Correlation Between First-line Immunotherapy and Second-line TKI Outcomes in Metastatic Renal Cell Carcinoma

ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma

BackgroundImmune-combinations have recently become the standard first-line treatment for patients with metastatic renal cell carcinoma (mRCC). This study evaluated the applicability of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model in predicting outcomes for patients treated with either immune-oncologic drug doublet (IO-IO) or immune-oncologic drug tyrosine kinase inhibitor combinations (IO-TKI). A secondary objective to compare the effectiveness of IO-IO versus IO-TKI within the IMDC risk groups over a short follow-up period.MethodsA retrospective analysis was conducted on 172 patients with mRCC treated with first-line immunotherapy combinations. Progression free survival (PFS), time to treatment failure 2 (TTF2), and overall survival (OS) were compared between IMDC risk categories. Model fit was assessed using the c-index. The inverse probability of treatment weighting (IPTW) method was used to adjust and compare outcomes between IO-IO and IO-TKI, except for IMDC favorable risk patients due to the small number of IO-IO cases.ResultsThe IMDC risk model demonstrated a c-index of 0.684 (OS) for entire cohort, 0.600 (PFS), 0.596 (TTF2), and 0.624 (OS) for IO-IO, and 0.667 (PFS), 0.702 (TTF2), and 0.751 (OS) for IO-TKI. In the IMDC intermediate and poor risk groups after IPTW adjustment, PFS (HR 0.72), TTF2 (HR 0.67), and OS (HR 0.74) did not significantly differ between IO-IO and IO-TKI. Specifically, in the IMDC intermediate risk group, PFS (HR 0.79), TTF2 (HR 0.69), and OS (HR 0.65) were longer in IO-TKI, though the differences were not statistically significant. In the IMDC poor risk group, PFS (HR 0.76), TTF2 (HR 0.77), and OS (HR 1.03) were comparable.ConclusionsThe impact of IMDC risk model on survival was modest in IO-IO, while remained statistically substantial in IO-TKI. Survival outcomes did not significantly differ between IO-IO and IO-TKI during the short follow-up period.

628 Background: Metastatic renal cell carcinoma (mRCC) treatment is partly informed by risk group. The two most commonly used prognostic models, the International Metastatic RCC Database Consortium (IMDC) and the Memorial Sloan-Kettering Cancer Center (MSKCC), stratify patients (pts) into favorable (0 risk factors [RFs]), intermediate (1–2 RFs) or high risk (≥3 RFs) groups. This study examined real-world outcomes according to IMDC and MSKCC RFs in sunitinib-treated pts with mRCC. Methods: Data were extracted on 19 June 2019 from a large, prospective German multicenter registry (STAR-TOR). Only pts with sufficient data for risk stratification by IMDC and MSKCC were included in this analysis. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The impact of RFs on survival was assessed using Cox’s regression analysis and the chi square test. Results: According to IMDC or MSKCC, 16.7% and 15.3%, 26.2% and 30.8%, 18.7% and 24.7%, and 38.5% and 29.2 of pts had 0, 1, 2 and ≥3 RFs, respectively. In IMDC intermediate pts, only < 1 year diagnosis to therapy (24.8%) was the most common RF; in MSKCC intermediate pts, < 1 year diagnosis to therapy with low hemoglobin (19.9%) were the most common. OS was not significantly different for pts with 0 vs 1 (p = 0.24), or 2 vs ≥3 (p = 0.16) IMDC RFs, but was significant according to MSKCC RFs (0 vs 1, p = 0.04; 2 vs ≥3, p < 0.01). OS was significantly longer for pts with 1 vs 2 RFs for IMDC (p = 0.03) and MSKCC (p = 0.04), but PFS was not (IMDC, p = 0.29; MSKCC, p = 0.12). OS was significantly longer for 0 vs 2, 0 vs ≥3, and 1 vs ≥3 RFs for IMDC and MSKCC RFs (all comparisons, p < 0.01). Similar results were observed for PFS with the exception of 0 vs 1 IMDC RF (p = 0.01). Conclusions: The intermediate risk group appears to be heterogeneous. OS for pts with 1 RF may align with the favorable risk group and pts with 2 RFs may align with the poor risk group.[Table: see text]

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†.

Real-world Outcome of Patients with Advanced Renal Cell Carcinoma and Intermediate- or Poor-risk International Metastatic Renal Cell Carcinoma Database Consortium Criteria Treated by Immune-oncology Combinations: Differential Effectiveness by Risk Group?

Sunitinib in Patients With Metastatic Renal Cell Carcinoma: Clinical Outcome According to International Metastatic Renal Cell Carcinoma Database Consortium Risk Group.

