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Purpose: High body mass index (BMI) may lead to improved immune-checkpoint blockade (ICB) outcomes in metastatic clear cell renal cell carcinoma (mccRCC). However, BMI is a crude body size measure. We investigated BMI and radiographically assessed body composition (BC) parameters association with mccRCC ICB outcomes. Experimental Design: Retrospective study of ICB-treated patients with mccRCC. BMI and BC variables [skeletal muscle index (SMI) and multiple adiposity indexes] were determined using pretreatment CT scans. We examined the associations between BMI and BC variables with ICB outcomes. Therapeutic responses per RECIST v1.1 were determined. We compared whole-transcriptomic patterns with BC variables in a separate cohort of 62 primary tumor samples. Results: 205 patients with mccRCC were included in the cohort (74% were male, 71% were overweight/obese, and 53% were classified as low SMI). High-BMI patients experienced longer overall survival (OS) than normal-weight patients [unadjusted HR, 0.66; 95% confidence interval (CI), 0.45–0.97; P = 0.035]. The only BC variable associated with OS was SMI [unadjusted HR comparing low vs. high SMI 1.65 (95% CI: 1.13–2.43); P = 0.009]. However, this OS association became nonsignificant after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium score and line of therapy. No OS association was seen for adiposity and no BC variable was associated with progression-free survival or radiological responses. Tumors from patients with low SMI displayed increased angiogenic, inflammatory, and myeloid signals. Conclusions: Our findings highlight the relevance of skeletal muscle in the BMI paradox. Future studies should investigate if addressing low skeletal muscle in metastatic patients treated with ICB can improve survival.

PURPOSE To assess the efficacy and safety of cabozantinib plus nivolumab in a phase II trial in patients with non–clear-cell renal cell carcinoma (RCC). PATIENTS AND METHODS Patients had advanced non–clear-cell renal carcinoma who underwent 0-1 prior systemic therapies excluding prior immune checkpoint inhibitors. Patients received cabozantinib 40 mg once daily plus nivolumab 240 mg once every 2 weeks or 480 mg once every 4 weeks. Cohort 1 enrolled patients with papillary, unclassified, or translocation-associated RCC; cohort 2 enrolled patients with chromophobe RCC. The primary end point was objective response rate (ORR) by RECIST 1.1; secondary end points included progression-free survival, overall survival, and safety. Next-generation sequencing results were correlated with response. RESULTS A total of 47 patients were treated with a median follow-up of 13.1 months. Objective response rate for cohort 1 (n = 40) was 47.5% (95% CI, 31.5 to 63.9), with median progression-free survival of 12.5 months (95% CI, 6.3 to 16.4) and median overall survival of 28 months (95% CI, 16.3 to not evaluable). In cohort 2 (n = 7), no responses were observed; one patient had stable disease > 1 year. Grade 3/4 treatment-related adverse events were observed in 32% treated patients. Cabozantinib and nivolumab were discontinued because of toxicity in 13% and 17% of patients, respectively. Common mutations included NF2 and FH in cohort 1 and TP53 and PTEN in cohort 2. Objective responses were seen in 10/12 patients with either NF2 or FH mutations. CONCLUSION Cabozantinib plus nivolumab showed promising efficacy in most non–clear-cell RCC variants tested in this trial, particularly those with prominent papillary features, whereas treatment effects were limited in chromophobe RCC. Genomic findings in non–clear-cell RCC variants warrant further study as predictors of response.

It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we performed whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identified myeloid-derived IL6 as a key mediator. Furthermore, a novel myeloid gene signature strongly correlated with disease recurrence and overall survival on uni- and multivariate analyses and is linked to TP53 inactivation across multiple data sets. Strikingly, effector T-cell gene signatures, infiltration patterns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppressive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduced metastatic development. Our findings suggest that myeloid inflammation promotes disease recurrence in ccRCC and is targetable as well as provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC. Significance: Improved understanding of factors that influence metastatic development in localized ccRCC is greatly needed to aid accurate prediction of disease recurrence, clinical decision-making, and future adjuvant clinical trial design. Our analysis implicates intratumoral myeloid inflammation as a key driver of metastasis in patients and a novel immunocompetent mouse model. This article is highlighted in the In This Issue feature, p. 2221

Purpose: MEDI0680 is a humanized anti–programmed cell death-1 (PD-1) antibody, and durvalumab is an anti-PD-L1 antibody. Combining treatment using these antibodies may improve efficacy versus blockade of PD-1 alone. This phase II study evaluated antitumor activity and safety of MEDI0680 plus durvalumab versus nivolumab monotherapy in immunotherapy-naïve patients with advanced clear-cell renal cell carcinoma who received at least one prior line of antiangiogenic therapy. Patients and Methods: Patients received either MEDI0680 (20 mg/kg) with durvalumab (750 mg) or nivolumab (240 mg), all intravenous, every 2 weeks. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included best overall response, progression-free survival (PFS), safety, overall survival (OS), and immunogenicity. Exploratory endpoints included changes in circulating tumor DNA (ctDNA), baseline tumor mutational burden, and tumor-infiltrated immune cell profiles. Results: Sixty-three patients were randomized (combination, n = 42; nivolumab, n = 21). ORR was 16.7% [7/42; 95% confidence interval (CI), 7.0–31.4] with combination treatment and 23.8% (5/21; 95% CI, 8.2–47.2) with nivolumab. Median PFS was 3.6 months in both arms; median OS was not reached in either arm. Because of adverse events, 23.8% of patients discontinued MEDI0680 and durvalumab and 14.3% of patients discontinued nivolumab. In the combination arm, reduction in ctDNA fraction was associated with longer PFS. ctDNA mutational analysis did not demonstrate an association with response in either arm. Tumor-infiltrated immune profiles showed an association between immune cell activation and response in the combination arm. Conclusions: MEDI0680 combined with durvalumab was safe and tolerable; however, it did not improve efficacy versus nivolumab monotherapy.

Purpose: To evaluate the association between neutrophil-to-lymphocyte ratio (NLR) and efficacy of avelumab plus axitinib or sunitinib. Experimental Design: Adult patients with untreated advanced renal cell carcinoma (RCC) with a clear-cell component, ≥1 measurable lesions, Eastern Cooperative Oncology Group performance status of 0 or 1, fresh or archival tumor specimen, and adequate renal, cardiac, and hepatic function were included. Retrospective analyses of the association between baseline NLR and progression-free survival (PFS) and overall survival (OS) in the avelumab plus axitinib or sunitinib arms were performed using the first interim analysis of the phase 3 JAVELIN Renal 101 trial (NCT02684006). Multivariate Cox regression analyses of PFS and OS were conducted. Translational data were assessed to elucidate the underlying biology associated with differences in NLR. Results: Patients with below-median NLR had longer observed PFS with avelumab plus axitinib [stratified HR, 0.85; 95% confidence interval (CI), 0.634–1.153] or sunitinib (HR, 0.56; 95% CI, 0.415–0.745). In the avelumab plus axitinib or sunitinib arms, respectively, median PFS was 13.8 and 11.2 months in patients with below-median NLR, and 13.3 and 5.6 months in patients with median-or-higher NLR. Below-median NLR was also associated with longer observed OS in the avelumab plus axitinib (HR, 0.51; 95% CI, 0.300–0.871) and sunitinib arms (HR, 0.30; 95% CI, 0.174–0.511). Tumor analyses showed an association between NLR and key biological characteristics, suggesting a role of NLR in underlying mechanisms influencing clinical outcome. Conclusions: Current data support NLR as a prognostic biomarker in patients with advanced RCC receiving avelumab plus axitinib or sunitinib.

Background This study assessed whether antiangiogenic treatment may potentiate immune checkpoint blockade in patients with advanced renal cell carcinoma. Patients and Methods This was an open-label, two-part, multicenter study involving treatment-naive patients with advanced renal cell carcinoma. Part 1 consisted of a phase I dose escalation and expansion of pazopanib plus pembrolizumab (combination therapy). Cohorts A and B received pazopanib in combination with pembrolizumab, whereas Cohort C received pazopanib monotherapy for 9 weeks before receiving the combination therapy. Part 2 was planned as a randomized three-arm study but was not conducted. Results Overall, 42 patients were enrolled (10 each in Cohorts A and B, 22 in Cohort C). The maximum tolerated dose was not reached and the recommended phase II dose was not declared, as Cohort C was closed early because of safety concerns. The overall response rates were 60% and 20% in Cohorts A and B, respectively. In Cohort C, the overall response rates were 33%, 25%, and 0% in the combination therapy, pembrolizumab monotherapy, and pazopanib monotherapy groups, respectively. The median progression-free survival rates were 21.95 months and 41.40 months in Cohorts A and B, respectively. Grade 3 or 4 adverse events (AEs) were observed in 90% of patients in Cohorts A and B. In Cohort C, the frequencies of grade 3 or 4 AEs, serious adverse events, and AEs leading to dose reduction were typically high in the combination therapy group. Conclusions Despite preliminary signs of efficacy, significant hepatotoxicity was observed in Cohorts A and B. The sequential schedule of pazopanib followed by pazopanib plus pembrolizumab showed reduced hepatotoxicity; however, other safety issues emerged with this approach.

PURPOSE The clinical utility of cell-free DNA (cfDNA) as a biomarker for advanced clear cell renal cell carcinoma (ccRCC) remains unclear. We evaluated the validity of cfDNA-based genomic profiling in a large cohort of patients with ccRCC with matched next-generation sequencing (NGS) from primary tumor tissues. MATERIALS AND METHODS We performed paired NGS of tumor DNA and plasma cfDNA using the MSK-IMPACT platform in 110 patients with metastatic ccRCC. Tissues were profiled for variants and copy number alterations with germline comparison. Manual cross-genotyping between cfDNA and tumor tissue was performed. Deep sequencing with a higher sensitivity platform, MSK-ACCESS, was performed on a subset of cfDNA samples. Clinical data and radiographic tumor volumes were assessed to correlate cfDNA yield with treatment response and disease burden. RESULTS Tumor tissue MSK-IMPACT testing identified 582 genomic alterations (GAs) across the cohort. Using standard thresholds for de novo variant calling in cfDNA, only 24 GAs were found by MSK-IMPACT in cfDNA in 7 of 110 patients (6%). With manual cross-genotyping, 210 GAs were detectable below thresholds in 74 patients (67%). Intrapatient concordance with tumor tissue was limited, including VHL (31.6%), PBRM1 (24.1%), and TP53 (52.9%). cfDNA profiling did not identify 3p loss because of low tumor fractions. Tumor volume was associated with cfDNA allele frequency, and VHL concordance was superior for patients with greater disease burden. CONCLUSION cfDNA-based NGS profiling yielded low detection rates in this metastatic ccRCC cohort. Concordance with tumor profiling was low, even for truncal mutations such as VHL, and some findings in peripheral blood may represent clonal hematopoiesis. Routine cfDNA panel testing is not supported, and its application in biomarker efforts must account for these limitations.

