INTRODUCTION:Patients with mRCC who achieve a complete response (CR) to immuno-oncology (IO) combinations have an excellent prognosis and may experience prolonged responses. However, real-world data on CR durability, mortality, and need for subsequent therapy remain limited. PATIENTS AND METHODS:Using the International mRCC Database Consortium (IMDC), we identified patients with mRCC who achieved a documented CR to first-line treatment between 2015 and 2022. We described baseline characteristics, time to next treatment (TTNT), time to second line (TT2L), overall survival (OS), and use of subsequent therapies in patients treated with a vascular endotelial growth factor receptor pathway targeted therapy vascular endotelial growth factor (VEGF), IO plus VEGF (IO-VE), or Ipilimumab plus Nivolumab (IOIO). RESULTS:CR was achieved with IO-VE in 25 of 610 (4.1%) patients, with IO-IO in 82 of 1313 (6.2%), and with VEGF in 46 of 2980 (1.5%) patients. OS in patients with CRs was not significantly different (log-rank P = .42) among the 3 treatment groups. After a median follow-up of 46.7 months, 4-year OS was for IO-VE 100% (95% CI, 100%-100%; HR ref), for IO-IO 92.9% (95% CI, 86.2%-100%; HR 1.89, 95% CI, 0.22-16.4), and for VEGF 94.8% (95% CI 88%-100%; HR 3.18, 95% CI 0.4-25.2). In the IO-VE cohort, 5 (20%) started second-line therapy, and 1 died; in IO-IO, 11 (13.4%) began second-line, and 5 (6.1%) died; and in VEGF, 17 (37%) started second-line, and 9 (19.6%) died. TTNT was not reached for any treatment, and TT2L was in IO-VE 46.8 months (95% CI, 27.5-NR), in IO-IO 30.2 months (95% CI, 21.5-NR), and in VEGF 23 months (95% CI, 14.3-51.7) (P = .66). IO rechallenge occurred in 20% (n = 1) of IO-VE and 63.6% (n = 7) of IO-IO patients receiving second-line, with CR to second-line in 2/8, PR in 4/8, standard deviation in 2/8, and no deaths. DISCUSSION:This real-world study confirms that achieving CR confers an excellent prognosis. However, CR does not guarantee a cure, as a subset of patients do experience a relapse. Retreatment with IO was frequent and effective. These results support the significance of CR but highlight the need for ongoing surveillance and tailored care.

Background Cabozantinib is approved as a subsequent therapy for patients with metastatic renal cell carcinoma (mRCC) based on the METEOR trial. However, only 5% of patients in this trial received prior immunotherapy. Objective Analyze the effectiveness of Cabozantinib in the second-line setting after different first-line treatments. Methods This retrospective study analyzed patients with mRCC who received second-line Cabozantinib between 2010 and 2023, using the International mRCC Database Consortium (IMDC). Patients were grouped by prior therapy and IMDC risk category. We assessed overall response rate (ORR), time to next treatment (TTNT), treatment duration (TD), and overall survival (OS). Results Among 603 patients (mean age 59 years), 31.5% had received IO-IO regimens, 24.5% IO-TKI combinations, and 34.3% TKI monotherapy as initial therapy. At Cabozantinib start, 13.8% were favorable-risk, 49.1% intermediate-risk, and 16.7% poor-risk per IMDC. The ORR for the overall cohort was 25.7%; median TTNT was 10.1 months; median TD was 8.9 months; and median OS was 19.0 months. Efficacy outcomes were consistent across first-line treatment groups. Conclusion This real-world analysis supports the effectiveness of Cabozantinib in the second-line setting, including among patients previously treated with immune checkpoint inhibitors. Prior treatment type did not significantly affect Cabozantinib outcomes.

BACKGROUND AND OBJECTIVE:Real-world evidence on the effectiveness of first-line immuno-oncology (IO)-based combinations or cabozantinib (CABO) over traditional targeted therapies in metastatic non-clear cell renal cell carcinoma (nccRCC) is limited. This study aims to compare the outcomes of first-line therapies for metastatic nccRCC according to histologic subtypes, including papillary renal cell carcinoma (RCC), unclassified RCC, and chromophobe RCC with or without sarcomatoid dedifferentiation. METHODS:Using the International Metastatic Renal Cell Carcinoma Database Consortium, patients with metastatic nccRCC who received (1) IO plus vascular endothelial growth factor (IOVE) combination therapy, (2) IOIO doublet therapy, (3) CABO monotherapy, (4) sunitinib or pazopanib (SUN/PAZ) monotherapy, or (5) mammalian target of rapamycin (mTOR) monotherapy were included. Baseline patient characteristics, clinician assessment of objective response rates (ORRs), and overall survival (OS) were compared across first-line therapy regimens. KEY FINDINGS AND LIMITATIONS:The most common nccRCC histology was papillary found in 725 (47%), and sarcomatoid dedifferentiation was found in 236 (15%) of the 1551 patients included. Within the papillary RCC cohort, ORRs and median OS were, respectively, 31% and 33.2 mo for IOVE, 26% and 31.9 mo for IOIO, and 37% and 30.7 mo for CABO, as compared with 13% and 17.2 mo for SUN/PAZ and 3.4% and 13.1 mo for mTOR. Within the sarcomatoid dedifferentiation cohort, receipt of IOIO was associated with the highest ORR and the longest median OS (39% and 31.9 mo, respectively). CONCLUSIONS AND CLINICAL IMPLICATIONS:Distinct patient outcomes were observed across histologic subtypes. More histology-specific strategies are required given the differential activity of first-line therapy regimens against each nccRCC histology.