IntroductionClinical trials show improved progression‐free survival (PFS) and overall survival (OS) in first‐line metastatic renal cell carcinoma (mRCC) patients with immunotherapy containing systemic anti‐cancer therapies (SACT). However, in the favourable international metastatic renal cell cancer database consortium (IMDC) group there is no trial evidence for OS benefit despite clear PFS improvement when comparing anti‐VEGF tyrosine kinase inhibitor (TKI) monotherapy and (immunotherapy and TKI) IO/TKI combinations.ObjectiveTo assess the impact of first‐line SACT choice on the clinical outcomes of PFS and OS in mRCC. To evaluate this impact of initial SACT for allcomers and the favourable IMDC group.MethodsA multicentre retrospective review of patients who started SACT for mRCC (01/01/2018–30/06/2021) at 17 UK NHS trusts. Patient demographics and IMDC group were analysed. Survival data were compared using Kaplan–Meier curves, and the statistical significance of differences in outcome between the groups was assessed with the log‐rank test. Univariable and multivariable Cox proportional hazard modelling estimate the hazard ratios (HRs) for survival outcomes associated with IMDC and treatment subtype.ResultsOne thousand three hundred and nineteen patients were identified with a median age of 64. 294 (22.3%), 695 (52.7%) and 321 (24.3%) were IMDC group favourable, intermediate and poor, respectively. 311 (23.6%), 197 (14.9%) and 778 (59%) patients received checkpoint inhibitor and anti‐CTLA4 monoclonal antibody (IO/IO), IO/TKI and TKI first‐line SACT across all IMDC groups. Significant PFS improvement favouring IO/TKI versus TKI was demonstrated in allcomers HR = 0.61. In the favourable risk group, Log rank testing demonstrated a significant benefit for IO/TKI over TKI for PFS (HR = 0.60, 95% CI [0.39, 0.91]) and OS (HR = 0.42, 95% CI [0.18, 0.99]).ConclusionIn this real‐world evidence cohort, we have shown OS and PFS benefit with IO/TKI versus TKI in the favourable IMDC risk group. This has not been previously reported from trial outcomes and would support use of front‐line IO/TKI in mRCC favourable risk patients.

In recent years, the standards of drug therapy for advanced kidney cancer have undergone significant changes associated with the appearance of the effective immune checkpoint inhibitors, as well as the high affinity second-generation multi-kinase inhibitors. One of the new tyrosine kinase inhibitors associated with the proven antitumor activity and safety in patients with advanced forms of renal cell carcinoma (RCC) is cabozantinib. The standards of drug therapy for advanced renal cancer have significantly changed in recent years with the emergence of effective anti-tumor immune response checkpoint inhibitors and high-affinity second-generation multikinase inhibitors. One of the novel tyrosine kinase inhibitors with proven antitumor activity and safety in patients with advanced renal cell cancer (RCC) is cabozantinib. In the first-line therapy for advanced renal cancer, the combination of cabozantinib with nivolumab became the regimen of choice in patients of all risk groups, according to International Metastatic RCC Database Consortium (IMDC), regardless of the presence of a sarcomatoid component in the tumor based on the results of the randomized phase III CheckMate 9ER clinical trial (n=651), which demonstrated a significant benefit of immune targeted therapy compared to sunitinib in terms of overall survival (OS; median 37.7 and 34.3 months, respectively), progression-free survival (PFS; median 16.6 and 8.3 months, respectively) and objective response rate (ORR; 55.7 and 28.4%, respectively). Cabozantinib monotherapy in the first-line therapy of advanced renal cancer in patients in the intermediate-risk and poor-risk groups is an alternative regimen reserved for patients with contraindications to anti-tumor immune response checkpoint inhibitors. This recommendation is based on the results of the open-label phase II RCT, CABOSUN (n=157), which showed a significant increase in PFS in the cabozantinib group compared to sunitinib (8.6 month vs 5.3 months, respectively). Also, cabozantinib is the drug of choice in papillary RCC due to the proven advantage in terms of PFS over sunitinib (9.0 and 5.6 months, respectively) demonstrated in the SWOG 1500 phase II RCT (n=152). Cabozantinib remains the drug of choice for second-line therapy of RCC resistant to anti-angiogenic therapy, based on the results of the phase III METEOR RCT, in which the drug showed a compelling advantage over everolimus for PFS (7.4 and 3.8 months, respectively) and OS (21.4 and 16.5 months, respectively). The article presents a detailed analysis of these studies.

Impact of modified Glasgow prognostic score on predicting prognosis and modification of risk model for patients with metastatic renal cell carcinoma treated with first line tyrosine kinase inhibitor.

