First-line Treatment Of mRCC Research Articles

A randomized, open-label, phase 3 trial of pembrolizumab plus epacadostat versus sunitinib or pazopanib as first-line treatment for metastatic renal cell carcinoma (KEYNOTE-679/ECHO-302)

BackgroundImmunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC.MethodsKEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1.ResultsOne-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2–14.3) and 10.3 months (2.7–13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2–44.1] and sunitinib/pazopanib (29.2% [18.6–41.8]). Grade 3–5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects.ConclusionsORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab.Clinical trial registrationClinicalTrials.gov; NCT03260894.

Nephrotoxicity Associated with Contemporary Renal Cell Carcinoma Regimens: A Systematic Review and Meta-Analysis

Background: The nephrotoxicity profile of contemporary first-line regimens for treatment of metastatic renal cell carcinoma (mRCC) has not been systematically studied in published clinical trials. Objective: To assess the rates of nephrotoxic events of contemporary first-line regimens for treatment of mRCC in comparison to vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) mono-therapy. Methods: We performed a systematic search of the literature looking for randomized clinical trials that contemplated National Comprehensive Cancer Network (NCCN) recommended first-line regimens for treating mRCC in which the control arm was a VEGF-TKI. Selected trials could either include an experimental arm of immune checkpoint inhibitor (ICI) plus VEGF-TKI combination or ICI-ICI combination. Nephrotoxic events were defined as proteinuria, hypertension, blood creatinine increase, acute kidney failure or nephritis, which were all described separately. Results: Five studies satisfied our inclusion criteria. Combination of ICI with VEGF-TKI showed a statistically significant higher degree of proteinuria compared to VEGF-TKI alone. There was no statistically significant difference in rates of hypertension between ICI-TKI and VEGF-TKI alone, but VEGF-TKI alone was statistically significantly more associated with hypertension than immunotherapy alone. Other renal toxicities, such as an increase in creatinine, acute kidney injury (AKI) and nephritis, were uncommon and not consistently reported in each trial. Conclusions: Contemporary regimens for first-line treatment of mRCC are associated with a higher grade of proteinuria than VEGF-TKI alone, while VEGF-TKI is more associated with hypertension than an ICI-ICI combination. Description of many renal toxicities across the studies reported have been diverse and a standardized definition across clinical trials would be helpful to reliably interpret the data regarding nephrotoxicity in the setting of treatment of renal cell carcinoma.

Sorafenib exhibits lower toxicity and comparable efficacy to sunitinib as a first-line treatment for metastatic renal cell carcinoma: A systematic review and meta-analysis.

To assess the safety and efficacy of sorafenib and sunitinib as first-line treatments for metastatic renal cell carcinoma (mRCC), to provide evidence-based support for clinical decision-making regarding rational drug use. Until May 10, 2023, a comprehensive search was conducted across PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, and Wanfang databases to identify clinical studies comparing sorafenib with sunitinib as first-line treatment for mRCC. The literature was screened, data extracted, and quality evaluated independently by 2 researchers. Meta-analysis was conducted using Revman5.4 software. A total of 3741 patients were enrolled in 20 studies. The meta-analysis results indicated that there were no significant differences in the 2- and 5-year progression-free survival (PFS) and overall survival (OS) rates between the sorafenib and sunitinib groups (P > .05). The disease control rate (DCR) was comparable between the 2 groups (P > .05), while the objective response rate (ORR) was higher in the sunitinib group (P = .03). However, subgroup analysis revealed no significant differences in ORR, DCR, 2- and 5-year PFS, and OS rates between sorafenib and sunitinib among both Asian populations as well as European and American populations (P > .05). In terms of drug-related adverse events, the incidence of grade ≥ 3 hypertension, leukopenia, neutropenia, thrombocytopenia, anemia, nausea and vomiting were significantly lower in the sorafenib group compared to the sunitinib group (P < .05). In the first-line treatment of mRCC, sorafenib exhibits comparable efficacy to sunitinib but with lower toxicity.