Background The worldwide COVID-19 public health pandemic has restructured clinical care of cancer patients throughout the world. The specific changes in the management of genitourinary (GU) cancers in different cancer centers due to COVID-19 are not known and some clinical scenarios remain controversial. We conducted an opinion survey to determine what changes in cancer treatment strategies are occurring due to the COVID-19 pandemic. Methods A 20-item online survey was sent on 05/25/20 to 170 expert GU medical oncologists from Europe and North America. The survey solicited responses to changes in GU cancer management in the setting of the COVID-19 pandemic. Data was collected and managed via a secure REDCap Database. Results Surveys were completed by 78 (45.8%) of 170 GU oncologists between 05/25/20 and 06/25/20. Clinical practice changes due to COVID-19 in at least one scenario were reported by 79.1% of responders, most pronounced in prostate cancer (71.8%) and least in urothelial cancer (23%). Preferences for change in management varied by country with 78% of US oncologists indicating a change in their practice (37/47), 57% for Canadian oncologists (4/7) and 79% in Europe (19/24). Conclusions This study suggests international practice changes are occurring in GU cancer care during the COVID-19 pandemic. The variability in practice changes between countries may reflect differences in COVID-19 case load during the timepoint of data collection. These results, based on expert opinion during this rapidly changing crisis, may inform the oncologic community regarding the effects of COVID-19 on genitourinary cancer care., Highlights: ∗ Genitourinary (GU) cancer management has been affected by COVID-19 around the world ∗ We present an expert opinion survey to define GU cancer care changes during COVID-19 ∗ Practice changes were reported by 79.1% of responders and differed between countries ∗ Consensus was noted in some areas while other clinical scenarios remain controversial, Genitourinary (GU) cancer management has been affected by COVID-19 around the world. We present an expert opinion survey to define GU cancer care changes during COVID-19. Practice changes were reported by 79.1% of responders and differed between countries. Consensus was noted in some areas while other clinical scenarios remain controversial.

Immune checkpoint blockade (ICB) therapy has substantially improved the outcomes of patients with many types of cancers, including renal cell carcinoma (RCC). Initially studied as monotherapy, immunotherapy-based combination regimens have improved the clinical benefit achieved by ICB monotherapy and have revolutionized RCC treatment. While biomarkers like PD-L1 and tumor mutational burden (TMB) are FDA approved as biomarkers for ICB monotherapy, there are no known biomarkers for combination immunotherapies. Here, we describe the clinical outcomes and genomic determinants of response from a phase Ib/II clinical trial on patients with advanced RCC evaluating the efficacy of lenvatinib, a multi-kinase inhibitor mainly targeting VEGFR and FGFR plus pembrolizumab, an anti-PD1 immunotherapy. Concurrent treatment with lenvatinib and pembrolizumab resulted in an objective response rate of 79% (19/24) and tumor shrinkage in 96% (23/24) of patients. While tumor mutational burden (TMB) did not predict for clinical benefit, germline HLA-I diversity strongly impacted treatment efficacy. Specifically, HLA-I evolutionary divergence (HED), which measures the breadth of a patient's immunopeptidome, was associated with both improved clinical benefit and durability of response. Our results identify lenvatinib plus pembrolizumab as a highly active treatment strategy in RCC and reveal HLA-I diversity as a critical determinant of efficacy for this combination. HED also predicted better survival in a separate cohort of patients with RCC following therapy with anti-PD-1–based combination therapy. Implications: These findings have substantial implications for RCC therapy and for understanding immunogenetic mechanisms of efficacy and warrants further investigation.

Background: Metastatic renal cell carcinoma (mRCC) management guidelines recommend brain imaging if clinically indicated and the rate of occult central nervous system (CNS) metastasis is not well-defined. Early detection could have major therapeutic implications, because timely interventions may limit morbidity and mortality. Patients and Methods: A retrospective review was performed to characterize patients with mRCC incidentally diagnosed with asymptomatic brain metastases during screening for clinical trial participation at Gustave Roussy and Memorial Sloan Kettering Cancer Center. Descriptive statistics and time-to-event methods were used to evaluate the cohort. Results: Across 68 clinical trials conducted between 2001 and 2019 with a median 14.1-month follow-up, 72 of 1,689 patients (4.3%) with mRCC harbored occult brain metastases. The International Metastatic RCC Database Consortium (IMDC) risk status was favorable (26%), intermediate (61%), and poor (13%), and 86% of patients had ≥2 extracranial sites of disease, including lung metastases in 92% of patients. CNS involvement was multifocal in 38.5% of patients, and the largest brain metastasis was >1 cm in diameter in 40% of the cohort. Localized brain-directed therapy was pursued in 93% of patients, predominantly radiotherapy. Median overall survival was 10.3 months (range, 7.0–17.9 months), and the 1-year overall survival probability was 48% (95% CI, 37%–62%). IMDC risk and number or size of lesions did not correlate with survival (log-rank, P=.3, P=.25, and P=.067, respectively). Conclusions: This large multi-institutional mRCC cohort study identified occult brain metastasis in a notable proportion of patients (4.3%) and highlights that the risk of asymptomatic CNS involvement extends to those with favorable risk features per IMDC risk assessment. These data provide rationale for brain screening in patients with advanced RCC.

Purpose:This was a multicenter, histology-agnostic, single-arm prospective phase II trial of therapeutic activity of everolimus, an oral mTORC1 inhibitor, in patients with advanced solid tumors that harbored TSC1/TSC2 or MTOR mutations.Patients and Methods:Patients with tumors with inactivating TSC1/TSC2 or activating MTOR mutations identified in any Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory were eligible. Patients were treated with everolimus 10 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Whole-exome sequencing was performed to identify co-occurring genomic alterations.Results:Between November 2015 and October 2018, 30 patients were enrolled at Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Tumors harbored TSC1 (13/30), TSC2 (15/30), concurrent TSC1 and TSC2 (1/30), or MTOR (1/30) mutations. The most common treatment-related adverse event of any grade was mucositis (8/30, 27%); 1 patient had fatal pneumonitis. Partial responses were seen in 2 patients [7%; 95% confidence interval (CI), 1%–22%]. Median progression-free survival was 2.3 months (95% CI, 1.8–3.7 months) and median overall survival (OS) was 7.3 months (95% CI, 4.5–12.7 months). There was no clear association between other genomic alterations and response. Of the 2 patients with objective response, 1 had upper tract urothelial carcinoma with biallelic inactivation of TSC1 and high tumor mutation burden, and the other had uterine carcinoma with biallelic TSC2-inactivating mutations and PEComa-like pathologic features.Conclusions:Everolimus therapy had a disappointing ORR (7%) in this pan-cancer, mutation-selected, basket study.See related commentary by Kato and Cohen, p. 3807

659 Background: Combination therapy with I/N can achieve long-term benefit in a sizable proportion of RCC pts, but broad application has been challenged by a high incidence of irAEs. Host features affecting antigen presentation are candidate determinants of irAE pathogenesis, and isolated reports have linked Human Leukocyte Antigen (HLA) variations to organ- specific irAEs. We analyzed data for pts treated on a phase 3 trial to investigate association of class 1 HLA variants with development of irAEs from I/N and develop a tool to predict risk for toxicity. Methods: We analyzed germline HLA + clinical data for 472 pts receiving I/N vs sunitinib (SUT). Based on allelic variants for HLA-A and B pts were categorized into 12 established HLA "Super-Types" (ST), sets of HLA variants with largely overlapping peptide binding specificity. We conducted uni- and multivariate (UV; MV) Cox proportional hazards regression to correlate HLA-ST variables with time to treatment-related AEs (TTrAE, grade 2+) in I/N pts using the Kaplan Meier method. Several MV HLA-ST models were developed on a discovery set (DISC; 2/3 random sample of I/N pts without replacement ) and compared using model concordance (c-index) on a validation set (VAL; remaining 1/3). Model coefficients were used to create a “HLA-ST score” that could be computed for individual pts. Results: 235 pts and 237 pts received I/N vs SUT and had available HLA data, respectively. On UV analysis for I/N, HLA-B07 ST had protective association TTrAE (HR= 0.65, 95% CI: 0.46,0.90; p= 0.010), while B62 associated adversely (HR=1.64, 95% CI: 1.12, 2.40; p=0.014). Relevant to the development of our model we identified interactions between several pairs of HLA ST. The HLA ST model with best performance in DISC (c-index= 0.606) and VAL (c-index=0.595) integrates B07, B62, A01, B08, and two interactions: B07-B08 and B07-A01. The model-generated HLA-ST score was significantly associated with TTrAE after adjusting for race, BMI, region, PDL1 status, and MSKCC risk score (DISC p= vs < median had significantly different TTrAE both in DISC (p=0.004) and VAL (p=0.009); again, no difference was observed in the SUT arm (p=0.5). The weighted HLA-ST score had no association with PFS or OS for I/N pts. Conclusions: In this large sample of I/N-treated patients, class I HLA variants were associated with the risk of developing irAEs. We developed a HLA ST based score that correlated with treatment toxicity independent of relevant clinical and demographic features. No association with TTrAE was seen in SUT-treated pts. These results highlight the potential of characterizing germline features to predict immune related toxicity upfront and deserves further study. Clinical trial information: NCT02231749 .

