Motzer, Robert J.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on the systemic therapy options for patients with advanced RCC and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Kidney Cancer.

Abstract Background Tumor cell phenotypes and anti-tumor immune responses are shaped by local metabolite availability, but intratumoral metabolite heterogeneity (IMH) and its phenotypic consequences remain poorly understood. In vitro mechanistic studies have demonstrated that the anti-tumor activity of lymphoid and myeloid cell populations is mediated by metabolite availability and signaling in the TME, raising the possibility that the immune response and metabolism of ccRCC tumors coevolve and jointly influence the likelihood that a patient responds to therapy.. However, both the broad patterns of coordination between metabolite abundance and TME cellular composition, as well as the precise cell populations producing metabolic phenotypes of interest, remain unknown. Methods To study IMH, we multiregionally profiled the metabolome, transcriptome, and genome of 187 tumor/normal regions from 31 clear cell renal cell carcinoma (ccRCC) patients. Using these measurements and additional multimodal metabolomic/transcriptomic profiling of ccRCC and other diseases, we developed computational models that can be used to understand RNA-metabolite covariation and ultimately impute metabolite levels from RNA sequencing data. Results Analysis of intratumoral metabolite-RNA covariation revealed that the immune composition of the microenvironment, and especially the abundance of myeloid cells, drove intratumoral metabolite variation. Motivated by the strength of RNA-metabolite covariation and the clinical significance of RNA biomarkers in ccRCC, we deployed and benchmarked a machine learning method (MIRTH) to impute metabolite levels directly from RNA sequencing data of primary and metastatic ccRCC tumors. We inferred metabolomic profiles from RNA sequencing data of ccRCC patients enrolled in 6 clinical trials, ultimately identifying specific metabolite biomarkers associated with response to anti-angiogenic agents. Conclusions Local metabolic phenotypes therefore emerge in tandem with the immune microenvironment and associate with therapeutic sensitivity. CDMRP DOD Funding: yes

The NCCN Guidelines for Kidney Cancer focus on the screening, diagnosis, staging, treatment, and management of renal cell carcinoma (RCC). Patients with relapsed or stage IV RCC typically undergo surgery and/or receive systemic therapy. Tumor histology and risk stratification of patients is important in therapy selection. The NCCN Guidelines for Kidney Cancer stratify treatment recommendations by histology; recommendations for first-line treatment of ccRCC are also stratified by risk group. To further guide management of advanced RCC, the NCCN Kidney Cancer Panel has categorized all systemic kidney cancer therapy regimens as “Preferred,” “Other Recommended Regimens,” or “Useful in Certain Circumstances.” This categorization provides guidance on treatment selection by considering the efficacy, safety, evidence, and other factors that play a role in treatment selection. These factors include pre-existing comorbidities, nature of the disease, and in some cases consideration of access to agents. This article summarizes surgical and systemic therapy recommendations for patients with relapsed or stage IV RCC.

5017 Background: HDCT/ASCT represents a curative salvage treatment for patients with GCT but is rarely used for other solid tumors. Patients undergoing HDCT/ASCT for hematologic neoplasms require revaccination for their childhood immunizations. Whether this is necessary in patients with GCT is unknown. Methods: In this prospective longitudinal study, patients with GCT undergoing HDCT-ASCT from 11/2010 to 5/2018 had serologies for Measles, Mumps, Rubella, Diphtheria, Tetanus, Polio, and Varicella Zoster measured before HDCT and at 3, 6, and in a subset, 12+ months after the last HDCT with results at these timepoints compared using descriptive statistics. In addition, titer levels at ≥6 months post-transplant were matched 1:1 for age and gender with HL patients who underwent HDCT/ASCT during the same time period. Immunity was compared between cohorts using the Cochran-Mantel-Haenszel test. Results: Of 80 patients with GCT (median age 30, 84% nonseminoma), 91% received 3 sequential transplants and 68 had repeat titers at ≥6 months. Immunity at baseline was >95% for Diphtheria, Tetanus and Polio and 89% for Varicella Zoster but lower for Measles (74%), Mumps (85%), and Rubella (83%) (Table). Compared to baseline, proportional immunity for all infections was similar at 3, 6, and 12 months post-transplant in the GCT population (≥6 months shown in Table). Matching resulted in 58 GCT-HL pairs. One-year immunity was numerically lower for most infections in the HL vs. GCT patients and significantly decreased for Measles and Rubella (Table). Conclusions: To our knowledge, this is the first study to assess vaccine titers following HDCT/ASCT for GCT. We demonstrate that HDCT/ASCT does not result in loss of immunity to childhood vaccines and that GCT patients retain protective titers more frequently than those with HL. However, 15-31% of GCT patients lack MMR immunity at baseline and at 1-year post-ASCT. Therefore, we recommend checking MMR titers at 1-year post-ASCT with revaccination of those lacking immunity. Titer evaluation and revaccination is not necessary for other childhood immunizations.[Table: see text]