T-Rex study: Quality of life assessment using novel CTCAE-PRO and FKSI-19 in first-line treatment of metastatic renal cell carcinoma with tivozanib.

e16549 Background: The efficacy and safety of tivozanib (TIVO) have been evaluated in pivotal randomized, clinical trials in first-line treatment of mRCC. We previously reported on effectiveness of our real-world T-Rex study. Here, we assessed the quality of life of tivozanib in a real-world patient population in Germany using NCCN-FACT FKSI-19 (FKSI-19) and tailored PRO-CTCAE questionnaires. Methods: Patients with mRCC were treated with tivozanib according to routine care in this non-interventional study (registered at BfARM #7296). Adverse events (AEs) were assessed by CTCAE 4.03. Patient reported outcomes (PRO) were assessed by Functional Kidney Cancer Symptom Index (FKSI)-19 and tailored PRO-CTCAE questionnaires, which were scored according to corresponding guidelines. Patients who reported detriments on PRO scales at any time during treatment were counted as impaired. The study was performed in accordance with the declaration of Helsinki. Results: A total of N = 32 pts. (59.4% male) received at least one cycle of treatment and were analysed. The mean age was 75.4 years (61-89) and 17 pts. (53.1%) were ≥75 years old. 93.8% had ECOG 0-1. IMDC risk was favourable/intermediate/poor in 21.8/68.8/9.4%. The most common G1/2 AEs reported by physicians were: diarrhea 34.4%, nausea 21.9%, hypotension/hypertension 15.6%. The most common G3/4 AEs were diarrhea 6.3%, cardiac dysfunction 6.3% and other 15.6%. CTCAE PRO revealed dry mouth 91.3%, fatigue 82.6%, anorexia 82.6% and dry skin 82.6% as the most frequent symptoms. CTCAE PRO that patients reported to be severe were fatigue 43.5%, dry mouth 39.1%, anorexia 34.8%, dry skin 34.8% and dysphonia 34.8%. The most frequent CTCAE PRO that interfered with usual activities were fatigue 78.3%, dyspnea 69.6% and problems with concentration 69.6%. The return rate for FKSI-19 questionnaires was 71%. Longitudinal assessment of FKSI-19 items will be reported at the meeting. Functional/wellbeing subscale indicated that all patients (100%) reported impairment for their ability to work, to enjoy life or their quality of life. FKSI-19 disease related symptom scores reported lack of appetite, lack of energy and sleep disturbances among respondents in 92.3%, 92.3% and 88.5%, respectively. Shortness of breath and diarrhea were recognized in 61.5% and 69.2% of respondents, respectively. Haematuria was reported in 7.7% and no patient complaint of fever (0%). Detailed analysis will be shown at the meeting. Conclusions: Our findings support the use of PROs to assess patient’s condition and well-being. CTCAE-PRO and FKSI-19 were able to describe impairments, which were highly relevant to patients, but may not routinely reported by physicians. Each tool adds valuable information to the complex pattern of patient’s experience during treatment. However, some items had a very low response rate and should be reconsidered for their relevance. Clinical trial information: 7296 .

Impact of sex on the efficacy of immune checkpoint inhibitors in kidney and urothelial cancers: a systematic review and meta-analysis