687 Background: The presence of sarcomatoid features in clear cell renal cell carcinoma (cRCC) has historically been associated with poor response to tyrosine kinase inhibitor (TKI) monotherapy and poor overall survival; however, immunotherapy (IO) combination therapies have shown more promise in treating this variant. Front-line anti-PD-1 based IO combinations used in ccRCC include ipilimumab/nivolumab (IO/IO) and several combinations of a VEGFR-targeted TKI with a PD-1 inhibitor (TKI/IO). Here, we compare progression-free survival after therapeutic 1st-line (PFS) and 2nd-line (PFS-2) in patients who received IO/IO vs TKI/IO combinations as 1st line treatment for metastatic ccRCC, and test whether the treatment effects differ based on the presence or absence of sarcomatoid dedifferentiation. Methods: A retrospective analysis was performed on patients with ccRCC initiating 1st line combination IO at Memorial Sloan Kettering Cancer Center between 1/1/2014 and 12/30/2020. Patient cohorts were defined by 1st line treatment type: IO/IO or TKI/IO. PFS and PFS-2 were estimated using the Kaplan-Meier method. Restricted mean survival time (RMST) was calculated for PFS and PFS-2 in each 1st line treatment group and modelled using a generalized linear model adjusted for IMDC risk. To test for heterogeneity of treatment effect among subgroups, sarcomatoid features (presence/absence) is included in the models and an interaction test is performed. Results: Ninety patients (28 sarcomatoid) received 1st line IO/IO and 83 (17 sarcomatoid) received 1st line TKI/IO. Median PFS time is 6.8 months (95% CI: 4.5, 12.2) for IO/IO and 21 months (95% CI: 15, 25) for TKI/IO, p=0.009. After adjusting for IMDC risk, and after 48 months of follow-up, RMST for PFS was 10 months for IO/IO and 24 months for TKI/IO (p=0.02) and RMST for PFS-2 was 20 months for IO/IO and 23 months for TKI/IO (p=0.24). In the RMST model, the interaction between treatment group and presence or absence of sarcomatoid features is not significant for PFS (0.95) or PFS-2 (0.29). Conclusions: For ccRCC patients treated with 1st line IO/IO or TKI/IO, adjusted RMST for PFS was significantly longer for the TKI/IO group, but there was no statistically significant difference in adjusted RMST for PFS-2. Anti-PD-1-based therapy is an effective approach to treating ccRCC with sarcomatoid features. [Table: see text]

Background No biomarkers have been established to predict treatment efficacy in renal cell carcinoma (RCC). In an exploratory retrospective analysis of a Phase 2 study, we constructed composite biomarker scores (CBSs) to predict progression-free survival (PFS) and overall survival (OS) in patients with metastatic RCC randomised to receive lenvatinib-plus-everolimus. Methods Of 40 biomarkers tested, the 5 most strongly associated with PFS (HGF, MIG, IL-18BP, IL-18, ANG-2) or OS (TIMP-1, M-CSF, IL-18BP, ANG-2, VEGF) were used to make a 5-factor PFS-CBS or OS-CBS, respectively. A 2-factor CBS was generated with biomarkers common to PFS-CBS and OS-CBS. Patients were divided into groups accordingly (5-factor-CBS high: 3−5, CBS-low: 0–2; 2-factor-CBS high: 1–2, CBS-low: 0). Results PFS/OS with lenvatinib-plus-everolimus were significantly longer in the 5-factor CBS-high group versus the CBS-low group (P = 0.0022/P P P = 0.0079, respectively); PFS was also significantly longer with lenvatinib-plus-everolimus versus lenvatinib (P = 0.0046). The 5-factor-CBS had a predictive role in PFS and OS after multivariate analysis. Similar trends were observed with the 2-factor-CBS for PFS (i.e., lenvatinib-plus-everolimus versus everolimus). Conclusions The 5-factor CBS may identify patients with metastatic RCC who would benefit from lenvatinib-plus-everolimus versus everolimus; additional validation is required. Clinical trial registration The clinical trial registration number is NCT01136733.

4514 Background: In the open-label, randomized, phase 3 CLEAR study, LEN + PEMBRO had significant PFS (primary endpoint) and OS (key secondary endpoint) benefits over SUN among pts with aRCC in the 1L setting (Motzer 2021, NEJM). We evaluated PFS on next-line therapy (“PFS2”) and explored the effect of subsequent anticancer therapy on OS in the LEN + PEMBRO and SUN treatment arms of CLEAR. Methods: PFS2 was defined as time from randomization to disease progression (as assessed by investigator) on next-line treatment or death from any cause (whichever occurred first). PFS2 was evaluated in all pts randomly assigned to LEN 20 mg orally QD + PEMBRO 200 mg IV Q3W (n=355) or SUN 50 mg orally QD (4 wks on/2 wks off) (n=357) using Kaplan-Meier estimates, and compared between treatment arms via a log-rank test stratified by geographic region and MSKCC prognostic groups. The HR and corresponding CI were estimated using the Cox regression model with Efron’s method for ties, using the same stratification factors. A post hoc analysis accounting for the effect of subsequent anticancer therapy on OS (time from randomization to death from any cause) in the LEN + PEMBRO and SUN arms using 2-stage estimation was conducted. Results: Among pts who received subsequent anticancer therapy in the LEN + PEMBRO (n=117 pts) and SUN (n=206 pts) arms (Table), median time to next-line therapy was 12.2 mos (range 1.45–37.36) and 6.4 mos (range 0.39–28.52), respectively. Median duration of first subsequent anticancer therapy was 5.2 mos (range 0.10–30.23) in the LEN + PEMBRO arm and 6.8 mos (range 0.03–30.72) in the SUN arm. Among all pts, PFS2 was longer with LEN + PEMBRO than with SUN (median not reached vs 28.7 mos; HR, 0.50; 95% CI 0.39–0.65; nominal P

Background We previously reported on a phase 2 study of everolimus plus bevacizumab across various nonclear cell renal cell carcinoma (nccRCC) histologies and observed encouraging activity among patients with papillary RCC (pRCC) and unclassified RCC (uRCC) with a major papillary component. We subsequently expanded the study to enroll additional patients with pRCC variants. Methods Everolimus plus bevacizumab was administered at standard doses until disease progression or intolerance to therapy. The primary endpoint was the 6-month progression-free survival (PFS) rate; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Correlative analyses included next-generation sequencing (NGS) from tumor and germline across >341 genes of interest. Results In addition to 19 patients with pRCC variants in the original cohort, 20 patients with similar features were enrolled on the expansion cohort (uRCC with papillary features [n = 24], pRCC [n = 14], and translocation-associated RCC with papillary features [n = 1]). Among 37 evaluable patients, the 6-month PFS rate was 78%, the median PFS was 13.7 months (95% CI, 10.8-16.4 months), and the ORR was 35%. With a median follow-up of 17.6 months, the median OS was 33.9 months (95% CI, 23.3-71.9). Tolerance was consistent with prior reports for everolimus plus bevacizumab. NGS results (n = 33) identified responses in patients with a wide spectrum of genomic alterations, including ARID1A, FH, and MET mutations. Conclusion The expansion cohort results confirm robust activity of everolimus plus bevacizumab in metastatic pRCC variants, supporting this regimen as a standard option for this patient population.

In the preceding two decades, several milestones have been reached in the management of patients with metastatic renal cell carcinoma (mRCC), including the development of novel targeted agents paralleling an increased understanding of the molecular biology of this disease process. Recently, a renewed enthusiasm for immunotherapy in the form of immune checkpoint blockade has resulted in significant strides in the treatment of mRCC. Despite these advances, treatment remains challenging for clinicians, and only modest survival benefits are observed with current treatment paradigms. The risk-stratification tools and investigated predictive and prognostic biomarkers in patients with mRCC are detailed in this review.

There is conflicting data regarding the role of PBAF complex mutations and response to immune checkpoint blockade (ICB) therapy in clear cell renal cell carcinoma (ccRCC) and other solid tumors. We assess the prevalence of PBAF complex mutations from two large cohorts including the pan-cancer TCGA project (n = 10,359) and the MSK-IMPACT pan-cancer immunotherapy cohort (n = 3700). Across both cohorts, PBAF complex mutations, predominantly PBRM1 mutations, are most common in ccRCC. In multivariate models of ccRCC patients treated with ICB (n = 189), loss-of-function (LOF) mutations in PBRM1 are not associated with overall survival (OS) (HR = 1.24, p = 0.47) or time to treatment failure (HR = 0.85, p = 0.44). In a series of 11 solid tumors (n = 2936), LOF mutations are not associated with improved OS in a stratified multivariate model (HR = 0.9, p = 0.7). In a current series of solid tumors treated with ICB, we are unable to demonstrate favorable response to ICB in patients with PBAF complex mutations. The clinical benefit from immunotherapy response in patients with mutations of genes forming the chromatin remodelling complex PBAF remains controversial. Here the authors show that PBAF complex mutations are not associated with favourable response in pan-cancer cohorts of patients treated with immune-checkpoint blockade.

Purpose: Translocation renal cell carcinoma (tRCC) is a rare, aggressive renal cell carcinoma (RCC) subtype. There is currently limited understanding on the role of molecular alterations in the pathogenesis and progression of these tumors. We investigated the association between somatic alterations and clinical outcomes in two independent cohorts profiled using DNA sequencing. Experimental Design: Twenty-two tRCCs underwent targeted sequencing [Memorial Sloan Kettering Cancer Center (MSK)-IMPACT]; a subset was profiled using exome-sequencing and combined with exome data from The Cancer Genome Atlas (TCGA) for analysis. The prognostic value of specific somatic aberrations, tumor mutation burden (TMB), and fraction of copy-number–altered genome (FCNAg) was explored. In TCGA cases, neoantigen prediction and immune cell deconvolution were performed using RNA-sequencing and exome data. Overall survival estimates were computed using the Kaplan–Meier method; time-on-treatment was calculated for 14 MSK-IMPACT patients who underwent systemic therapy. Associations between molecular features and outcomes were evaluated using nonparametric testing. Results: Copy-number aberrant tRCCs were associated with poor overall survival (P = 0.03). Pediatric patients had tumors with lower FCNAg (P = 0.01). In one adult case with two chronologically distinct tumor samples sequenced, we confirmed that copy-number events occurred early during evolution. TERT promoter mutations were found exclusively in high-stage tumors. We found that tRCCs displayed distinct angiogenesis and PD-L1 gene expression profiles compared with other RCC subtypes. Conclusions: Tumors molecularly defined by increased copy-number variations were associated with aggressive disease in tRCC. A higher burden of genomic events in adults compared with pediatric cases likely reflects a more aggressive clinical course. The unique immunophenotypic characteristics of tRCC merit further exploration.

