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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Mesenchymal-epithelial transition (MET) signaling pathway plays a role in the pathogenesis of selected patients with papillary renal cell carcinoma (PRCC). In the phase II PAPMET trial (ClinicalTrials.gov identifier: NCT02761057), cabozantinib significantly prolonged progression-free survival and improved objective response rate compared with sunitinib in patients with advanced PRCC. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized phase II, open-label trial, 147 patients with advanced PRCC who have received up to one previous therapy (excluding vascular endothelial growth factor-directed agents) were assigned to sunitinib, cabozantinib, crizotinib, or savolitinib. Ultimately, savolitinib and crizotinib arms were closed because of futility. With a median follow-up of 17.5 months, the median OS was 21.5 months (95% CI, 12.0 to 28.1) with cabozantinib and 17.3 months (95% CI, 12.8 to 21.8) with sunitinib (hazard ratio, 0.83; 95% CI, 0.51 to 1.36; P = .46). The OS landmark estimates for cabozantinib and sunitinib were 50% versus 39% at 24 months and 32% versus 28% at 36 months. In conclusion, we observed no significant difference in OS across treatment arms. Although cabozantinib represents a well-supported option for advanced PRCC, the lack of survival benefit underscores the need to develop novel therapies for this disease.

Abstract: Background: Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) has emerged as a powerful complement to tissue NGS, offering a noninvasive and serially conductible test. Its application holds promise in enhancing the assessment of spatial and temporal molecular tumor heterogeneity, thus providing valuable insights into cancer progression and treatment response. In this study, we explore the mutational landscape of renal cell carcinoma (RCC) patients through comprehensive profiling of mutations in ctDNA and matched tissue samples, aiming to elucidate the concordance and clinical significance of molecular alterations detected in both circulating and tissue-derived DNA. Methods: From the Tempus multimodal database, we retrospectively analyzed de-identified NGS data from patients with RCC that had dual tissue (Tempus xT, 648 genes) and ctDNA testing (Tempus xF, 105 genes). Patients with matched samples (collected +/- 90 days of one another) were included. We evaluated socio-demographic and clinical characteristics and select pathogenic somatic short variants (PSSV) and copy number variants [(amplifications and deletions, two copy number losses (CNL)]. Concordance analyses were restricted to the 105 genes tested on the ctDNA panel and further restricted to short variants, with the exception of amplifications and CNL detected by both xF and xT. Analysis was further stratified by metastatic status (n=260, metastatic, n=120 non-metastatic) prior to collection of both xT and xF. Results: Among all patients (n=393), the median age was 61 years, and 71% were male. The patient cohort comprised a diverse population based on race, with 75% white, 12% African American, 4.8% Asian and 8% others. The median time from tissue to blood collection was 21 days (IQR, 7, 39). 67% (n=265) and 68% (n=266) had metastatic disease at the time of tissue and blood collection, respectively. The most common tissue sites were kidney (49%, n=189), bone (11%, n=43), lung (9%, n=34), lymph node (8%, n=29), liver (6%, n=23), and brain/CNS (4%, n=17). Genes harboring the most common PSSV in tissue included VHL (59% n=232), PBRM1 (31%, n=123), SETD2 (23%, n=91), TP53 (14%, n=54), BAP1 (12%, n=46) and TERT (11%, n=45). Genes with common PSSV in ctDNA included TP53 (23%, n=91), VHL (18%, n=69), BAP1 (6%, n=23), PBRM1 (5%, n=21), PTEN (4%, n=15), KRAS (4%, n=14) and NF2 (4%, n=14). The combination of tissue and ctDNA testing increased the detection of mutations (Table 1). There was higher concordance between somatic alterations in select genes among patients with metastases vs. non-metastases, including BAP1 (55.9% vs. 9.1%), TP53 (36.8% vs. 9.1%), VHL (32.3% vs. 12.5%), ARID1A (25% vs. 16.7%), and ATM (25% vs. 0%). Table 1: Detection of genetic mutations in tissue and ctDNA testing Conclusions: The analysis conducted in this study highlights the complementary nature of ctDNA profiling alongside tissue-based NGS in RCC, demonstrating an increased detection of mutations. Particularly, we observed a higher concordance between ctDNA and tissue profiling in individuals with metastatic disease, suggesting the potential utility of ctDNA analysis in advanced stages of RCC. Further research is warranted to elucidate how longitudinal ctDNA analysis can delineate biomarkers of response and resistance at both the mutation and ctDNA fraction levels. Understanding these dynamics could offer valuable insights into disease progression and guide personalized treatment strategies for RCC patients. DOD CDMRP Funding: no

