Serial plasma and CSF cell-free tumor DNA (cf-tDNA) tracking in diffuse midline glioma patients undergoing treatment with ONC201.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2012-2012
Author(s):  
Evan Cantor ◽  
Kyle Wierzbicki ◽  
Rohinton Tarapore ◽  
Chase Thomas ◽  
Rodrigo Cartaxo ◽  
...  
Keyword(s):  
Tumor Size ◽  
Clinical Decision Making ◽  
Phase 1 ◽  
Complete Response ◽  
Clinical Decision ◽  
Experimental Therapy ◽  
Plasma Samples ◽  
Mri Scans ◽  
Tumor Dna ◽  
Diffuse Midline Glioma

2012 Background: Diffuse midline glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. There are few available means of monitoring the disease beyond serial MRI scans, making clinical decision making slow, difficult, and often reactive. Methods: We conducted a multi-site phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n=24) underwent serial lumbar puncture (baseline, 2 and 6 months) for cell-free tumor DNA (cf-tDNA) analysis at time of MRI. Additionally, patients on all arms of the trial at the University of Michigan underwent serial plasma collection. CSF collection was feasible in this cohort, with no procedural complications. We collected a total of 96 plasma samples and 53 CSF samples from 29 patients, including those with H3F3A (H3.3) (n=13), HIST13HB (H3.1) (n= 4), and unknown H3 status/not biopsied (n=12) [range of 0-8 CSF samples and 0-10 plasma samples]. We performed digital droplet polymerase chain reaction (ddPCR) analysis and/or amplicon-based electronic sequencing (Oxford Nanopore) of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Results: Preliminary analysis of samples (n=58) demonstrates a correlation between changes in tumor size and H3K27M cf-tDNA VAF, when removing samples with concurrent bevacizumab. Analysis of remaining CSF and plasma samples is ongoing, including analysis of novel biomarkers of response. In multiple cases, early reduction in CSF cf-tDNA predicts long-term clinical response (>1 year) to ONC201 and does not increase in cases of later-defined pseudo-progression (radiation necrosis). For example, a now 9-year old patient with thalamic H3K27M-mutant DMG underwent treatment with ONC201 after initial radiation and developed an increase in tumor size at 4 months post-radiation (124% baseline) of unclear etiology at the time. Meanwhile, her ddPCR declined from baseline 6.76% VAF to <1%, which has persisted, with now near complete response (85% tumor reduction) at 30 months on treatment from diagnosis. Conclusions: In summary, we present the feasibility and utility of serial CSF/plasma monitoring of a promising experimental therapy for DMG.

scholarly journals EPCT-03. SERIAL PLASMA AND CSF CELL-FREE TUMOR DNA (CF-TDNA) TRACKING IN DIFFUSE MIDLINE GLIOMA PATIENTS UNDERGOING TREATMENT WITH ONC201

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i46-i47
Author(s):  
Evan Cantor ◽  
Kyle Wierzbicki ◽  
Rohinton S Tarapore ◽  
Chase Thomas ◽  
Rodrigo Cartaxo ◽  
...  
Keyword(s):  
Tumor Size ◽  
Phase 1 ◽  
Complete Response ◽  
Experimental Therapy ◽  
Plasma Samples ◽  
Oxford Nanopore ◽  
Procedural Complications ◽  
Unclear Etiology ◽  
Tumor Dna ◽  
Diffuse Midline Glioma