IntroductionTherapies for metastatic renal cell carcinoma (mRCC) have evolved significantly, making treatment decisions more complex. We used machine learning (ML) to identify subgroups of patients who have a high probability of response to first line systemic treatment.MethodsPatients from the International mRCC Database Consortium (IMDC) with mRCC and treatment response measured to first-line were identified, and a ML classification and regression tree analysis was conducted, in which we grew a complex tree up to a depth of 30 with a minimum node split size of 2 with no constraints on the cost-complexity parameter. The resulting tree was pruned according to the cost-complexity parameter that minimized the leave one out cross-validated error rate and had a minimum bucket size of 25 patients.Results2,549 patients were included, 73.2% male, 13.5% non-clear cell histology, 70.3% nephrectomy. 19.4%, 54.2%, and 26.4% had favorable, intermediate and poor IMDC risk respectively. First line treatment regimens consisted of VEGF inhibitors (51.5%), IO-IO combinations (32.3%), and IO-TKI combinations (16.2%). The ORR was 36.0% overall, with 29.6% for VEGF inhibitors, 39.1% for IO-IO, and 50.2% for IO-TKI combinations. ML identified 5 hierarchal variables, therapy type, nephrectomy, lung metastasis, other sites of metastasis, and age, that divided patients into 7 different categories with different response probabilities. VEGF therapy showed the poorest response, with no additional variables able to predict response. The highest ORR was observed in patients treated with IO-TKI and nephrectomy (54.9%); and in those treated with IO-IO, nephrectomy, and only lung metastasis (59.8%). Factors associated with poorer ORR included non-clear cell histology, older age, bone and liver metastases, poor performance status, elevated neutrophils, and poor IMDC risk score.ConclusionThis large-scale ML analysis identified five key clinical variables that predict treatment response in mRCC, with treatment type emerging as the primary determinant. These results suggest that treatment selection for mRCC could potentially be optimized by considering these hierarchical variables, though further validation is needed.

4549 Background: NIVO IPI has demonstrated durable overall survival (OS) benefit with long-term follow-up in patients with mRCC. Real world outcomes and benchmarks for subgroups as well as conditional survival (CS) are required in the real world. Methods: Patients with mRCC treated with 1L NIVO IPI from the IMDC were analyzed, including various subgroups of interest. Outcomes reported will be objective response rates (ORR), median overall survival (mOS) and conditional survival (CS). CS is defined as survival among patients who were alive and on treatment after the requisite 3-month interval landmarks, as estimated using the Kaplan–Meier method. CS was calculated at landmarks while patients were still on treatment, and at landmarks regardless of treatment. Results: 2115 patients received 1L NIVO IPI; 148/1042/549 were categorized by IMDC risk group as favorable/intermediate/poor risk; 90% of patients had clear-cell histology, 32% had bone metastases, and 14% had sarcomatoid features. Median follow-up was 34 months (m); median duration of treatment was 4.8 m, and median time to next treatment was 11.2 m. 66% of patients received second-line treatment. ORR was 39.5% (8.3% CR) with primary progression seen in 28 mOS was longer in clear cell (47.8 m) than in non–clear cell (26.3 m) (p<0.001). mOS was significantly shorter in patients with sarcomatoid features (34.2 vs 47.0 m; p=0.02 mOS was also different by IMDC risk group: 53.3 m for favorable, 45.7 m for intermediate and 18.8 m for poor risk patients (p<0.001); and by response: 4-year was OS of 93.6% for patients with CR, 60.1% for PR, 43.6% for SD and 15.4% for patients with PD (p<0.001). CS during 1L NIVO IPI is detailed in Table 1 with greater survival with each successive landmark. Conclusions: We provide real-world benchmark survival results for patients with mRCC treated with 1L NIVO IPI, including subgroup analysis regarding the presence of sarcomatoid features, IMDC risk group, and ORR. Conditional survival provides a key understanding of a patient’s prognosis after having been on therapy or been alive for at certain time points. This is essential information for patient counselling and clinical trial design. Conditional survival (CS) through time landmarks, either on treatment or regardless of treatment. Landmark(mo) CS on NIVO IPI (N) CS on treatment If patient is still on therapy past landmarkmo (95% CI) CS (N) regardless of treatment continuation CS regardless of treatment continuationIf patient survived past landmarkmo (95% CI) 0 1965 41.4 (37.7–45.3) 2038 40.2 (36.7–44.5) 3 1129 54.5 (49.7–67.3) 1826 44.6 (40.7–49.4) 6 822 93.0 (60.9–NR) 1626 49.2 (44.6–53.5) 9 627 93.0 (84.2–NR) 1436 53.5 (49.2–59.2) 12 483 114 (84.2–NR) 1276 56.9 (51.1–66.8) 24 210 NR (NR–NR) 805 93.0 (72.8–NR) 36 101 NR (NR–NR) 519 NR (93.0–NR)