4533 Background: Next generation sequencing (NGS) of ctDNA can complement tissue NGS and is a non-invasive test that can be conducted serially, with the potential to enhance assessment of spatial and temporal molecular tumor heterogeneity. Here, we investigated mutations in RCC patients from ctDNA and matched tissue genomic profiling. Methods: From the Tempus multimodal database, we retrospectively analyzed de-identified NGS data from patients (pts) with RCC that had dual tissue (Tempus xT, 648 genes) and ctDNA testing (Tempus xF, 105 genes). Pts with matched samples (collected +/- 90 days of one another) were included. Clinical characteristics and select pathogenic somatic short variants (PSSV) and copy number variants [(amplifications and deletions, two copy number losses (CNL)] were evaluated. Concordance analyses were restricted to the 105 genes tested on the ctDNA panel and further restricted to short variants, with the exception of amplifications and CNL detected by both xF and xT. Results: Among all pts (n=393), the median age was 61 years and 71% were male. Median time from tissue to blood collection was 21 days (IQR, 7, 39). 67% (n=265) and 68% (n=266) had metastatic disease at the time of tissue and blood collection, respectively. The most common tissue sites were kidney (49%, n=189), bone (11%, n=43), lung (9%, n=34), lymph node (8%, n=29), liver (6%, n=23), and brain/CNS (4%, n=17). Genes harboring the most common PSSV in tissue included VHL (59% n=232), PBRM1 (31%, n=123), SETD2 (23%, n=91), and TP53 (14%, n=54). Genes with common PSSV in ctDNA included TP53 (23%, n=91), VHL (18%, n=69), BAP1 (6%, n=23), and PBRM1 (5%, n=21). The combination of tissue and ctDNA testing increased detection of mutations (Table). There was higher concordance between somatic alterations in select genes among patients with metastases. Conclusions: This analysis shows that ctDNA profiling is complementary to tissue based NGS in RCC and can increase the detection of mutations. Concordance between ctDNA and tissue profiling increased in individuals with metastatic disease. Future research is warranted to understand how longitudinal ctDNA analysis can define biomarkers of response and resistance at the mutation and ctDNA fraction levels. [Table: see text]

4554 Background: Some studies have demonstrated that Latino patients (pts) with mccRCC have worse clinical outcomes than NHW pts. It is unclear if this disparity is related to biological differences and/or social determinants of health (SDOH). Herein, we investigate clinical-genomic features and outcomes among Latinos and NHW pts with ccRCC. Methods: Pts with mccRCC treated at UCSD were retrospectively identified from an institutional database. Pts with genomic sequencing on tumor tissue samples were included. Pts were categorized as Latino or NHW based on self-identification. Logistic regression was applied for the presence of divergent frequencies of somatic mutations. Cox regression models evaluated the effect of additional factors, including tumor genomic alterations and clinical features, on overall survival (OS). Results: The analysis included 135 pts with mccRCC, of whom 62 were Latinos. There were no significant differences in age at diagnosis (61 vs 62 years), BMI (28 in both), sex (76% vs 71% males), presence of sarcomatoid/rhabdoid features (38% vs 30%), and number of metastatic sites (71% vs 68% with >1 site). Compared to NHW, Latino pts had higher rates of IMDC intermediate/poor risk disease (85% vs 59%, p

Lessons learnedThe combination of carotuximab with axitinib did not provide a benefit over axitinib monotherapy in patients with metastatic clear cell renal cell carcinoma who had previously progressed on one or more vascular endothelial growth factor (VEGF)-targeted therapies. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels.BackgroundEndoglin is an angiogenic receptor expressed on proliferating tumor vessels and renal cell carcinoma (RCC) stem cells that is implicated as a mechanism of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors. This study evaluated an antiendoglin monoclonal antibody (carotuximab, TRC105) combined with axitinib in patients with advanced or metastatic clear cell renal cell carcinoma (mccRCC) who had progressed following one or more prior VEGF inhibitors.MethodsTRAXAR was a multicenter, international randomized 1:1 (stratified by ECOG, 0 vs. 1), phase II study of carotuximab combined with axitinib versus axitinib alone in mccRCC patients who had progressed following one or more prior VEGF inhibitors. The primary endpoint was progression-free survival (PFS) assessed by independent central review (ICR) per RECIST 1.1 RESULTS: A total of 150 patients were randomized. The combination therapy resulted in shorter median PFS by RECIST 1.1 than axitinib monotherapy (6.7 vs. 11.4 months). The combination was tolerated similarly to axitinib monotherapy, and there were no treatment related deaths. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels.ConclusionThe combination of carotuximab with axitinib did not demonstrate additional efficacy over single agent axitinib in patients with mccRCC who progressed following one or more prior VEGF inhibitor treatment.