Abstract Diffuse midline glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n=24) underwent serial lumbar puncture (baseline, 2, 6 months) for cell-free tumor DNA (cf-tDNA) analysis at time of MRI. Additionally, patients on all arms of the trial at the University of Michigan underwent serial plasma collection. CSF collection was feasible in this cohort, with no procedural complications. We collected 96 plasma samples and 53 CSF samples from 29 patients, including those with H3F3A (H3.3) (n=13), HIST13HB (H3.1) (n= 4), and unknown H3 status/not biopsied (n=12) [range of 0–8 CSF samples and 0–10 plasma samples]. We performed digital droplet polymerase chain reaction (ddPCR) analysis and/or amplicon-based electronic sequencing (Oxford Nanopore) of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Preliminary analysis of samples demonstrates a correlation between changes in tumor size and H3K27M cf-tDNA VAF, when removing samples with concurrent bevacizumab. In multiple cases, early reduction in CSF cf-tDNA predicts long-term clinical response (&gt;1 year) to ONC201, and does not increase in cases of later-defined pseudo-progression (radiation necrosis). For example, a now 9-year old patient with thalamic H3K27M-mutant DMG underwent treatment with ONC201 after initial radiation and developed increase in tumor size at 4 months post-radiation (124% baseline) of unclear etiology at the time. Meanwhile, her ddPCR declined from baseline 6.76% VAF to &lt;1%, which has persisted, with now near complete response (15% tumor reduction) at 30 months on treatment from diagnosis. In summary, we present the feasibility and utility of serial CSF/plasma monitoring of a promising experimental therapy for DMG.

BIOM-28. SERIAL PLASMA AND CSF CELL-FREE TUMOR DNA (cf-tDNA) TRACKING IN DIFFUSE MIDLINE GLIOMA PATIENTS UNDERGOING TREATMENT WITH ONC201

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi16-vi17
Author(s):  
Evan Cantor ◽  
Kyle Wierzbicki ◽  
Rohinton Tarapore ◽  
Karthik Ravi ◽  
Jack Wadden ◽  
...  
Keyword(s):  
Phase 1 ◽  
Plasma Samples ◽  
University Of Michigan ◽  
Clinical Tool ◽  
Spinal Cord Glioma ◽  
Mri Scans ◽  
The University ◽  
Tumor Dna ◽  
Diffuse Midline Glioma ◽  
Tumor Area

Abstract Diffuse midline glioma (DMG) with H3K27M mutation is a lethal childhood brain cancer, with limited means of monitoring beyond serial MRI scans. We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients on Arm D of the trial (n=24) underwent serial lumbar puncture (baseline, 2 and 6-months) for cell-free tumor DNA (cf-tDNA) analysis at time of MRI. Additionally, patients on all arms of the trial at the University of Michigan underwent serial plasma collection. We collected a total of 96 plasma-samples and 53 CSF-samples from 29 patients. We performed ddPCR analysis of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal tumor area on MRI). For our H3F3A-mutated (K27M) patients, cf-tDNA was positive in 53/62 plasma samples (sensitivity 85.4%) and 28/29 CSF samples (sensitivity 96.5%) and overall specificity of 100%. There was no direct correlation between percent-change in tumor-area and plasma (p=0.47) or CSF VAF (p=0.89), implying that VAF provided information supplemental to radiographic assessments. “Spikes” in plasma cf-tDNA VAF (increase of ≥25%) co-occurred with progression in 2/9 (22%) cases and preceded progression in 5/9 cases (55%) by an average of 1.22 months. In CSF, spikes preceded progression in 4/6 cases (66%) by an average of 1.8 months. Two patients had increases in tumor-area with no increase in plasma VAF; both were later confirmed as pseudo-progressors, suggesting additional potential utility of cf-tDNA VAF monitoring. A 14yo male with spinal cord glioma received concurrent bevacizumab with ONC201, which resulted in a decrease in tumor area but continued increase in plasma VAF, predicting radiologic progression at the next time. In summary, we present data which suggests monitoring serial CSF/plasma H3K27M tDNA is a promising clinical tool. Changes in cf-tDNAVAF over time appear to correlate with response, predict progression, and differentiate pseudo-progression.