PurposeTo analyze and summarize the efficacy of immune checkpoint inhibitor (ICI) alone or in combination therapy for renal cell carcinoma (RCC) and urothelial carcinoma (UC) stratified by sex.MethodsThree databases were queried in October 2022 for randomized controlled trials (RCTs) analyzing RCC and UC patients treated with ICIs. We analyzed the association between sex and the efficacy of ICIs in RCC and UC patients across several clinical settings. The outcomes of interest were overall survival (OS) and progression-free survival for the metastatic setting and disease-free survival (DFS) for the adjuvant setting.ResultsOverall, 16 RCTs were included for meta-analyses and network meta-analyses. In the first-line treatment of metastatic RCC (mRCC) and UC (mUC) patients, ICI-based combination therapies significantly improved OS compared to the current standard of care, regardless of sex. Adjuvant ICI monotherapy reduced the risk of disease recurrence in female patients with locally advanced RCC (pooled hazard ratio [HR]: 0.71, 95% confidence interval [CI] 0.55–0.93) but not in male patients, and, conversely, in male patients with muscle-invasive UC (pooled HR: 0.80, 95%CI 0.68–0.94) but not in female patients. Treatment ranking analyses in the first-line treatment of mRCC and mUC showed different results between sexes. Of note, regarding adjuvant treatment for RCC, pembrolizumab (99%) had the highest likelihood of improved DFS in males, whereas atezolizumab (84%) in females.ConclusionsOS benefit of first-line ICI-based combination therapy was seen in mRCC and mUC patients regardless of sex. Sex-based recommendations for ICI-based regimens according to the clinical setting may help guide clinical decision-making.

Cost-effectiveness of Nivolumab Plus Cabozantinib Versus Cabozantinib as First-Line Treatment of Metastatic Renal Cell Carcinoma

ObjectivesWe first evaluated the cost-effectiveness of nivolumab plus cabozantinib compared with cabozantinib alone as a first-line treatment of metastatic renal cell carcinoma (mRCC) from a US healthcare payer perspective. In the present study, we found that nivolumab plus cabozantinib was not cost-effective compared with cabozantinib alone for first-line treatment of mRCC. MethodsThis economic evaluation study used a 3-state partitioned survival model to assess the cost-effectiveness of nivolumab plus cabozantinib versus cabozantinib alone. The observed Kaplan-Meier curves for overall survival and PFS were digitized from the CheckMate 9ER and CABOSUN trials and the long-term survivals (over a lifetime horizon) beyond the end of the trial were extrapolated using the Log-Logistic model. The cost and health preference data were collected from published literature before. ResultsThe estimated cost for nivolumab plus cabozantinib group was 654 851.32 USD, which was higher than 312 360.47 USD estimated for cabozantinib alone group, resulting in an incremental cost (IC) of 342 490.85 USD. Compared with cabozantinib alone group, nivolumab plus cabozantinib group gains 1.19 QALYs, resulting the ICER was 288 443.23 USD per QALY. One-way sensitivity analysis suggested the cost of nivolumab, the discount rate, and the cost of cabozantinib had a great impact on the ICER. The cost-effectiveness acceptability curves showed the probability of nivolumab plus cabozantinib being cost-effective was 9.9% at a threshold of 150,000 USD per QALY. ConclusionThe findings of this economic evaluation suggest nivolumab plus cabozantinib is unlikely to be cost-effective compared with cabozantinib alone as first-line treatment for mRCC at WTP thresholds of 150,000 USD per QALY from the perspective of US payers. A substantial price reduction for nivolumab would be needed to achieve favorable cost-effectiveness.

Cost-effectiveness analysis of anlotinib versus sunitinib as first-line treatment for metastatic renal cell carcinoma in China.

Sunitinib was approved several years ago as a first-line drug for treating metastatic renal cell carcinoma (mRCC); however, its high price and broad side effects when administered at the standard dose have limited its clinical use. A clinical trial (NCT02072031) confirmed that anlotinib could be used as the first-line treatment for mRCC. This study was conducted to evaluate the cost-effectiveness of anlotinib as a first-line treatment for mRCC compared to that of sunitinib in China. A Markov model was established to compare the cost-effectiveness of anlotinib with that of sunitinib. Clinical data were obtained from a multi-center phase II trial (clinical trial information: NCT02072031). Utility values were obtained from the literature. Total costs were calculated from a Chinese societal perspective. A sensitivity analysis was conducted to assess the model uncertainty. The life-year (LY), quality-adjusted life-year (QALY), and incremental cost-effectiveness ratio were calculated. The base-case analysis over a lifetime horizon of 10 years showed that the anlotinib group had 2.196 LYs and 1.487 QALYs at a total cost of $68,597.84. The sunitinib group had 2.194 LYs and 1.432 QALYs at a total cost of $88,060.02. This resulted in incremental cost-effectiveness ratios (ICER) of anlotinib versus sunitinib of $-9,210,858.93 per LYs and $-354,117.07 per QALYs, suggesting that anlotinib is a more effective and less costly strategy than sunitinib. Anlotinib may be a more cost-effective first-line treatment strategy for mRCC than sunitinib in China.

