Background In CheckMate 214 (median follow-up, 25.2 months), nivolumab plus ipilimumab yielded greater overall survival (OS) benefit than sunitinib in patients with intermediate-/poor-risk advanced renal cell carcinoma (aRCC). Health-related quality of life (HRQoL) assessed by the Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19) was also more favorable for the nivolumab plus ipilimumab group than the sunitinib group. We investigated whether HRQoL scores can predict OS of patients with 5 years follow-up in CheckMate 214. Patients and Methods CheckMate 214 was an open-label, phase III trial in previously untreated aRCC (N = 1096). Patients with intermediate-/poor-risk disease (International mRCC Database Consortium prognostic >= 1; n = 847) were randomized to either nivolumab plus ipilimumab or sunitinib monotherapy. Pooled data for OS and FKSI-19 total and subscales (disease-related symptoms [DRS], DRS-physical [DRS-P], and function/well-being [FWB]) were analyzed. Relationships between HRQoL and OS were assessed using Cox proportional hazard models with baseline and longitudinal scores. Associations between HRQoL changes and OS were assessed by landmark analyses. Results Patients with higher FKSI-19 total and subscale scores at baseline had longer OS than patients with lower scores (HR <= 0.834; P < .0001). Longitudinal models indicated stronger associations between HRQoL and OS (HR <= 0.69; P < .001 for each). At 3 months after randomization, patients with stable/improved HRQoL versus baseline had longer median OS than patients with worsened/unobserved HRQoL versus baseline (55.9 and 26.0 months, respectively; HR = 0.56; 95% CI, 0.46-0.67; P < .0001). Results at 6-, 9-, and 12-month landmarks were consistent with these findings. Conclusion In aRCC, patient-reported outcomes are important for HRQoL and prognostic evaluation. Clinicaltrials.gov Identifier NCT02231749; https://clinicaltrials.gov/ct2/show/NCT02231749.

Background: In the phase II/III RELATIVITY-047 trial, a novel fixed-dose combination (FDC) of nivolumab plus relatlimab (NIVO + RELA; a programmed death-1 and a lymphocyte-activation gene 3 inhibitor, respectively) significantly improved progres-sion-free survival (PFS) versus NIVO in patients with previously untreated unresectable or metastatic melanoma (median follow-up, 13.2 months) with stable health-related quality of life (HRQoL), although grade three or four treatment-related adverse events (TRAEs) were more frequent with the combination. Updated HRQoL results (median follow-up, 19.3 months) are presented. Methods: Patients were randomised to receive intravenous NIVO + RELA (480 mg and 160 mg, respectively) or NIVO (480 mg) every 4 weeks. HRQoL was assessed using the Functional Assessment of Cancer Treatment-Melanoma (FACT-M) and EQ-5D-3L ques-tionnaires at baseline, before dosing at each treatment cycle, and at follow-up (posttreatment) visits. Results: Consistent with the initial analysis, HRQoL remained stable with NIVO + RELA on treatment and was similar to that with NIVO. Mean changes from baseline did not exceed clinically meaningful thresholds. HRQoL results were consistent across instruments and scales/subscales. Despite an increased rate of grade three or four TRAEs with NIVO + RELA versus NIVO, the proportion of patients reporting that they were bothered 'quite a bit' or 'very much' by TRAEs was low and comparable between treatments. Conclusion: Results from the RELATIVITY-047 trial show that the PFS benefit with NIVO + RELA FDC over NIVO was obtained with stable patient-reported HRQoL, sup-porting NIVO + RELA as a first-line treatment option for patients with advanced melanoma.(c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