Combination chemotherapy versus temozolomide (TMZ) for patients with MGMT methylated (m-MGMT) glioblastoma (GBM): Results of cellworks omics biosimulation—MyCare-015.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14501-e14501
Author(s):  
Michael Castro ◽  
Nirjhar Mundkur ◽  
Anusha Pampana ◽  
Aftab Alam ◽  
Aktar Alam ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Clinical Decision Making ◽  
Drug Effects ◽  
Standard Of Care ◽  
Clinical Decision ◽  
Phase Iii ◽  
Patient Specific ◽  
Experimental Therapy ◽  
Newly Diagnosed ◽  
Current Standard

e14501 Background: UKT-03 evaluated TMZ plus Lomustine in a single arm phase II trial in newly diagnosed GBM patients. An overall survival of 23 months was a substantial improvement over historical experience. Patients with m-MGMT v. unmethylated tumors had a 2-yr survival of 75% and median survival not reached compared to 20% and 12.5 months, respectively. These data formed the basis for NOA-9, a randomized phase III trial in newly diagnosed, m-MGMT GBM which randomized 141 patients to standard therapy or experimental therapy with Lomustine and TMZ every 6 weeks. A superiority for the combination was observed: 48.1 v. 31.4 months for the standard arm in the ITT analysis. Nevertheless, many neurooncologists are reluctant to adopt this approach. The current standard of care uses single biomarker, m-MGMT, in contrast to comprehensive pathway analysis (CPA). We sought to determine if CPA could discriminate more effectively among each patient’s likelihood of benefiting from combination treatment. Methods: Cellworks Singula employs a novel Cellworks Omics Biology Model (CBM) to predict patient-specific biomarker and phenotype response of personalized GBM avatars to drug agents, radiation, and targeted therapies. The CBM was developed and validated using PubMed to generate protein network maps of patient-specific activated and inactivated disease pathways. CBM was used to simulate the TMZ and TMZ-Lomustine therapies for each patient in a TCGA cohort of 368 GBM patients. Omics data including methylation, whole exome sequencing, and copy number alterations were input into CBM. The Singula Composite Inhibition Score (CIS) was calculated based on the measured quantitative drug effects. Results: Though incremental gain from the combination was seen in all patients, CIS varied across the population with relative scores ranging from 32-82, with best responders have more than twice the benefit. Conclusions: CPA shows that m-MGMT is an excellent biomarker for determining the likelihood of benefit from TMZ and lomustine, with the caveat that CBM identifies 18% could be spared from TMZ exposure and would benefit from Lomustine alone. Otherwise, these data lend support for evolving the standard of care with combination therapy for patients with m-MGMT GBM and should help overcome a reluctance to employing combination therapy. Additionally, CBM has utility to individualize clinical decision making. [Table: see text]

Development of a composite biomarker-based calculator to predict the probability of pathologic complete response (pT0) after neoadjuvant pembrolizumab (pembro) in muscle invasive bladder cancer (MIBC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 539-539
Author(s):  
Andrea Necchi ◽  
Joshua J. Meeks ◽  
Marco Bandini ◽  
Leigh Ann Fall ◽  
Daniele Raggi ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Clinical Decision Making ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Clinical Decision ◽  
Curve Analysis ◽  
Risk Calculator ◽  
Net Benefit ◽  
Decision Curve Analysis ◽  
Post Therapy

539 Background: The PURE01 study (NCT02736266) evaluates the use of pembro before radical cystectomy (RC) in MIBC. We assessed selected individual and combined biomarkers for predicting pT0 response after pembro, and developed a tool that may be used as an aid for clinical decision-making. Methods: Patients (pts) enrolled in the PURE01 were clinical (c) stage T≤4aN0M0 MIBC. Analysis to date included a comprehensive genomic profiling (FoundationONE assay), programmed cell-death-ligand-1 (PD-L1) combined positive score assessment (CPS, Dako 22C3 antibody) and whole transcriptome (Decipher assay) and RNA-seq profiling of pre/post therapy samples. Multivariable logistic regression analyses (MVA) evaluated baseline cT-stage and biomarkers in association with pT0 response. Corresponding coefficients were used to develop a risk calculator based on the tumor mutational burden (TMB), CPS, Immune190 signature score, and cT-stage. Decision-curve analysis was performed. Results: Complete biomarker data was available for 84 pts. Increasing TMB, CPS, and Immune190 scores showed a linear positive correlation with the pT0 probability in logistic regression (p=0.02, p=0.004, p=0.02). The c-index of the risk calculator was 0.79. Decision-curve analysis found the net-benefit of the model was higher than the “treat-all” option within the clinically-meaningful threshold probabilities of achieving a pT0 of 40-60%. Within this range, adding the Immune190 score improved the model over TMB and CPS. A significant decrease in median TMB values was observed (p=0.005) in 24 matched RC, versus a non-significant change in median CPS in 38 matched RC. Molecular subtyping switching was observed in 20/31 matched cases (64.5%), most frequently to the luminal-infiltrated subtype (80%). Conclusions: The study presents the first composite biomarker-based pT0 probability calculator for optimal pt selection. Pending validation, the model may be used to recommend neoadjuvant pembro to very selected MIBC pts. The observed changes in biomarker features in post-therapy samples may have an impact on future adjuvant strategies. Clinical trial information: NCT02736266.

