Factors associated with efficacy of FOLFIRI/aflibercept in patients with metastatic colon cancer

Objective: to compare the efficacy and toxicity of aflibercept and bevacizumab in combination with fOLfIRI in secondline therapy for patients with metastatic colon cancer.Materials and methods. we performed a retrospective analysis of data on patients with metastatic colon cancer treated in 9 clinics in the Russian federation. The inclusion criteria were as follows: metastatic or locally advanced colon cancer; treatment with bevacizumab or aflibercept plus fOLfIRI in the second-line therapy. The primary outcome measure was progression-free survival (PfS). Secondary outcome measures included objective response rate and incidence of adverse events.Results. A total of 271 patients with metastatic colon cancer who received second-line therapy with bevacizumab (n = 81) or aflibercept (n = 190) between 2014 and 2018 were selected for this study. Study groups were matched for main prognostic signs. The objective response rate was 18.1 % in the bevacizumab group and 20.5 % in the aflibercept group (p = 0.7). The median PfS was 5 months (95 % confidence interval 3.8–6.1) in the aflibercept group and 7 months (95 % confidence interval 0.81–2.1) in the bevacizumab group (hazard ratio 1.4; 95 % confidence interval 0.99–2.1; p = 0.04). multivariate regression analysis demonstrated that the type of the targeted drug independently had no effect on PfS (hazard ratio 1.3; 95 % confidence interval 0.9–1.9; p = 0.2). we observed no statistically significant differences in the incidence of complications of any grades between the groups (58 % vs 72 %, p = 0.1). Patients receiving aflibercept were more likely to develop grade III–Iv arterial hypertension (2 % vs 9.5 %) and diarrhea (0 % vs 5.4 %), whereas thrombotic complications were more common in the bevacizumab group (10 % vs 1.8 %).Conclusion. we observed no significant differences in objective response rate and PfS between patients with metastatic colon cancer receiving bevacizumab or aflibercept in combination with fOLfIRI as second-line therapy. The toxicity profiles were different. Our findings can be used for choosing an optimal targeted drug for second-line treatment.

Bevacizumab (BV) plus chemotherapy is broadly used in advanced ovarian cancer (OC). However, the efficacy of BV-based regimens for advanced OC patients is not satisfactory. Therefore, it is urgent to explore the predictive genetic biomarkers for BV.Tumor tissues from advanced OC patients receiving BV-based regimens were analyzed with a 150-gene targeted panel for next generation sequencing. The associations between gene alterations or clinicopathology features and progression-free survival (PFS) were analyzed by Kaplan–Meier curves or Cox regression. The association of the genetic alteration in potential predictive genes and expressions of 11 vascular endothelial growth factor-related genes were analyzed in The Cancer Genome Atlas cohort using 292 OC cases.Sixty two Chinese advanced OC patients treated with BV-based therapy were included. The median PFS of was 6.9 months, and objective response rate was 14.5%. In multivariate Cox regression analysis, the status of endothelial growth factor receptor (EGFR) (hazard ratio = 6.39, 95% confidence interval [CI] 2.25–18.13, P < .001) and human epidermal growth factor receptor 2 (HER2) (hazard ratio = 3.58, 95% CI 1.27–10.08, P = .016) were significantly correlated with PFS. MYC Proto-Oncogene amplification seemed to have a positive trend (hazard ratio = 0.21, 95% CI 0.05–1.02, P = .052). Moreover, EGFR and HER2 alterations were not prognostic factors of overall survival for OC in The Cancer Genome Atlas OC cohort. The vascular endothelial growth factor-related signature analysis indicated vascular endothelial factor A expression was upregulated with EGFR alterations (P = .034) which may be involved in BV resistance, and HER2 alterations were associated with hypoxia inducible factor 1 subunit alpha overexpression significantly (P = .029).EGFR or HER2 alterations are negative predictors of PFS for OC patient treated with BV plus chemotherapy. Therefore, the clinicians may consider to use alternative regimens such as anti-EGFR or anti-HER2 targeted therapy instead of BV-based regimens on these patients when standard care fail.