4578 Background: Nivolumab in combination with cabozantinib (N+C) has demonstrated significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS), compared with sunitinib as a first-line (1L) treatment for aRCC in the phase 3 CheckMate (CM) 9ER trial. As there are no head-to-head trials comparing N+C with pembrolizumab in combination with axitinib (P+A), this study compared the efficacy of N+C with P+A as 1L treatment in aRCC. Methods: An MAIC was conducted using individual patient data on N+C (N = 323) from the CM 9ER trial (median follow-up: 23.5 months) and published data on P+A (N = 432) from the KEYNOTE (KN)-426 trialof P+A (median follow-up: 30.6 months). Individual patients within the CM 9ER trial population were reweighted to match the key patient characteristics published in KN-426 trial, including age, gender, previous nephrectomy, International Metastatic RCC Database Consortium risk score, and sites of metastasis. After weighting, hazards ratios (HR) of PFS, duration of response (DoR), and OS comparing N+C vs. P+A were estimated using weighted Cox proportional hazards models, and ORR was compared using a weighted Wald test. All comparisons were conducted using the corresponding sunitinib arms as an anchor. Results: After weighting, patient characteristics in the CM 9ER trial were comparable to those in the KN-426 trial. In the weighted population, N+C had a median PFS of 19.3 months (95% CI: 15.2, 22.4) compared to a median PFS of 15.7 months (95% CI: 13.7, 20.6) for P+A. Using sunitinib as an anchor arm, N+C was associated with a 30% reduction in risk of progression or death compared to P+A, (HR: 0.70, 95% CI: 0.53, 0.93; P = 0.015; table). In addition, N+C was associated with numerically, although not statistically, higher improvement in ORR vs sunitinib (difference: 8.4%, 95% CI: -1.7%, 18.4%; P = 0.105) and improved DoR (HR: 0.79; 95% CI: 0.47, 1.31; P = 0.359). Similar OS outcomes were observed for N+C and P+A (HR: 0.99; 95% CI: 0.67, 1.44; P = 0.940). Conclusions: After adjusting for cross-trial differences, N+C had a more favorable efficacy profile compared to P+A, including statistically significant PFS benefits, numerically improved ORR and DoR, and similar OS.[Table: see text]

Mixture cure models (MCMs) explore survival heterogeneity when there is potential for cure by estimating cure rates and the survival function of the uncured. We propose a novel unified network meta-analysis (NMA) framework to simultaneously estimate relative treatment effects on both outcomes of MCMs.

4502 Background: In CM 214, when compared to sunitinib (S), nivolumab plus ipilimumab (N+I) was associated with both clinical benefit and improved HRQoL as first-line treatment for intermediate/poor (I/P)-risk patients (pts). This analysis investigates the direct association between HRQoL and clinical outcomes in aRCC pts. Methods: I/P-risk population included 425 and 422 pts in the N+I and S arms, respectively. HRQoL was assessed using the FKSI-19 (Total Score and Disease Related Symptoms [DRS]). Three separate analyses (A, B, and C) were conducted. A: Changes in individual item scores from baseline to last assessment prior to progression were descriptively assessed. B: For each FKSI-19 score, multivariable Cox regression, adjusted for treatment and stratification factors, was used to evaluate the prognostic significance of baseline and time-dependent HRQoL scores in separate models. Hazard ratios (HR) were calculated based on the risk of death per improvement in HRQoL scores, defined using the clinically meaningful change threshold (5 points for FKSI-19 Total and 3 points for DRS). Pts with overall survival (OS) events were censored if their survival event was not within 12 weeks of the last available HRQoL assessment. C: The association between HRQoL change status (ie, improvement or maintenance vs. worsening from baseline in the FKSI-19 Total Score), irrespective of treatment arm, and OS was further assessed using a landmark analysis at the month 6 (mo-6) landmark. Additional landmark time points were explored in sensitivity analysis. Results: Items related to fatigue and perceived bother of the side-effects of treatment had the largest percentage of pts worsening prior to progression. In both baseline and time-dependent HRQoL analyses, OS was independently associated with both HRQoL measures. Higher (better) baseline scores were associated with significantly reduced risk of death (HR [95% CI] for FKSI-19 Total Score and DRS was 0.83 [0.80-0.87] and 0.80 [0.76-0.84], respectively). Every 5-point increase (improvement) in FKSI-19 Total Score and 3-point increase in DRS was associated with a 31% decreased risk of death ( P < 0.01). At mo-6, 301 pts showed improvement or maintenance in HRQoL. Pts with improved/stable HRQoL had a 52% reduction in risk of death compared to pts who had worsened (HR 0.48 [95% CI: 0.39-0.59]). Conclusions: Results demonstrate there is an association between HRQoL and clinical outcomes in CM 214. Baseline HRQoL scores are a potential predictor for survival in aRCC, and HRQoL changes are informative for pts’ expected survival. HRQoL change status at mo-6 was significantly and positively associated with subsequent survival. Thus, patient-reported outcomes may be useful for both describing pt experience in clinical trials and providing valuable clinical insights during routine practice. Clinical trial information: NCT02231749.

