Introduction Une comparaison indirecte entre NIVO+RELA et NIVO+IPI, 2 options thérapeutiques avec une association d’immunothérapies approuvées pour les patients atteints d’un mélanome avancé, a été précédemment menée à l’aide des données individuelles des patients des essais cliniques pivots RELATIVITY-047 (RELA-047; NIVO+RELA vs NIVO) et CheckMate 067 (CM-067; NIVO+IPI ou NIVO vs IPI). Nous présentons ici les résultats obtenus à partir des données actualisées à 3 ans de l’essai RELA-047. Matériel et méthodes La pondération de la probabilité inverse de traitement a été utilisée pour ajuster les déséquilibres entre les caractéristiques initiales des patients des 2 essais. Les gels des bases de données ont été sélectionnés pour aligner au mieux la durée du suivi dans RELA-047 (médiane de 34 mois) et CM-067 (médiane de 38 mois). La survie sans progression (PFS) selon l’investigateur, les taux de réponse objective (ORR) confirmée selon l’investigateur, la survie globale (OS), la survie spécifique au mélanome (MSS), les effets indésirables liés au traitement (TRAE) et les TRAE entraînant l’arrêt du traitement ont été analysés. La PFS, l’OS et l’ORR ont été évalués dans les sous-groupes clés. La PFS, l’OS et la MSS ont été comparées à l’aide des courbes de Kaplan-Meier et des Hazard Ratios (HR); les ORR ont été comparés à l’aide des odds ratios (OR). Le bras NIVO pondéré de chaque essai a été comparé pour une validation de la méthodologie. Résultats Après pondération, les caractéristiques initiales clés étaient équilibrées entre NIVO+RELA (n=339) et NIVO+IPI (n=297). Les résultats d’efficacité après pondération étaient similaires entre NIVO+RELA et NIVO+IPI, ainsi qu’entre les bras NIVO. Des résultats similaires entre les bras NIVO valident la méthodologie utilisée. Dans l’ensemble des sous-groupes, l’efficacité semblait similaire entre les traitements, bien que des tendances favorables à NIVO+IPI aient été observées pour l’ORR chez les patients atteints d’une maladie BRAF mutée ou avec un taux de LDH>2×LSN. Les TRAE étaient moins fréquents avec NIVO+RELA (23 %) par rapport à NIVO+IPI (61%); les TRAE tous grades entraînant l’arrêt du traitement sont survenus chez 17 % et 41 % des patients, respectivement. Discussion Conformément aux résultats précédents, ces données de comparaison de traitement actualisées suggèrent que le traitement de 1L avec NIVO+RELA pourrait avoir une efficacité comparable à celle de NIVO+IPI, tout en présentant une toxicité moindre, chez les patients atteints d’un mélanome avancé. Les résultats doivent être interprétés avec prudence en raison des différences dans la conception des études et des évolutions du paysage thérapeutique. Des recherches sont en cours pour déterminer quels patients répondent le mieux à chaque association. Conclusion Conformément aux résultats précédents, ces données de comparaison de traitement actualisées suggèrent que le traitement de 1L avec NIVO+RELA pourrait avoir une efficacité comparable à celle de NIVO+IPI, tout en présentant une toxicité moindre, chez les patients atteints d’un mélanome avancé.