Background One of the main challenges in the management of renal cell carcinoma (RCC) is risk-stratifying patients who present with metastatic disease. Tumor size is an important predictor of survival in the localized setting; however, this feature has not been explored fully in patients presenting with M1 RCC. Objective To assess the impact of tumor size on survival in patients with metastatic RCC who underwent cytoreductive nephrectomy (CN). Design, setting, and participants We queried the Memorial Sloan Kettering (MSK) nephrectomy database for patients who presented with M1 disease and underwent CN between 1989 and 2016 (n = 304). Primary tumor size was obtained from pathology reports. Data from the International Metastatic Database Consortium (IMDC) were used for validation purposes (n = 778). Outcome measurements and statistical analysis Overall survival (OS) estimates were computed using the Kaplan-Meier method. Cox regressions were used to test the association between tumor size and OS in univariate and multivariable analyses. Tumors ≤4 cm were compared with larger masses. Secondary analyses were performed to assess the robustness of these findings. Results and limitations Clear cell tumors ≤4 cm were significantly associated with improved OS in both the MSK (hazard ratio [HR]: 0.35, 0.17–0.72, p = 0.004) and IMDC (HR 0.54, 0.36–0.83, p = 0.004) cohorts. The association was observed even after adjusting for known prognostic factors (HR 0.40, 0.14–1.14, p = 0.09 and HR: 0.54, 0.33–0.90, p = 0.02 in the MSK and IMDC cohorts, respectively). Limitations of this study include the absence of patients who were considered poor surgical candidates as well as potential selection bias. Conclusions The primary tumor size ≤4 cm was independently associated with improved OS in patients with metastatic clear cell RCC who underwent CN. Additionally, the association between primary size and survival was found to be nonlinear. These findings suggest that there is a group of small metastatic RCCs that can convey a better overall prognosis. The potential role of primary tumor size when risk stratifying patients with M1 RCC should be explored further to determine its utility during clinical decision making. Patient summary We evaluated the impact of small tumor size on prognosis in patients with metastatic kidney cancer who undergo removal of the primary tumor. Very small masses (≤4 cm) were associated with better prognosis in patients with clear cell tumors.

Summary Background Obesity is associated with an increased risk of developing clear cell renal cell carcinoma (RCC) but, paradoxically, obesity is also associated with improved oncological outcomes in this cancer. Because the biological mechanisms underlying this paradoxical association are poorly understood, we aimed to identify transcriptomic differences in primary tumour and peritumoral adipose tissue between obese patients and those at a normal weight. Methods In this cohort study, we assessed data from five independent clinical cohorts of patients with clear cell RCC aged 18 years and older. Overweight patients were excluded from each cohort for our analysis. We assessed patients from the COMPARZ phase 3 clinical trial, a cohort from the Cancer Genome Atlas (TCGA), and a Memorial Sloan Kettering (MSK) observational immunotherapy cohort for their inclusion into our study. We assessed overall survival in obese patients (those with a body-mass index [BMI] ≥30 kg/m2) and in patients with a normal weight (BMI 18·5–24·9 kg/m2, as per WHO's BMI categories), defined as the time from treatment initiation (in the COMPARZ and MSK immunotherapy cohorts) or surgery (in the TCGA cohort) to the date of any-cause death or of censoring on the day of the last follow-up. We also evaluated and validated transcriptomic differences in the primary tumours of obese patients compared with those of a normal weight. We compared gene-expression differences in peritumoral adipose tissue and tumour tissue in an additional, prospectively collected cohort of patients with non-metastatic clear cell RCC (the MSK peritumoral adipose tissue cohort). We analysed differences in gene expression between obese patients and those at a normal weight in the COMPARZ, TCGA, and peritumoral adipose tissue cohorts. We also assessed the tumour immune microenvironment in a prospective cohort of patients who had nephrectomy for localised RCC at MSK. Findings Of the 453 patients in the COMPARZ trial, 375 (83%) patients had available microarray data, pretreatment BMI measurements, and overall survival data for analyses, and we excluded 119 (26%) overweight patients, leaving a final cohort of 256 (68%) patients from this study for our analyses. From 332 patients in the TCGA cohort, we evaluated clinical and demographic data from 152 (46%) patients with advanced (ie, stages III and IV) clear cell RCC treated by nephrectomy; after exclusion of 59 (39%) overweight patients, our final cohort consisted of 93 (61%) patients. After exclusion of 74 (36%) overweight patients from the initial MSK immunotherapy study population of 203 participants, our final cohort for overall survival analysis comprised 129 (64%) participants. We found that overall survival was longer in obese patients than in those with normal weight in the TCGA cohort, after adjustment for stage or grade (adjusted HR 0·41, 95% CI 0·22–0·75), and in the COMPARZ clinical trial after adjustment for International Metastatic RCC Database (IMDC) risk score (0·68, 0·48–0·96). In the MSK immunotherapy cohort, the inverse association of BMI with mortality (HR 0·54, 95% CI 0·31–0·95) was not significant after adjustment for IMDC risk score (adjusted HR 0·72, 95% CI 0·40–1·30). Tumours of obese patients showed higher angiogenic scores on gene-set enrichment analysis-derived hallmark gene set angiogenesis signatures than did those of patients at a normal weight, but the degree of immune cell infiltration did not differ by BMI. We found increased peritumoral adipose tissue inflammation in obese patients relative to those at a normal weight, especially in peritumoral fat near the tumour. Interpretation We found aspects of the tumour microenvironment that vary by BMI in the tumour and peritumoral adipose tissue, which might contribute to the apparent survival advantage in obese patients with clear cell RCC compared with patients at a normal weight. The complex interplay between the clear cell RCC tumour and peritumoral adipose tissue microenvironment might have clinical relevance and warrants further investigation. Funding Ruth L Kirschstein Research Service Award, American Society of Clinical Oncology Young Investigator Award, MSK's Ludwig Center, Weiss Family Kidney Research Fund, Novartis, The Sidney Kimmel Center for Prostate and Urologic Cancers, and the National Institutes of Health (National Cancer Institute) Cancer Center Support Grant.

PURPOSE Non–clear-cell renal cell carcinoma (nccRCC) encompasses approximately 20% of renal cell carcinomas and includes subtypes that vary in clinical and molecular biology. Compared with clear cell renal cell carcinoma, nccRCC demonstrates limited sensitivity to conventional vascular endothelial growth factor– and mammalian target of rapamycin–directed agents, indicating a need for better therapies. Characterizing the genomic landscape of metastatic nccRCC variants may help define novel therapeutic strategies. PATIENTS AND METHODS We retrospectively analyzed tumor tissue from patients with metastatic nccRCC who consented to genomic analysis of their tumor and germline DNA. A hybridization capture–based assay was used to identify single nucleotide variants and small insertions and deletions across more than 340 cancer-associated genes with germline comparison. Clinical actionability of somatic mutations was assessed using OncoKB levels of evidence. Microsatellite instability (MSI) in the tumor was investigated. RESULTS Of 116 patients included in the analysis, 57 (49%) presented with de novo metastatic disease, and 59 (51%) presented with localized disease that later metastasized. Subtype classifications included unclassified (n = 41; 35%), papillary (n = 26; 22%), chromophobe (n = 17; 15%), translocation associated (n = 13; 11%), and other (n = 19; 16%). Of all tumors, 15 (13%) had putative driver somatic alterations amenable to targeted therapies, including alterations in MET, TSC1/2, and an ALK translocation. Of 45 patients who had germline testing, 11 (24%) harbored mutations, seven of which could potentially guide therapy. Of 115 available tumors for analysis, two (1.7%) had high and six (5%) had intermediate MSI status. CONCLUSION The mutation profiles of metastatic nccRCC vary by subtype. Comprehensive analysis of somatic mutations, germline mutations, and MSI, interpreted via an annotated precision oncology knowledge base, identified potentially targetable alterations in 22% of patients, which merits additional investigation.

Renal cell carcinoma stands out as one of the most immune-infiltrated tumors in pan-cancer comparisons. Features of the tumor microenvironment heavily affect disease biology and may affect responses to systemic therapy. With evolving frontline options in the metastatic setting, several immune checkpoint blockade regimens have emerged as efficacious, and there is growing interest in characterizing features of tumor biology that can reproducibly prognosticate patients and/or predict the likelihood of their deriving therapeutic benefit. Herein, we review pertinent characteristics of the tumor microenvironment with dedicated attention to candidate prognostic and predictive signatures as well as possible targets for future drug development.Significance:Tumor microenvironment features broadly characterizing angiogenesis and inflammatory signatures have shown striking differences in response to immune checkpoint blockade and antiangiogenic agents. Integration of stromal and immune biomarkers may hence produce predictive and prognostic signatures to guide management with existing regimens as well as future drug development.

Background Despite guidelines recommending genetic counseling for patients with early-onset renal cell carcinoma (RCC), studies interrogating the spectrum of germline mutations and clinical associations in patients with early-onset RCC are lacking. Objective To define the germline genetic spectrum and clinical associations for patients with early-onset RCC diagnosed at age ≤46 yr who underwent genetic testing. Design, setting, and participants We retrospectively identified patients with early-onset RCC who underwent germline testing at our institution from February 2003 to June 2020. Outcome measurement and statistical analysis The frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined. Clinical characteristics associated with mutation status were analyzed using two-sample comparison (Fisher’s exact or χ2 test). Results and limitations Of 232 patients with early-onset RCC, 50% had non–clear-cell histology, including unclassified RCC (12.1%), chromophobe RCC (9.7%), FH-deficient RCC (7.0%), papillary RCC (6.6%), and translocation-associated RCC (4.3%). Overall, 43.5% had metastatic disease. Germline P/LP variants were identified in 41 patients (17.7%), of which 21 (9.1%) were in an RCC-associated gene and 20 (8.6%) in a non–RCC-associated gene, including 17 (7.3%) in DNA damage repair genes such as BRCA1/2, ATM, and CHEK2. Factors associated with RCC P/LP variants include bilateral/multifocal renal tumors, non–clear-cell histology, and additional extrarenal primary malignancies. In patients with only a solitary clear-cell RCC, the prevalence of P/LP variants in RCC-associated and non–RCC-associated genes was 0% and 9.9%, respectively. Conclusions Patients with early-onset RCC had high frequencies of germline P/LP variants in genes associated with both hereditary RCC and other cancer predispositions. Germline RCC panel testing has the highest yield when patients have clinical phenotypes suggestive of underlying RCC gene mutations. Patients with early-onset RCC should undergo comprehensive assessment of personal and family history to guide appropriate genetic testing. Patient summary In this study of 232 patients with early-onset kidney cancer who underwent genetic testing, we found a high prevalence of mutations in genes that increase the risk of cancer in both kidneys and other organs for patients and their at-risk family members. Our study suggests that patients with early-onset kidney cancer should undergo comprehensive genetic risk assessment.

INTRODUCTION AND OBJECTIVE:Transcriptomic profiling of the renal cell carcinoma (RCC) tumor microenvironment (TME) has recently revealed gene signatures predictive of response to systemic therapy i...

