Saadettin Kilickap

Background and Objectives: This study aimed to compare the real-world outcomes of first-line pembrolizumab monotherapy (Mono-IO) versus pembrolizumab plus platinum-based chemotherapy (IO + ChT) in patients with metastatic non-small cell lung cancer (mNSCLC) and a PD-L1 tumor proportion score (TPS) ≥ 50%. Materials and Methods: This retrospective, multicenter, real-world study evaluated 148 patients with mNSCLC and PD-L1 expression ≥ 50% who received either first-line Mono-IO or IO + ChT. Overall survival (OS), progression-free survival (PFS), and clinical benefit rate were compared between the two treatment strategies. Additionally, clinical prognostic factors, patterns of progression, and post-progression treatments were analyzed. Survival outcomes were assessed using Kaplan–Meier estimates, multivariable Cox regression, and restricted mean survival time (RMST) analysis. Results: Patients in the Mono-IO group were significantly older (median 69 vs. 63 years; p < 0.001) and had a higher proportion of ECOG PS 2 (35.3% vs. 5.2%; p < 0.001). No significant differences were observed between Mono-IO and IO + ChT in median OS (32.0 vs. 26.0 months; p = 0.559) or PFS (19.6 vs. 19.4 months; p = 0.572). In an exploratory multivariable analysis adjusting for organ-specific metastases and antibiotic exposure, ECOG PS ≥ 1 (aHR: 1.86, 95% CI: 1.16–2.97; p = 0.009), antibiotic use (aHR: 1.85, 95% CI: 1.16–2.95; p = 0.010), and liver metastasis (aHR: 2.58, 95% CI: 1.16–5.74; p = 0.020) were independent predictors of worse OS. Conversely, PD-L1 TPS ≥ 90% (aHR: 0.56, 95% CI: 0.35–0.91; p = 0.018) was independently associated with superior OS. In exploratory subgroup analysis, a numerical survival trend favoring Mono-IO was observed in patients with PD-L1 TPS ≥ 90%, although this finding remains hypothesis-generating. Following disease progression, 64.7% of patients received no further systemic therapy. Conclusions: In this real-world cohort, no statistically significant differences in OS or PFS were detected between Mono-IO and IO + ChT; however, the wide confidence intervals do not exclude clinically meaningful differences, and equivalence cannot be inferred from these data. PD-L1 TPS ≥ 90% may potentially serve as a biomarker to identify patients who derive benefit from monotherapy, although this exploratory finding requires validation in larger cohorts. Given that the majority of patients did not transition to subsequent therapy in routine practice, likely reflecting multifactorial host frailty and rapid disease evolution, first-line therapeutic optimization warrants careful individualized consideration.

PURPOSE: Primary bone sarcomas, including osteosarcoma, chondrosarcoma, and Ewing sarcoma, have poor prognoses, with 5-year overall survival (OS) rates of < 20%-30% in metastatic or recurrent disease. Although tyrosine kinase inhibitors (TKIs) targeting angiogenic and oncogenic pathways have shown efficacy in phase II trials, there is a lack of supporting real-world data. This study aimed to evaluate the efficacy and safety of TKI use in patients with advanced bone sarcomas in a real-world setting. MATERIALS AND METHODS: This multicenter, retrospective study included 72 patients with advanced or metastatic osteosarcoma, chondrosarcoma, or Ewing sarcoma who received at least one TKI (regorafenib, pazopanib, sorafenib, or cabozantinib) at multiple centers in Türkiye. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method. Adverse events were recorded and graded according to standard criteria. RESULTS: The median age was 28.5 years (range, 17-72 years), and 62.5% (n = 45) of the patients were male. The most frequently used TKIs were regorafenib (n = 31, 43.1%) and pazopanib (n = 22, 30.6%); in the majority of patients (n = 68, 94.4%), TKIs were used as second-line or subsequent treatment. The median PFS for the entire cohort was 4.8 months (95% CI, 3.05 to 6.48), and the median OS was 9.9 months (95% CI, 6.48 to 13.25). In histologic subgroup analyses, the median PFS was 4.4 months for osteosarcoma, 4.8 months for chondrosarcoma, and 5.4 months for Ewing sarcoma. Adverse events were observed in 50% (n = 36) of patients, and 89.2% (n = 58) of these were grade 1-2. Dose reduction was required in 27.8% (n = 20) of patients, and permanent treatment discontinuation due to toxicity was necessary in 6.9% (n = 5) of patients. CONCLUSION: In this real-world cohort, although TKIs were associated with limited survival outcomes, they had an acceptable safety profile in patients with advanced bone sarcomas. These findings are consistent with the results of phase II studies and suggest that TKIs may be a treatment option for patients who have disease progression after standard therapies.