Advances in the first-line treatment of metastatic melanoma raised the need for earlier assessment of clinical trials using intermediate endpoints that may reach statistical maturity sooner than overall survival (OS) without being influenced by subsequent treatments. We evaluated progression-free survival (PFS), time-to-next-treatment-or-death (TNTD) and objective response rate (ORR) as potential surrogate endpoints (SEs) for OS within the phase II/III RELATIVITY-047 trial (n=714) using patient-level data with ≥21 months of follow-up. Individual-level (IL) correlations with OS were derived from copula functions and measured by Spearman’s (ρ) and Kendall’s (τ) rank correlation coefficients for PFS and TNTD, and by an odds ratio (OR) for ORR. Patients were clustered in 8 non-overlapping regions according to their country of enrolment for trial-level (TL) surrogacy assessment. Within each region treatment effects on PFS, TNTD and OS were calculated by Cox-proportional-hazards models. TL correlations between the SEs and OS were estimated by weighted linear regression and measured by coefficient of determination (R2). Sensitivity of the results were tested with respect to alternative geographic clustering. At the IL, ORR and TNTD were strongly correlated with OS, whereas PFS showed moderate correlation with OS. At the TL, PFS and ORR showed moderate correlation with OS with wide uncertainty whereas TNTD had strong correlation with OS with narrower margin of uncertainty. Alternative geographic clustering of patients had marginal impact on the IL (≤ 0.02 change in all measures for all SEs) and modest impact on TL correlations (≤ 0.08 change in R2 for all SEs).Table: 1102PCorrelationILTLρ [95% CI]τ [95% CI]R2 [95% CI]PFS - OS0.70 [0.68, 0.72]0.51 [0.45, 0.58]0.71 [0.35, 1.00]TNTD - OS0.84 [0.81, 0.86]0.66 [0.63, 0.69]0.95 [0.87, 1.00]ORR - OSOR10.60 [6.77-14.43]0.64 [0.21, 1.00] Open table in a new tab Within the RELATIVITY-047 trial, TNTD-OS surrogacy was stronger and more stable than PFS-OS and ORR-OS surrogacy. The strength of each surrogacy relationship analyzed in this study and their relative order were consistent with those previously reported from other immune-checkpoint inhibitor studies.

Survival heterogeneity poses challenges for assessing long-term clinical and economic value of immune checkpoint inhibitors. This study aimed to visualize unobservable heterogeneity in survival among 1L I/P-risk aRCC patients treated with NIVO+IPI in the Checkmate 214 trial using PMMs.

This analysis aimed to explore survival heterogeneity and estimate proportion of potential long-term survivors (LTS) among previously untreated, I/P risk aRCC patients who received immune-checkpoint inhibitors (ICIs) NIVO+IPI in the CheckMate 214 trial by applying mixture cure models (MCMs).

CM 025 demonstrated superior overall survival (OS), and improved safety and tolerability for NIVO in the treatment of previously treated aRCC pts compared with EVE based on 14-months (mos) minimum follow-up. Here, we report results with extended minimum follow-up of 87.7 mos, clinical characteristics of pts with ≥ 7 yrs of OS, and long-term OS and progression-free survival (PFS) predictions based on these data. Pre-treated pts with predominantly clear cell aRCC were randomised (1:1) to NIVO 3 mg/kg IV every two weeks or EVE 10 mg orally once daily until progression or unacceptable toxicity. The primary endpoint was OS; secondary endpoints included objective response (ORR), PFS (investigator-assessed using RECIST v1.1), and safety. Additional post-hoc analyses were conducted in pts with OS ≥ 7 yrs. Long-term PFS and OS were predicted by extrapolating observed trial data over a 15-yr horizon and beyond. With ≥ 7 yrs of follow-up, OS benefit for NIVO (n = 410) vs EVE (n = 411) was maintained (7-yr OS: 18% vs 11%; HR 0.74; 95% CI: 0.63-0.86) and PFS favored NIVO vs EVE (7-yr PFS: 4% vs 0%; HR 0.84; 95% CI: 0.72–0.99). Additional post-hoc analyses in pts with OS ≥ 7 yrs indicated similar baseline characteristics (age, gender, and race) as all-comers. Distributions of favorable, intermediate, and poor risk (per MSKCC criteria) were 50.0%, 39.7%, and 10.3% and 71.4%, 25.7%, and 2.9% for NIVO (n = 58) and EVE (n = 35), respectively. In pts with OS ≥ 7 yrs, NIVO was associated with higher ORR (48% vs 20%), and longer median duration of response (41.9 vs 24.0 mos) and median PFS (15.5 vs 9.5 mos) than EVE. Long-term predictions estimated higher survival rates at 15 yrs in the NIVO arm when compared with the EVE arm. NIVO continues to demonstrate significant survival benefit vs EVE at ≥ 7 yrs follow-up, which is expected to be sustained over a pts lifetime. Analyses of pts with OS ≥ 7 yrs in the trial further highlight the likelihood of better treatment response and greater lifetime survival benefits observed with NIVO vs EVE.