307 Background: Nivolumab + ipilimumab (N+I) demonstrated durable, long-term survival in the phase 3 CheckMate 214 trial as first-line treatment for intermediate/poor (I/P)-risk patients (pts) with aRCC. After a minimum follow-up of 5 years, N+I maintained superior overall survival and response benefits vs sunitinib (S) in both I/P-risk pts and across all randomized pts. We report the HRQoL results from the 5-year follow-up. Methods: Pts were randomized 1:1 to receive N 3 mg/kg + I 1 mg/kg every 3 weeks (wks) for 4 cycles followed by N 3 mg/kg every 2 wks or S 50 mg/d orally for 4 wks (6-wk cycle). HRQoL was assessed using the FKSI-19, FACT-G, and EQ-5D-3L instruments at baseline (BL) and on day 1 of wks 1 and 4 of the first 2 cycles, on day 1 of wks 1 and 5 of the next 2 cycles, and on day 1 of wk 1 of subsequent cycles. The analyses included mixed-model repeated measures (MMRM) for change from BL across 59 months (while on-treatment) and time to confirmed deterioration (TCD). Bother with treatment side effects (item GP5 in FKSI-19) was assessed using a generalized estimating equations model with response dichotomized as minimal bother (“not at all” or “a little bit”) vs notable bother (“somewhat”, “quite a bit”, and “very much”). Results: 1096 pts were randomized to N+I (I/P-risk: 425; favorable [F]-risk: 125) and S (I/P-risk: 422; F-risk: 124). In the overall and I/P-risk populations, N+I pts reported improved mean FKSI-19 total scores over time compared with a decline observed with S. Overall changes from BL through 59 months favored N+I over S with significant differences between arms observed for all outcomes (Table). Median TCD was significantly longer with N+I vs S for all FKSI-19 scores, as well as FACT-G total and physical domains for both populations ( P < 0.05). Pts in the N+I arm were 76% (odds ratio [95% CI]: 0.24 [0.16–0.35]) and 73% (0.27 [0.18–0.40]) less likely to be notably bothered by side effects than pts in the S arm in the total and I/P-risk populations, respectively. Conclusions: Pts reported HRQoL benefits with N+I vs S. Treatment with N+I showed a decreased risk of being bothered by treatment side effects and of experiencing clinically meaningful deterioration in HRQoL in contrast with S. These results suggest that the superior efficacy of N+I over S comes with the additional benefit of improved long-term HRQoL. Clinical trial information: NCT02231749. [Table: see text]

