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Melanomas frequently harbour somatic mutations in BRAF (40%) or NRAS (20%). Impact of NRAS mutations on the therapeutic outcome of immune checkpoint inhibitors (ICI) remains controversial. Potential correlation of the NRAS mutational status and programmed cell death ligand-1 (PD-L1) expression in melanoma is unknown. Advanced, non-resectable melanoma patients with known NRAS mutation status treated with first-line ICI between 06/2014 and 05/2020 in the prospective multicenter skin cancer registry ADOREG were included. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to NRAS status were analysed. A multivariate Cox model was used to analyse factors associated with PFS and OS; survival was analysed using the Kaplan–Meier approach. Among 637 BRAF wild-type patients, 310 (49%) had an NRAS mutation with Q61R (41%) and Q61K (32%). NRAS -mutated (NRAS mut) melanomas were significantly more often located on the lower extremities and trunk (p = 0.001); nodular melanoma was the most common subtype (p < 0.0001). No significant differences were found for PFS and OS for anti-PD1 monotherapy (2-year PFS 39%, [95% confidence interval (CI), 33–47] in NRAS mut patients and 41% [95% CI, 35–48] in NRAS -wild type (NRAS wt) patients; 2-year OS was 54% [95% CI, 48–61] in NRAS mut patients and 57% [95% CI, 50–64] in NRAS wt patients) and anti-PD1 plus anti-CTLA4 therapy between both cohorts (2-year PFS was 54% [95% CI, 44–66] in NRAS mut patients and 53% [95% CI, 41–67] in NRAS wt patients; 2-year OS was 58% [95% CI, 49–70] in NRAS mut patients and 62% [95% CI, 51–75] in NRA Swt patients). The ORR to anti-PD1 was 35% for NRAS wt patients and 26% for NRAS mut patients and 34% compared to 32% for combinational therapy. Data on PD-L1 expression was available in 82 patients (13%). PD-L1 expression (> 5%) was not correlated to NRAS mutational status. In multivariate analysis, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group performance status ≥ 1, and brain metastases were significantly associated with a higher risk of death in all patients. The PFS and OS were not affected by NRAS mutational status in patients treated with anti-PD1-based ICI. Similar ORR was seen in NRAS wt and NRAS mut patients. Tumour PD-L1 expression did not correlate with NRAS mutational status. • PFS and OS were not affected by NRAS mutational status in patients treated with anti-PD1-based ICI. • Similar response rates to anti-PD1-based ICI were seen for NRAS mut and NRAS wt patients. • There was no correlation between NRAS mutation status and programmed cell death ligand-1 expression. [ABSTRACT FROM AUTHOR]

Anti-PD-(L)1 immunotherapies improve survival in multiple cancers but remain ineffective for most patients. We applied machine-learning algorithms and multivariate analyses on baseline medical data to estimate their relative impact on overall survival (OS) upon anti-PD-(L)1 monotherapies. This prognostic/predictive study retrospectively analysed 33 baseline routine medical variables derived from computed tomography (CT) images, clinical and biological meta-data. 695 patients with a diagnosis of advanced cancer were treated in prospective clinical trials in a single tertiary cancer centre in 3 cohorts including systemic anti-PD-(L)1 (251, 235 patients) versus other systemic therapies (209 patients). A random forest model combined variables to identify the combination (signature) which best estimated OS in patients treated with immunotherapy. The performance for estimating OS [95%CI] was measured using Kaplan–Meier Analysis and Log–Rank test. Elevated serum lactate dehydrogenase (LDHhi) and presence of liver metastases (LM+) were dominant and independent predictors of short OS in independent cohorts of melanoma and non-melanoma solid tumours. Overall, LDHhiLM+ patients treated with anti-PD-(L)1 monotherapy had a poorer outcome (median OS: 3.1[2.4–7.8] months]) compared to LDHlowLM-patients (median OS: 15.3[8.9-NA] months; P < 0.0001). The OS of LDHlowLM-patients treated with immunotherapy was 28.8[17.9-NA] months (vs 13.1[10.8–18.5], P = 0.02) in the overall population and 30.3[19.93-NA] months (vs 14.1[8.69-NA], P = 0.0013) in patients with melanoma. LDHhiLM+ status identifies patients who shall not benefit from anti-PD-(L)1 monotherapy. It could be used in clinical trials to stratify patients and eventually address this specific medical need. • A baseline machine learning-derived signature predicted survival on immunotherapy. • LDHhi (elevated serum LDH) and LM+ (liver metastasis) forecasted short survival. • LDHlow LM-forecasted longer survival with immunotherapy than other systemic therapies. • LDH LM status could guide clinical decision making for advanced cancer patients. [ABSTRACT FROM AUTHOR]

The aim of this multi-center, retrospective/prospective cohort observational study was to evaluate outcomes in routine clinical practice of first-line chemo-immunotherapy with cis/carboplatin, pemetrexed and pembrolizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) in 33 Italian centers. The outcome measure was to evaluate overall survival (OS) in a real-world patient population. Secondary endpoints were: progression-free survival (PFS), objective response rate (ORR), duration of response (DoR) and incidence of treatment-related adverse events (AEs). 1068 patients were enrolled at the time of data cut-off (January 31st, 2023), and 812 (76.0%) belonged to the retrospective cohort. Median age was 66 years (27−85), ECOG PS was ≥ 2 in 91 (8.6%) patients; 254 (23.8%) patients had brain metastases at baseline; 38 (3.6%) patients had tumor with PD-L1 expression ≥ 50%. After a median follow-up of 17.0 months (95% CI, 16.1–17.9), median OS was 16.1 months (95% CI, 14.4–18.8) and PFS was 9.9 months (95% CI, 8.8–11.2). Median DoR (n = 493) was 14.7 months (95% CI, 13.6–17.1). ORR was 43.4% (95% CI, 40.4–46.4). Any-grade AEs occurred in 636 (59.6%) patients and grade ≥ 3 in 253 (23.7%) patients. Most common grade ≥ 3 AEs were neutropenia (6.3%) and anemia (6.3%). First-line chemo-immunotherapy was effective and tolerable in this large, real-world Italian study of patients with advanced non-squamous NSCLC. Our results were in line with the KEYNOTE-189 registration study, also considering the low number of PD-L1 ≥ 50% patients included in our study. [Display omitted] • Chemo-immunotherapy is the standard front-line treatment for advanced non-squamous NSCLC. • Real-world data about platinum, pemetrexed and pembrolizumab regimen are needed. • We conducted a retrospective-prospective real-world study in 33 Italian Centers. • KEYNOTE-189 regimen was effective and safe in daily clinical practice. [ABSTRACT FROM AUTHOR]