4505 Background: First-line nivolumab plus ipilimumab (NIVO+IPI) provided substantial long-term survival benefits over sunitinib (SUN) in patients (pts) with advanced renal cell carcinoma (aRCC) in the CheckMate 214 trial. We now report final efficacy and safety data in the intent-to-treat (ITT) population and by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk. Methods: Pts with clear cell aRCC were randomized 1:1 to NIVO 3 mg/kg + IPI 1 mg/kg Q3W×4 then NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN 50 mg once daily for 4 weeks on, 2 weeks off. Efficacy endpoints included overall survival (OS), and independent radiology review committee (IRRC)-assessed progression-free survival (PFS) and objective response rate (ORR) in intermediate/poor-risk (I/P; primary), ITT (secondary), and favorable-risk (FAV; exploratory) pts. Response was assessed using RECIST v1.1. Results: With 9 years median follow-up, OS was improved with NIVO+IPI vs SUN in ITT (HR 0.71) and I/P (HR 0.69) pts. The probability of OS at 108 months was 31% vs 20% in ITT pts and 30% vs 19% in I/P pts, respectively. In pts with FAV risk, the HR for OS improved from 1.45 at first report (Motzer NEJM 2018) to 0.80 at 9 years, showing a delayed benefit with NIVO+IPI vs SUN. OS probabilities at 108 months were 35% vs 22% in FAV pts, respectively (Table). The probability of PFS at 96 months with NIVO+IPI vs SUN was 23% vs 9% in ITT pts, 25% vs 9% in I/P pts, and 13% vs 11% in FAV pts. The probability of remaining in response through 96 months with NIVO+IPI vs SUN was 48% vs 19% in ITT pts, 50% vs 23% in I/P pts, and 36% vs not available (NA) in FAV pts. No new treatment-related deaths occurred in either arm. Additional subgroup analyses will be presented. Conclusions: In the longest and final phase 3 follow-up (9 years) of a first-line checkpoint inhibitor combination in aRCC, milestone rates of OS and PFS and durable response remained higher with NIVO+IPI vs SUN. No new safety signals emerged. NIVO+IPI remains a standard first-line option in aRCC. Clinical trial information: NCT02231749 . ITT I/P FAV Arm; n NIVO+IPI; 550 SUN; 546 NIVO+IPI; 425 SUN; 422 NIVO+IPI; 125 SUN; 124 mOS (95% CI), mo 53 (46–64) 38 (32–44) 47 (35–56) 26 (22–33) 78 (65–92) 67 (56–80) 108-mo OS probabilities (95% CI), % 31 (27–35) 20 (16–23) 30 (26–35) 19 (15–23) 35 (27–44) 22 (15–30) mPFS (95% CI), mo 12 (10–16) 12 (10–15) 12 (9–17) 9 (7–11) 13 (10–18) 29 (23–43) 96-mo a PFS probabilities (95% CI), % 23 (18–27) 9 (5–15) 25 (20–31) 9 (4–15) 13 (6–22) 11 (3–27) ORR per IRRC (95% CI); CR, % 39 (35–44); 12 33 (29–37); 3 42 (38–47); 12 27 (23–32); 3 30 (22–38); 13 52 (43–61); 6 mDOR (95% CI), mo 76 (59–NE) 25 (20–33) 83 (54–NE) 20 (16–26) 61 (23–NE) 33 (25–51) 96-mo a DOR probabilities (95% CI), % 48 (39–55) 19 (10–31) 50 (41–58) 23 (13–36) 36 (17–56) NA b a 96-mo probabilities reported due to small numbers of pts at risk at 108 mo. b No pts remain at risk. CR, complete response; DOR, duration of response; m, median; NE, not estimable.

494 Background: Immuno-oncology (IO)-based combination therapy with or without anti-vascular endothelial growth factor (VE) has become a standard of care for mnccRCC. However, real-world evidence on the effectiveness of contemporary therapies over traditional targeted therapies against mnccRCC is limited. Methods: Using the IMDC, patients with mnccRCC were classified into five subgroups based on 1L therapies: IOIO, IOVE, CABO, SUN/PAZ, and mammalian target of rapamycin (mTOR). Baseline patient characteristics, clinician assessment of objective response rates (ORRs) as per RECIST 1.1, and overall survival (OS) were compared across 1L therapies. Results: Of 1551 patients with mnccRCC, 180 (11.6%), 90 (5.8%), 45 (2.9%), 1039 (70.0%), and 197 (12.7%) received IOIO, IOVE, CABO, SUN/PAZ, and mTOR, respectively. The most common histology was papillary in 725 (46.7%), followed by unclassified in 287 (18.5%), chromophobe in 200 (12.9%), and translocation in 84 (5.4%), while sarcomatoid dedifferentiation was found in 236 (15.2%). The IMDC prognostic categories (favourable/intermediate/poor) differed significantly across 1L therapies: IOIO (6.7%/52.3%/40.9%), IOVE (26.9%/44.9%/28.2%), CABO (16.1%/53.2%/30.7%), SUN/PAZ (16.1%/53.2%/30.7%), and mTOR (9.6%/51.4%/39.0%). For the papillary subtype, ORRs and median OS were better in IOIO (26.1% and 31.9 months), IOVE (31.0% and 33.2 months), and CABO (36.8% and 30.7 months) than in SUN/PAZ (12.8% and 17.2 months) and mTOR (3.4% and 13.1 months), whereas for the unclassified subtype, CABO did not appear to be as effective as IOIO and IOVE. For the chromophobe and translocation subtypes, there was no significant relationship between 1L therapies and the outcomes. IOIO was associated with the highest ORR and the longest median OS for mnccRCC with sarcomatoid dedifferentiation. Conclusions: Contemporary therapies seem to be effective against mnccRCC, although histology-specific strategies may guide personalized treatment selection. Histologic subtype IOIO IOVE CABO SUN/PAZ mTOR p-value Papillary (n = 54) (n = 31) (n = 25) (n = 499) (n = 116) ORR, n (%) 12/46 (26.1%) 9/29 (31.0%) 7/19 (36.8%) 52/407 (12.8%) 3/87 (3.4%) <0.001 Median OS (95% CI), months 31.9 (20.3–NA) 33.2 (18.6–NA) 30.7 (17.5–48.7) 17.2 (15.3–19.6) 13.1 (11.1–15.4) 0.002 Unclassified (n = 50) (n = 20) (n = 10) (n = 179) (n = 28) ORR, n (%) 14/45 (31.1%) 5/17 (29.4%) 0/7 (0%) 22/149 (14.8%) 1/22 (4.5%) 0.018 Median OS (95% CI), months 18.8 (13.8–29.0) 15.5 (11.1–NA) 7.6 (2.1–NA) 13.6 (11.0–16.7) 6.1 (3.6–9.5) <0.001 mnccRCC with sarcomatoid dedifferentiation (n = 47) (n = 12) (n = 2) (n = 141) (n = 34) ORR, n (%) 16/41 (39.0%) 2/10 (20.0%) 0/2 (0%) 16/106 (15.1%) 1/26 (3.8%) 0.003 Median OS (95% CI), months 31.9 (19.3–NA) 14.0 (2.1–NA) 14.3 (7.6–NA) 12.8 (7.0–13.9) 6.6 (3.6–12.5) <0.001