Purpose:Dual inhibition of glucose and glutamine metabolism results in synergistic anticancer effects in solid tumor models. Telaglenastat, an investigational, small-molecule, glutaminase inhibitor, exhibits modest single-agent activity in renal cell carcinoma (RCC) patients. This phase Ib trial evaluated telaglenastat plus cabozantinib or everolimus, agents known to impair glucose metabolism in patients with metastatic RCC (mRCC).Patients and Methods:mRCC patients received escalating doses of telaglenastat [400–800 mg per os (p.o.) twice daily] in a 3 + 3 design, plus either everolimus (10 mg daily p.o.; TelaE) or cabozantinib (60 mg daily p.o.; TelaC). Tumor response (RECISTv1.1) was assessed every 8 weeks. Endpoints included safety (primary) and antitumor activity.Results:Twenty-seven patients received TelaE, 13 received TelaC, with median 2 and 3 prior therapies, respectively. Treatment-related adverse events were mostly grades 1 to 2, most common including decreased appetite, anemia, elevated transaminases, and diarrhea with TelaE, and diarrhea, decreased appetite, elevated transaminases, and fatigue with TelaC. One dose-limiting toxicity occurred per cohort: grade 3 pruritic rash with TelaE and thrombocytopenia with TelaC. No maximum tolerated dose (MTD) was reached for either combination, leading to a recommended phase II dose of 800-mg telaglenastat twice daily with standard doses of E or C. TelaE disease control rate (DCR; response rate + stable disease) was 95.2% [20/21, including 1 partial response (PR)] among 21 patients with clear cell histology and 66.7% (2/3) for papillary. TelaC DCR was 100% (12/12) for both histologies [5/10 PRs as best response (3 confirmed) in clear cell].Conclusions:TelaE and TelaC showed encouraging clinical activity and tolerability in heavily pretreated mRCC patients.

Purpose: Patients discontinuing immuno-oncology regimens may experience periods of disease control without need for ongoing anticancer therapy, but toxicity may persist. We describe treatment-free survival (TFS), with and without toxicity. Patients and Methods: Data were analyzed from the randomized phase III CheckMate 214 trial of nivolumab plus ipilimumab (n = 550) versus sunitinib (n = 546) for treatment-naïve, advanced renal cell carcinoma (aRCC). TFS was estimated by the 42-month restricted mean times defined by the area between Kaplan–Meier curves for two time-to-event endpoints defined from randomization: time to protocol therapy cessation and time to subsequent systemic therapy initiation or death. TFS was subdivided as TFS with and without toxicity by counting days with ≥1 grade ≥3 treatment-related adverse event (TRAE). Results: At 42 months since randomization, 52% of nivolumab plus ipilimumab and 39% of sunitinib intermediate/poor-risk patients were alive; 18% and 5% surviving treatment-free, respectively. Among favorable-risk patients, 70% and 73% of nivolumab plus ipilimumab and sunitinib patients were alive; 20% and 9% treatment-free. Over the 42-month period, mean TFS was over twice as long after nivolumab plus ipilimumab than sunitinib for intermediate/poor-risk (6.9 vs. 3.1 months) and three times as long for favorable-risk patients (11.0 vs. 3.7 months). Mean TFS with grade ≥3 TRAEs was a small proportion of time for both treatments (0.6 vs. 0.3 months after nivolumab plus ipilimumab vs. sunitinib for intermediate/poor-risk, and 0.9 vs. 0.3 months for favorable-risk patients). Conclusions: Patients initiating first-line nivolumab plus ipilimumab for aRCC spent more survival time treatment-free without toxicity versus those on sunitinib, regardless of risk group.

Summary Clear cell renal cell carcinomas (ccRCCs) are highly immune infiltrated, but the effect of immune heterogeneity on clinical outcome in ccRCC has not been fully characterized. Here we perform paired single-cell RNA (scRNA) and T cell receptor (TCR) sequencing of 167,283 cells from multiple tumor regions, lymph node, normal kidney, and peripheral blood of two immune checkpoint blockade (ICB)-naive and four ICB-treated patients to map the ccRCC immune landscape. We detect extensive heterogeneity within and between patients, with enrichment of CD8A+ tissue-resident T cells in a patient responsive to ICB and tumor-associated macrophages (TAMs) in a resistant patient. A TCR trajectory framework suggests distinct T cell differentiation pathways between patients responding and resistant to ICB. Finally, scRNA-derived signatures of tissue-resident T cells and TAMs are associated with response to ICB and targeted therapies across multiple independent cohorts. Our study establishes a multimodal interrogation of the cellular programs underlying therapeutic efficacy in ccRCC.

Purpose: Fumarate hydratase–deficient renal cell carcinoma (FH-RCC) is a rare, aggressive form of RCC associated with hereditary leiomyomatosis and RCC syndrome. Evidence for systemic therapy efficacy is lacking. Experimental Design: We studied clinical and genomic characteristics of FH-RCC, including response [objective response rate (ORR)] to systemic therapies and next-generation sequencing (NGS). Patients with metastatic FH-RCC, defined by presence of pathogenic germline or somatic FH mutation plus IHC evidence of FH loss, were included. Results: A total of 28 of 32 included patients (median age 46; range, 20–74; M:F, 20:12) underwent germline testing; 23 (82%) harbored a pathogenic FH germline variant. Five (16%) were negative for germline FH mutations; all had biallelic somatic FH loss. Somatic NGS (31/32 patients) revealed co-occurring NF2 mutation most frequently (n = 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4; P < 0.001) but higher fraction of genome altered (18.7% vs. 10.3%; P = 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (n = 18, ORR 44%), VEGF monotherapy (n = 15, ORR 20%), checkpoint inhibitor therapy (n = 8, ORR 0%), and mTOR monotherapy (n = 4, ORR 0%). No complete responses were seen. Median overall and progression-free survival were 21.9 months [95% confidence interval (CI): 14.3–33.8] and 8.7 months (95% CI: 4.8–12.3), respectively. Conclusions: Although most FH-RCC tumors are due to germline FH alterations, a significant portion result from biallelic somatic FH loss. Both somatic and germline FH-RCC have similar molecular characteristics, with NF2 mutations, low tumor mutational burden, and high fraction of genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results.

Background Mutations in the promoter region of the TERT gene have been detected in a variety of cancers. These mutations can potentially lead to unlimited cell divisions and result in poor clinical prognosis. Objective To determine the role and relevance of TERT promoter region mutations in both clear cell (ccRCC) and non–clear cell (nccRCC) renal cell carcinoma using ultra-deep and whole-genome sequencing methods on primary tumor samples. Design, setting, and participants DNA from 281 kidney tumors (147 ccRCC and 134 nccRCC) was sequenced between 2013 and 2015, and clinical outcomes for these patients from a single institution were retrospectively analyzed. Outcome measurements and statistical analysis Differences in patient characteristics and mutational status were tested using Fisher's exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. Survival times were estimated using the Kaplan-Meier method and differences were tested using the log-rank test. Results and limitations TERT mutations occurred in 12.2% of ccRCC and 10.4% of nccRCC cases. In >80% of the cases, mutations were located at C228T and were found to co-occur only rarely with other relevant RCC driver genes. The median follow-up among survivors overall was 2.5 yr (range 0.1–18.3). TERT promoter mutations were significantly associated with cancer-specific survival in ccRCC (hazard ratio 2.68, 95% confidence interval 1.19–6.01; p =0.013). In nccRCC, TERT mutations were significantly associated with larger tumors and metastatic development. Assessment of further relevant clinical associations was precluded in the nccRCC group by the heterogeneous and small sample size. Conclusions Our data suggests that TERT mutational status reflects a distinct pathogenesis with an aggressive disease course in RCC. Stratifying patients with this unique tumorigenesis that leads to poor clinical outcomes could be a putative target for novel therapeutics. Patient summary We show a previously unrecognized frequency of TERT promoter mutations in both clear cell and non–clear cell renal cell carcinoma. TERT promoter mutations were associated with some worse outcomes in patients with clear cell renal cell carcinoma.

Background Immune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor–receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy. Patients and methods This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists' review using Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan–Meier method were used. Results Seventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti–programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti–PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity. Conclusions In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI.

Purpose: To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor. Patients and Methods: This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1–3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks. Results: A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with FGFR fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day. Conclusions: Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.

Purpose: Genomic alterations in key components of PI3K/mTOR pathway have been proposed as candidate predictive markers for rapalog therapy in renal cell carcinoma (RCC). We tested this hypothesis in patients from a randomized phase II trial of everolimus versus sunitinib. Patients and Methods: Archival specimens collected at baseline were analyzed with targeted next-generation sequencing (NGS). Focus of interest were alterations in key PI3K pathway components. PTEN expression was assessed by IHC. Association between molecular findings and treatment outcomes was investigated; same associations were tested for 2 everolimus-treated trial cohorts in gastric and hepatocellular carcinoma (HCC). Results: Among 184 everolimus-treated patients with RCC with NGS data, mutation rates in genes of interest were 6% (TSC1), 4.4% (TSC2), and 8.2% (mTOR); 44% harbored alterations in ≥1 PI3K pathway component. For subjects with presence versus absence of mutations in TSC1, TSC2, or mTOR progression-free survival (PFS) neither differed on univariate analysis (HR, 1.0; P = 0.895) nor on multivariate testing stratified by MSKCC risk group and other established prognostic factors (HR, 1.1; P = 0.806). Everolimus-treated patients with retained (n = 50) versus lost (n = 50) PTEN IHC expression had median PFS of 5.3 months versus 10.5 months (HR, 2.5; P < 0.001). Such differences were not seen with sunitinib (10.9 months vs. 10.3 months; HR, 0.8; P = 0.475). Molecular findings did not correlate with outcomes in gastric and HCC cohorts. Conclusions: Association between mutation status for TSC1/TSC2/mTOR and therapeutic outcome on everolimus was not confirmed. Clinically meaningful differences in PFS were seen based on PTEN expression by IHC, lost in >50% of patients.

Introduction Small renal masses (SRMs) with evidence of clear cell renal cell carcinoma (ccRCC) are understudied. Current algorithms for the management of SRMs include surgical resection, ablation, and active surveillance. We sought to identify genomic biomarkers that could potentially refine the management of ccRCC in SRMs, especially in patients being evaluated for active surveillance. Methods We identified patients who had SRMs (4 cm or less) at time of surgery, had sequencing performed on their primary tumor and had a diagnosis of ccRCC. Patients were selected from 3 publicly available cohorts, The Cancer Genome Atlas ( n = 110), University of Tokyo ( n = 37), The International Cancer Genome Consortium ( n = 31), and from our own institutional prospective database ( n = 25). Among this cohort we analyzed mutations present in at least 5% of tumors, assessing for the enrichment of mutations and progression-free survival using the composite endpoint of recurrence or death of disease. Analysis was adjusted for multiple testing. A Cox regression model was used to assess clinical variables with significant mutations. Results In total, 203 patients were available for analysis. Median follow-up was 43.1 months among survivors. Mutations in VHL, PBRM1, SETD2, BAP1, KDM5C , and MTOR were present in more than 5% of tumors. Twenty-three patients (11.3%) had recurrence or died of their disease. Mutations in KDM5C were associated with inferior survival from either recurrence or death from disease, adjusted P 0.033. Conclusions We identified mutations in SRMs in ccRCC that are associated with recurrence and lethality. The strongest association was seen in those with KDM5C mutations. Use of these genomic biomarkers may improve stratification of patients with SRMs and for those who may be appropriate for active surveillance. Prospective evaluation of these markers is needed.