323 Background: In CheckMate 9ER, patients (pts) with aRCC were randomized 1:1 to nivolumab 240 mg IV Q2W + cabozantinib 40 mg PO QD (N+C; n = 323) or sunitinib (S) 50 mg PO (4 weeks of 6-week cycles; n = 328). As reported previously, at a median follow-up of 18.1 months, N+C led to superior progression-free and overall survival and more favorable HRQoL than S. We report results of HRQoL analyses for 32.9-months follow-up. Methods: Disease-related symptoms (DRS) were evaluated using the FKSI-19 instrument and HRQoL with the EQ-5D-3L visual analogue scale (VAS). Change from baseline (BL) was assessed using mixed-model repeated measures (MMRM), adjusting for baseline scores and stratification factors, and included all common timepoints (at BL and every 6 wks) through week 151. Time to deterioration analysis was conducted for first (TFD), confirmed (TCD) and definitive (TDD) deterioration events using Kaplan-Meier estimates and Cox proportional hazards models. Bother with treatment side effects (item GP5 in FKSI-19) was assessed using a generalized estimating equations model with response dichotomized as minimal bother (“not at all” or “a little bit”) vs notable bother (“somewhat”, “quite a bit”, and “very much”). HRQoL endpoints were exploratory and P-values are nominal and descriptive. Results: Group mean scores over time show that HRQoL was maintained or improved from BL with N+C while reductions were observed with S. Overall changes from BL though week 151 favored N+C with nominal significant differences between treatments observed for all scores except functional well-being (FWB; Table). Similarly, decreased risk of deterioration was observed with N+C vs S for all scores except FWB, irrespective of the deterioration definition used (TFD, TCD, TDD). Pts in N+C arm were 48% (odds ratio: 0.52 [95% CI, 0.35-0.77]) less likely to be notably bothered by side effects than pts in S arm. Conclusions: Pts continued to report improved HRQoL with N+C compared to S. Treatment with N+C reduced the risk of meaningful deterioration in HRQoL scores, regardless of the definition of deterioration and showed a decreased risk of being bothered by treatment side effects in contrast to S. These results suggest that the superior efficacy of N+C over S with the additional benefit of improved HRQoL is maintained with longer follow-up. Clinical trial information: NCT03141177. [Table: see text]

BackgroundIn the CheckMate 9ER trial, patients with advanced renal cell carcinoma who received first-line nivolumab plus cabozantinib had significantly better progression-free survival compared with those given sunitinib. In this study, we aimed to describe the patient-reported outcome (PRO) results from CheckMate 9ER.MethodsIn this open-label, randomised, phase 3 trial done in 125 cancer centres, urology centres, and hospitals across 18 countries, patients aged 18 years or older with previously untreated advanced renal cell carcinoma with a clear-cell component, a Karnofsky performance status of 70% or more, and available tumour tissue were randomly assigned (1:1) via interactive response technology to nivolumab 240 mg intravenously every 2 weeks plus oral cabozantinib 40 mg per day, or oral sunitinib 50 mg per day monotherapy for 4 weeks in 6-week cycles. The primary endpoint of progression-free survival was reported previously. PROs were analysed as prespecified exploratory endpoints at common timepoints (at baseline and every 6 weeks) until week 115. Disease-related symptoms were evaluated using the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and global health status was assessed with the three-level EQ-5D (EQ-5D-3L) visual analogue scale (VAS) and UK utility index. PRO analyses were done in the intention-to-treat population. Change from baseline was assessed using mixed-model repeated measures. A time-to-deterioration analysis was done for first and confirmed deterioration events. This study is registered with ClinicalTrials.gov, NCT03141177, and is closed to recruitment.FindingsBetween Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to nivolumab plus cabozantinib and 328 to sunitinib. Median follow-up was 23·5 months (IQR 21·0–26·5). At baseline, patients in both groups reported low symptom burden (FKSI-19 disease-related symptoms version 1 mean scores at baseline were 30·24 [SD 5·19] for the nivolumab plus cabozantinib group and 30·06 [5·03] for the sunitinib group). Change from baseline in PRO scores indicated that nivolumab plus cabozantinib was associated with more favourable outcomes versus sunitinib (treatment difference 2·38 [95% CI 1·20–3·56], nominal p<0·0001, effect size 0·33 [95% CI 0·17–0·50] for FKSI-19 total score; 1·33 [0·84–1·83], nominal p<0·0001, 0·45 [0·28–0·61] for FKSI-19 disease-related symptoms version 1; 3·48 [1·58–5·39], nominal p=0·0004, 0·30 [0·14–0·47] for EQ-5D-3L VAS; and 0·04 [0·01–0·07], nominal p=0·0036, 0·25 [0·08–0·41] for EQ-5D-3L UK utility index), reaching significance at most timepoints. Nivolumab plus cabozantinib was associated with decreased risk of clinically meaningful deterioration for FKSI-19 total score compared with sunitinib (first deterioration event hazard ratio 0·70 [95% CI 0·56–0·86], nominal p=0·0007; confirmed deterioration event 0·63 [0·50–0·80], nominal p=0·0001).InterpretationPROs were maintained or improved with nivolumab plus cabozantinib versus sunitinib. Compared with sunitinib, nivolumab plus cabozantinib significantly delayed time to deterioration of patient-reported outcome scores. These results suggest a benefit for nivolumab plus cabozantinib compared with sunitinib in the treatment of patients with advanced renal cell carcinoma.FundingBristol Myers Squibb.

