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Cabozantinib is a widely used multikinase-inhibitor for the treatment of metastatic renal cell carcinoma (mRCC). This study analyzed the efficacy of cabozantinib in real world, including heavily pretreated patients. Antitumor activity was observed in various treatment lines; moreover, we observed that an alternative treatment schedule improves PFS when compared to continuous dosing. No new safety signals emerged from our analysis. Background: The multikinase-inhibitor Cabozantinib is a widely used treatment strategy in metastatic renal cell carcinoma (mRCC), either in combination with the programmed cell death protein-1 (PD-1) inhibitor nivolumab or as monotherapy. Cabozantinib is given continuously at a dose of 60 mg once daily when used as a single agent and at 40 mg when combined with nivolumab. Treatment-related adverse events (TRAE's) were shown to occur frequently. Objective: We aimed to assess the safety and efficacy of cabozantinib in patients with mRCC. Patients were treated in various lines. Furthermore, we analyzed the impact of an alternative treatment schedule in patients not able to maintain continuous dosing. Patients: This is a single center retrospective study from the Medical University of Vienna. Outcome Measurements and Statistical Analysis: Overall response rates (ORR), progression free survival (PFS) and overall survival (OS) were evaluated for the entire cohort, by treatment line and by treatment schedule. Results: Between January 2014 until April 2021, 71 patients received cabozantinib. Sixty-seven patients were eligible for full evaluation. By IMDC cr iter ia, 32.4%, 59.2%, and 8.5% were classified as favorable, intermediate and poor risk respectively. Cabozantinib was offered as a 2nd-line or 3rd-line treatment in 38.0% and 32.4% of patients, respectively. An alternative treatment schedule was offered in 39.1% of patients. Objective responses were found in 43.3% (CR 6%) of patients and the median PFS was 10.8 months (95% CI: 5.5-16.2). When compared to continuous dosing, an alternative treatment schedule was associated with longer PFS (12.2 months (95% CI: 0-25.5) vs. 6.1 months (95% CI: 0.37-11.8) (P = .014, HR 0.46 (95% CI: 0.24-0.86), respectively) and a lower frequency and severity of TRAE's. Conclusions: Safety and efficacy of cabozantinib in real world is comparable to what has been observed in the pivotal trials, irrespective of the treatment line. An alternative schedule may further improve efficacy and safety. [ABSTRACT FROM AUTHOR]

We profiled the genomes of over 12,0 0 0 advanced prostate cancer samples and probed a large clinicogenomic database with ~10 0 0 patients to clarify the impact MYCamp in PCa. Results suggest that MYCamp advanced PCa has limited targeted therapies and is an aggressive subset of advanced prostate cancer found disproportionately more common in men with African ancestry. Background: MYC is a commonly amplified, potentially targetable gene in prostate cancer (PCa). We sought to define the molecular, immunologic, and clinicodemographic landscape of MYC amplification (MYCamp) in advanced PCa to establish a rationale for personalized treatment combinations. Methods: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on PCa tumor samples. MYCamp = copy number =6 (CN). Patients treated between January 2011 and December 2020 were selected from a nationwide deidentified (280 clinics) EHR-derived clinicogenomic database (CGDB). Results: Of 12,528 hormone-sensitive and castrate-resistant (CRPC) samples, MYCamp was detected in 10.6% (median CN = 8). MYCamp was more frequent in men with African versus European ancestry (12.9% vs. 10.2% P = .002), in metastatic vs. primary tissue (15.7% vs. 6.2% P < .001), and enriched in metastatic liver lesions (20.2%), but inversely associated with high microsatellite-instability (0.8% vs. 2.4%, P < .001). MYC CN =15 was associated with PD-L1 expression (26.1% vs. 9.8%, P = .025). Amplification of AR, RAD21,LYN, CCND1,ZNF703,FGF3/4/19, and FGFR1 was enriched in MYCamp vs. MYCwt (all P < .001). In liquid samples with tumor fraction [TF] > 0, MYCamp was detected in 2.0% (28/1,402), and 4.5% (20/445) with TF > 20%. In the CGDB, (67 MYCamp and 658 MYCwt), patients received similar treatments; most received hormone therapies (35.8% MYCamp vs. 31.5% MYCwt) or chemotherapy (37.3% MYCamp vs. 27.7% MYCwt) as first therapy after CGP report. Conclusion: MYCamp defines a biologically distinct subset of PCa patients and is characterized with multiple proxies of advanced disease. These data suggest that MYCamp may be prognostic; independent cohorts are needed to validate these findings. [ABSTRACT FROM AUTHOR]

