considering the competing risk of cancer-caused death. RESULTS: During a median follow-up of 36 months, 34 patients (25.6%) had deceased, with a median OS of 99 months in the entire cohort. There were no significant differences in comorbidities between the Enz and AA groups. Time to PSA progression (TTPP: HR 0.81, 95% CI 0.51-1.30, P = 0.375) and CSS (HR 1.32, 95% CI 0.55-3.44, P = 0.5141) were comparable between the two groups. However, intriguingly, there was a trend towards shorter OS in patients treated with AA plus prednisone compared to Enz (HR 0.57, 95% CI 0.29-1.12, P = 0.0978, median of 99 and 69 months in Enz and AA groups, respectively). CIF analysis revealed that nmCRPC patients treated with AA plus prednisone were more likely to result in non-cancer-caused death than those treated with Enz (HR 5.22, 95% CI 1.88-14.50, P = 0.0014). CONCLUSIONS: Our real-world survival analysis suggests that while AA plus prednisone may demonstrate comparable treatment efficacy to Enz in the context of nmCRPC, there may be an increased risk of non-cancer-caused death. Physicians should take into consideration this information when making treatment decisions for patients with nmCRPC.

Re-challenging chemotherapy after pembrolizumab in platinum-refractory urothelial carcinoma.

OBJECTIVES: To assess the real-world clinical benefit of re-challenging chemotherapy after pembrolizumab in patients with metastatic urothelial carcinoma (mUC), as there have been several reports suggesting that programmed cell death protein-1/programmed death-ligand 1inhibitors can restore platinum sensitivity. PATIENTS AND METHODS: Of 236 patients treated with pembrolizumab, we excluded 45 patients who did not experience progressive disease (PD) for pembrolizumab during the follow-up and 86 patients who discontinued pembrolizumab by the diagnosis of PD followed by the best supportive care. A total of 105 patients were identified for a logistic regression propensity score model to compare the survival outcomes between patients treated with continuing pembrolizumab (80) and re-challenging chemotherapy (25) after the diagnosis of PD for pembrolizumab. RESULTS: A median overall survival (OS) from PD for pembrolizumab was 11 months in 105 patients. Of 25 patients treated with re-challenging chemotherapy, platinum-including chemotherapy (gemcitabine and cisplatin; gemcitabine/cisplatin/paclitaxel [GCP]; methotrexate and vinblastine and adriamycin and cisplatin; and methotrexate and carboplatin and vinblastine MCAVI) was offered in 20 patients (80%). The objective response rate (ORR) for the first-line chemotherapy in the 105 patients was 30%, with a comparable ORR in 25 patients treated with re-challenging chemotherapy of 28%. GCP as a re-challenging regimen was offered in 12 of 25 (48%) patients. The ORR for the GCP regimen was 50%. Propensity score matching was performed using putative clinical factors, from which 34 patients were identified as pair-matched groups. The OS for patients treated with re-challenging chemotherapy was significantly longer than continuing pembrolizumab (a median of 13.9 and 5.8 months, respectively: P = 0.048). CONCLUSION: Re-challenging chemotherapy including platinum agents after PD with pembrolizumab offers clinical benefits in patients with mUC.

Concurrent palliative radiation with pembrolizumab for platinum-refractory urothelial carcinoma is associated with improved overall survival.

Background and Purpose: Pembrolizumab has now become a standard of care in metastatic urothelial carcinoma (mUC), although the treatment effect of the drug substantially differs among individuals. Emerging evidence suggests that radiotherapy exerts a synergistic effect with PD-1 blockade. We sought to elucidate the survival outcomes in patients who underwent palliative radiation with the pembrolizumab treatment. Methods: We retrospectively investigated our multi-institutional dataset of 235 platinum-refractory mUC patients treated with pembrolizumab as second-line treatment, collected from January 2018 and October 2021. Propensity score matching was performed to reduce biases by potential confounding factors for overall survival (OS). Results: With a median follow-up of 6.8 months, the median OS from the initiation of pembrolizumab was 13 months in 235 patients. Palliative radiation was performed in 71 (30.2%) patients for whom the median radiation dose and fraction were 30 Gy and 10 fractions, respectively. Irradiated sites were bone in 24 (33.8%), lymph node in 17 (23.9%), lung in 3 (4.2%), brain in 8 (11.3%), and other sites in 19 (26.8%). OS from the initiation of pembrolizumab was significantly longer in patients who underwent concurrent palliative radiation with pembrolizumab (39 patients: median OS: 21 months) than in both patients with palliative radiation before pembrolizumab (32 patients: median OS: 9 months) (p = 0.001) and those without palliative radiation throughout the follow-up (164 patients: median OS: 13 months) (p = 0.019). After the propensity-score matching by putative confounding factors, longer OS in patients treated with concurrent palliative radiation with pembrolizumab (n = 36) was still observed compared to patients without the concurrent palliative radiation (n = 36) in the pair matched cohort (median OS of 29 and 13 months, respectively, p = 0.033). Conclusions: Our findings suggest that the concurrent administration of palliative radiation with pembrolizumab offers a favorable effect on OS in platinum-refractory mUC patients.