ICIs transformed the treatment of advanced melanoma with substantial improvements in OS. Establishing valid SEs for OS enables earlier assessment of randomized controlled trials (RCTs) of ICIs due to lengthy follow-up required to observe mature OS data. We examined progression-free survival (PFS), time-to-next treatment (TNT) and objective response rate (ORR) as potential SEs for OS in 1L advanced melanoma by pooling patient-level data from 4 RCTs (CheckMate [CM] 066, 067, 069 & 511) of nivolumab, ipilimumab, and their combinations. Individual-level (IL)-correlation measures - Spearman's (ρ) & Kendall's (τ) rank correlation coefficients for PFS and TNT, and an odds ratio (OR) for survival due to presence of objective response - were derived from copula models. For the trial-level (TL)-correlation, surrogacy equations and coefficients of determination (R2) between the treatment effects on SEs and OS were estimated via regression. Primary analyses used all patients (n=1865) from all RCTs. Sensitivity of the results were tested with respect to BRAF-status and removal of CM 069 due to imbalances in subsequent systemic therapy and ICI use between the arms of this study. At the IL, ORR was strongly correlated with OS, whereas both PFS & TNT showed moderate correlation with OS. All SEs were moderately correlated with OS at the TL (Table). Removing CM 069 from the analyses only marginally affected IL-correlations (≤ 0.01 change in ρ and τ, 4.5% change in the OR) but greatly strengthened TL-correlations for all SEs (R2 ≥ 0.87 with significantly narrower 95% CIs for all SEs). IL-correlations were insensitive to BRAF status, whereas TL-correlations were slightly stronger for the BRAF wild-type.Table: 816PCorrelationρ [95% CI]τ [95% CI]R2 [95% CI]PFS - OS0.72 [0.71, 0.73]0.53 [0.49, 0.57]0.71 [0.23, 1.00]TNT - OS0.77 [0.76, 0.78]0.58 [0.55, 0.62]0.75 [0.32, 1.00]ORR - OSOR12.29 [9.78-14.80]0.62 [0, 1.00] Open table in a new tab With moderate-to-strong correlation to OS on both levels, all candidate SEs can assist predictions for OS benefits of ICIs with a range of uncertainty depending on BRAF-status and subsequent treatment patterns.

In the CM 9ER trial, nivolumab plus cabozantinib (N+C) was associated with both increased survival and improved HRQoL in 1L aRCC patients (pts) at 23.5 months follow-up when compared to sunitinib (S). We investigated the association between HRQoL and overall survival (OS) and progression-free survival (PFS).

Overall survival (OS) is essential in cost-effectiveness analyses; however, it may not be available from the initial database-locks (DBLs) of a randomized trial. This research compared predicted long-term mean OS gains between the arms of the phase 3 RELATIVITY-047 study (nivolumab [NIVO]+relatlimab [RELA] versus NIVO) obtained from extrapolated OS using reported trial data and from three approaches indirectly modeling OS from progression free survival (PFS).