BACKGROUND:Attrition rates for patients with mRCC are not well characterized in the era of immunoncology (IO)-based combinations. This study aims to quantify real-world attrition rates by line of therapy, analyze associated clinical predictors, and describe treatment sequencing across multiple international centers. METHODS:IMDC data for patients with mRCC who received first line Nivolumab + Ipilimumab (IO-IO) or IO- Vascular Endothelial Growth Factor receptor targeted therapy (VEGFR TT) (IO-VE) were included. Clinical and pathologic characteristics and outcomes were extracted. Chi-square tests were used to compare categorical variables between patients who received second line and those who did not. A logistic regression model was used to assess predictors of second line therapy initiation. RESULTS:A total of 1411 patients were identified, of whom 995 patients were treated with first line IO-IO and 434 with IO-VE. Of them, 935 (704 first line IO-IO and 231 first line IO-VE) stopped first line and were suitable for second line therapy. Reasons for stopping first line included progressive disease (PD) in 41.1%, toxicity in 24.4%, death in 3.9%, complete response in 1.5% and other in 28.3%. Among second line suitable patients, 544 (58.2%) started any second line whereas 391 (41.8%) did not. Patients who stopped first line for PD were more likely to initiate second line than those who stopped for other reasons (57.9% vs. 17.6%, P < .00001). Patients who received second line were more likely to have clear-cell histology (77.2% vs. 66.8%, P = .04), without sarcomatoid features (57.2 vs. 44.8%, P = .02), a Karnofsky performance score (KPS) of 80 or higher (80.1 vs. 73.9%, P = .01), and bone metastases (39.0 vs. 28.1%, P = .0009). (Table 2). After adjusting for IMDC criteria, only age and reason for stopping first line remained significant predictors of receiving second line therapy. Among 353 patients who stopped second line, 199 (56.4%, overall 21.3%) started third line therapy. Of the 139 patients who stopped third line, 80 (57.6%, overall 8.6%) started fourth line therapy. CONCLUSIONS:In this real-world analysis, we found that just over half of suitable patients received the subsequent line of therapy post first line. We were able to identify age and reason for stopping first line as predictors of second line therapy initiation.

Background and objective: Patients receiving immune checkpoint blockade (ICB) therapy may experience periods of prolonged disease control without a need for systemic therapy. Treatment-free survival (TFS) is an important measure for this period, but no data are available for patients with metastatic renal cell carcinoma (mRCC) starting first-line agents. Our aim was to analyze TFS outcomes for patients with mRCC starting first-line therapy. Methods: We analyzed data for patients with mRCC starting first-line systemic therapy with VEGFR-targeted monotherapy, an ICB + VEGFR combination, or an ICB doublet from February 1, 2014 to February 1, 2023 from the multicenter International Metastatic RCC Database Consortium (IMDC) database. We estimated 36-mo TFS as the difference in restricted mean survival time between (1) the time to first-line therapy discontinuation and (2) the time to subsequent systemic therapy initiation. Key findings and limitations: The study population included 3758 patients receiving either first-line VEGFR monotherapy (n = 2635), an ICB + VEGFR combination (n = 354), or doublet ICB (n = 769) were included. For the IMDC favorable-risk cohort, the 36-mo TFS estimate was 3.1 mo (95% confidence interval [CI] 1.5-4.6) for the VEGFR monotherapy group and 3.7 mo (95% CI 0.2-7.2) for the ICB + VEGFR group. For the IMDC intermediate-/poor-risk cohort, TFS was 2.1 mo (95% CI 1.4-2.8) for the VEGFR monotherapy group, 3.7 mo (95% CI 1.0-6.4) for the ICB + VEGFR group, and 5.3 mo (95% CI 3.8-6.8) for ICB doublet group. Limitations include the retrospective design and an inability to quantify time spent with adverse events. Conclusions and clinical implications: Our study demonstrates that patients with IMDC intermediate or poor risk treated with ICB doublet therapy experienced longer TFS than those treated with VEGFR monotherapy in the first-line setting. These results emphasize the utility of TFS as an informative endpoint and provide survival estimates to inform decision-making in mRCC. Patient summary: For patients with metastatic kidney cancer, we compared the survival time free from a second treatment line for different first-line treatment options. The results show that the time free from second-line treatment was longer when first- line treatment was with a combination of two immunotherapy drugs (ipilimumab and nivolumab) in comparison to other treatment options. Association of Urology. Published by Elsevier B.V. All rights are e for text and data mining, AI training, and similar technologies.