Evaluation of the effectiveness and tolerability of sunitinib and pazopanib in the first line treatment of metastatic renal cell carcinoma

Introduction. It is known that sunitinib and pazopanib are effective in the first-line and subsequent treatment of metastatic renal cell carcinoma (mRCC). This study aims to investigate the effectiveness and tolerability of sunitinib and pazopanib in the first-line treatment of mRCC. Material and methods. This study included 78 patients followed up in our clinic due to a diagnosis of mRCC, who received pazopanib or sunitinib treatment between 2006 and 2020. Along with clinical and laboratory findings, survival times obtained with each treatment and medication side effects were assessed. Sunitinib and pazopanib were compared in terms of effectiveness (ORR, PFS and OS) and tolerability. Results. The patients’ median age at diagnosis was 55 years (25–81). In the first-line treatment, 54 patients (69.2%) received sunitinib and 24 (30.8%) received pazopanib. The comparison of sunitinib and pazopanib yielded an ORR of 66.7% vs. 45.8% (p = 0.08), PFS of 24 months vs. 19 months (p = 0.66) and OS of 27 months vs. 30 months (p = 0.73), respectively. The most common side effect was hypothyroidism in those on sunitinib (25.9%) and nausea-vomiting in those on pazopanib (41.7%). In our study, hemoglobin ≥ 13 g/dL, an ECOG PS of 0–1 and the occurrence of hypothyroidism as a medication side effect were found to be predictive factors of PFS for both agents. An International Metastatic RCC Database Consortium score corresponding to the poor risk group was associated with a poor PFS. Conclusions. This study, which provides current real-world data, confirms that sunitinib and pazopanib have similar effectiveness and side-effect profiles in the first-line treatment of mRCC.

Characterizing IMDC prognostic groups in contemporary first-line combination therapies for metastatic renal cell carcinoma (mRCC).

308 Background: The combination of immuno-oncology agents (IO) ipilimumab and nivolumab (IPI-NIVO) and combinations of IO with vascular endothelial growth factor targeted therapies (IOVE) have demonstrated efficacy in clinical trials for the first-line treatment of mRCC. This study seeks to establish real-world clinical benchmarks based on the International mRCC Database Consortium (IMDC) criteria using vascular endothelial growth factor targeted therapy (VEGF-TT) treated patients for context. Methods: The IMDC database (IMDConline.com) was used to identify patients with mRCC who received first-line IPI-NIVO, IOVE (axitinib/pembrolizumab, lenvatinib/pembrolizumab, cabozantinib/nivolumab, or axitinib/avelumab) and VEGF-TT (sunitinib or pazopanib) from 2002-2021. The primary endpoint was overall survival (OS) and was calculated from time of initiation of first-line therapy to death or last follow up. Log-rank tests were conducted to compare favorable, intermediate, and poor risk OS outcomes within treatment groups. Overall response rates (ORR) and complete response (CR) rates were calculated based on physician assessment of best clinical response. Results: In total, 692 patients received IPI-NIVO, 244 received IOVE, and 7152 received VEGF-TT. Baseline characteristics for IPI-NIVO, IOVE, and VEGF-TT, respectively, were as follows: median age (interquartile range) 63 (56-69), 64 (57-70), and 63 (56-70); male 72%, 74%, and 72% (p=0.74); non-clear cell histology 15%, 10%, and 13% (p=0.15); sarcomatoid features 24%, 15%, and 13% (p&lt;0.0001); brain metastasis 8%, 4%, and 8% (p=0.04); liver metastasis 18%, 14%, and 18% (p=0.17); underwent nephrectomy 61%, 79% and 80% (p&lt;0.0001). OS and ORR are reported in the table. P-values (log rank) for OS between risk groups were significant for IPI-NIVO (p&lt;0.0001), IOVE (p=0.0005), and VEGF-TT (p&lt;0.0001). Conclusions: These findings provide real-world survival and response benchmarks for contemporary first-line mRCC treatments and could be helpful for patient counselling. In addition, these findings mirror the efficacy of combination therapies established in clinical trials against VEGF-TT monotherapy. IMDC criteria continue to risk stratify patients in these novel combination therapies.[Table: see text]