FP NMA models estimate comparative effectiveness of time to event outcomes accounting for time-varying hazards. However, as many power and order combinations can be fitted to the data, the optimal model choice is not straightforward. We developed an algorithm that improves model selection based on predictive accuracy and clinical plausibility, in a case study in first-line advanced renal cell carcinoma (1L aRCC). Forty-four candidate FP models were considered. Convergent models were ordered with respect to deviation information criteria (DIC). Next, face validity of time varying hazard ratios was assessed to determine any exclusion of first-or-second order models, based on a set of prespecified criteria. Model fit was assessed by comparing the predictive accuracy of median survival, landmark survival at 24 months, and restricted mean survival time with observed trial data. Clinical plausibility of long-term survival extrapolations and hazard functions were examined to complete the selection process of viable models, among which the model with the lowest DIC was chosen. The algorithm was applied in the FP NMA of randomized controlled trials evaluating progression-free survival (PFS) and overall survival (OS) in 1L aRCC. Indicated by the lowest DIC only, the second-order model (P1=-2, P2=-2) for PFS and the first-order model (P1=-2) for OS led to clinically implausible survival extrapolations. For PFS, 6 models were considered viable, although all these models performed imperfectly against available trial data. For OS, second-order models overfitted the relatively immature trial data, generating implausible hazard patterns and were therefore excluded altogether; 3 models were considered viable. The first-order model (P1=-1) was selected as most plausible for PFS and OS. While DIC remains an effective measure for assessing fit to observed data, FP models with low DICs may be clinically implausible. Applying this decision algorithm improved the predictive accuracy of model estimates, aligning with clinical expectations.

Nivolumab (NIVO) showed improved HRQoL versus everolimus in the phase 3, randomized CheckMate 025 trial of patients (pts) with previously treated mRCC. However, HRQoL data from RW settings are limited. Here, we report HRQoL outcomes for pts receiving NIVO for previously treated mRCC in 2 European RW studies. As a part of the IO-Synthesise RCC initiative, data for adult pts with mRCC who received second- (2L) or third-line (3L) NIVO monotherapy were pooled from the French WITNESS (NCT03455452) and German NORA (NCT02940639) prospective, noninterventional studies. HRQoL measures included the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19) and EQ-5D-3L utility index (UI) and visual analog scale (VAS). All pts with a baseline HRQoL assessment were included. Data from 306 pts (France, N = 105; Germany, N = 201) were pooled. Median age was 70 years, 74.5% were male. In pts with available data, 75.5% had a Karnofsky performance score (KPS) > 70%. NIVO was given as 2L in 83.3%. Baseline characteristics were mostly consistent between French and German pts; a higher proportion of French pts with available data had a KPS ≤ 70% (37.6% vs 16.9%) and a lower proportion had prior nephrectomy (65.7% vs 86.4%). Completion rates for all individual measures/subscales were > 70% at week 6 and ∼47% at month 18. Results are summarized in the table; no significant HRQoL decrements were observed and a numerical trend for improved FKSI-19 total and disease-related symptoms (DRS) subscale scores was seen at most timepoints.Table: 1460PMean change from baseline (95% CI)Week 6Month 3Month 6Month 9Month 12Month 18FSKI-19n = 221n = 192n = 128n = 99n = 84n = 47Total0.53 (–0.76, 1.82)–0.25 (–1.83, 1.33)0.68 (–1.40, 2.77)1.62 (–0.42, 3.65)2.71a (0.38, 5.04)1.28 (–1.39, 3.95)DRS0.43 (–0.24, 1.11)–0.26 (–1.09, 0.56)–0.01 (–1.10, 1.08)0.38 (–0.65, 1.40)1.58a (0.40, 2.76)1.05 (–0.46, 2.56)EQ-5D-3LUIn = 208 0.0 (–0.03, 0.04)n = 184 –0.02 (–0.06, 0.02)n = 125 –0.05 (–0.10, 0.01)n = 94 –0.04 (–0.10, 0.01)n = 80 –0.02 (–0.09,0.06)n = 44 –0.02 (–0.11, 0.06)VASn = 192 –0.01 (–2.91, 2.89)n = 170 1.25 (–1.82, 4.32)n = 118 1.44 (–2.85, 5.73)n = 91 1.56 (–3.17, 6.28)n = 75 –3.24 (–9.31, 2.82)n = 43 –6.09 (–13.09, 0.91)aP < 0.05 vs baseline. Open table in a new tab aP < 0.05 vs baseline. Despite the challenge of suboptimal HRQoL completion rates in RW settings, pooled HRQoL data from these pts with mRCC receiving 2L or 3L NIVO in France and Germany appear to complement results from CheckMate 025 and suggest pts with previously treated mRCC maintain HRQoL after receiving NIVO.