As the novel severe acute respiratory syndrome coronavirus-2 related pandemic - Corona Virus Disease 2019 (COVID-19) has emerged, decision making in the context of cancer treatment has become more complex. The apprehension of using drugs that could adversely affect infected patients, the risk of not using life-saving treatments and the complexities related to the type of cancer itself, all must be taken into consideration before proceeding with treatment. Data from large registries such as COVID-19 and Cancer Consortium, Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) and NCI COVID-19 in Cancer Patients Study will hopefully provide granularity on the outcomes of patients with cancer who are infected with COVID-19. As these efforts are underway, this review aims to shed light on the management of patients with genitourinary malignancies being treated with systemic therapies while infected with COVID-19.

PurposeAmplifications of receptor tyrosine kinases (RTKS) are therapeutic targets in multiple tumor types (e.g. HER2 in breast cancer), and amplification of the chromosome 4 segment harboring the three RTKs KIT, PDGFRA, and KDR (4q12amp) may be similarly targetable. The presence of 4q12amp has been sporadically reported in small tumor specific series but a large-scale analysis is lacking. We assess the pan-cancer landscape of 4q12amp and provide early clinical support for the feasibility of targeting this amplicon.Experimental designTumor specimens from 132,872 patients with advanced cancer were assayed with hybrid capture based comprehensive genomic profiling which assays 186-315 genes for all classes of genomic alterations, including amplifications. Baseline demographic data were abstracted, and presence of 4q12amp was defined as 6 or more copies of KIT/KDR/PDGFRA. Concurrent alterations and treatment outcomes with matched therapies were explored in a subset of cases.ResultsOverall 0.65% of cases harbored 4q12amp at a median copy number of 10 (range 6-344). Among cancers with >100 cases in this series, glioblastomas, angiosarcomas, and osteosarcomas were enriched for 4q12amp at 4.7%, 4.8%, and 6.4%, respectively (all p < 0.001), giving an overall sarcoma (n = 6,885) incidence of 1.9%. Among 99 pulmonary adenocarcinoma cases harboring 4q12amp, 50 (50%) lacked any other known driver of NSLCC. Four index cases plus a previously reported case on treatment with empirical TKIs monotherapy had stable disease on average exceeding 20 months.ConclusionWe define 4q12amp as a significant event across the pan-cancer landscape, comparable to known pan-cancer targets such as NTRK and microsatellite instability, with notable enrichment in several cancers such as osteosarcoma where standard treatment is limited. The responses to available TKIs observed in index cases strongly suggest 4q12amp is a druggable oncogenic target across cancers that warrants a focused drug development strategy.Implications for practiceCoamplification of the receptor tyrosine kinases (rtks) KIT/KDR/PDGFRA (4q12amp) is present broadly across cancers (0.65%), with enrichment in osteosarcoma and gliomas. Evidence for this amplicon having an oncogenic role is the mutual exclusivity of 4q12amp to other known drivers in 50% of pulmonary adenocarcinoma cases. Furthermore, preliminary clinical evidence for driver status comes from four index cases of patients empirically treated with commercially available tyrosine kinase inhibitors with activity against KIT/KDR/PDGFRA who had stable disease for 20 months on average. The sum of these lines of evidence suggests further clinical and preclinical investigation of 4q12amp is warranted as the possible basis for a pan-cancer drug development strategy.