Real-world assessment of response to anti-programmed cell death 1 therapy in advanced cutaneous squamous cell carcinoma

e20679 Background: Nivolumab (Nivo) is applicable for all metastatic or unresectable non-small cell lung cancer (NSCLC), however only some patients benefit from it. Therefore, identifying biomarkers predicting efficacy is a crucial topic in the “real world’’ setting. We conducted a retrospective study to analyze the impact of metastatic status on the effect of Nivo in NSCLC patients. Methods: This is a retrospective multicenter study conducted by the three medical centers in Japan. All patients treated with Nivo from January 2016 to July 2016 in these centers were retrospectively reviewed. We collected clinical data including age, sex, smoking history, performance status (PS), and metastatic cites (lymph nodes: lym, liver, brain, bone, pleural effusion, and intrapulmonary metastasis: lung) at the time of starting Nivo treatment. We investigated relationship between metastatic sites and progression free survival (PFS) of Nivo. Patients were followed-up until 30th September 2016. Results: Two hundred and one patients treated with Nivo were enrolled. At the time of administration of Nivo, median age was 68 years old, 137 patients were male, 155 patients had history of smoking status, 152 patients were PS 0 or 1, and 46 patients had squamous cell carcinoma (SQ). For all participants, median PFS was 2.5 months. In univariate analysis, female (hazard ratio (HR): 1.43, 95% confidence interval (CI): 1.02-2.00; p = 0.036), never-smoker (HR: 1.51 , 95% CI: 1.05 – 2.17; p = 0. 0262), PS 2 or more (HR: 1.68, 95% CI: 1.17-2.41; p = 0.0045), metastasis to liver (HR: 2.02, 95% CI: 1.30-3.15; p = 0.0015), brain (HR: 1.42, 95% CI: 0.99-2.03; p = 0.0574), bone (HR: 1.42, 95% CI: 1.01-1.98; p = 0.0642), lung (HR: 1.57, 95% CI: 1.13-2.20; p = 0.0076), and malignant pleural effusion (HR: 1.47, 95% CI: 1.06-2.04; p = 0.0195) had significantly correlated with poor PFS. In multivariate analysis, liver metastasis (HR: 1.59, 95% CI: 0.97-2.61; p = 0.0642) and malignant pleural effusion (HR: 1.47, 95%CI: 1.04–2.07; p = 0.0294) had significantly correlated with poor PFS. Conclusions: Liver metastasis and malignant pleural effusion were independent poor prognostic factors of Nivo treatment in NSCLC patients. (UMIN-ID: UMIN000025908)

LBA348 Background: In the phase III AXIS trial, second-line therapy with axitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib for mRCC. We conducted a multicenter, randomized, open-label, phase III trial to compare PFS of axitinib vs sorafenib as first-line therapy. Methods: Patients with untreated, measurable (RECIST v1.0), clear‑cell mRCC and Eastern Cooperative Oncology Group performance status (PS) 0 or 1 were randomized 2:1 to axitinib 5 mg twice daily (BID) or sorafenib 400 mg BID. Randomization was stratified by PS. Primary endpoint was PFS per independent radiology committee. The study had 90% power to detect a 78% PFS improvement from 5.5 mo with sorafenib to 9.8 mo with axitinib, corresponding to a hazard ratio (HR) of 0.561 (overall 1-sided α=0.025). Results: Patients (N=288) were mainly from Eastern Europe (51%), Asia (25%), North America (14%), or South America (10%).Patient baseline characteristics for axitinib (n=192) vs sorafenib (n=96) included: median age, 58y vs 58y; male, 70% vs 77%; white, 71% vs 69%; favorable risk, 49% vs 55%; PS 0, 57% vs 57%; nephrectomy, 85% vs 90%. Median (m) PFS was 10.1 vs 6.5 mo with axitinib vs sorafenib (HR adjusted for PS, 0.767; 95% confidence interval [CI], 0.559–1.053; 1‑sided P=0.0377). In patients with PS 0 and 1, respectively, mPFS with axitinib vs sorafenib was 13.7 vs 6.6 mo (HR, 0.644; 95% CI, 0.419–0.991; 1‑sided P=0.022) and 6.5 vs 6.4 mo (HR, 0.931; 95% CI, 0.585–1.482; 1‑sided P=0.38). Objective response rates (ORRs) with axitinib vs sorafenib were 32.3% vs 14.6% (1‑sided P=0.0006 adjusted for PS). Overall survival data were not mature. All-grade all‑causality adverse events (≥20%) with axitinib vs sorafenib were diarrhea (50% vs 40%), hypertension (49% vs 29%), weight decreased (37% vs 24%), fatigue (33% vs 26%), decreased appetite (29% vs 19%), palmar-plantar erythrodysesthesia (26% vs 39%), dysphonia (23% vs 10%), asthenia (21% vs 16%), and hypothyroidism (21% vs 7%). Conclusions: The study did not achieve its primary endpoint statistically, but axitinib demonstrated numerically longer mPFS and significantly higher ORR vs sorafenib, with an acceptable safety profile, as first-line therapy for mRCC. Clinical trial information: NCT00920816.