4558 Background: Combination systemic therapies (ST) including immunotherapy (IO) and Tyrosine Kinase Inhibitors (TKI) have become the standard of care for management of metastatic clear cell carcinoma (ccRCC). Several expression (GE) signatures have been reported to predict TKI response with the aim of identifying the optimal ST regimen (IO/IO or IO/TKI) per patient. However, these gene signatures were developed and evaluated using data from individual trials with clinically distinct patient cohorts, fundamentally impeding their general application to diverse and heterogeneous patient populations. We therefore sought to identify genes consistently and directly associated with progression-free survival (PFS) with TKI ST across several trials. Methods: We applied a stratified, weighted concordance model to identify genes consistently demonstrating statistically significant association with PFS in the sunitinib TKI arm in four large randomized controlled trials (RCTs) of ST in ST-naïve ccRCC patients: COMPARZ (Motzer et al, 2013), Checkmate 214 (Motzer et al, 2018), IMmotion 151 (Rini et al, 2019), and Javelin 101 (Motzer et al, 2019). Concordant genes with Benjamini-Hochberg adjusted p-value (pAdj) ≤ 0.01 were selected. Of these, genes significantly associated with PFS on Cox proportional hazard regression (pAdj ≤ 0.05) in at least 3 of the 4 datasets were selected. Ontologic process and pathway enrichment analyses (OPPEA) against several ontologic databases were peformed using Metascape (Zhou et al, 2019). Results: We identified 2,794 statistically significant genes demonstrating concordant association with PFS across all 4 datasets (1087 patients); 71 genes were significantly associated with PFS on univariate post-hoc analysis in ≥3 of the datasets. OPPEA of these results identified significant enrichment in genes associated with cell cycle, cell division, and VEGFA-VEGFR2 pathways (Table 1). Although 5 genes in our set overlapped with published angiogenesis GES, the majority of these genes constitute entirely novel transcriptomic correlates of response to sunitinib. Conclusions: We developed a robust meta-gene signature consisting of genes directly and consistently associated with TKI response using data from several clinical trials. This gene signature is readily applicable to heterogeneous patient populations treated with anti-VEGF therapies. [Table: see text]

12092 Background: Endocrine immune-related adverse events (irAEs) to anti-PD-(L)1 ICI, including hypophysitis, autoimmune insulin-dependent diabetes mellites (ICI-DM), and primary adrenal insufficiency (AI), are rare but often associated with long term co-morbidities. AI from anti-PD-(L)1 ICI without CTLA-4 blockade is not well characterized in the literature. Long term outcomes for AI including need for replacement steroids and cortisol levels are unknown. Methods: We performed a single center retrospective analysis of patients treated with ICI including anti-programmed cell death protein-1 (Anti-PD-1: nivolumab or pembrolizumab), anti-programmed death-ligand-1 (anti-PD-L1: atezolizumab or cemiplimab) and diagnosed with ICI induced AI by a board-certified endocrinologist from 1/1/2011 to 12/31/2021. Patients treated with anti-CTLA-4 based therapy were not included. Patient baseline characteristics, presenting symptoms at the time of AI diagnosis, and treatment with corticosteroids were obtained by chart review. Baseline labs were collected at the time of AI and during routine patient follow-up. Descriptive statistics are reported for the cohort. Results: Twenty-nine patients were identified, 27 diagnosed with secondary and 2 diagnosed with primary AI. The median age was 63 (range 39-84), 18 (62%) males and 11 (38%) females, 14 (48%) receiving anti-PD(L)-1 monotherapy and 22 receiving anti-PD(L)-1 combination therapy either with chemotherapy (7, 24%), targeted therapy (6, 21%) or other/investigational therapy (2, 7%). The common tumor types were 6 renal cell carcinoma, 4 urothelial carcinoma, 4 melanoma, 15 others. The common presenting symptoms were 26 (90%) with fatigue,16 (55%) weakness, 11 (38%) nausea/vomiting, 4 (14%) headaches and 2 (7%) arthralgias. The common concomitant irAEs were 16 (55%) hypothyroidism, 8 (28%) acute kidney injury, 7 (24%) colitis, 6 (21%) joint pain, 3 (10%) pneumonitis & dermatitis. Eleven (38%) patients were treated with high dose steroids. Median follow-up time for survivors in the cohort was 24 months (range 7-68). Median cortisol level at time of AI diagnosis was 1.1 (IQR 0.9, 2.7; n = 27) and 1.8 (IQR 0.6, 6.4; n = 10) at last follow-up (median lab follow-up 39 months, range 29-58); 7 of 10 patients with available data had cortisol < 5.0 at last follow-up. For secondary AI patients, median ACTH at time of diagnosis was 2.3 (IQR 2.0, 5.0; n = 21) and 2.0 (IQR 2.0, 7.2; n = 7) at last follow-up. Twenty-two of 23 patients with available data continued replacement steroids at last follow-up. Conclusions: AI associated with anti-PD(L)-1 ICI is primarily secondary. Cortisol and ACTH levels remain low even during long-term follow-up. Most patients need long-term replacement steroids. Systemic and comprehensive follow-up for patients who develop AI due to anti-PD(L)-1 ICI is needed to confirm these findings.

4526 Background: Molecular profiles of renal cell carcinoma (RCC) tumors are associated with systemic treatment (ST) responses and clinical outcomes. However, the molecular profiles of RCC brain metastases (BM) and their correlation with ST response and clinical outcomes are not well characterized. Effective management of BM with locoregional therapies including stereotactic radiosurgery (SRS) is critical as ST advances have improved overall survival (OS). Therefore, we sought to identify the clinical and genomic features of RCC BM in a large cohort of patients treated with SRS. Methods: We performed an institutional retrospective analysis of RCC BM patients treated with SRS and evaluated corresponding genomic next generation sequencing (NGS) data via a targeted sequencing panel (MSK-IMPACT). A comparison cohort of all institutional patients with available NGS data was utilized to investigate genes enriched in our BM cohort using Fisher exact testing. Kaplan Meier analyses were performed for OS and intracranial progression-free survival (iPFS). Clinical factors and genes mutated in ≥ 10% of samples were assessed per patient using Cox proportional hazards models, and per individual BMs using clustered competing risks regression with a competing risk of death. Results: From 2010-2021, 91 RCC BM patients underwent SRS for 212 BMs, including 86% clear cell and 14% non-clear cell RCC. NGS data was available for 76 patients (84%), including 18 resected BMs, 26 extra-cranial metastatic lesions (EM), and 32 primary kidney tumors (Table 1). Median follow-up was 3.2 years with median OS of 21 months (m) and median iPFS of 7.8m. Karnofsky performance status ≥80 and extracranial disease control were significantly associated with improved OS on multivariable analyses (MVA; p=0.049 and 0.01, respectively). No clinical variables were significantly associated with iPFS on MVA. At the BM level, SETD2 alterations approached significance for improved iPFS (HR=0.35; 95%CI 0.11, 1.05; p=0.06). Enrichment in SMARCA4 alterations was seen in the BM cohort as compared to primary kidney and EM samples from patients without BM (17% vs 1% vs 2%, p

4536 Background: Front-line therapy with immunotherapy combinations is standard of care for metastatic ccRCC, with ipilimumab/nivolumab (IO/IO) and several combinations of a VEGFR-targeted tyrosine kinase inhibitor with a PD-1 inhibitor (TKI/IO) showing superior efficacy to TKI monotherapy. PFS-2 evaluates the ability to be salvaged by 2nd line therapy and is a surrogate for overall survival (OS). PFS-2 was compared in patients receiving 1st line IO/IO vs TKI/IO for metastatic ccRCC. Methods: A retrospective analysis was performed on patients with ccRCC treated at Memorial Sloan Kettering Cancer Center between 1/1/2014 and 12/30/2020, in cohorts defined by 1st line: IO/IO or TKI/IO. PFS-2 is defined as time from start of 1st line to progression on next therapy, or death. Patients without a PFS-2 event were censored at a prespecified cutoff date. Objective response rate to 1st (ORR1st) and 2nd (ORR2nd) line are compared with the Fisher’s exact test. OS, PFS-2, and time on therapy are estimated with the Kaplan-Meier method and compared with the log-rank test. Results: One hundred seventy-three patients received 1st line IO/IO (N = 90) or 1st line TKI/IO (N = 83); respectively, 52 and 40 patients had a PFS-2 event. 1st line TKI/IO regimens included: 34% axitinib/pembrolizumab, 29% lenvatinib/pembrolizumab, 25% axitinib/avelumab, 11% other. More IO/IO patients had brain metastases and intermediate/poor MSKCC risk category (respectively p = 0.007, p < 0.001). ORR1st and median months on 1st line were higher with TKI/IO vs IO/IO (65% vs 39%, p < 0.001; 16.1 vs 5.1, p < 0.001). ORR2nd was higher with IO/IO vs TKI/IO (47% vs 13%, p < 0.001), and median months on 2nd line was not significantly different (7.7 vs 7.1, p = 0.30). Median PFS-2 for TKI/IO was 44 months (95% CI: 27, 53) vs 23 months (95% CI: 16, 47) for IO/IO, p = 0.13. For TKI/IO and IO/IO groups, respective PFS-2 at 12 months was 86% (95% CI 77, 92) and 74% (95% CI 63, 82); PFS-2 at 36 months was 51% (95% CI 39, 63) and 42% (95% CI 30, 53). OS was not significantly different (p = 0.32; 3 year OS: IO/IO 60%, 95% CI 47, 71; TKI/IO 62%, 95% CI 49, 73). (Table) Conclusions: In patients receiving 1st line IO/IO or TKI/IO, ORR2nd was higher with IO/IO and median PFS-2 was numerically higher with TKI/IO, but no statistically significant difference in PFS-2 or OS was seen. These findings suggest that IO/IO and TKI/O are both acceptable 1st line treatment strategies in ccRCC. [Table: see text]