scholarly journals 3T DCE-MRI Radiomics Improves Predictive Models of Complete Response to Neoadjuvant Chemotherapy in Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Stefania Montemezzi ◽  
Giulio Benetti ◽  
Maria Vittoria Bisighin ◽  
Lucia Camera ◽  
Chiara Zerbato ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Predictive Models ◽  
Clinical Decision Making ◽  
Complete Response ◽  
Clinical Decision ◽  
Feature Reduction ◽  
Support Vector ◽  
Dce Mri ◽  
Neo Adjuvant Chemotherapy ◽  
Response To Neoadjuvant Chemotherapy

ObjectivesTo test whether 3T MRI radiomics of breast malignant lesions improves the performance of predictive models of complete response to neoadjuvant chemotherapy when added to other clinical, histological and radiological information.MethodsWomen who consecutively had pre-neoadjuvant chemotherapy (NAC) 3T DCE-MRI between January 2016 and October 2019 were retrospectively included in the study. 18F-FDG PET-CT and histological information obtained through lesion biopsy were also available. All patients underwent surgery and specimens were analyzed. Subjects were divided between complete responders (Pinder class 1i or 1ii) and non-complete responders to NAC. Geometric, first order or textural (higher order) radiomic features were extracted from pre-NAC MRI and feature reduction was performed. Five radiomic features were added to other available information to build predictive models of complete response to NAC using three different classifiers (logistic regression, support vector machines regression and random forest) and exploring the whole set of possible feature selections.ResultsThe study population consisted of 20 complete responders and 40 non-complete responders. Models including MRI radiomic features consistently showed better performance compared to combinations of other clinical, histological and radiological information. The AUC (ROC analysis) of predictors that did not include radiomic features reached up to 0.89, while all three classifiers gave AUC higher than 0.90 with the inclusion of radiomic information (range: 0.91-0.98).ConclusionsRadiomic features extracted from 3T DCE-MRI consistently improved predictive models of complete response to neo-adjuvant chemotherapy. However, further investigation is necessary before this information can be used for clinical decision making.

scholarly journals Prolactin ≤1 ng/mL predicts macroprolactinoma reduction after cabergoline therapy

2020 ◽  
Vol 182 (2) ◽  
pp. 177-183
Author(s):  
Daham Kim ◽  
Cheol Ryong Ku ◽  
Kyungwon Kim ◽  
Hyein Jung ◽  
Eun Jig Lee
Keyword(s):  
Tumor Size ◽  
Prolactin Level ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Post Treatment ◽  
Size Reduction ◽  
Multivariable Logistic Regression Analysis ◽  
High Dose ◽  
Pituitary Hormone ◽  
Level 1