Background: Programmed cell death protein 1 (PD-1) inhibitors are approved as second-line (2L) therapy for patients (pts) with ESCC. TMB is a predictive biomarker of response to immune checkpoint blockade in multiple cancers, but its role in ESCC is unclear. Here, we retrospectively investigated the association between TMB and clinical outcomes in the phase 3 RATIONALE-302 study of anti-PD-1 antibody tislelizumab (TIS) vs investigator-chosen chemotherapy (ICC) as 2L treatment for advanced unresectable/metastatic ESCC (NCT03430843). Methods: Genomic profiling was assessed on tumor tissues collected at baseline using BurningRock OncoScreen Plus 520 NGS panel to determine TMB status. Median progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Objective response rate (ORR) was calculated using the binomial exact method. Cox model was applied to assess the effect of TMB on survival outcomes. Hazard ratio (HR) and 95% confidence interval (CI) for OS and PFS in TMB subgroups were estimated. Results: Of 512 pts enrolled, 209 had evaluable tumor samples (TIS, n=105; ICC, n=104). Using the widely used cutoff of 10 mutations per megabase (mut/Mb), numerically higher ORR and survival benefit with TIS over ICC were observed in the high TMB (TMB-H) vs the low TMB (TMB-L) subgroup (Table). The predictive effect of TMB on survival outcomes was not significant (interaction p-value = 0.0537 for PFS, 0.5374 for OS); however, the effect became significant using the increased cutoff of 12 mut/Mb (TMB-H prevalence = 16.7%; interaction p-value = 0.0267 for PFS, 0.0175 for OS). Conclusions: TMB status may play a role in predicting clinical outcomes in pts with advanced ESCC treated with TIS versus ICC, especially when a higher TMB cutoff is chosen. These findings need further prospective validation. Acknowledgments: This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Sophie Cook, PhD, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd. Table. Clinical outcomes by TMB status (cutoff 10 mut/Mb) TMB status TMB-H TMB-L Treatment TIS ICC TIS ICC n (% in TMB BEP, N=209) 27 (12.9) 31 (14.8) 78 (37.3) 73 (34.9) ORR, % (95% CI) 33.3 (16.5, 54.0) 6.5 (0.8, 21.4) 16.7 (9.2, 26.8) 17.8 (9.8, 28.5) Median PFS, months (95% CI) 2.4 (1.4, 5.5) 2.3 (1.3, 2.9) 1.4 (1.3, 2.7) 2.7 (1.5, 3.3) PFS HR (95% CI) 0.52 (0.28, 0.97) 1.06 (0.73, 1.53) Interaction p-value 0.0537 Median OS, months (95% CI) 6.1 (4.2, 18.6) 4.7 (3.4, 7.0) 8.6 (4.6, 11.8) 7.0 (4.6, 8.6) OS HR (95% CI) 0.58 (0.32, 1.04) 0.72 (0.50, 1.03) Interaction p-value 0.5374 TMB-adjusted OS HR (95% CI) 0.68 (0.5, 0.92) BEP, biomarker evaluable population; CI, confidence interval; HR, hazard ratio; ICC, investigator chosen chemotherapy; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; TIS, tislelizumab; TMB-H, high tumor mutational burden; TMB-L, low tumor mutational burden; TMB-adjusted OS HR, overall HR adjusted for the impact of TMB on OS Citation Format: Lin Shen, Yongqian Shu, Kuaile Zhao, Taroh Satoh, Zhendong Chen, Eric Van Cutsem, Guohua Yu, Jun Wu, Chih-Hung Hsu, Sung Bae Kim, Wenting Du, Yang Shi, Ruiqi Huang, Qiao Li, Jingwen Shi, Yun Zhang, Kato Ken. Association of tumor mutational burden (TMB) and clinical outcomes with tislelizumab versus chemotherapy in esophageal cell carcinoma (ESCC) from RATIONALE-302 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT077.