Serum C-reactive Protein Level Predicts Overall Survival for Clear Cell and Non-Clear Cell Renal Cell Carcinoma Treated with Ipilimumab plus Nivolumab.

Serum C-reactive protein (CRP) is known to be a biomarker for systemic inflammatory reactions. In the present study, we sought to measure the predictive value of serum CRP level for metastatic renal cell carcinoma (mRCC) treated with first-line ipilimumab and nivolumab using our real-world clinical dataset including non-clear cell RCC (nccRCC). The clinical record of patients who underwent the first-line ipilimumab plus nivolumab treatment for mRCC including ccRCC and nccRCC from 2018 to 2021 was retrospectively analyzed. All patients were diagnosed with either intermediate or poor-risk group defined by IMCD (international metastatic RCC database consortium). In total, 74 patients were involved. The median age was 68 years and 24 (32.4%) patients deceased during the follow-up. Forty-five (61%) and 29 (39%) patients were classified into intermediate and poor-risk groups. The one-year overall survival (OS) rate and objective response rate were 65% and 41% for all 74 mRCC patients, respectively. The receiver operating characteristic curve identified 1.0 mg/dL of serum CRP level as an ideal cut-off for predicting overall survival (OS). Serum CRP > 1.0 mg/dL and nccRCC were the independent predictors for OS in 74 mRCC patients. OS for patients with CRP > 1 mg/dL was significantly shorter than those with CRP < 1 mg/dL in both ccRCC (58 patient: p = 0.009) and nccRCC (16 patients: p = 0.008). The present study indicated that serum CRP level is a prognostic indicator for OS in both ccRCC and nccRCC patients treated with the first-line ipilimumab plus nivolumab treatment.

Alanine-Serine-Cysteine Transporter 2 Inhibition Suppresses Prostate Cancer Cell Growth In Vitro.

Alanine-serine-cysteine transporter 2 (ASCT2) has been associated with increased levels of metabolism in various malignant tumors. However, its biological significance in the proliferation of prostate cancer (PCa) cells remains under investigation. We used the cBioPortal database to assess the effect of ASCT2 expression on the oncological outcomes of 108 PCa patients. To evaluate the function of ASCT2 in castration-sensitive PCa (CSPC) and castration-resistant PCa (CRPC), LNCaP cells and the ARV7-positive PCa cell line, 22Rv1, were assessed using cell proliferation assays and Western blot analyses. The ASCT2 expression level was associated with biochemical recurrence-free survival after prostatectomy in patients with a Gleason score ≥ 7. In vitro experiments indicated that the growth of LNCaP cells after combination therapy of ASCT2 siRNA and enzalutamide treatment was significantly reduced, compared to that following treatment with enzalutamide alone or ASCT2 siRNA transfection alone (p < 0.01, 0.01, respectively). After ASCT2 inhibition by siRNA transfection, the growth of 22Rv1 cells was significantly suppressed as compared with negative control siRNA via downregulation of ARV7 both in fetal bovine serum and androgen-deprivation conditions (p < 0.01, 0.01, respectively). We demonstrated that ASCT2 inhibition significantly reduced the proliferation rates of both CSPC and CRPC cells in vitro.

Combined α-methylacyl-CoA racemase inhibition and docetaxel treatment reduce cell proliferation and decrease expression of heat shock protein 27 in androgen receptor-variant-7-positive prostate cancer cells.

BACKGROUND: Disease progression in castrate-resistant prostate cancer (PCa) is most commonly driven by the reactivation of androgen receptor (AR) signaling and involves AR splice variants including ARV7. MATERIALS AND METHODS: We used the ARV7-positive PCa cell line, 22Rv1, to study the relationship of the PCa marker α-methylacyl-CoA racemase (AMACR), AR, and ARV7 in PCa. RESULTS: Docetaxel addition but not AMACR inhibition decreased the proliferation of 22Rv1 cells. The combination of AMACR inhibition and docetaxel treatment resulted in a maximum reduction of cell proliferation. The Western blotting analysis revealed that both AR and ARV7 expression were significantly decreased with the use of charcoal-stripped serum following AMACR inhibition and docetaxel treatment. AMACR inhibition and docetaxel treatment in the charcoal-stripped serum condition reduced the proliferation of 22Rv1, possibly via the downregulation of the heat shock protein 27. CONCLUSION: Using cell proliferation and Western blot analysis, we demonstrated that AMACR inhibition and docetaxel treatment, under androgen deprivation conditions, significantly reduced the proliferation of ARV7 positive cancer cells and decreased the levels of AR and ARV7 expression, possibly via downregulation of heat shock protein 27.