Objective assessment of activities of daily living (ADL) in non-small cell lung cancer (NSCLC) remains limited despite its clinical importance. The Londrina ADL protocol enables standardized evaluation of real-life functional performance. This study aimed to evaluate performance-based ADL in NSCLC and identify determinants of impaired ADL performance. In this prospective cross-sectional controlled study, 23 NSCLC patients who had completed adjuvant treatment and 27 healthy controls underwent pulmonary function testing, muscle strength assessment, a 6-minute walk test (6MWD), quality-of-life evaluation, and Londrina ADL testing. Group comparisons, correlations, and multivariable linear regression were performed. Performance-based ADL is markedly impaired in NSCLC, and reduced exercise capacity is the principal determinant of real-life functional limitation. Objective ADL assessment may support early, capacity-targeted rehabilitation to preserve independence. NSCLC patients showed significantly longer Londrina ADL completion times than controls (335.6 ± 63.7 s vs 270.7 ± 34.4 s; P < .001) with reduced pulmonary function, muscle strength, and exercise capacity. Within NSCLC, ADL time correlated inversely with 6MWD ( r = −0.579, P = .004). Functional exercise capacity was the only independent predictor of ADL performance (β = −0.498, P = .022), and the model explained 36.1% of the variance in Londrina ADL completion time ( R ² = 0.361).

A 50-year-old man with weight loss and fatigue was diagnosed with a grade 2 liver-metastatic neuroendocrine tumor (NET). Dual-tracer molecular imaging was performed for staging and characterization. While ¹⁸ F-FDG PET/CT showed focal high uptake in a gallbladder lesion (SUVmax: 10) and non-FDG-avid liver metastases, ⁶⁸ Ga-DOTATATE PET/CT revealed intense somatostatin receptor expression in the primary pancreatic lesion and liver metastases, but no uptake in the gallbladder. This discordant “flip-flop” pattern typically suggests high-grade dedifferentiation. However, histopathology following cholecystectomy revealed a low-grade intracholecystic papillary neoplasm (ICPN). This case highlights that discordant FDG-positive/SSTR-negative foci in NET patients can represent rare premalignant mimics rather than aggressive tumor biology.

Background/Objectives: We aimed to evaluate the real-world outcomes of first-line osimertinib in patients with advanced EGFR-mutant non-small cell lung cancer, together with the progression patterns, including the management and outcomes of oligoprogressive disease in the real-world setting. Methods: Patients who received first-line osimertinib at 33 oncology centers across Türkiye were retrospectively analyzed. Results: The median (IQR) age of 143 patients was 59.4 (50.9–68.9), 62.9% were female, and 68.5% were non-smokers. The most frequently identified EGFR mutations were exon 19 deletion (64.3%) and exon 21 L858R (28.7%). The median progression-free survival (PFS) was 17.6 months (95% CI 14.6–20.6). Exon 19 deletion subgroup had significantly longer median PFS than exon 21 L858R subgroup (22.0 vs. 11.7 months; HR = 0.40 [95% CI 0.25–0.64]; p < 0.001). Of the patients who experienced disease progression, 51.2% had oligoprogression. Among these, 81.8% received local ablative treatments (LATs) while continuing osimertinib. The median time to osimertinib discontinuation was significantly longer in patients treated with LATs than in those who continued osimertinib without LATs (8.5 vs. 3.0 months; p = 0.001). In the overall cohort, 12- and 24-month overall survival (OS) rates were 93.0% and 82.5%, respectively. The median OS was significantly longer in patients with oligoprogression compared to those with systemic progressive disease (57.7 vs. 36.5 months; p = 0.007). Any-grade and grade ≥ 3 osimertinib-related adverse events occurred in 55.2% and 6.3% of patients, respectively. Conclusions: This study supports the real-world effectiveness and tolerability of first-line osimertinib. Oligoprogression was associated with longer OS compared with systemic progression, and the integration of LATs in carefully selected patients with oligoprogression may be associated with prolonged osimertinib treatment duration and favorable post-progression outcomes.