BackgroundSmall-cell lung cancer (SCLC) is a highly aggressive type of lung cancer. Lurbinectedin is recommended as second-/third-line treatment for advanced, previously treated SCLC.Materials and methodsLURBICLIN is a nationwide, non-interventional, retrospective chart review study, based on the cohort of consecutive patients enrolled in the named patient use for lurbinectedin in France.ResultsA total of 312 patients were included. Lurbinectedin was delivered as second-line therapy in 138 (44%) patients. Grade 3-4 treatment-related adverse events were observed in 28 (9%) and 15 (5%) patients, respectively. Objective response rate (ORR) to lurbinectedin was 22% in the intention-to-treat population. After a median follow-up of 20.8 months, median progression-free survival (PFS) was 1.9 months [95% confidence interval (CI) 1.8-2.0 months]. At multivariate analysis, chemotherapy-free interval (CTFI) ≥ 90 days was an independent predictor of higher PFS [hazard ratio (HR) = 0.64, 95% CI 0.50-0.84, P < 0.0001]. The median overall survival (OS) was 4.7 months (95% CI 4.0-5.4 months). At multivariate analysis, performance status < 2 and CTFI ≥ 90 days were independent predictors of higher OS (HR = 0.71, 95% CI 0.53-0.95, P = 0.03; and HR = 0.58, 95% CI 0.44-0.76, P < 0.0001, respectively). Overall, 147 (47%) patients had initiated subsequent systemic treatments.ConclusionsLURBICLIN confirms the activity of lurbinectedin in patients with SCLC with a manageable safety profile. Lurbinectedin monotherapy provides an alternative option for SCLC patients.

Long Term Outcome Patterns and Risk Factors for Early Mortality and Disease Progression in ALK-Positive Anaplastic Large Cell Lymphoma

Treatment of Stage IV(A–B) nasopharyngeal carcinoma by induction-concurrent chemoradiotherapy and accelerated fractionation: Impact of chemotherapy schemes

P2.01-68 High NLR Is Poor Predictive Biomarker for NSCLC Treated with PD-1 Inhibitor in Real World Practice

Background:The evidence base for optimum third-line therapy for metastatic colorectal cancer (mCRC) is not conclusive. Recent studies have demonstrated the efficacy of regorafenib as third-line therapy in mCRC. This indirect meta-analysis compared the efficacy and safety of regorafenib with other available third-line therapies for mCRC.Methods:A literature search for randomized controlled trials (RCTs) was conducted in PubMed, Embase, and Cochrane Library for studies evaluating the efficacy and safety of fruquintinib, regorafenib, TAS-102, and nintedanib as third-line therapies in patients with mCRC. Overall survival (OS) and progression-free survival (PFS) were the primary outcomes, while objective response rate (ORR) and safety were the secondary outcomes. Hazard ratio (HR) and relative risk (RR) with their respective 95% confidence interval (CI) were used for analysis of survival, clinical response, and safety data. An adjusted indirect meta-analysis with placebo as the common comparator was performed.Results:We identified eight RCTs comparing regorafenib (two studies), fruquintinib (two studies), TAS-102 (three studies), and nintedanib (one study) against placebo. The OS with regorafenib was significantly better when compared with nintedanib (HR = 0.66; 95% CI: 0.45, 0.95, p = 0.02) but was similar to that of fruquintinib (HR = 1.01; 95% CI: 0.67, 1.52, p = 0.94) and TAS-102 (HR = 0.97; 95% CI: 0.68, 1.38, p = 0.88). The PFS and ORR for regorafenib were slightly better than those of TAS-102 (PFS: HR = 0.86, 95% CI: 0.54, 1.37, p = 0.5; ORR: RR = 1.13, 95% CI: 0.11, 11.05, p = 0.92) and nintedanib (PFS: HR = 0.68, 95% CI: 0.42, 1.10, p = 0.12; ORR: not reported) but were lower than those for fruquintinib (PFS: HR = 1.53, 95% CI: 0.93, 2.52, p = 0.08; ORR: RR = 0.68269, 95% CI: 0.045, 10.32, p = 0.79). Safety analysis showed that the RR of adverse events (AEs) was lesser in patients treated with regorafenib in comparison with that in patients treated with fruquintinib, but was similar to that in patients treated with nintedanib and TAS-102.Conclusion:Regorafenib has efficacy similar to that of TAS-102 and better safety when compared with fruquintinib. Considering the mechanism of action of regorafenib, which targets multiple factors in the angiogenic pathway, it could be an ideal option for treatment in the beyond second-line setting.