TPS752 Background: CAIX is a cell surface glycoprotein expressed in >90% of ccRCC but rarely in normal tissues, providing a target for imaging and therapeutic application. Radiolabeling the anti-CAIX monoclonal antibody girentuximab with 89Zr has shown promise as a novel PET tracer and labeling with 177Lu promise as a therapeutic agent in ccRCC (Muselaers, Eur Urol, 2016). Targeted delivery of radiation to ccRCC cells may prime the immune response by enhancing tumor antigen presentation, providing rationale for combining 177Lu-girentuximab with the anti-PD-1 antibody, nivolumab. This phase 2, open-label, single arm study (NCT05239533) is being conducted to evaluate 177Lu-girentuximab in combination with nivolumab in pts with previously treated ccRCC. Methods: Pts with biopsy-proven ccRCC, progressive disease after prior systemic therapy including ≥1 immunotherapy (IO) agent, adequate organ/marrow function, and ≥1 evaluable lesion by RECIST 1.1 that is also avid on 89Zr-girentuximab PET will be enrolled. There is no limit on number of prior lines of systemic therapy, but pts who stopped IO for immune toxicity are excluded. Treatment consists of 177Lu-girentuximab every 12-14 weeks for a maximum of 3 doses plus nivolumab 240mg every 2 weeks until progressive disease (PD) or unacceptable toxicity. Due to expected cumulative myelosuppression, each subsequent 177Lu-girentuximab dose to the same patient is reduced by 25% (dose 2 = 75% of dose 1; dose 3 = 75% of dose 2). Tumor imaging is performed every 12 weeks. Pts will be evaluated in a safety lead-in phase followed by an expansion phase. In the safety lead-in phase, the MTD of 177Lu-girentuximab in combination with nivolumab will be determined with a 3+3 design using a starting dose of 1804 MBq/m2 (75% of single agent MTD). For cohort 2, dose escalation to 2405 MBq/m2 (single agent MTD) or de-escalation to 1353 MBq/m2 will be based on dose-limiting toxicities. In the expansion phase, a Simon 2-stage optimal design is used to evaluate the primary endpoint of response rate by RECIST 1.1 within 24 weeks. With ≥1 response in the first Simon stage (n=10; includes pts treated at MTD in the safety lead-in phase), a second stage will open (n=19) for a total of 29 pts with ≥3 responses indicating the regimen worthy of further study. Secondary endpoints include PFS, OS, and toxicity including a continuous safety monitoring rule during expansion. Exploratory imaging with 89Zr-girentuximab PET is performed at baseline and before each 177Lu-girentuximab dose with results correlated with RECIST response on conventional imaging. In addition, whole body planar and SPECT imaging are performed after each 177Lu-girentuximab dose to evaluate distribution, lesion uptake and dosimetry of 177Lu-girentuximab. The trial is currently accruing to the safety lead-in phase. Clinical trial information: NCT05239533 .

Background Next-generation sequencing (NGS) studies of matched pairs of primary and metastatic tumors in renal cell carcinoma (RCC) have been limited to small cohorts. Objective To evaluate the discordance in somatic mutations between matched primary and metastatic RCC tumors. Design, setting, and participants Primary tumor (P), metastasis (M), and germline DNA from 60 patients with RCC was subjected to NGS with a targeted exon capture–based assay of 341 cancer-associated genes. Somatic mutations were called using a validated pipeline. Outcome measurements and statistical analysis Mutations were classified as shared (S) or private (Pr) in relation to each other within individual P-M pairs. The concordance score was calculated as (S−Pr)/(S+Pr). To calculate enrichment of Pr/S mutations for a particular gene, we calculated a two-sided p value from a binomial model for each gene with at least ten somatic mutation events, and also implemented a separate permutation test procedure. We adjusted p values for multiple hypothesis testing using the Benjamini-Hochberg procedure. The mutation discordance was calculated using Mann-Whitney U tests according to gene mutations or metastatic sites. Results and limitations Twenty-one pairs (35%) showed Pr mutations in both P and M samples. Of the remaining 39 pairs (65%), 14 (23%) had Pr mutations specific to P samples, 12 (20%) had Pr mutations to M samples, and 13 (22%) had identical somatic mutations. No individual gene mutation was preferentially enriched in either P or M samples. P-M pairs with SETD2 mutations demonstrated higher discordance than pairs with wild-type SETD2 . We observed that patients who received therapy before sampling of the P or M tissue had higher concordance of mutations for P-M pairs than patients who did not (Mann-Whitney p =0.088). Conclusions Our data show mutation discordance within matched P-M RCC tumor pairs. As most contemporary precision medicine trials do not differentiate mutations detected in P and M tumors, the prognostic and predictive value of mutations in P versus M tumors warrants further investigation. Patient summary In this study we evaluated the concordance of mutations between matched primary and metastatic tumors for 60 kidney cancer patients using a panel of 341 cancer genes. Forty-seven patients carried nonidentical cancer gene mutations within their matched primary-metastatic pair. The mutation profile of the primary tumor alone could compromise precision in selecting effective targeted therapies and result in suboptimal clinical outcomes.

Background Malignant angiomyolipoma is an uncommon tumor of the class of perivasciular epithelioid cell neoplasms (PEComas). These tumors are characteristically driven by deleterious mutations in the tumor suppressors TSC1 and TSC2, whose gene products typically act to inhibit mTOR. There are several cases of malignant angiomyolipoma which exhibit transient responses to mTOR inhibitors, forming the basis of current practice guidelines in malignant PEComa. However the tumors ultimately acquire resistance, and there is no well-established second-line option. Despite the increasing prevalence of immunotherapy across a wide range of solid tumors, little is known about the immune infiltrate and PD-L1 expression of angiomyolipoma. Furthermore, there is no reported case on the treatment of malignant angiomyolipoma with an immune checkpoint inhibitor. Case presentation A 38 year-old man presented with gross hematuria and was diagnosed with renal epithelioid angiomyolipoma. Despite surgical resection, the tumor recurred and metastasized. Targeted genomic sequencing revealed a deleterious mutation in TSC2, and the patient was treated with the mTOR inihbitor everolimus. The patient went on to have a partial response but ultimately progressed. He was then treated with the anti-PD-1 immune checkpoint inhibitor nivolumab, and achieved a durable near-complete response which is ongoing after two years of treatment. Immunohistochemical staining of tumor tissue revealed strong PD-L1 expression and a brisk T-cell infiltrate. Conclusions We report on the first durable systemic treatment of malignant epithelioid angiomyolipoima with the use of PD-1 antibody nivolumab. Given the absence of prospective clinical trials in this exceedingly rare disease, particularly in the second-line setting, immune checkpoint inhibitors like nivolumab should be considered.

Background Combination treatment with immune checkpoint inhibitors and antiangiogenic drugs has shown encouraging preliminary antitumor activity across various tumor types including advanced or metastatic renal cell carcinoma (aRCC). The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab in combination with antiangiogenic tyrosine kinase inhibitors or ipilimumab. Long-term outcomes from this study for the combination of nivolumab plus sunitinib or pazopanib in aRCC are presented. Methods Patients with aRCC received nivolumab plus either sunitinib (50 mg/day, 4 weeks on/2 weeks off; N + S) or pazopanib (800 mg/day; N + P) until progression/unacceptable toxicity. The nivolumab starting dose was 2 mg/kg every 3 weeks, with planned escalation to 5 mg/kg every 3 weeks. Primary endpoints were safety and tolerability; antitumor activity was a secondary endpoint. Results Arm N + S enrolled 33 patients, 19 of whom were treatment-naïve; this arm advanced to the expansion phase. Median follow-up was 50.0 months. Patients experienced high frequencies of adverse events (AEs) including treatment-related AEs (100%), grade 3/4 treatment-related AEs (82%), and treatment-related AEs leading to discontinuation (39%). Investigator-assessed objective response rate (ORR) was 55% (18/33) and median progression-free survival (PFS) was 12.7 months. Median overall survival (OS) was not reached. Arm N + P enrolled 20 patients, all had ≥1 prior systemic therapy; this arm was closed due to dose-limiting toxicities and did not proceed to expansion. Median follow-up was 27.1 months. Patients treated with N + P experienced high frequencies of AEs including treatment-related AEs (100%), grade 3/4 treatment-related AEs (70%), and treatment-related AEs leading to discontinuation (25%). Investigator-assessed ORR was 45% (9/20) and median PFS was 7.2 months. Median OS was 27.9 months. Conclusions The addition of standard doses of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities limiting future development of either combination regimen. While there was no adverse impact on response and the OS outcome was notable, the findings suggest that the success of combination regimens based on immune checkpoint inhibitors and antiangiogenic drugs may be dependent on careful selection of the antiangiogenic component and dose. Trial registration Clinicaltrials.gov identifier: NCT01472081. Registered 16 November 2011. Electronic supplementary material The online version of this article (10.1186/s40425-018-0420-0) contains supplementary material, which is available to authorized users.

Background Systemic responses to cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) are variable and difficult to anticipate. The authors aimed to determine the association of CN with modifiable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors and oncological outcomes. Methods Consecutive patients with mRCC referred for potential CN (2009-2019) were reviewed. The primary outcome was overall survival (OS); variables of interest included undergoing CN and the baseline number of modifiable IMDC risk factors (anemia, hypercalcemia, neutrophilia, thrombocytosis, and reduced performance status). For operative cases, the authors evaluated the effects of IMDC risk factor dynamics, measured 6 weeks and 6 months after CN, on OS and postoperative treatment disposition. Results Of 245 treatment-naive patients with mRCC referred for CN, 177 (72%) proceeded to surgery. The CN cases had fewer modifiable IMDC risk factors (P = .003), including none in 71 of 177 patients (40.1%); fewer metastases (P = .011); and higher proportions of clear cell histology (P = .012). In a multivariable analysis, surgical selection, number of IMDC risk factors, metastatic focality, and histology were associated with OS. Total risk factors changed for 53.8% and 57.2% of the patients from the preoperative period to 6 weeks and 6 months after CN, respectively. Adjusted for preoperative IMDC risk scores, an increase in IMDC risk factors at 6 weeks and 6 months was associated with adverse OS (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.13-2.19; P = .007; HR, 2.52; 95% CI, 1.74-3.65; P Conclusions IMDC risk factors are dynamic clinical variables that can improve after upfront CN in select patients, and this suggests a systemic benefit of cytoreduction, which may confer clinically meaningful prognostic implications.