Objective The aim of this study was to evaluate the cost-utility of nivolumab plus ipilimumab (NIVO + IPI) versus other first-line therapies for advanced melanoma in the United States (US) from the third-party payer perspective. Methods This analysis estimated total expected life-years (LYs), quality-adjusted LYs (QALYs), and costs for first-line treatments of advanced melanoma during a 30-year time horizon using indirect treatment comparisons based on time-varying hazard ratios (HRs) and a three-state partitioned survival model. Overall survival (OS) and progression-free survival reference curves were extrapolated based on 5-year follow-up from the phase III Checkmate 067 trial (NCT01844505). Comparators of NIVO + IPI were NIVO, IPI, pembrolizumab, dabrafenib plus trametinib, encorafenib plus binimetinib (ENCO + BINI), and vemurafenib plus cobimetinib. Drug acquisition costs, treatment administration costs, follow-up time, subsequent therapy data, and adverse event frequencies were obtained from published sources. Utility weights were estimated from Checkmate 067, which compared NIVO + IPI or NIVO monotherapy with IPI monotherapy as first-line therapy in advanced melanoma. A 3% annual discount rate was applied to costs and outcomes. Sensitivity scenarios for BRAF-mutant subgroups were conducted. Results NIVO + IPI was estimated to generate the longest OS and the highest total costs versus all comparators, accruing 6.99 LYs, 5.70 QALYs, and $469,469 over the 30-year time horizon. The incremental cost utility of NIVO + IPI versus comparators ranged from $2130 per QALY (versus ENCO + BINI) to $76,169 per QALY (versus NIVO). In all base-case and most sensitivity analyses, the incremental cost-utility ratios for NIVO + IPI were below $100,000 per QALY. Conclusions NIVO + IPI is estimated to be a life-extending and cost-effective treatment versus other therapies in the US, with base-case incremental cost-utility ratios below $100,000 per QALY.

Background: Anti-PD-1-based therapies prolong survival in advanced melanoma, but disease progression is common. This study evaluated treatment patterns and overall survival (OS) after anti-PD-1 progression. Methods: Retrospective data from patients with advanced melanoma and progression on anti-PD-1 treatment between 2014 and 2019 were taken from Flatiron Health, which reflects largely community practice. Treatment patterns and OS were analyzed for BRAF mutant (mt) and wild-type (wt) subgroups; OS was also examined across all patients. Results: Progression following anti-PD-1 was recorded for 679 patients. Median OS ranged from 5.0 to 11.3 months. Of 275 BRAFmt and 374 BRAFwt patients, 113 (41.1%) and 228 (61.0%) received no subsequent therapy, respectively. However, 48.4% of BRAFmt and 57.8% of BRAFwt patients continued anti-PD-1 treatment beyond progression. Conclusion: This real-world study underscores the need for effective treatments for advanced melanoma post-progression on anti-PD-1 therapy.

To review existing correlation analyses evaluating candidate surrogate endpoints (SEs) for OS in advanced melanoma. A TLR was conducted in Embase and Medline to identify meta-analyses (MAs) reporting on SEs for OS published prior to October 2020. Study design, patient/clinical characteristics, study treatments, and correlations between SEs and OS were evaluated for evidence synthesis and comparison. All seven MAs identified prior randomised clinical trials in advanced melanoma. Treatments included any immunotherapy (n=5), any systemic therapy vs dacarbazine (n=1), and immunotherapy or targeted therapy (n=1). Of four MAs reporting exclusively on unresectable disease, two reported correlation measures between the treatment effects on PFS and OS weighted for sample size and treatment effect precision (random or fixed effects modelling); Pearson’s correlation measure varied from 0.71-0.89 in one MA and coefficients of determination (R2) ranged from 0.72-0.82 in the other, depending on weighting. In both MAs, sensitivity analyses improved the correlation estimates; namely these were analyses limiting trials to phase III, trials with larger sample sizes, or removing or reducing trials allowing crossover. This TLR captured three MAs that included mixed populations (e.g., NSCLC) along with advanced melanoma; these showed more equivocal associations between PFS and OS. However, subanalyses to include only the advanced melanoma trials in one MA resulted in better correlation estimates between the treatment effects on PFS and OS as compared with the overall group (R2 0.61 vs 0.37). Beyond PFS, other candidate SEs included 1- and 2-year OS rates (n=2), and disease control rate and objective response rate (both n=2). The review suggests PFS is a promising SE for OS in advanced melanoma. Additionally, the correlation estimates between PFS and OS improved with increased study sample size, restricting the evidence base to only phase III studies, or to studies with minimal or no crossover.