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.

5061 Background: The phase 3 JAVELIN Renal 101 trial (NCT02684006) in treatment-naive patients with advanced renal cell carcinoma (aRCC) demonstrated significantly improved progression-free survival (PFS; hazard ratio [HR], 0.69; 95% CI, 0.56, 0.84; P < 0.001) and higher objective response rate (ORR; 51.4% vs 25.7%) with avelumab + axitinib vs sunitinib (Motzer RJ, et al. N Engl J Med. 2019;380:1103-15). NLR has emerged as a potential prognostic biomarker in aRCC; elevated NLR is associated with poorer prognosis. Here, we describe the association of NLR with the efficacy of avelumab + axitinib from JAVELIN Renal 101. Methods: We examined baseline NLR and its association with efficacy outcomes. PFS, best overall response (per blinded independent central review using RECIST 1.1), and overall survival (OS) data from the avelumab + axitinib arm from the first interim analysis of JAVELIN Renal 101 were analyzed (data cutoff, June 20, 2018). Multivariate Cox regression analyses of PFS and OS were also conducted. Results: In the avelumab + axitinib arm, patients with < median NLR (N = 217) had longer observed PFS (stratified HR, 0.85; 95% CI, 0.634, 1.153) and longer observed OS (stratified HR, 0.51; 95% CI, 0.300, 0.871) than patients with ≥ median NLR (N = 217). The ORR was 57.1% in patients with < median NLR vs 47.5% in patients with ≥ median NLR, with complete response in 5.5% vs 1.4%. Multivariate analysis showed that low NLR was associated with longer PFS and OS by treating baseline NLR as either a continuous variable or a binary variable (dichotomized by median). Conclusions: Low NLR was associated with better observed treatment outcomes in patients with aRCC who received avelumab + axitinib. Clinical trial information: NCT02684006 .

Objective To evaluate patient‐reported outcome (PRO) data from the IMmotion150 study. The phase 2 IMmotion150 study showed improved progression‐free survival with atezolizumab plus bevacizumab vs sunitinib in patients with programmed death‐ligand 1 (PD‐L1)+ tumours and suggested activity of atezolizumab monotherapy in previously untreated metastatic renal cell carcinoma (mRCC). Patients and methods Patients with previously untreated mRCC were randomised to atezolizumab 1200 mg intravenously (i.v.) every 3 weeks ( n = 103), the atezolizumab regimen plus bevacizumab 15 mg/kg i.v. every 3 weeks ( n = 101), or sunitinib 50 mg orally daily (4 weeks on, 2 weeks off; n = 101). The MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) were administered on days 1 and 22 of each 6‐week cycle. Time to deterioration (TTD), change from baseline in MDASI core and RCC symptom severity, interference with daily life, and BFI fatigue severity and interference scores were reported for all comers. The TTD was the first ≥2‐point score increase over baseline. Absolute effect size ≥0.2 suggested a clinically important difference with checkpoint inhibitor therapy vs sunitinib. Results Completion rates were >90% at baseline and ≥80% at most visits. Delayed TTD in core and RCC symptoms, symptom interference, fatigue, and fatigue‐related interference was observed with atezolizumab (both alone and in combination) vs sunitinib. Improved TTD (hazard ratio [HR], 95% confidence interval [CI]) was more pronounced with atezolizumab monotherapy: core symptoms, 0.39 (0.22–0.71); RCC symptoms, 0.22 (0.12–0.41); and symptom interference, 0.36 (0.22–0.58). Change from baseline by visit, evaluated by the MDASI, also showed a trend favouring atezolizumab monotherapy vs sunitinib. Small sample sizes may have limited the ability to draw definitive conclusions. Conclusion PROs suggested that atezolizumab alone or with bevacizumab maintained daily function compared with sunitinib. Notably, symptoms were least severe with atezolizumab alone vs sunitinib (IMmotion150; ClinicalTrials.gov Identifier: NCT01984242).