Objective The association between prolactin level variation and prolactinoma size reduction remains unclear. This study aimed to determine the prolactin level cut-off predictive of a tumor size reduction. Design Retrospective cohort study. Methods We reviewed medical records of patients with prolactinoma who received primary cabergoline therapy and for whom complete data on pituitary hormone assays and sellar MRI at baseline and 3 months post treatment were available. We tested whether the certain prolactin level after 3 months post treatment predicted better response. Results Prolactin levels normalized in 109 (88.6%) of 123 included macroprolactinoma patients. The mean tumor size reduction was 22.9%, and patients in the lowest prolactin tertile (≤0.7) had the highest frequency of tumor size reductions of ≥20% (73.7 vs 52.9% and 45.9% in tertiles 2 (>0.7 to 2.6) and 3 (>2.6 to 20), P = 0.015). Patients with prolactin levels ≤1 ng/mL exhibited larger tumor size reductions vs those with prolactin levels of 1–20 (27.2 ± 18.3% vs 19.5 ± 13.9%, P = 0.014), 1–10 (19.3 ± 13.7%, P = 0.017) and 1–5 ng/mL (19.2 ± 14.3%, P = 0.039). A multivariable logistic regression analysis revealed that a prolactin level ≤1 ng/mL at 3 months and high-dose cabergoline therapy were significantly associated with tumor size reductions of ≥20% (odds ratio (OR): 2.8, 95% confidence interval (CI): 1.2–6.7, P = 0.017; OR: 2.0, 95% CI: 1.0–3.9, P = 0.043). Conclusions A prolactin level ≤1 ng/mL at 3 months after cabergoline treatment was correlated with a significant tumor size reduction in patients with macroprolactinoma. This finding may help clinical decision making when treating macroprolactinoma patients.

scholarly journals ASCO 2021—an update on metastastic colorectal cancer

2021 ◽  
Author(s):  
Lukas Weiss
Keyword(s):  
Colorectal Cancer ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Circulating Tumor Dna ◽  
Novel Therapies ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Integrate Analysis ◽  
Tumor Dna ◽  
Antibody Drug

SummaryThe 2021 ASCO Annual Meeting provided updates on novel therapies in rare subgroups of metastatic colorectal cancer, such as immunotherapy in microsatellite instable colorectal cancer and antibody–drug conjugate therapy in HER2-positive disease. Furthermore, the concept of anti-EGFR rechallenge therapy has received additional momentum with data from the CHRONOS trial in regard to treating patients in later lines as well as how to integrate analysis of circulating tumor DNA in clinical decision-making.

The impact of tumor size on survival in T3 non-small cell lung-cancer with direct extension.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20033-e20033
Author(s):  
Clara H. Kim ◽  
Michelle C. Salazar ◽  
Jessica R. Hoag ◽  
Joshua E. Rosen ◽  
Brian N. Arnold ◽  
...  
Keyword(s):  
Adjuvant Chemotherapy ◽  
Adjuvant Therapy ◽  
Tumor Size ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Adjuvant Chemoradiation ◽  
Direct Extension ◽  
Cox Proportional Hazard Models ◽  
N Stage ◽  
The Impact

e20033 Background: Tumor size is an important prognostic variable that affects clinical decision-making in NSCLC including the use of adjuvant therapy. However, the association between tumor size and survival in a subset of patients who have T3 NSCLC with direct extension into nearby structures (T3dx) has not been explicitly characterized. We hypothesize that tumor size impacts survival and prognosis within this cohort. Methods: Patients with T3dxin 2006-2013 who underwent lobectomy or pneumonectomy were identified in the National Cancer Database. Patients who received neoadjuvant therapy or had positive margins were excluded. Tumor size was categorized based on cutoffs used by current staging guidelines and patients were stratified by pathologic N stage (see table). Cox proportional hazard models were used to measure the independent impact of tumor size on survival. Results: Overall, 0.1-3cm tumors exhibit superior 5-year survival compared to 3.1-5cm and >5cm tumors. Tumor size is significantly associated with survival in N0 patients but not in N1 and N2 patients. Use of adjuvant chemotherapy is associated with improved survival in the overall cohort and all subgroups; however, use of adjuvant chemoradiation may be associated with inferior survival in the overall cohort. Conclusions: Larger tumor size is associated with inferior survival in T3dx in the absence of nodal disease. T3dx requires a more tailored approach to adjuvant therapy than other T3 subgroups. Adjuvant chemotherapy appears to benefit all patients with T3dx; however, the role of adjuvant chemoradiation is less clear. [Table: see text]