BackgroundPleural mesothelioma (PM) has a poor prognosis, and immune checkpoint inhibitors (ICIs) have reshaped first-line therapy. However, real-world data comparing first-line immunotherapy with chemotherapy ± targeted therapy and defining optimal second-line strategies in Chinese patients remain limited. This multicenter retrospective real-world study aimed to compare survival outcomes between first-line immunotherapy and chemotherapy-based regimens and to evaluate the effectiveness of different subsequent systemic therapies in patients with PM.MethodsThis multicenter retrospective real-world cohort included patients with pathologically confirmed PM who received at least one line of systemic therapy at tertiary hospitals in China between January 2015 and January 2025. Patients were grouped by first-line regimen (immunotherapy vs. chemotherapy ± targeted therapy). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Generalized propensity scores with overlap weighting (OW) were used to balance baseline covariates, followed by weighted Kaplan-Meier and Cox regression analyses. For post-first-line analyses, chemo-start and immuno-start cohorts were used to compare OS across second-line chemotherapy, chemo-immunotherapy, and dual immunotherapy. Hazard ratio (HR), 95% confidence interval (CI), and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were reported.ResultsSeventy-eight patients were included (chemotherapy ± targeted, n=50; immunotherapy, n=28; median follow-up, 35.7 months). After weighting, first-line immunotherapy improved OS vs. chemotherapy ± targeted therapy (weighted HR, 0.47; 95% CI: 0.23–0.95) and showed a trend toward longer PFS (weighted HR, 0.64; 95% CI: 0.34–1.17). OS benefit was greater in patients with ECOG PS 0–1 (HR, 0.44; 95% CI: 0.21–0.93), non-epithelioid histology (HR, 0.30; 95% CI: 0.10–0.97), or no prior radiotherapy (HR, 0.29; 95% CI: 0.12–0.68). In multivariate models, first-line immunotherapy (HR, 0.34; 95% CI: 0.13–0.90) and prior radiotherapy (HR, 0.35; 95% CI: 0.14–0.86) were independent protective factors for OS. ORR and DCR were similar between groups, and immune-related adverse events occurred in 14/28 (50.0%) immunotherapy patients, mostly grade 1–2, with no immune-related deaths. In the chemo-start cohort, second-line dual immunotherapy improved OS vs. chemo-immunotherapy (HR, 0.13; 95% CI: 0.03–0.62) but not vs. chemotherapy alone (HR, 0.43; 95% CI: 0.17–1.11), and chemo-immunotherapy did not differ from chemotherapy (HR, 2.08; 95% CI: 0.94–4.57). In the smaller immuno-start cohort, no significant OS differences were seen between second-line strategies (weighted Cox P=0.31).ConclusionsIn this multicenter real-world Chinese cohort, first-line immunotherapy was associated with a clinically meaningful OS improvement in PM, particularly among patients with good PS, non-epithelioid histology, or no prior radiotherapy. Dual immunotherapy may be a promising second-line option after chemotherapy, warranting confirmation in larger prospective studies.

A Transcriptomic-Based Tool to Predict Gemcitabine Sensitivity in Advanced Pancreatic Adenocarcinoma

BackgroundThis study aimed to investigate the efficacy and safety of chemotherapy combined with programmed cell death protein 1 (PD-1) inhibitors in the treatment of advanced cervical cancer and the effect of optimal combination timing on prognosis.MethodsFrom March 2020 to December 2021, the clinical data of 116 patients with advanced cervical cancer who received PD-1 inhibitors combined with chemotherapy were collected. The clinical characteristics and adverse events of the patients were recorded until the cut-off date of follow-up. The primary endpoints were progression-free survival (PFS), the objective response rate (ORR), and safety; the secondary endpoints were the disease-control rate (DCR) and overall survival (OS). Multivariate Cox proportional hazards regression was used to analyze the prognostic factors affecting the PFS of patients and to assess the effect of the timing of combination therapies on PFS.ResultsIn total, 85 patients from 4 study centers were included in this study. The median PFS was 10.3 months [95% confidence interval (CI): 9.47–11.13 months], the ORR was 44.7%, the DCR was 75.3%, and the median OS was not reached. The multivariate Cox proportional hazards regression analysis showed that the early combination of chemotherapy with a PD-1 inhibitor provided better PFS than the late combination [hazard ratio (HR) 0.40, 95% CI: 0.24–0.67, P=0.001]. Lymph node metastasis (HR 2.04, 95% CI: 1.24–3.38, P=0.005), and previous treatment (HR 1.79, 95% CI: 1.09–3.00, P=0.023) were also independent risk factors for PFS. During the treatment and follow-up periods, the overall incidence of adverse events in this study was 56.5%, and that of grade ≥3 adverse events was 12.9%. Thrombocytopenia, neutropenia, anemia, and hypothyroidism were the main treatment-related adverse events, all of which were tolerated, and no serious adverse events leading to death were observed. There were no treatment-related deaths.ConclusionsPD-1 inhibitors combined with chemotherapy have good efficacy and controllable safety in patients with advanced cervical cancer. The early combination of PD-1 inhibitors and chemotherapy may provide better survival benefits than the late combination for patients.