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non–clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.

4563 Background: We previously reported no difference in favorable response rate (FRR) or PFS for TIP vs BEP. Here we present results of a pre-planned analysis of biomarkers of outcome. Methods: HCG and AFP were drawn on days 1 and 15 of each cycle and rates of decline classified as satisfactory [S] or unsatisfactory [US] by MSK (Motzer JCO 2007) and GETUG (Fizazi Lancet Oncol 2014) methods. IHC for ERCC1, RAD51, PARP1, HER-2, and p-AKT was performed on pre-treatment tumor samples. An H-score (0 – 300) was calculated for each stain (H = stain intensity [0 – 3] x % positive cells [0-100]). H-score and marker decline category were correlated with FRR (PR + CR) and PFS. Patients (pts) who received disease-stabilizing chemotherapy were excluded from marker analyses. Results: Of 91 pts, 80 did not receive disease-stabilizing treatment with 79 having sufficient marker values for analysis by the MSK method and 75 by GETUG. By MSK, 49 had S decline vs 30 US; by GETUG, 34 S vs 41 US. FRR and PFS were improved for pts with S vs US decline by both methods and remained significant by the MSK method when stratified by IGCCCG group (Table). IHC (n=77) quality was adequate in 71 to 73 pts (varied by stain) and was positive (H >0) for PARP in 68/73, ERCC1 in 54/71, RAD51 in 54/73, p-AKT in 5/72, and HER2 in 4/72. Only PARP1 was associated with outcome with worse PFS for the lowest expression tertile (H < 180; p=0.013). Conclusions: PARP1 expression and tumor marker decline rates, particularly by MSK method, were significantly associated with outcome to initial chemotherapy in int/poor risk GCT. Future trials incorporating marker decline into treatment allocation and validating the prognostic effect of PARP1 expression are warranted. Clinical trial information: NCT01873326. [Table: see text]

4515 Background: The phase 2 IMmotion150 study showed improved PFS with atezo + bev vs sun in patients (pts) whose tumors were PD-L1+ and corroborated the activity of atezo monotherapy in previously untreated mRCC. This study offers an opportunity to evaluate PROs with immunotherapy and VEGF-directed therapy alone and in combination. Methods: Pts randomized to atezo 1200 mg IV q3w alone or with bev 15 mg/kg IV q3w, or sun 50 mg po qd for 4 wk on/2 wk off completed the MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) q3w of each 6-wk cycle until progression (RECIST 1.1). Time to deterioration (TTD; first ≥ 2-point score increase over baseline [BL]) and change from BL (effect size [ES] ≥ 0.2 suggests a clinically important difference vs sun) in MDASI symptom severity and interference and BFI fatigue severity and interference scores are reported for all-comers. Results: Completion rates were > 90% at BL and ≥ 80% at most visits across arms. BL PRO scores indicating mild symptoms and interference were similar across arms. Delayed TTD of symptom severity and interference with daily life was seen with atezo vs sun and atezo + bev vs sun and was longest with atezo alone (Table). Pts reported milder symptoms and less interference during the first 6 cycles with atezo vs sun: ES mean (range) was 0.36 (0.07-0.68) for core symptom severity and 0.36 (0.04-0.83) for symptom interference. The 5 worst pt-reported symptoms during tx (dry mouth, fatigue, rash, drowsiness, lack of appetite) were all in the sun arm; all 16 symptoms measured were milder with atezo vs sun. Conclusions: PROs suggest that atezo alone or with bev maintained daily function with minimal symptom interference vs sun. Clinical activity, safety and PRO data for atezo support its investigation in adjuvant tx of high-risk RCC pts (IMmotion010; NCT03024996). Clinical trial information: NCT01984242. [Table: see text]