Real-world patterns of care and attrition of la/mUC patients eligible for systemic therapy following PD-1/L1 inhibitors are not well understood. In an ambispective chart review of patients with la/mUC after PD-1/L1 discontinuation, only one third received subsequent treatment. Prior to the introduction of novel therapies, real-world outcomes following treatment with PD-1/L1 inhibitor therapy were poor. Introduction: The patterns of care and attrition of locally advanced or metastatic urothelial carcinoma (la/mUC) patients eligible for systemic therapy following PD-1/L1 inhibitors are unclear. The objective of this study was to evaluate the clinical characteristics and treatment patterns among patients with la/mUC following discontinuation of first-line (1L) or second-line (2L) PD-1/L1 inhibitor therapy. Methods: An ambispective, multisite, chart review study was conducted in the United States, including patients with la/mUC. Eligible patients had initiated and subsequently discontinued PD-1/L1 therapy in the 1L or 2L setting for la/mUC between May 2016 and July 2018; with follow-up through October 2019. Patient characteristics, treatments, and overall survival (OS) were described. Patients had the option to complete a 1-time patient reported outcomes (PRO) survey. Results: Among 300 patients included in the chart review, 198 (66%) received 1L PD- 1/L1 inhibitor and 102 (34%) received 2L PD-1/L1 inhibitor. Following discontinuation of PD-1/L1 inhibitor therapy, 34% (n = 68) received subsequent therapy in 2L and 29% (n = 30) in third-line (3L). The median OS post-1L PD-1/L1 inhibitor was 9.4 (95% CI 8.6-NA) and 2.5 months (95% CI 2.24-3.50) for those who received and did not receive subsequent therapy, respectively. Following 2L PD-1/L1 inhibitor discontinuation, the median OS was 5.7 (95% CI 5.1-7.8) and 3.98 (95% CI 3.29-4.87) months for those who received and did not receive subsequent therapy, respectively. Among those with PRO data, 64% reported experiencing cancer-related pain and 29.6% received an opioid. Only 12.7% reported having a caregiver, requiring approximately 13 h/d of service. Conclusion: The symptom and caregiver burden are high among real-world patients with la/mUC who discontinued 1L or 2L PD-1/L1 inhibitors and outcomes are dismal, with a minority receiving subsequent therapy. Patterns of care in the setting of 1L maintenance avelumab and novel agents require further investigation. [ABSTRACT FROM AUTHOR]

Nivolumab-ipilimumab has become the standard of care in the frontline setting for intermediate-/poor-risk metastatic renal cell carcinoma (mRCC). This regimen is associated with survival improvement but significant toxicity. Antiprogrammed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1) monotherapy may provide response and offers a better safety profile. In this context, nivolumab-ipilimumab has been postulated as a rescue treatment after antiePD-1/PD-L1 therapy. Recent retrospective data has shown positive results, and several nonrandomized clinical trials (NRCTs) have evaluated this strategy. Therefore, we performed a meta-analysis of available NRCTs to clarify the efficacy and safety of salvage nivolumab-ipilimumab in mRCC after prior antiePD-1/PD-L1 monotherapy. We searched PubMed, Medline, Embase, and the Cochrane Central Register of Controlled Trials to identify clinical trials investigating the efficacy and safety of salvage nivolumab-ipilimumab after prior antiePD-1/PD-L1 in patients with mRCC. Only phase II NRCTs were available for the analysis. The pooled effect of single proportions with a 95% confidence interval (CI) was used as the measure of effect (overall response rate [ORR] and incidence of grade x 3 adverse events). Four studies accounting for 237 patients were included. All patients received prior antiePD-1/PD-L1 monotherapy. The pooled ORR of salvage nivolumab-ipilimumab after prior antiePD-1/PD-L1 failure was 10.0% (95% CI, 6%-14%; I2 = 41%; P = .17). The incidence of grade ≥ 3 irAEs was 27.0% (95% CI, 20%-35%; I2 = 0%; P = .56). The results of this analysis suggest that the use of salvage nivolumab-ipilimumab in mRCC after prior antiePD-1/PDL1 has limited activity with a 10% ORR, and a non-negligible toxicity with 1 of 4 patients developing grade x 3 immune-related adverse events. [ABSTRACT FROM AUTHOR]

Understanding the impact of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) expression becomes increasingly important in renal cell carcinoma (RCC) owing to increasing therapeutic implications. However, little is known in noneclear-cell RCC about the relevance of those immune checkpoint surrogates. Here, we suggest that PD-1/PD-L1 expression in papillary RCC does not have prognostic impact, neither for type 1 nor type 2. However, in advanced disease, further evaluation according to PD-1/PD-L1 is warranted. Background: Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) play a decisive role as prognostic markers in clear-cell renal cell carcinoma (RCC). To date, the role of PD-1/PD-L1 as a prognostic marker in papillary RCC (pRCC) remains scarce. Patients and Methods: Patients' sample collection was a joint collaboration of the nationwide PANZAR consortium e a multicenter study. Medical history and tumor specimens were collected from 245 and 129 patients with pRCC types 1 and 2, respectively. Expression of PD-1 and PD-L1 was determined by immunohistochemistry in pRCC and tumor-infiltrating mononuclear cells. Results: Of 374 pRCC specimens, 204 type 1 and 97 type 2 were evaluable for PD-1 and PD-L1 expression analysis. In total, PD-1 and PD-L1 expression were found in 8 (4.9%) of 162 and 12 (7.2%) of 166 evaluable pRCC type 1 specimens. Comparably, PD-1 and PD-L1 expression were found in 2 (2.4%) of 83 and 5 (6.2%) of 81 evaluable pRCC type 2 specimens. Hardly any clinically relevant associations between PD-1 and PD-L1 positivity and clinicopathologic or clinical courses were observed, neither in pRCC type 1 nor type 2. Conclusion: The analysis of a large pRCC cohort from a multicenter consortium revealed no impact of PD-1/PD-L1 expression on prognosis in patients with pRCC with predominantly limited disease status, neither for type 1 nor type 2. However, the impact of PD-1 and PD-L1 in more advanced pRCC disease needs further elucidation. [ABSTRACT FROM AUTHOR]