Growth Analysis of Untreated Meningiomas under Observation

2021 ◽  
Author(s):  
Charles F. Opalak ◽  
Adam P. Sima ◽  
Matthew Thomas Carr ◽  
Andrew Rock ◽  
Aravind Somasundaram ◽  
...  
Keyword(s):  
Linear Regression ◽  
Clinical Decision Making ◽  
Geometric Mean ◽  
Clinical Decision ◽  
Growth Patterns ◽  
Growth Potential ◽  
Linear Regression Models ◽  
Mri Scans ◽  
Magnetic Resonance Imaging Mri

Abstract Background When meningiomas are small or asymptomatic, the decision to observe rather than treat requires balancing the growth potential of the lesion with the outcome and side effects of treatment. The aim of this study is to characterize the growth patterns of untreated meningiomas to better inform the clinical decision-making process. Methods Patients with meningiomas were identified from 2005 to 2015. Those without treatment who had been followed for 1.5 years, with three magnetic resonance imaging (MRI) scans, were identified. Scans were measured with orthogonal diameters, geometric mean diameters, and volumes using the ABC/2 method. Regression modeling determined what growth pattern these parameters best approximated. Results Two hundred and fifteen MRI scans for 34 female (82.9%) and 7 male (17%) patients with 43 tumors were evaluated. Initial tumor volumes ranged from 0.13 to 9.98 mL. The mean and median initial volumes were 2.44 and 1.52 mL, respectively. Follow-up times ranged from 21 to 144 months, with a median of 70 months. There were 12 tumors (28%) whose growth rates were significantly greater than zero. For all tumors, use of a linear regression model allowed accurate prediction of the future size using prior data. Conclusion Three-quarters of presumptive meningiomas managed conservatively do not grow significantly. The remainder have significant growth over time, and the behavior could be approximated with linear regression models.

Nivolumab plus cabozantinib (N+C) versus sunitinib (S) for advanced renal cell carcinoma (aRCC): Outcomes by baseline disease characteristics in the phase 3 CheckMate 9ER trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4553-4553
Author(s):  
Andrea B. Apolo ◽  
Thomas Powles ◽  
Mauricio Burotto ◽  
Maria Teresa Bourlon ◽  
James J Hsieh ◽  
...  
Keyword(s):  
Clinical Decision Making ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Clinical Decision ◽  
Lesion Size ◽  
First Line ◽  
Phase 3 ◽  
Risk Status ◽  
Disease Characteristics

4553 Background: First-line N+C significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) vs S in aRCC patients (pts) in the phase 3 CheckMate 9ER trial, leading to FDA approval of N+C in this setting. A deeper understanding of how baseline disease characteristics may impact clinical outcomes with N+C vs S may inform clinical decision making. Methods: Pts with clear cell aRCC were randomized to N 240 mg IV Q2W + C 40 mg PO QD vs S 50 mg PO QD (4 weeks of 6-week cycles). In this post hoc exploratory analysis, PFS, OS, and ORR were evaluated across pt subgroups defined by baseline IMDC risk status, organ sites of metastases (mets), number of organs with any lesions, or target lesion size. Consistent with primary/secondary efficacy endpoints in ITT pts, PFS and ORR were evaluated per RECIST v1.1 by blinded independent central review in subgroups. Results: Median follow-up in ITT pts was 23.5 months. PFS, OS, and ORR (including complete response [CR]) outcomes are summarized in the table across subgroups: IMDC risk (favorable [FAV], intermediate [I], poor [P]); number of organs with ≥ 1 target/nontarget lesion (T/NT; 1 and ≥ 2); sum of diameters of target lesions (sDTL; < and ≥ median [72.1 mm]), and in pts with liver, bone, or lung mets. The PFS HR favored N+C vs S and median (m) PFS was longer with N+C vs S across all subgroups. The OS HR also favored N+C vs S across most subgroups. ORR ranged from 38%–66% (N+C) vs 10%–44% (S) across subgroups, and CR benefits were seen with N+C in most subgroups. Additional outcomes including landmark OS and response details in subgroups will be reported. Conclusions: Consistent with outcomes in ITT pts, efficacy benefits with N+C vs S were observed regardless of IMDC risk status, organ site of mets, or extent of tumor burden at baseline. These results support N+C as a new first-line treatment option for pts with aRCC. Clinical trial information: NCT03141177. [Table: see text]

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