Objective: Biopsychosocial distress is a common yet often underestimated complication in cancer care. We sought to translate and evaluate the psychometric properties of SupportScreen distress assessment tool in Brazil. Methods: A cancer cohort study was conducted at a public hospital in Brazil. The SupportScreen tool underwent transcultural translation into Portuguese. Eligible patients completed the SupportScreen, Distress Thermometer (DT), Hospital Anxiety and Depression Scale (HADS), and Functional Assessment of Cancer Therapy‐General version (FACT‐G). Statistical analyses included confirmatory and exploratory factor analyses (CFA and EFA), comparisons with established distress tools, and assessments of associations with patients' characteristics. Results: A total of 302 patients were assessed (M:F 35.4%:64.6%; median age: 55). Most patients were diagnosed with breast (29.1%) and gastrointestinal cancer (20.5%), at advanced disease stage (78.8%). CFA identified optimal models for emotional and physical distress; EFA revealed two factors for the logistics of medical care: practical and medical system distress. The concurrent validity of subscales demonstrated significant correlations between distress domains. Sensitivity analyses indicated good performance of emotional and physical domains in identifying distress compared to gold standard criteria. Female patients were more likely to report high emotional distress, while younger age and late disease stage were associated with higher physical distress. Additionally, late disease stage was linked to higher practical distress. Conclusion: Emotional and physical domains demonstrated validity and reliability, aligning with validated measures. Logistics of medical care distress revealed practical and medical system dimensions, expanding understanding of patient challenges. The SupportScreen tool exhibited concurrent validity and sensitivity in identifying distress. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the clinical significance of subtyping (type 1 vs 2) of papillary renal cell carcinoma (PRCC) in patients treated with targeted therapy, as well as the concordance, sensitivity and positive predictive value (PPV) of local review pathology review. Methods: Patients with advanced refractory PRCC were randomised to receive sunitinib or cabozantinib, crizotinib or savolitinib, stratified by PRCC subtype (type 1, type 2, or not otherwise specified [NOS]/mixed) by local review. Central review was retrospectively conducted by three expert genitourinary pathologists who independently reviewed cases. The sensitivity and PPV of local review were estimated and outcomes [objective response rate (ORR), progression‐free survival (PFS)] were summarised for treatment groups stratified by subtypes by central review. Results: Amongst the 147 patients reviewed, the prevalence of individual subtypes varied by local or central review (type 1: 17.7% vs 29.3%; type 2: 53.1% vs 45.6%; NOS/mixed: 29.3% vs 25.2%), respectively. Individual cases were frequently reclassified and local pathology review demonstrated low sensitivity (type 1: 48%, 95% confidence interval [CI] 33, 65; type 2: 67%, 95% CI 55, 78; NOS/mixed: 43%, 95% CI 27, 61). The PPVs of local review were 80%, 57.7% and 37% for type 1, 2 and NOS/mixed, respectively. Compared to sunitinib, cabozantinib demonstrated improved PFS for both type 1 and type 2 PRCC subgroups (7.4 vs 9.0 and 2.9 vs 5.6 months, respectfully) as well as higher ORR. Conclusions: The PRCC subtype assignment did not identify a subset of patients with greater clinical benefit from cabozantinib, with significant discordance between local and central review. Our findings confirm the limited clinical value of pathological subtyping of metastatic PRCC, in line with the recent World Health Organisation 2022 guidelines. Patient summary: In this study, categorising papillary renal cell carcinoma into type 1 or 2 subtypes showed limited concordance between central and local pathological review and did not enrich for patients more likely to benefit from cabozantinib in the S1500 PAPMET trial. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors targeting the PD-1 pathway have greatly changed clinical management of metastatic urothelial carcinoma and metastatic renal cell carcinoma. However, response rates are low, and biomarkers are needed to predict for treatment response. Immunohistochemical quantification of PD-L1 was developed as a promising biomarker in early clinical trials, but many shortcomings of the four different assays (different antibodies, disparate cellular populations, and different thresholds of positivity) have limited its clinical utility. Further limitations include the use of archival specimens to measure this dynamic biomarker. Indeed, until PD-L1 testing is standardized and can consistently predict treatment outcome, the currently available PD-L1 assays are not clinically useful in urothelial and renal cell carcinoma. Other more promising biomarkers include tumor mutational burden, profiles of tumor infiltrating lymphocytes, molecular subtypes, and PD-L2. Potentially, a composite biomarker may be best but will need prospective testing to validate such a biomarker.

We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.

BACKGROUND: Biomarker-guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell-free circulating DNA (cfDNA) next-generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies. A secondary objective was to determine whether the frequency of genomic alterations (GAs) differed between lower tract mUC (mLTUC) and upper tract mUC (mUTUC). METHODS: Patients from 13 academic medical centers in the United States who had a diagnosis of mUC between 2014 and 2017 and for whom cfDNA NGS results were available were included. cfDNA profiling was performed using a commercially available platform (Guardant360) targeting 73 genes. RESULTS: Of 369 patients with mUC, 294 were diagnosed with mLTUC and 75 with mUTUC. A total of 2130 GAs were identified in the overall mUC cohort: 1610 and 520, respectively, in the mLTUC and mUTUC cohorts. In the mLTUC cohort, frequently observed GAs were similar between cfDNA NGS and historical tumor tissue studies, including tumor protein p53 (TP53) (P = 1.000 and .115, respectively), AT-rich interaction domain 1A (ARID1A) (P = .058 and .058, respectively), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (P = .058 and .067, respectively), erb-b2 receptor tyrosine kinase 2 (ERBB2) (P = .565 and .074, respectively), and fibroblast growth factor receptor 3 (FGFR3) (P = .164 and .014, respectively). No significant difference was observed with regard to the frequency of GAs between patients with mLTUC and mUTUC. CONCLUSIONS: Among patients with mUC for whom no tumor tissue was available, cfDNA NGS was able to identify a similar profile of GAs for biomarker-driven clinical trials compared with tumor tissue. Despite the more aggressive clinical course, cases of mUTUC demonstrated a circulating tumor DNA genomic landscape that was similar to that of mLTUC. Cancer 2018;124:2115-24. © 2018 American Cancer Society.