To evaluate PFS as a surrogate endpoint for OS by modelling association between the treatment effects on each endpoint using RCTs investigating first-line (1L) therapies for advanced melanoma. A systematic literature review was conducted to identify trials reporting OS and PFS in 1L advanced melanoma evaluating any pharmacological interventions. The surrogacy relationship was assessed using bivariate random-effects meta-analysis and weighted linear regression. Validity and predictive accuracy of the estimated surrogacy equations were assessed via leave-one-out cross-validation (LOOCV). The primary analysis was conducted using all trials meeting the proportional hazards assumption (n=23) with crossover-adjusted hazard ratios (HRs) where available. Sensitivity analyses were also conducted by restricting the evidence base to: (1) phase II and III immune checkpoint inhibitor trials (n=5), (2) phase III trials (n=17), (3) trials with no crossover permitted or trials that provided adjusted crossover estimates (n=7), and (4) trials in the previous analysis set plus trials with unreported crossover descriptions (n=19). Of 23 trials identified from the SLR and eligible for the primary analysis (9,737 patients), the estimated correlation coefficient was 0.72 (95% confidence interval [CI]: 0.50-0.85). Correlation estimates in the sensitivity analyses ranged from 0.71 to 0.88, with sensitivity analyses (2) and (3) reporting relatively stronger point estimates for correlations: 0.88 (95% CI: 0.71-0.95) and 0.87 (95% CI: 0.45-0.98), respectively. In LOOCV, alignment between observed and predicted OS HRs was ≥90% for the primary analysis and sensitivity analysis (2), and >95% in sensitivity analyses (1), (3), and (4). Results suggest a moderate correlation between PFS and OS across all analyses. Given the clinical effects of subsequent treatments, the restriction of the evidence base to trials adjusting for crossover may be important in the 1L cohort, as supported by the improved correlation in the sensitivity analyses.

Aims: We assessed the suitability of real-world data (RWD) as an external control for analysis of overall survival (OS) compared with clinical trial data (CTD) in advanced melanoma. Methods: OS among adults receiving ipilimumab for advanced melanoma was compared between trials (CTD group) and the Flatiron Health database (RWD group) using Cox models. Adjusted analyses accounted for differences in baseline factors; missing data were addressed through multiple imputation. Results: After adjusting for baseline factors and accounting for missingness, OS was similar in the CTD (n = 241) versus RWD groups (n = 816; hazard ratio: 0.98; 95% CI: 0.75-1.26). Conclusion: Flatiron Health data is suitable to construct external control groups for OS in advanced melanoma trials after adjusting for baseline factors and missing data.

BACKGROUND:Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation.METHODS:In this phase 2-3, global, double-blind, randomized trial, we evaluated relatlimab and nivolumab as a fixed-dose combination as compared with nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary end point was progression-free survival as assessed by blinded independent central review.RESULTS:The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P = 0.006 by the log-rank test). Progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group.CONCLUSIONS:The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals. (Funded by Bristol Myers Squibb; RELATIVITY-047 ClinicalTrials.gov number, NCT03470922.).