Efficacy and safety of anti-vascular endothelial growth factor therapies in older patients for first line treatment of metastatic renal cell carcinoma.

Backgroundimmunotherapy became the first line treatment of metastatic renal cell carcinoma (mRCC). Nevertheless, a better understanding of the specificities of targeted therapies (TT) in the elderly population could be helpful in order to improve the management of mRCC in this population. The aim of this retrospective study was to assess efficacy and safety of sunitinib and sorafenib used as first-line TT in 70 years older patients compared to younger patients.MethodsData were retrospectively collected for all consecutive mRCC patients receiving first line TT treatment by sunitinib or sorafenib for mRCC from January 2006 to November 2017. Patients were divided into two groups according to the age using a cut-off at 70 years old. Median progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method and compared using log-rank test.ResultsIn total, 147 patients were included; 94 (63.9%) were <70 and 53 (36.1%) were 70 years old or more. First line TT used was sunitinib in 123 (83.7%) patients or sorafenib in 24 (16.3%) patients. Median PFS was 8 months for elderly patients vs. 6 in younger group (P=0.68). Median OS were 26 vs. 36 months (P=0.08). Severe induced toxicity was more frequent among elderly patients: 34 (64.2%) vs. 46 patients (48.9%) (P=0.07). Rate of treatment discontinuation due to toxicity was 22 patients (23.4%) in younger group vs. 28 patients (52.8%) in the elderly group (P=0.0005). Results were similar in the 2 groups regarding the type of toxicities.ConclusionsOur results suggest similar efficacy of anti-vascular endothelial growth factor (VEGF) agents as first-line treatment for mRCC among younger and older patients with an age cut-off of 70 years. Safety results suggest that these drugs can be safely used for older patients with a need of caution regarding toxicity prevention.

Dual immune check point blockade or immune check point-tyrosine kinase inhibitor combination: as a first-line treatment in metastatic renal cell carcinoma?

To discuss treatment decisions in the first-line setting of metastatic renal cell carcinoma (mRCC). Immune check point inhibitor (ICI) combinations have replaced sunitinib as the standard of care in the first-line treatment of mRCC. Dual ICI treatment with nivolumab and ipilimumab was shown to significantly improve overall survival and objective response rates. Similarly, the ICI-tyrosine kinase inhibitor combinations pembrolizumab and axitinib and nivolumab and cabozantinib have demonstrated superiority in terms of overall survival, objective response rates and progression-free survival versus sunitinib. The lack of both comparative trials and predictive markers impedes individualized treatment decisions. Clinicians are left to make treatment choices based on clinical and biological factors. These factors may include differences in toxicity profiles, the rate of complete remission, a clinical situation that requires urgent tumor shrinkage, the presence of inflammation, histological or immune-histochemical features and others. In the absence of comparative trials, clinical and biological factors may facilitate the choice between various treatment options in the first-line setting of mRCC. In addition, both the experience of the physician with a specific treatment together with patient's preferences and expectations of systemic therapy may be part of the decision-making process.

Comparative efficacy and safety of immunotherapy in the first-line treatment of metastatic renal cell carcinoma: a systematic review and network meta-analysis.