Metastatic melanoma (MM) is commonly treated with a combination of nivolumab and ipilimumab, regardless of tumor PD-L1 expression. We conducted a population-based study including all patients with MM (except ocular melanoma) treated in Denmark with first-line combination therapy or anti-PD-1 monotherapy since January 2017. Baseline data including known prognostic characteristics were used in multivariable and propensity-matched score (PMS) analyses to assess progression-free survival (PFS), melanoma-specific survival (MSS), and overall survival (OS) according to PD-L1 expression. We identified 1341 eligible patients, with known PD-L1 status for 1081 patients (43% PD-L1 ≥ 1%, 57% PD-L1 < 1%). PD-L1 ≥ 1% was an independent positive prognostic biomarker for survival in the overall cohort (MSS: HR 0.66, CI 0.52–0.83, p < 0.001). In the PMS PD-L1 ≥ 1% cohort, combination therapy showed similar clinical outcomes to monotherapy (PFS: HR 1.41, CI 0.94–2.11, p = 0.101; MSS: HR 1.21, CI 0.70–2.11, p = 0.49; OS: HR 1.17, CI 0.68–2.00, p = 0.567). In contrast, in the PMS PD-L1 < 1% and in the PMS PD-L1 < 1% BRAF WT cohorts, combination therapy improved PFS (respectively with HR 0.70, CI 0.53–0.93, p = 0.013; and HR 0.54, CI 0.37–0.78, p = 0.001), but did not reach statistically significant improvements of MSS (HR 0.72, CI 0.50–1.02, p = 0.065; and HR 0.79, CI 0.51–1.21, p = 0.278) or OS (HR 0.78, CI 0.56–1.08, p = 0.135; and HR 0.81, CI 0.54–1.21, p = 0.305) compared to monotherapy. Our findings support previous exploratory analyses of Checkmate-067, highlighting that improved clinical outcomes with combination therapy are not established in unselected patients with high (≥1%) tumor PD-L1 expression. • PD-L1 ≥ 1% is an independent positive prognostic biomarker in metastatic melanoma • PD-L1 ≥ 1% did not derive additional benefit from anti-CTLA-4 over anti-PD-1 alone • Combination therapy demonstrated improved PFS only in patients with PD-L1 < 1% [ABSTRACT FROM AUTHOR]

Platinum-based combination chemotherapy is the standard treatment for patients with chemotherapy-eligible metastatic urothelial carcinoma (mUC). Immune-checkpoint inhibitors (ICIs) are currently assessed in this setting. This review aimed to assess the role of ICIs alone or in combination as first-line treatment in chemotherapy-eligible patients with mUC. Multiple databases were searched for articles published until November 2020. Studies were deemed eligible if they compared overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), complete response rates (CRRs), durations of response (DORs) and adverse events (AEs) in chemotherapy-eligible patients with mUC. Three studies met our eligibility criteria. ICI combination therapy was associated with significantly better OS and PFS, higher CRR and longer DOR than chemotherapy alone (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.76–0.94, P = 0.002; HR: 0.80, 95% CI: 0.71–0.90, P = 0.0002; odds ratio [OR]: 1.48, 95% CI: 1.12–1.96, P = 0.006; and mean difference: 1.39, 95% CI: 0.31–2.46, P = 0.01, respectively). ICI-chemotherapy combination therapy was also associated with significantly better OS and PFS, higher ORR and CRR and longer DOR than chemotherapy alone. Although OS and PFS benefits of ICI combination therapy were larger in patients with high expression of programmed death-ligand 1 (PD-L1), PD-L1 low expression patients also had a benefit; HR for OS (high PD-L1: HR 0.79 versus low PD-L1: HR 0.89) and PFS (high PD-L1: HR 0.74 versus low PD-L1: HR 0.82). ICI monotherapy was not associated with better oncological outcomes but was associated with better safety outcomes than chemotherapy alone. Our analysis indicates a superior oncologic benefit to first-line ICI combination therapies in patients with chemotherapy-eligible mUC over standard chemotherapy. In contrast, ICI monotherapy was associated with favorable safety outcomes compared with chemotherapy but failed to show its superiority over chemotherapy in oncological benefits. PD-L1 status alone cannot help guide treatment decision-making. However, caution should be exercised in interpreting the conclusions drawn from this study, given that there is the heterogeneity of the population of interest, risk of bias and the nature of the studies evaluated whose data remain immature or unpublished. • ICIs are currently assessed for patients with chemotherapy-eligible mUC. • ICIs used in combination are superior to chemotherapy in oncological benefits. • ICI monotherapy efficacy is not superior to that of chemotherapy alone. • PD-L1 alone is not a sufficiently robust, reliable and reproducible biomarker. • The analyses include the heterogeneity of the population and risk of bias. [ABSTRACT FROM AUTHOR]