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).

Long-term (minimum 60-month) follow-up from the CheckMate 214 study showed high OR rate (42%) and durable response benefits with a yet to be reached median duration of response (DoR) for I/P risk aRCC patients treated with N+I. This led to sustained survival plateaus implying the possibility of long-term survivors (LTS), which can be estimated via mixture cure models (MCMs). MCMs were applied to model OS and DoR separately for I/P risk patients achieving OR with N+I in the trial. In both analyses, LTS were only subject to risk of non-disease-related (NDR) mortality (who also remained in response until death in DoR analysis), whereas non-LTS were subject to extra disease-related risk for their OS/DoR which were modeled via parametric distributions. Age- and gender-specific NDR mortality rates were obtained from the UK Office of National Statistics. Patient-level data from the trial were used to simultaneously estimate the fraction of LTS and OS/DoR for non-LTS through maximum likelihood methods. Candidate models were evaluated based on statistical fit criteria and their visual fits to the observed response and hazard trends in the trial. Auxiliary analyses explored the association of estimated fraction of LTS with age, gender, risk group, Karnofsky performance status and prior nephrectomy/radiotherapy using progression-free survival data of the entire I/P risk patients treated with N+I. Estimated proportion of LTS among the responders was 72.8% [95% CI: 63.3%-80.5%] from the best-fitting model (log-normal) to the OS data and 58.9% [95% CI: 48.8%-68.4%] from the best-fitting model (log-normal) to the DoR data. Ranges of estimated proportion of LTS were narrow across all candidate models: 72.8%-74.3% in OS analysis and 58.4%-61.0% in DoR analysis. No statistically significant association was observed between estimated proportions of LTS and the covariates. OR to N+I is associated with higher estimated likelihood of long-term survivorship. Robustness of the results with respect to model choice indicate that MCMs can adequately capture the long-term trend and the underlying heterogeneity in the survival of the responders.

In clinical trials, crossover from assigned control treatments onto other experimental treatments or alternatives often creates difficulties in estimating the underlying comparative efficacy and CE of experimental treatments. We examined the impact of adjusting crossover from everolimus to nivolumab in the third- or later-line treatment in the phase III CheckMate 025 trial on the estimated relative efficacy and CE of nivolumab in pre-treated patients with aRCC.