479 Background: Cabozantinib is approved as a subsequent therapy for patients with metastatic renal cell carcinoma (mRCC) based on the METEOR trial. However, only 5% of patients in this trial received prior immunotherapy. Methods: We identified patients with mRCC from the IMDC who were treated with cabozantinib in the second-line (2L) setting from 2010 to 2023. These patients were stratified by IMDC risk groups and first-line (1L) treatment. We analyzed overall response rate (ORR), time to next treatment (TTNT), treatment duration (TD), overall survival (OS) and performed a multivariable analysis adjusted by IMDC criteria at 2L. Results: A total of 603 patients were identified. Baseline characteristics are summarized in the table. For the entire cohort, the ORR was 25.7%, TTNT was 10.1 months (mo), TD was 8.9 mo and mOS was 19 mo. Among patients treated with 1L ipilimumab/nivolumab (n=190), anti-PD1 + TKI (n=148), and TKI alone (n=207), cabozantinib showed an ORR of 27.2%, 26.4%, and 25%, respectively; a median TTNT of 9.9, 10.3, and 9.7 mo; a median TD of 9.4, 8.2, and 8.3 mo. Median OS was 18.6, 17.6, and 21.3 mo, respectively. A multivariable analysis was unable to demonstrate that first-line ORR (CR/PR vs SD vs PD) or TTNT (< 12 vs ≥ 12 mo) predicts for second-line cabozantinib ORR in the overall cohort and by first-line therapy type. Specifically, patients with stable disease or with partial and complete response in 1L were associated with an OR for a response of 0.99 (95% CI 0.52-1.92) or 1.23 (95% CI 0.61-2.49), respectively. Similarly, a first-line TTNT of ≥12 months had an OR for response of 1.04 (95% CI 0.59-1.82). Conclusions: This study demonstrates that cabozantinib maintains efficacy comparable to that observed in the METEOR trial in a real-world setting, including in patients with prior immunotherapy combination therapies. Efficacy of 1L treatment does not predict efficacy of 2L cabozantinib. Baseline characteristics. Variable Overall (N = 603) IO-IO (N = 190) IO-TKI (N = 148) TKI Alone (N = 207) Other (N = 58) p-value Non clear cell histology 107 (17.7) 33 (17.4) 26 (17.6) 28 (13.5) 20 (34.5) 0.003 Nephrectomy 416 (69.0) 97 (51.1) 110 (74.3) 166 (80.2) 43 (74.1) <0.001 1st line IMDC Risk Fav/Int/Poor 83 (13.8)/296 (49.1)/101 (16.7) 10 (5.3)/100 (52.6) /46 (24.2) 37 (25)/62 (41.9) /20 (13.5) 29 (14)/99 (47.8)/27 (13) 7 (12.1)/35 (60.3)/8 (13.8) <0.001 2nd line IMDC risk Fav/Int/Poor 56 (9.3)/269 (44.6)/108 (17.9) 7 (3.7)/90 (47.4)/45 (23.7) 25 (16.9)/63 (42.6)/24 (16.2) 19 (9.2)/87 (42.0)/32 (15.5) 5 (8.6)/29 (50.0)/7 (12.1) 0.002 Greater than 1 site of Metastasis 473 (78.4) 146 (76.8) 114 (77.0) 161 (77.8) 45 (77.6) 0.722 Brain Metastasis 36 (6.0) 18 (9.5) 5 (3.4) 13 (6.3) 0 (0.0) 0.022 Bone Metastasis 221 (36.7) 74 (38.9) 60 (40.5) 70 (33.8) 17 (29.3) 0.326 Liver Metastasis 106 (17.6) 32 (16.8) 26 (17.6) 39 (18.8) 9 (15.5) 0.926

The advent of checkpoint immunotherapy has dramatically changed the outcomes for patients with cancer. However, a considerable number of patients have little or no response to therapy. We review recent findings on the connection between the gut microbiota and the immune system, exploring whether this link could enhance the effectiveness of immunotherapy. Clinical studies have reported specific types of bacteria in larger quantities at baseline in responders than in non-responders, especially Akkermansia mucinifila, Ruminococcaceae, Faecalibacterium, and Lachnospiraceae. Following the consumption of a high-fiber diet, bacteria in the gut ferment dietary fiber to short-chain fatty acids (SCFAs), like acetate, propionate, and butyrate. Some of the SCFAs nurture intestinal epithelial cells, and some enter the bloodstream. Here SCFAs can activate DC8 + cytotoxic T-cells to induce cancer cell death. High fiber intake in the diet was associated with a reduced risk of progression or death during checkpoint immunotherapy. Recent findings demonstrate that high-fiber plant-based diets such as the Mediterranean Diet positively influence the gut microbiota whereas antibiotics and proton pump inhibitors can negatively influence outcomes of cancer immunotherapy by changing the gut microbiota. This narrative review provides evidence of an association between types of bacteria and their metabolites and favorable responses to checkpoint immunotherapy. Prospective clinical trials are needed to determine if diet interventions can improve treatment outcomes.