286 Background: RCC accounts for ~80%‒90% of all kidney cancers worldwide. The mRCC treatment landscape is rapidly changing with the approval of new therapies; data describing real-world (RW) treatment patterns and sequencing are limited. This study investigates the characteristics, treatment patterns, and sequencing for mRCC patients in the RW (December 2015‒May 2020) and post-dual immuno-oncology therapy (IO-IO) approval in the United States (April 2018‒May 2020). Methods: Adults diagnosed with mRCC between December 2015 and May 2020 were selected from the Flatiron electronic medical record database for this retrospective study. The study cohort was required to have ≥ 1 month of medical data from the initial mRCC diagnosis date (index date). We used descriptive statistics to analyze baseline patient characteristics, treatment patterns, and sequencing. Results: Of 3,524 patients with mRCC (overall cohort, December 2015–May 2020), most were male (68.5%) and had clear cell histology (68.2%). The median age at metastatic diagnosis was 68 years (range, 23–85) and the median follow-up from index date was 328 days. Based on IMDC risk score, 75.8% of patients were categorized as intermediate/poor risk and 23.2% as favorable risk (1% missing). Systemic therapy for RCC was initiated in 79.1% (N = 2788) of patients. The most common treatments for first-line (1L) therapy were tyrosine kinase inhibitor (TKI) monotherapy (mono; 56.4%), IO-IO (19.1%), IO-TKI (9.5%), IO mono (6.9%), and others (8.1%). Second-line (2L) therapy was received by 1303 patients; treatment sequences are presented in the table below. Among patients who received IO-based therapy in the 1L (N = 990), 11% were retreated with IO on any subsequent line. When stratified by clear cell and non-clear cell histology, similar treatment patterns and sequences were observed. Among patients who initiated 1L treatment post-April 2018 (N = 1395), the most common treatments for 1L therapy were IO-IO (36.9%) and TKI mono (32.7%). Among patients who received 2L treatment after initiating 1L post-April 2018 (N = 486), TKI mono followed by IO mono, and IO-IO followed by TKI mono were the most prescribed sequences (Table). Conclusions: Following approval of IO-based therapies for 1L, RW treatment patterns for mRCC are evolving; IO-IO has become the most common 1L therapy received by all patients initiating treatment for mRCC. [Table: see text]

285 Background: In the phase III, open-label CheckMate 9ER trial (NCT03141177), patients with aRCC were randomized 1:1 (stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk score, tumor programmed death ligand 1 expression, geographic region) to nivolumab 240 mg IV Q2W + cabozantinib 40 mg PO QD (N+C; n = 323) or sunitinib (S) 50 mg PO (4 weeks of 6-week cycles; n = 328) for first-line treatment until disease progression or unacceptable toxicity (max N treatment, 2 years). N+C met primary and secondary efficacy endpoints by significantly improving progression-free survival, overall survival, and objective response rate versus S in aRCC patients with a clear cell component. Here, we present in-depth health-related quality of life (HRQoL) patient-reported outcome (PRO) results, including overall between-group comparisons of treatment groups and time to confirmed deterioration (TCD). Methods: PROs in all randomized patients were an exploratory endpoint assessed using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19) and EQ-5D-3L instruments. PRO assessments at baseline, common on-treatment scheduled visits, and common follow-up visits for both arms were analyzed. Changes from baseline were assessed using mixed-model repeated measures (MMRM), adjusting for baseline scores and stratification factors. TCD was calculated from Kaplan–Meier estimates and Cox proportional hazards models. Results: Median follow-up for overall survival was 18.1 months. PRO completion rates were > 90% at baseline, and ≥ 80% at all on-treatment assessments (≥ 10 patients) through week 91 in both arms. The overall least squares mean difference in change from baseline favored N+C over S in FKSI-19 (all domains) and in EQ-5D-3L. Patients treated with N+C experienced less treatment burden, with decreased risk of confirmed deterioration across most measurements versus S, including FKSI-19 total, disease-related symptoms (DRS), DRS-physical (DRS-P), DRS-emotional (DRS-E), functional well-being (FWB), and EQ-5D-3L visual analog scale (VAS) scores (Table). Conclusions: Patients reported statistically significant HRQoL benefits with N+C versus S. Treatment with N+C significantly reduced the risk of deterioration in HRQoL scores, including in disease-related symptoms of kidney cancer. These results suggest that the superior efficacy of N+C over S comes with the additional benefit of improved HRQoL. Clinical trial information: NCT03141177 . [Table: see text]