BackgroundPneumonitis related to immune checkpoint blockade is uncommon but can be severe, fatal or chronic. Steroids are first-line treatment, however, some patients are refractory or become resistant to steroids. Like many immune-related adverse events, little is known regarding the outcomes and optimal management of patients in whom steroids are ineffective.MethodsWe performed a single-center retrospective cohort study at a high-volume tertiary cancer center to evaluate the clinical course, management strategies and outcomes of patients treated for immune checkpoint pneumonitis with immune modulatory medications in addition to systemic steroids. Pharmacy records were queried for patients treated with both immune checkpoint blockade and receipt of additional immune modulators. Records were then manually reviewed to identify patients who received the additional immune modulators for immune checkpoint pneumonitis.ResultsFrom 2013 to 2020, we identified 26 patients treated for immune checkpoint pneumonitis with additional immune modulators in addition to steroids. Twelve patients (46%) were steroid-refractory and 14 (54%) were steroid-resistant. Pneumonitis severity included grade 2 (42%) or grade 3–4 (58%). Additional immune modulation consisted of tumor necrosis factor-alpha inhibitor (77%) and/or mycophenolate (23%). Durable improvement in pneumonitis following initiation of additional immune modulators occurred in 10 patients (38%), including three patients (12%) in whom pneumonitis resolved and all immunosuppressants ceased. The rate of 90-day all-cause mortality/hospice referral was 50%. At last follow-up, mortality attributable to pneumonitis was 23%. In addition to mortality from pneumonitis and cancer, 3 patients (12%) died due to infections possibly associated with immunosuppression.ConclusionsSteroid-refractory or -resistant immune checkpoint pneumonitis is uncommon but associated with significant morbidity and mortality. Additional immunomodulators can yield durable improvement, attained in over one third of patients. An improved understanding of the underlying biology of immune-related pneumonitis will be crucial to guide more precise and effective treatment strategies in the future.

Background This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. Methods Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients). Results Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. Conclusions Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer. Clinical trial registration ClinicalTrials.gov, NCT01058707.

Purpose: We report our experience with next-generation sequencing to characterize the landscape of actionable genomic alterations in renal cell carcinoma (RCC). Experimental Design: A query of our institutional clinical sequencing database (MSK-IMPACT) was performed that included tumor samples from 38,468 individuals across all cancer types. Somatic variations were annotated using a precision knowledge database (OncoKB) and the available clinical data stratified by level of evidence. Alterations associated with response to immune-checkpoint blockade (ICB) were analyzed separately; these included DNA mismatch repair (MMR) gene alterations, tumor mutational burden (TMB), and microsatellite instability (MSI). Data from The Cancer Genome Atlas (TCGA) consortium as well as public data from several clinical trials in metastatic RCC were used for validation purposes. Multiregional sequencing data from the TRAcking Cancer Evolution through Therapy (TRACERx) RENAL cohort were used to assess the clonality of somatic mutations. Results: Of the 753 individuals with RCC identified in the MSK-IMPACT cohort, 115 showed evidence of targetable alterations, which represented a prevalence of 15.3% [95% confidence interval (CI), 12.7%–17.8%). When stratified by levels of evidence, the alterations identified corresponded to levels 2 (11.3%), 3A (5.2%), and 3B (83.5%). A low prevalence was recapitulated in the TCGA cohort at 9.1% (95% CI, 6.9%–11.2%). Copy-number variations predominated in papillary RCC tumors, largely due to amplifications in the MET gene. Notably, higher rates of actionability were found in individuals with metastatic disease (stage IV) compared with those with localized disease (OR, 2.50; 95% CI, 1.16–6.16; Fisher's P = 0.01). On the other hand, the prevalence of alterations associated with response to ICB therapy was found to be approximately 5% in both the MSK-IMPACT and TCGA cohorts and no associations with disease stage were identified (OR, 1.35; 95% CI, 0.46–5.40; P = 0.8). Finally, multiregional sequencing revealed that the vast majority of actionable mutations occurred later during tumor evolution and were only present subclonally in RCC tumors. Conclusions: RCC harbors a low prevalence of clinically actionable alterations compared with other tumors and the evidence supporting their clinical use is limited. These aberrations were found to be more common in advanced disease and seem to occur later during tumor evolution. Our study provides new insights on the role of targeted therapies for RCC and highlights the need for additional research to improve treatment selection using genomic profiling.

TPS399 Background: Combination therapy with the PD-1 inhibitor pembrolizumab and the vascular endothelial growth factor (VEGF) inhibitor lenvatinib showed antitumor activity as first-line treatment for advanced clear cell RCC (ccRCC) in the phase 3 KEYNOTE-581/CLEAR study (NCT02811861). Antitumor activity has also been shown with the hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (MK-6482) in ccRCC and with MK-1308A (coformulation of pembrolizumab and the CTLA-4 inhibitor quavonlimab) in non–small cell lung cancer. Therefore, HIF-2α or CTLA-4 inhibition with a PD-1 and VEGF inhibition backbone combination may provide additional benefit as first-line treatment in ccRCC. This open-label, randomized, phase 3 study (NCT04736706) will compare first-line treatment with the novel combination therapies pembrolizumab + belzutifan + lenvatinib (arm A) or MK-1308A + lenvatinib (arm B) with pembrolizumab + lenvatinib (arm C) for advanced RCC. Methods: Approximately 1,431 adults with metastatic ccRCC, measurable disease per RECIST v1.1, and KPS score ≥70% who had not previously undergone systemic therapy for advanced ccRCC will be enrolled. Patients will be randomly assigned 1:1:1 to arm A (belzutifan 120 mg + lenvatinib 20 mg orally once daily [QD] + pembrolizumab 400 mg IV every 6 weeks [Q6W]), arm B (MK-1308A [quavonlimab 25 mg + pembrolizumab 400 mg] IV [Q6W] and lenvatinib 20 mg orally QD), or arm C (pembrolizumab 400 mg IV [Q6W] + lenvatinib 20 mg orally QD). Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event; patients will receive pembrolizumab and MK-1308A for up to 18 cycles (̃2 years). Stratification factors are International mRCC Database Consortium (IMDC) score (favorable vs intermediate vs poor), region of the world (North America vs Western Europe vs rest of world), and sarcomatoid features (yes vs no). Response will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review (BICR) at week 12 from randomization, Q6W through week 78, and every 12 weeks thereafter. Adverse events and serious adverse events will be monitored throughout the study and for 90 days after treatment. Dual primary end points are progression-free survival per RECIST v1.1 by BICR and overall survival for arm A or arm B versus arm C in patients with IMDC intermediate/poor status and in all patients regardless of IMDC status. Secondary end points are objective response rate and duration of response per RECIST v1.1 by BICR, patient-reported outcomes, and safety. The study is recruiting patients at sites across, Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT04736706.

TPS396 Background: Hand-foot skin reaction (HFSR) is associated with the use of multi-targeted tyrosine kinase inhibitors sharing vascular endothelial growth factor receptor inhibitory (VEGFRi) activity (e.g., cabozantinib, regorafenib, sorafenib, sunitinib). HFSR affects the palms and soles with edema, erythema, hyperkeratosis, pain, and bullae/blisters impacting quality-of-life, activities of daily living, and consistent VEGFRi dosing. HFSR incidence differs among VEGFRi, ranging from 5-69% (all grades) and 1-19% (grade 3). Topical urea has marginal benefit, and to date, there are no regulatory authority approved HFSR treatments. The pathogenesis of HFSR has been partially associated with impaired vascular repair mechanisms resulting from inhibition of VEGF signaling. Nitric oxide (NO) has been reported to induce VEGF upregulation at a moderate concentration. We hypothesized that topical stimulation of VEGF signaling through OQL011, an NO donor, will safely and effectively mitigate HFSR. Methods: NOVA-II is a phase 2, double-blind, randomized vehicle-controlled trial evaluating the safety and efficacy of OQL011 for the treatment of moderate to severe HFSR. Subjects receiving a VEGFRi (either mono- or combination therapy) and have Grade ≥2 HFSR per NCI CTCAE v5.0 for palmar plantar erythrodysesthesia (PPE) were eligible. For Part 1, 31 subjects were randomized (2:1) and received 0.2% OQL011 topical ointment or vehicle TID for 6 weeks. The primary endpoint is the proportion of patients who achieve an NCI CTCAE v5.0 for PPE Grade 0 or 1 by Week 3. An investigator global assessment (IGA) scale is being developed to assess HFSR recovery, and a secondary endpoint will measure the proportion of patients who have improvement in HFSR severity and achieve an IGA score of clear (0) or almost clear (1) by Week 3 and/or Week 6. A Chi-square test will be used to detect a difference between the treatment arm and the vehicle-control arm. Additionally, the IGA score will be validated by assessing the inter- & intra-rater reliability. The correlation between IGA, NCI CTCAE v5.0 for PPE, and patient outcomes including Visual Analog Scale of Pain, HFSR Quality of Life questionnaire will also be reported. This study began enrolling patients in December 2019 and completed the last patient Visit in August 2021. Data lock, unblinding and data analysis will be completed by mid-November. Clinical trial information: NCT04088318.

Background Several phase 3 studies reported positive results for combinations of Immune-Oncology (IO) and Vascular Endothelial Growth Factor (VEGF) targeted therapies in patients with metastatic clear cell Renal Cell Carcinoma (ccRCC). However, there are limited data on outcomes to systemic therapy after IO-VEGF combinations. Methods A retrospective analysis was performed on patients with metastatic ccRCC treated at the Memorial Sloan Kettering Cancer Center and Cleveland Clinic who initiated systemic therapy post IO-VEGF including combinations with VEGF receptor (VEGFR) tyrosine kinase inhibitors (IO-TKI) and combinations with the anti-VEGF monoclonal antibody bevacizumab (IO-Bev). The study objectives were to evaluate the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) on systemic therapy post IO-VEGF. RECIST v1.1 criteria were used to determine radiological responses and progression. Survival estimates were evaluated with the Kaplan-Meier methods and the log-rank test from the start of systemic therapy post IO-VEGF to the event of interest. Results A total of fifty-nine patients were treated post discontinuation of IO-VEGF regimens which included IO-Bev (n = 35; 59%) and IO-TKI (n = 24; 41%). Fifty-eight patients (98%) received IO-VEGF regimens as part of a clinical trial. Subsequent therapies included cabozantinib (n = 22; 37%), axitinib (n = 18; 31%), pazopanib (n = 4; 7%), lenvatinib and everolimus (n = 4; 7%), mTOR inhibitor monotherapy (n = 3; 5%), axitinib and dalantercept (n = 2; 3%), sunitinib (n = 1; 2%), sorafenib (n = 1; 2%), and treatment with agents on unreported clinical trials (n = 4; 7%). Patients treated on unreported clinical trials were excluded from the efficacy analysis. Post IO-VEGF, the ORR was 25% and median PFS was 12.0 months (95% CI, 8.2–24.5). Median OS was 24.5 months (95% CI, 12–NE) and 12 months OS rate was 63.3% (95% CI, 48.6–74.9). We observed no differences post IO-VEGF OS when comparing IO- TKI vs IO-Bev (Log-rank p = 0.73). Conclusions Post IO-VEGF, most patients received VEGFR-TKIs. In this setting, VEGFR-TKIs demonstrated clinical activity and remain a viable option for salvage therapy after progression on IO-VEGF.