Background: Metastatic renal cell carcinoma (mRCC) is notably resistant to chemotherapy and radiotherapy. However, tyrosine kinase inhibitors (TKIs) and checkpoint immunotherapy have significantly improved outcomes. Still, about 20% of patients experience disease progression as their best response to TKIs, and 16–63% endure severe toxicities, reducing quality of life. Optimizing dosing is therefore essential. Therapeutic drug monitoring (TDM) is a promising strategy for individualizing treatment. The TKI-TDM trial aims to identify a therapeutic plasma concentration range for six TKIs (axitinib, cabozantinib, pazopanib, sorafenib, sunitinib, tivozanib) in mRCC patients. Material and methods: This prospective observational study will enroll mRCC patients with at least 6 months of stable disease or regression on TKI therapy. Blood samples will be collected during routine care. Plasma concentrations of TKIs and metabolites will be measured using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. These levels will be correlated with clinical outcomes including objective response rate, progression-free survival, overall survival, and toxicity. Genetic analysis of UGT1A1 polymorphisms will explore their influence on pazopanib metabolism and response. Interpretation: Identifying plasma TKI levels associated with efficacy and reduced toxicity could minimize under- or overdosing, improving outcomes and quality of life. TDM may allow dose adjustments early in therapy, improving therapeutic management and reducing healthcare costs. Findings may also inform treatment of other cancers using TKIs or TKI-immunotherapy combinations. The trial (clinicaltrials.gov NCT04659343) is expected to conclude in 2028, with results in 2029.

4532 Background: Therapies for mRCC have evolved significantly, making treatment decisions more complex. We used machine learning (ML) to identify whether this could help identify subgroups of patients who have a high probability of response. Methods: Patients from IMDC were identified and a ML classification and regression tree analysis was conducted, in which we grew a complex tree up to a depth of 30 with a minimum node split size of 2 with no constraints on the cost-complexity parameter. The resulting tree was pruned according to the cost-complexity parameter that minimized the leave one out cross-validated error rate and had a minimum bucket size of 25 patients. Results: 2,549 patients were included, 73.2% male, 13.5% non-clear cell histology, 70.3% nephrectomy, and 19.4%, 54.2%, and 26.4% had favorable, intermediate and poor IMDC risk respectively. 1L treatment regimens consisted of VEGF inhibitors (51.5%), IO-IO combinations (32.3%), and IO-TKI combinations (16.2%). The ORR was 36.0% overall, with 29.6% for VEGF inhibitors, 39.1% for IO-IO, and 50.2% for IO-TKI combinations. ML identified 5 hierarchal variables —therapy type, prior nephrectomy (PN), lung metastasis (LM), other metastases, and age— that divided patients into 7 different categories with different response probabilities (see Table). VEGF therapy showed the poorest response, with no additional variables able to predict response. The best ORR was observed in patients treated with IO-TKI and PN; and in those treated with IO-IO, PN, and only lung metastasis. Factors associated with poorer responses included non-clear cell histology, older age, bone and liver metastases, poor performance status, elevated neutrophils, and poor IMDC risk score. Conclusions: This large-scale ML analysis identified five key clinical variables that predict treatment response in mRCC, with treatment type emerging as the primary determinant. These results suggest that treatment selection for mRCC could potentially be optimized by considering these hierarchical variables, though further validation is needed. ML analysis results: Groups of patients and associated outcomes. Risk Groups N (%) ORR (%) Odd Ratio TTNT 18-month survival 1) VEGF 1313 (51.5) 29.6 Ref. 9.4 (8.6-10.3) 0.62 (0.59-0.65) 2) IO-IO or IO-TKI and no PN 443 (17.4) 35.0 1.28 (1.02-1.60) 10.2 (8.8-11.3) 0.59 (0.55-0.65) 3) IO-IO and PN a) No LM 137 (5.4) 29.2 0.98 (0.66-1.43) 17.2 (10.6-30.1) 0.85 (0.78-0.92) b) LM and other met 267 (10.5) 43.8 1.87 (1.42-2.44) 13.0 (10.1-20.5) 0.78 (0.72-0.83) c) Only LM 85 (3.3) 60.0 3.56 (2.28-5.63) 39.2 (14.4-NA) 0.93 (0.87-0.99) 4)IO-TKI and PN a) Age 70+ 78 (3.2) 43.6 1.84 (1.15-2.91) 35.7 (19.8-NA) 0.80 (0.71-0.91) b) Age < 70 226 (8.9) 58.4 3.34 (2.50-4.47) 24.7 (22.4-36.4) 0.88 (0.84-0.93) Overall 2549 36.0 11.5 (10.7-12.2) 0.68 (0.67-0.70)