Nivolumab+ipilimumab continues to show persistent, significant overall survival (OS) benefit versus sunitinib in 1L aRCC patients with I/P risk for more than five years, as demonstrated in CheckMate 214 (NCT02231749). This study assessed the stability of lifetime OS predictions for both treatment arms using trial data with a minimum of up to 5 years of follow-up. OS hazard ratios (HRs) were calculated for nivolumab+ipilimumab versus sunitinib with minimum 18, 24, 37, 42, and 60 months of follow-up. Parametric models, including traditional distributions and cubic splines were used to fit observed OS data. Extrapolations were corrected with background mortality, while model performance was evaluated based on the NICE DSU guidance 14 and 21. Stability of lifetime OS predictions was assessed by comparing extrapolation functional forms, and survival (mean and landmark rates) across all DBLs. Across all DBLs, OS HRs were stable and the proportional hazards assumption was upheld, granting dependent modelling as the best option. The log-normal distribution consistently provided the best fit in both dependent and independent models, whereas the exponential and gamma distributions were the worst two fits. Log-normal fits to earlier DBLs slightly underestimated observed OS rates in later DBLs. Respectively, predicted 5-year OS rates using the 18-month DBL were 39.9% and 29.7% for nivolumab+ipilimumab and sunitinib, increasing to 41.9% and 31.6% using the 60-month DBL, and were conservative versus landmark trial OS. Mean lifetime OS estimations for nivolumab+ipilimumab and sunitinib increased by 0.56 and 0.45 life years using the 60-month versus the 18-month DBL. Despite underestimations versus observed data from the 60-month DBL, the log-normal distribution remains the most appropriate functional form for both nivolumab+ipilimumab and sunitinib in all DBLs. Subsequent nivolumab use following sunitinib may explain appropriateness of the log-normal distribution and its ability to capture the hazard profile of the sunitinib arm.

We conducted an SLR of RCTs to evaluate intermediate and long-term efficacy measures, such as disease-free survival (DFS) and overall survival (OS), for adjuvant treatments in localized RCC.

First-line treatment of aRCC has evolved from tyrosine kinase inhibitor (TKI) monotherapy in recent years, following approvals of immuno-oncology (IO) combination therapies. Dual IO combination (nivolumab+ipilimumab [NIVO+IPI]) and IO+TKI therapies (pembrolizumab+axitinib [PEMBRO+AXI] and nivolumab+cabozantinib [NIVO+CABO]) have demonstrated clinical benefit over sunitinib and are now recommended in international treatment guidelines. Pazopanib showed non-inferiority to sunitinib. This study assessed the cost-effectiveness of 1L aRCC treatments for an intention-to-treat population utilized in France from an all-payer perspective. A three-state partitioned survival model (progression-free disease, progressed disease, and death) was developed with a one-week cycle length and a 15-year time horizon. The model used patient characteristics and utilities (EQ-5D-3L) from the CheckMate 9ER trial (NCT03141177). Health state-specific utilities were calculated using the French value set. Multi-dimensional treatment effect network meta-analyses (NMAs) were used to estimate time-varying relative treatment effects on progression-free survival and overall survival relative to the anchor treatment sunitinib. All costs (€; cost year: 2020) were French-specific; costs and effects were discounted by 2.5% annually. Outcomes of interest were total costs, quality-adjusted life-years (QALYs), life-years (LYs), and the incremental cost-utility ratio (ICUR). Univariate deterministic analysis (DSA) assessed robustness of the Results: The cost-efficiency frontier was only comprised of two treatments: pazopanib and NIVO+IPI. The ICUR for NIVO+IPI vs. pazopanib was estimated at €219,344/QALY. NIVO+IPI was associated with the highest LYs (5.69) and QALYs (3.59). NIVO+IPI strictly dominated PEMBRO+AXI (Δ€/ΔQALY: 10,507/-0.428) and NIVO+CABO (Δ€/ΔQALY: 63,792/-0.221), and pazopanib strictly dominated sunitinib (Δ€/ΔQALY 21,333/-0.116). Among parameters tested in the DSA, key ICUR drivers were the estimates from the multi-dimensional treatment effect NMAs. Results were insensitive to modification of the structuring choices. Over a 15-year time horizon, NIVO+IPI resulted in the highest survival and QALY gains among all 1L treatments and resulted in lower costs compared with PEMBRO+AXI or NIVO+CABO.

Programmed death receptor-1 inhibitors (PD-1i) are important agents in the treatment of advanced non-small cell lung cancer (NSCLC). In Greece, PD-1i were reimbursed for advanced NSCLC initially as second-line (2L) monotherapy (August 2016) and, subsequently, as first-line (1L) monotherapy (January 2017). This study assessed the demographic characteristics, treatment patterns and outcomes for patients (pts) with NSCLC in Greece.