With the advances in immune checkpoint inhibitor therapy, several novel treatment options for metastatic renal cell carcinoma (mRCC) patients have recently emerged. The present study explored the optimal first-line immunotherapy for mRCC through a Bayesian network meta-analysis of the latest research data. PubMed, MEDLINE, EMBASE, American Society of Clinical Oncology (ASCO) meeting abstracts, and the Cochrane Library were searched up to July 2020 to identify any randomized controlled trials related to immunotherapy in the first-line treatment of mRCC. The primary outcome was progressionfree survival, and the secondary outcomes were overall survival and grade 3-4 adverse events. The network meta-analysis included 4,049 patients from 5 randomized controlled trials. Avelumab plus axitinib and pembrolizumab plus axitinib were the best treatment options in terms of progression-free survival. For overall survival, pembrolizumab plus axitinib had a 77.89% probability of being the preferred treatment. For adverse events, there was an 89.21% probability that pembrolizumab plus axitinib was the regimen with the worst side effects. Through a meta-analysis of the latest available first-line immunotherapy progression-free survival and overall survival data for mRCC, this study found that pembrolizumab plus axitinib might be the best immunotherapy option for first-line treatment. However, attention should be paid to the potential adverse events of this regimen.

PDIGREE: An adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704).

TPS366 Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN (A031203) trials. Combination immunotherapy with VEGF therapies has shown benefit over sunitinib in the JAVELIN 101 and KEYNOTE 426 trials. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter phase III trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1 mg/kg and NIVO 3 mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, International Metastatic RCC Database Consortium (IMDC) intermediate or poor risk, Karnofsky performance status &gt;70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480 mg IV every 4 weeks; pts with progression of disease (PD) switch to CABO 60 mg oral daily; pts with non-CR/non-PD are randomized to NIVO 480 mg IV every 4 weeks versus NIVO 480 mg IV every 4 weeks with CABO 40 mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include progression-free survival, 12-month CR rate, overall response rate based on RECIST 1.1 and iRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR, tissue-based and plasma-based biomarkers will be assessed. Updated enrollment through January 2021 will be presented. Clinical trial information: NCT03793166 .

Efficacy and safety of immunological checkpoint inhibitors combined with anti-angiogenic drugs in first-line treatment of metastatic renal cell carcinoma: a systematic review and meta-analysis.

BackgroundImmune checkpoint inhibitors (ICIs) have shown promising results for the second-line treatment of metastatic renal cell carcinoma (mRCC). Several randomized controlled trials have so far also evaluated the efficacy of ICIs for first-line treatment of mRCC. In this study, we conducted a meta-analysis of relevant studies to further clarify the efficacy and safety of ICIs combined with anti-angiogenic drugs for the treatment of mRCC.MethodsWe searched the PubMed, Embase, and Cochrane libraries for RCT trials of ICIs combined with anti-angiogenic drugs for first-line treatment of mRCC published before November 20, 2019. A meta-analysis was conducted based on methodological recommendations by the Cochrane Collaboration.ResultsFour articles with a total of 2,967 patients met the inclusion criteria. Our meta-analysis revealed that progression-free survival (PFS) and objective response rate (ORR) were significantly improved in the experimental group while there was no significant difference in overall survival (OS) (HR 0.75, 95% CI: 0.67–0.84; HR 1.43, 95% CI: 1.07–1.91; HR 0.74, 95% CI: 0.53–1.03). After stratification for PD-L1 expression, OS, PFS, and ORR of PD-L1 positive patients were significantly increased in the experimental group (HR 0.74, 95% CI: 0.56–0.96; HR 1.66, 95% CI: 1.11–2.49; HR 0.65, 95% CI: 0.57–0.75).ConclusionsImmunological checkpoint inhibitors combined with anti-angiogenic drugs as a first-line treatment for mRCC improve PFS and ORR. This effect is more pronounced in PD-L1 positive patients, where ICIs also improve OS. ICIs do not increase the incidence of adverse events.