BACKGROUND:Clinical prediction models are increasingly used to guide treatment in patients with early breast cancer. The Danish Breast Cancer Group (DBCG) has developed a prognostic standard mortality rate index (PSI) for prediction of excess mortality based on 5 years of endocrine therapy. In this study, we aimed to evaluate the clinical utility of the PSI. METHODS:In this nationwide, prospective cohort study, we included postmenopausal Danish women aged 50 years or older with invasive oestrogen receptor-positive and HER2-negative resected breast cancer registered in the DBCG clinical database (close to all Danish women newly diagnosed with invasive breast cancer are registered in the national database). All participants were assigned a PSI category. Patients in the PSI 1 category were recommended 5 years of endocrine therapy; patients in PSI 2, 3, or 4 category were recommended endocrine therapy plus adjuvant chemotherapy according to Danish national guidelines. The primary endpoint was standard mortality ratio. Univariable and multivariable analyses for standard mortality ratio, overall survival, and recurrence-free survival were performed applying Kaplan-Meier, cumulative incidence, Poisson regression, and Fine-Gray subdistribution hazards model. FINDINGS:25 027 women diagnosed with breast cancer between Aug 1, 2013, and Dec 31, 2018, and registered with the DBCG clinical database were identified. 8921 of those registered were eligible, assigned a PSI category (6704 [75%] PSI 1, 1300 [15%] PSI 2, 745 [8%] PSI 3, and 172 [2%] PSI 4), and included in the study. 8514 [96%] of 8830 women initiated endocrine therapy and 91 had an unknown therapy status. Adherence at 4·5 years was 67·8% (66·6-69·0) in the PSI 1 group and 72·3% (70·5-74·3) in the PSI 2-4 groups. Crude standard mortality ratio was 0·89 (95% CI 0·85-0·95) with PSI 1, 1·71 (95% CI 1·47-1·97) with PSI 2, and 2·39 (95% CI 1·99-2·88) with PSI 3-4. Compared with patients who completed adjuvant therapy with PSI 1, relative risk (RR) for excess mortality was 1·33 (95% CI 1·01-1·76) for patients with PSI 2 whereas patients with PSI 3-4 retained an excess mortality (RR 2·31, 95% CI 1·74-3·05) even with completed therapy. INTERPRETATION:These data validate the clinical use of the PSI tool for risk adapted treatment allocation. In patients with PSI 1, the omission of chemotherapy was not associated with excess mortality overall and a distinct better outcome was seen in patients with completed endocrine therapy versus those who had not completed. With completed adjuvant therapy, excess mortality was low for patients with PSI 2, whereas patients with PSI 3-4 had high excess mortality, potentially warranting intensified treatment and requiring further investigation. FUNDING:None.

600 Background: The outcomes of patients with brain metastases from renal cell carcinoma (RCC) are not well characterized due to exclusion of these patients from clinical trials. Methods: Using the IMDC, patients with brain metastases from RCC at the initiation of first-line therapy were analyzed. Baseline patient characteristics, brain-directed local therapies, clinician assessment of best overall response as per RECIST 1.1, and overall survival (OS) were compared across first-line therapies, namely immuno-oncology (IO)-based combination therapy (IO/IO or IO/vascular endothelial growth factor (VEGF)) and anti-VEGF monotherapy (sunitinib or pazopanib). Results: The overall cohort of patients with brain metastases included 775 patients, consisting of 78/1298 (6.0%) and 697/8633 (8.1%) in the IO-based and anti-VEGF cohorts, respectively (p = 0.009). Among the baseline patient characteristics, only the proportion of patients receiving whole-brain radiotherapy differed significantly across the IO-based and anti-VEGF cohorts with proportions of 25.0% and 55.7%, respectively (p < 0.001). Best overall response in all disease sites was 3.4% complete response (CR), 25.9% partial response (PR), 39.7% stable disease (SD), and 31% progressive disease (PD) in the IO-based cohort, whereas it was 0.7% CR, 29.6% PR, 36.7% SD, and 33.0% PD in the anti-VEGF cohort (p = 0.223). The following factors were significantly associated with longer OS on multivariable analysis: IMDC favourable-/intermediate-risk (HR 0.49, 95% CI 0.37–0.65; p < 0.001), IO-based combination therapy (HR 0.51, 95% CI 0.29–0.92; p = 0.026), neurosurgery (HR 0.62, 95% CI 0.47–0.83; p = 0.001), and stereotactic radiosurgery (HR 0.64, 95% CI 0.49–0.84; p = 0.001). Conclusions: Patients with brain metastases receiving IO-based combination therapy may have longer OS than those receiving anti-VEGF monotherapy. Brain-directed local therapies including neurosurgery and stereotactic radiosurgery were associated with longer OS. [Table: see text]

The mannose receptor (MR/CD206) is a marker of M2-like tumor-associated macrophages. Membrane CD206 can be shed, releasing the receptor as a soluble protein (sCD206), which can be measured in serum. Here, we investigated the biomarker potential of sCD206 in patients with metastatic renal cell carcinoma (mRCC). Serum sCD206 was measured by an enzyme-linked immunosorbent assay in 88 mRCC patients and 20 healthy controls (HCs). At diagnosis, serum sCD206 was elevated in patients with intermediate-risk mRCC according to the Memorial Sloan Kettering Cancer Center (MSKCC) risk score, compared to both HCs and patients with favorable MSKCC risk score. Furthermore, sCD206 levels correlated with both sCD163 and C-reactive protein. Soluble CD206 levels decreased after treatment initiation (p < .0001 at 5 weeks) but with a tendency toward elevated levels at time of progression, compared to baseline (p = .06). In univariate survival analysis, high levels of serum sCD206 at baseline was a significant risk factor associated with reduced overall survival (hazard ratio [HR] = 1.37, 95% confidence interval: 1.12-1.67, p = .002). Stratified by clinical risk scores, increased sCD206 was still a statistically significant risk factor of overall mortality (p < .01) in the intermediate-risk group by both the MSKCC (HR = 1.48) and the newer International Metastatic RCC Database Consortium (IMDC) score (HR = 1.53). Furthermore, addition of sCD206 as a dichotomized variable to the IMDC risk score enabled separation of the intermediate-risk group into two groups with survival comparable to those with favorable and poor risk, respectively. Overall, sCD206 is a potential add-on biomarker for mRCC patients in the intermediate-risk group of the current clinical risk scores.