To the authors' knowledge, outcomes and prognostic tools have yet to be clearly defined in patients with metastatic renal cell carcinoma (mRCC) who are treated with immuno-oncology (IO) checkpoint inhibitors (programmed death-ligand 1 [PD-L1] inhibitors). In the current study, the authors aimed to establish IO efficacy benchmarks in patients with mRCC and update patient outcomes in each International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic class. A retrospective analysis was performed using the IMDC database with data from 38 centers. It included patients with mRCC who were treated with ≥1 line of IO. Overall response rates (ORRs), duration of treatment (DOT), and overall survival (OS) were calculated. Patients were stratified using IMDC prognostic factors. A total of 687 patients (90% with clear cell and 10% with non-clear cell) were included. The ORR was 27% in evaluable patients (461 patients). In patients treated with first-line nivolumab and ipilimumab (49 patients), the combination of PD-L1 inhibitor and vascular endothelial growth factor inhibitor (72 patients), and PD-L1 inhibitor (51 patients), the ORR was 31%, 39%, and 40%, respectively, and the median DOT was 8.3 months, 14.7 months, and 8.3 months, respectively. The ORR for second-line, third-line, and fourth-line nivolumab was 22%, 24%, and 26%, respectively. The median DOT was 5.7 months, 6.2 months, and 8.3 months, respectively, in the second-line, third-line, and fourth-line settings. When segregated into IMDC favorable-risk, intermediate-risk, and poor-risk groups, the median OS rates for the first-line, second-line, third-line, and fourth-line treatment settings were not reached (NR), NR, and NR, respectively (P = .163); NR, 26.7 months, and 7.4 months, respectively (P < 0. 0001); 36.1 months, 28.2 months, and 11.1 months, respectively (P = .016); and NR, NR, and 6.7 months, respectively (P = .047). The ORR was not found to deteriorate from the first-line to the fourth-line of IO therapy. In the second line through fourth line, the IMDC criteria appropriately stratified patients into favorable-risk, intermediate-risk, and poor-risk groups for OS.

Immuno-oncology (IO) improves the prognosis of advanced renal cell carcinoma (RCC). Since research has so far been limited to clinical trials, we herein focused on the effects of IO-tyrosine kinase inhibitor (TKI) combination therapy in real-world clinical settings. We conducted a retrospective study on 125 patients with advanced RCC who received IO-TKI combination therapy or TKI monotherapy. Oncological outcomes were assessed by progression-free survival (PFS) and overall survival (OS), and prognostic factors for PFS and OS were investigated. We then evaluated PFS and OS based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). The IO-TKI group showed significantly longer median PFS (18.6 months vs. 10.1 months, p=0.008) and OS (not reached vs. 34.2 months, p=0.041) than the TKI group. A multivariate analysis identified the Karnofsky performance risk score, first-line therapy (IO-TKI combination therapy or TKI monotherapy), and high C-reactive protein levels as poor prognostic factors for both PFS and OS. PFS did not significantly differ in IMDC favorable-risk patients between the groups but was significantly longer in IMDC intermediate- and poor-risk patients in the IO-TKI group than in the TKI group. OS did not significantly differ in IMDC favorable- and intermediate-risk patients between the groups but was significantly longer in IMDC poor-risk patients in the IO-TKI group. We demonstrated the advantage of IO-TKI combination therapy compared to TKI monotherapy in real-world clinical settings. However, in IMDC favorable patients PFS and OS did not significantly differ to TKI monotherapy. This may indicate the need for caution when selecting treatment options for IMDC favorable-risk patients.

Characterization of Patients With Poor-Risk Metastatic Renal-Cell Carcinoma: Results From aPooled Clinical Trials Database.

Characterization of Patients With Metastatic Renal Cell Carcinoma Experiencing Complete Response to First-line Therapies: Results From the International Metastatic Renal Cell Carcinoma Database Consortium.

IntroductionRenal cell carcinoma (RCC) is one of the most common types of urogenital cancer. The introduction of immune-based combinations, including dual immune-checkpoint inhibitors (ICI) or ICI plus tyrosine kinase inhibitors (TKIs), has radically changed the treatment landscape for metastatic RCC, showing varying efficacy across different prognostic groups based on the International Metastatic RCC Database Consortium (IMDC) criteria.Materials and methodsThis retrospective multicenter study, part of the ARON-1 project, aimed to evaluate the outcomes of favorable-risk metastatic RCC patients treated with immune-based combinations or sunitinib. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate. We carried out a survival analysis by a Cox regression model.ResultsA total of 524 favorable-risk patients were included in the analysis. After a median follow-up of 37.2 months, the median OS in the overall population was 56.1 months. There was no significant difference in OS between patients receiving sunitinib and those receiving TKI + ICI combinations (p = 0.761). Patients on TKI + ICI had significantly longer PFS compared to patient treated with sunitinib (30.7 vs 22.9 months, p = 0.007). Analysis of OS and PFS based on metastatic site revealed that patients with bone metastases benefited more from ICI plus TKI (56 patients with bone metastases receiving IO + TKI, 38 received pembrolizumab plus axitinib, 15 cabozantinib plus nivolumab and 3 pembrolizumab plus lenvatinib), while sunitinib was more effective for pancreatic and glandular metastases. Additionally, the number of metastatic sites played a role, with TKI plus ICI showing superiority in patients with a single metastatic site. The time from RCC diagnosis to metastatic disease also impacted outcomes, with TKI plus ICI being more effective in patients with a shorter interval (i.e., < 36 months).ConclusionsThe choice between upfront combination or monotherapy for metastatic favorable prognosis RCC remains a current issue. While combination therapy offers prolonged PFS, it does not necessarily translate to improve OS compared to sunitinib. This real-world study supports the superiority in terms of PFS of TKI plus ICI vs TKI monotherapy but not in OS. Probable, other clinical factors should be taking into account to make clinical treatment decisions in this setting.

Des myalgies vagues et des vagues musculaires