Pembrolizumab plus axitinib and nivolumab plus ipilimumab as first-line treatments of advanced intermediate- or poor-risk renal-cell carcinoma: a number needed to treat analysis from the Brazilian private perspective

Background Considering clinical benefits of new combination therapies for metastatic renal-cell carcinoma (mRCC), this study aims to calculate the number needed to treat (NTT) and the cost of preventing an event (COPE) for pembrolizumab plus axitinib (P + A), and nivolumab plus ipilimumab (N + I) as first-line treatments, from the Brazilian private perspective. Methods Overall survival (OS) and progression-free survival (PFS) data for intermediate- and poor-risk groups were obtained from KEYNOTE-426 and CHECKMATE-214 trials for P + A and N + I, respectively, versus sunitinib as mRCC first-line treatment. Results Considering a 12-month time horizon, 6 patients should be treated with P + A to prevent one death with sunitinib use, resulting in a COPE of 3,893,903 BRL. Using N + I, NNT for 12-month OS rate was 13 compared to sunitinib, with a COPE of 6,357,965 BRL. Regarding PFS data, NNT was also 6 when comparing P + A versus sunitinib, with an estimated COPE of 3,893,903 BRL. Estimated NNT was 20 comparing N + I and sunitinib, resulting in a COPE of 10,172,744 BRL. Cost differences between two treatment options, reached more than 6 million BRL for PFS, and 2 million BRL for OS. Conclusion At the 12-month landmark, P + A suggests better economic scenario versus N + I as first-line mRCC treatment option for intermediate- and poor-risk groups, through an indirect comparison using sunitinib as a common comparator.

Immunotherapy and tyrosine kinase inhibitors in first-line treatment of metastatic renal cell carcinoma-Which strategy when?

Immuntherapien mit Checkpoint-Inhibitoren haben beim metastasierten klarzelligen Nierenzellkarzinom (mRCC) zu einem Paradigmenwechsel geführt und einen neuen Standard in der Erstlinie etabliert. Einschließlich der bekannten Monotherapie mit Tyrosinkinaseinhibitoren ist das Spektrum an medikamentösen Therapieoptionen somit breiter geworden. In diesem Beitrag sollen anhand der aktuellen Studiendaten sowie Leitlinienempfehlungen mögliche Faktoren zur individuellen Therapieplanung in der Erstlinie des mRCC diskutiert werden. Hierbei ist das wichtigste Leitkriterium das Risikoprofil. Daneben sind Effektivität und Verträglichkeit der Substanzen, sowie Tumorlast, Alter und Präferenzen der Patienten sowie Überlegungen zur Sequenztherapie für die Therapiewahl ausschlaggebend. Real-world-Daten für die neuen Kombinationstherapien, Biomarker für eine personalisierte Medizin sowie Studien zur optimalen Sequenztherapie beim mRCC werden benötigt.

PDIGREE: An adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704).

TPS5100 Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN (A031203) trials. Combination immunotherapy with VEGF therapies has shown benefit over sunitinib in the JAVELIN 101 and KEYNOTE 426 trials. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter phase 3 trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1 mg/kg and NIVO 3 mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, International Metastatic RCC Database Consortium (IMDC) intermediate or poor risk, Karnofsky performance status &gt; 70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480 mg IV every 4 weeks; pts with progression of disease (PD) switch to CABO 60 mg oral daily; pts with non-CR/non-PD are randomized to NIVO 480 mg IV every 4 weeks versus NIVO 480 mg IV every 4 weeks with CABO 40 mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include progression-free survival, 12-month CR rate, overall response rate based on RECIST 1.1 and irRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR, tissue-based and plasma-based biomarkers will be assessed. Updated enrollment through May 2020 will be presented. Clinical trial information: NCT03793166 .

Anlotinib for Patients With Metastatic Renal Cell Carcinoma Previously Treated With One Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor: A Phase 2 Trial.