BACKGROUND:Nivolumab plus ipilimumab (NIVO+IPI) has demonstrated superior overall survival (OS) and durable response benefits versus sunitinib (SUN) with long-term follow-up in patients with advanced renal cell carcinoma (aRCC). We report updated analyses with 8 years of median follow-up from CheckMate 214. PATIENTS AND METHODS:Patients with aRCC (N = 1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W × four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN (50 mg) once daily for 4 weeks on, 2 weeks off. The endpoints included OS, independent radiology review committee (IRRC)-assessed progression-free survival (PFS), and IRRC-assessed objective response rate (ORR) in intermediate/poor-risk (I/P; primary), intent-to-treat (ITT; secondary), and favorable-risk (FAV; exploratory) patients. RESULTS:With 8 years (99.1 months) of median follow-up, the hazard ratio [HR; 95% confidence interval (CI)] for OS with NIVO+IPI versus SUN was 0.72 (0.62-0.83) in ITT patients, 0.69 (0.59-0.81) in I/P patients, and 0.82 (0.60-1.13) in FAV patients. PFS probabilities at 90 months were 22.8% versus 10.8% (ITT), 25.4% versus 8.5% (I/P), and 12.7% versus 17.0% (FAV), respectively. ORR with NIVO+IPI versus SUN was 39.5% versus 33.0% (ITT), 42.4% versus 27.5% (I/P), and 29.6% versus 51.6% (FAV). Rates of complete response were higher with NIVO+IPI versus SUN in all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups (ITT, 12.0% versus 3.5%; I/P, 11.8% versus 2.6%; FAV, 12.8% versus 6.5%). The median duration of response (95% CI) with NIVO+IPI versus SUN was 76.2 versus 25.1 months [59.1 months-not estimable (NE) versus 19.8-33.2 months] in ITT patients, 82.8 versus 19.8 months (54.1 months-NE versus 16.4-26.4 months) in I/P patients, and 61.5 versus 33.2 months (27.8 months-NE versus 24.8-51.4 months) in FAV patients. The incidence of treatment-related adverse events was consistent with previous reports. Exploratory post hoc analyses are reported for FAV patients, those receiving subsequent therapy based on their response status, clinical subpopulations, and adverse events over time. CONCLUSIONS:Superior survival, durable response benefits, and a manageable safety profile were maintained with NIVO+IPI versus SUN at 8 years, the longest phase III follow-up for a first-line checkpoint inhibitor combination therapy in aRCC.

Background: Genetic variants of UGT1A1, involved in glucuronidation and clearance of bilirubin, are associated with reduced bilirubin metabolization and drug-induced isolated hyperbilirubinemia. We studied the impact of the UGT1A1*28 polymorphism on drug-induced isolated hyperbilirubinemia in metastatic renal cell carcinoma patients treated with pazopanib, cabozantinib, and axitinib. Methods: We genotyped the UGT1A1*28 TA6/TA6-TA6/TA7-TA7/TA7 polymorphism and correlated with median baseline, on-treatment and peak bilirubin levels during therapy, incidence of grade-1- or -2 (G1/2)-hyperbilirubinemia and time-to-G1-hyperbilirubinemia. Results: Of the 66 patients treated with pazopanib, 29 received axitinib and 28 cabozantinib upon progression. Median baseline bilirubin was higher in TA7/TA7-carriers versus TA6/TA6+TA6/TA7-carriers at start of pazopanib (P < .0001), cabozantinib (P < .0001), and axitinib (P = .007). During pazopanib therapy, median bilirubin increased 1.4-fold in TA7/TA7+TA6/TA7-carriers but not in TA6/TA6-carriers. On cabozantinib, bilirubin increased 1.5-fold in TA7/TA7-carriers but not in TA6/TA6+TA6/TA7-carriers. Axitinib did not increase bilirubin in any genotype. Peak bilirubin in TA7/TA7- versus TA6/TA6+TA6/TA7-carriers was higher on pazopanib (P < .0001) or cabozantinib (P < .0001). With pazopanib, G1-hyperbilirubinemia occurred in 57% of TA7/TA7- and 12% of TA6/TA6+TA6/TA7-carriers (P = .0009) and G2-hyperbilirubinemia in 36% and 6% of the patients, respectively (P = .004). On cabozantinib, G1-hyperbilirubinemia occurred in 100% of TA7/TA7- and 5% of TA6/TA6+TA6/TA7-carriers (P < .0001) and G2-hyperbilirubinemia in 33% and 0% of the patients, respectively (P = .04). On axitinib, no correlation between the genotypes and G1/2-hyperbilirubinemia was observed. Conclusion: We validate the previously described impact of the UGT1A1*28 polymorphism on isolated bilirubin increase on pazopanib. We report for the first time that cabozantinib also interferes with UGT1A1 and causes isolated bilirubin increase.

Background Primary tumor removal by cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma patients has been investigated in the context of various treatment regimens. Two randomized controlled trials investigated the role and timing of cytoreductive nephrectomy in the era of targeted therapy and demonstrated that upfront nephrectomy should no longer be performed when patients require systemic therapy. Superiority of checkpoint immunotherapy agents has led to a paradigm change from targeted therapies to immunotherapy-based first-line treatment in patients with primary metastatic disease; thus, deferred cytoreductive nephrectomy needs to be verified in the immunotherapy setting. Furthermore, a need exists for personalizing treatment choices for the individual patient to avoid unnecessary overtreatment. Methods/design To explore the impact of cytoreductive nephrectomy in this patient group receiving checkpoint immunotherapy, we initiated a randomized, controlled trial comparing deferred cytoreductive nephrectomy with no surgery. The trial integrates a comprehensive translational research program with specimen sampling for biomarker analysis. Discussion The trial aims to show that deferred cytoreductive nephrectomy improves overall survival in patients with synchronous metastatic renal cell carcinoma, and furthermore, to identify relevant biomarkers for personalized renal cancer management. Trial registration ClinicalTrials.gov NCT03977571 June 6, 2019.