Introduction: Immune checkpoint inhibitors (ICIs) have transformed the treatment of metastatic melanoma; however, predictive markers of therapeutic response remain poorly defined. This study systematically assesses clinical, histological, and molecular predictors associated with survival outcomes in melanoma patients treated with ICIs. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines, a systematic search was conducted in MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies published between January 2018 and October 2025. Eligible studies reported associations between predictive factors and overall survival (OS) or progression-free survival (PFS) in adult melanoma patients receiving ICIs. Pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) from univariate (UVA) and multivariate analyses (MVA) were synthesized using random-effects meta-analyses. Results: Sex was not a consistent predictor (contradictory effects; PFS heterogeneity I2 ≈ 90%), whereas older age predicted worse OS (MVA continuous: HR 1.05, 95% CI 1.02-1.08; UVA ≥ 65 vs. <65: HR 1.70, 95% CI 1.36-2.12). Poor performance status, assessed using the Eastern Cooperative Oncology Group (ECOG) scale, strongly predicted inferior outcomes (ECOG ≥ 1 vs. 0: MVA OS HR 2.01, 95% CI 1.61-2.51; MVA PFS HR 1.49, 95% CI 1.18-1.88; ECOG ≥ 2 vs. <2: MVA OS HR 2.24, 95% CI 1.79-2.81). Elevated lactate dehydrogenase (LDH) was consistently associated with poorer survival (MVA OS HR 1.71, 95% CI 1.53-1.91; MVA PFS HR 1.61, 95% CI 1.41-1.85), whereas body mass index (BMI) > 25 kg/m2 was associated with improved OS (HR 0.82, 95% CI 0.68-0.98). Higher disease burden predicted worse prognosis (Stage IV vs. III: MVA OS HR 1.57, 95% CI 1.16-2.13; >2 metastatic sites vs. ≤2: MVA OS HR 2.38, 95% CI 1.40-4.07; brain metastases: MVA OS HR 1.69, 95% CI 1.30-2.20; MVA PFS HR 1.52, 95% CI 1.00-2.33). Histologic and molecular factors showed prognostic value: ulceration worsened OS (UVA HR 2.08, 95% CI 1.25-3.44) and PFS (UVA HR 2.97, 95% CI 1.39-6.32); acral subtype had poorer OS than cutaneous melanoma (MVA HR 2.99, 95% CI 1.63-5.48); high tumor mutational burden (TMB) improved PFS (UVA HR 0.47, 95% CI 0.33-0.70); and cutaneous immune-related adverse events (irAEs) were associated with favorable outcomes (skin disorders: UVA OS HR 0.26, 95% CI 0.14-0.47; UVA PFS HR 0.50, 95% CI 0.34-0.74). In contrast, detectable circulating tumor DNA (ctDNA) predicted markedly worse PFS (MVA HR 4.72, 95% CI 2.31-9.65) and a non-significant trend toward worse OS (MVA HR 3.34, 95% CI 0.96-11.67). Liver metastases and programmed death-ligand 1 (PD-L1) expression were not significantly associated with survival. Discussion: This meta-analysis synthesizes evidence on clinicopathologic, laboratory, and histopathologic predictors of immunotherapy outcomes in metastatic melanoma. Performance status, age, LDH, BMI, and metastatic burden consistently correlated with prognosis, while ulceration, disease stage, and TMB emerged as key histologic determinants. Conversely, PD-L1 and gender showed no consistent predictive value, whereas cutaneous immune-related adverse events and ctDNA reflected favorable and poor outcomes, respectively. These findings highlight the multifactorial nature of immunotherapy response and support the further development of integrated prognostic models to refine patient stratification and optimize treatment outcomes.