Introduction: Sequential therapy with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) is effective in some patients with metastatic renal cell carcinoma (mRCC) progressed from or were intolerant to a prior TKIs. Anlotinib is a multi-kinase inhibitor targeting VEGFR1/2/3, PDGFR and FGFR, which has demonstrated efficacy and safety in first-line treatment of mRCC. This study assessed the potential of anloitnib as second-line treatment for patients with mRCC after prior one VEGFR-TKI.Methods: This is a single-arm, open-label, phase 2 study. Patients progressed after or were intolerant to sorafenib or sunitinib were enrolled. Anlotinib was administrated orally 12 mg once daily for 14 days every 3 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), safety and quality of life (QoL).Results: Forty three patients were enrolled and 42 received anlotinib, of whom 32 progressed after and 10 were intolerant to sorafenib or sunitinib. Median PFS were 14.0 months (95% CI 8.3–20.3) and 8.5 months (95% CI 5.6–16.6) for overall population and patients progressed after a previous VEGFR-TKI, respectively. Median OS was 21.4 months (95% CI 16.0–34.5), confirmed ORR and DCR were 16.7 and 83.3% in overall population. The most common adverse events included diarrhea (47.6%), hypertension (45.2%), hand and foot syndrome (42.9%), and fatigue (40.5%). Grade 3 hematological adverse events occurred in four cases, while no grade 4 hematological adverse events was observed.Conclusions: Anlotinib showed promising efficacy as well as favorable safety as second-line treatment for patients with mRCC.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02072044.

PDIGREE: An adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704).

TPS760 Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN trials. Combination immunotherapy with VEGF therapies have shown benefit in the JAVELIN 101 and KEYNOTE 426 trials over sunitinib. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter, phase 3 trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1mg/kg and NIVO 3mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, IMDC intermediate or poor risk, Karnofsky performance status &gt;70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480mg IV every 4 weeks, pts with progression of disease (PD) switch to CABO 60mg oral daily, and pts with non-CR/non-PD are randomized to NIVO 480mg IV every 4 weeks versus NIVO 480mg IV every 4 weeks with CABO 40mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS rate will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include PFS, 12-month CR rate, ORR based on RECIST 1.1 and irRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR and association of IL-6 with treatment benefit will be assessed. Other tissue-based and plasma-based biomarkers are planned. Updated enrollment will be presented. Clinical trial information: NCT03793166.

Real-World Effectiveness and Tolerability of Pazopanib as First Targeted Therapy in Metastatic Renal Cell Carcinoma: A Retrospective Chart Review in Latin America

Pazopanib is approved in Latin America as first targeted therapy for patients with metastatic renal cell carcinoma (mRCC). A retrospective chart review of adult patients with mRCC who initiated pazopanib as first targeted therapy between January 2011 and March 2016 was conducted among oncology care centers in Argentina, Brazil, Chile, Colombia, and Mexico. Patient characteristics, treatment patterns, overall survival (OS), progression-free survival (PFS), and adverse events were summarized. A total of 156 charts of patients with mRCC receiving first-line pazopanib were reviewed (29, 54, 27, 28, and 18 patients from Argentina, Brazil, Chile, Colombia, and Mexico, respectively). The mean age at initial mRCC diagnosis was 61.6years, 73.7% were male, and 51.3% were Hispanic. The median dose of pazopanib was 800mg and the median time from initial mRCC diagnosis to pazopanib start was 2.2months. The median time on treatment was 10.0months. At the time of data extraction, 16.7% of patients remained on pazopanib, with clinical progression listed as the main reason for discontinuation. Subsequent therapy was received by 25.6% of patients; the most common were everolimus (9.6%) and axitinib (5.8%). Overall, median PFS and OS were 10.8 and 16.9months, respectively, and varied across countries. The most common all-grade adverse events were diarrhea (44.9%), asthenia/fatigue (43.6%), and nausea (28.8%). Pazopanib was used for first-line mRCC treatment in a clinically diverse patient population across Latin America. Real-world PFS and tolerability were similar to clinical studies of pazopanib. Novartis Pharmaceuticals Corporation, Inc.