Nivolumab is currently widely used in the treatment of lung cancer. Studies have been conducted using flat doses of 240 mg and 3 mg/kg. In fact, studies involving a small number of patients have begun to explore low-dose immunotherapies. The literature on the optimal dose of immunotherapy, the use of weight based, or fixed doses is very recent and has become a one of the subject of ongoing research. This multicenter study included 716 patients with NSCLC. Patients receiving standard doses of 3 mg/kg and 240 mg of nivolumab were divided into subgroups based on their weight. Patients weighing 80 kg have already received a flat dose. However, patients weighing < 80 kg who received a flat dose were considered to be receiving high-dose therapy. Conversely, patients weighing more than 80 kg who received a flat dose were maintained on a low dose. Therefore, overall survival, progression-free survival, and toxicity were examined according to weight-based usage. The median progression free survival (PFS) for those receiving a 3 mg/kg dose was 6 months, whereas it was 9.8 months for those receiving a flat dose (p < 0.001). The median (metastatic overall survival) OS for those receiving a 3 mg/kg dose was 12 months, whereas it was 14 months for those receiving a 240 mg dose (p = 0.03). This study was based on real-world data. Therefore, our results may be instructive regarding the nivolumab dose, which is a commonly used treatment for NSCLC patients. Our results suggest that a flat dose may be preferred in all groups and as a subgroup, especially in patients weighing < 80 kg.

Background: Sulfatase 2 (SULF2) is an extracellular enzyme involved in the modulation of multiple oncogenic signaling pathways and has been implicated in tumor progression across several malignancies. However, its prognostic significance in surgically resected non-small cell lung cancer (NSCLC) remains incompletely defined. Methods: SULF2 expression was evaluated by immunohistochemistry in tumor specimens from patients with stage I–III NSCLC who underwent curative-intent surgical resection between 2009 and 2016. Expression levels were quantified using an H-score-based system and categorized as low or high. Associations between SULF2 expression, clinicopathological characteristics, and survival outcomes, including overall survival (OS) and disease-free survival (DFS), were analyzed using Kaplan–Meier estimates and Cox proportional hazards models. Eighty-three patients were included, of whom 65 (78.3%) were male; 42.2% had stage I disease, 32.5% stage II, and 25.3% stage III. Results: SULF2 expression was detected in 94.0% of tumors, with 43 patients (51.8%) classified as high and 40 (48.2%) as low expression based on H-score. Overall survival and DFS did not differ significantly between SULF2-low and SULF2-high groups (log-rank p = 0.213 and p = 0.660, respectively). Median OS was 113.2 months (95% CI: 84.0–142.4) in the SULF2-low group and 54.9 months (95% CI: 39.4–186.9) in the SULF2-high group, while median DFS was 88.3 months (95% CI: 46.5–130.2) and 53.3 months, respectively, with numerically shorter survival in the SULF2-high group. Subgroup analyses stratified by pathological stage and histological subtype revealed no significant associations between SULF2 expression and survival outcomes. In multivariate analysis, SULF2 expression was not independently associated with either OS or DFS. Conclusions: SULF2 expression was highly prevalent in surgically resected NSCLC; although higher expression showed numerically poorer survival, this difference did not reach statistical significance.

Immune checkpoint inhibitors such as nivolumab have brought meaningful benefits to patients with advanced non-small cell lung cancer (NSCLC), yet many patients still experience limited responses. Vitamin D is a key modulator of immune function, and deficiency is common in individuals with cancer. Given its potential role in shaping immunotherapy response, we retrospectively assessed whether baseline vitamin D levels were associated with clinical outcomes in advanced NSCLC patients treated with nivolumab. We retrospectively analyzed patients with stage IV NSCLC treated with nivolumab across multiple centers, predominantly as second-line therapy. Prior to nivolumab initiation, all patients were confirmed to be negative for common driver mutations, including EGFR, ALK, ROS1, and other actionable genomic alterations. Baseline serum 25-hydroxyvitamin D levels were measured prior to nivolumab initiation, and patients were categorized as having severe deficiency (< 10 ng/mL), deficiency (10–20 ng/mL), or sufficient levels (≥ 20 ng/mL). The presence of liver metastases was recorded at baseline. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared with log-rank tests. Multivariable Cox proportional hazards models adjusted for age, sex, ECOG performance status, liver metastasis, and other metastatic sites were used to evaluate the independent prognostic value of vitamin D status. Objective response rates (ORR) were assessed in patients with available radiologic data. A total of 890 patients were screened, and after excluding those with missing baseline vitamin D data, 305 patients were included in the analysis. The median age was 64 years (range 34–85), and 68% of patients were male. Vitamin D levels were < 10 ng/mL in 30%, 10–20 ng/mL in 44%, and ≥ 20 ng/mL in 26% of patients. Patients with severe vitamin D deficiency were numerically older (median age 65 vs. 63 years) and had higher rates of ECOG PS ≥ 2 (15.1% vs. 7.5%) and squamous histology (37.6% vs. 27.5%), though these differences were not statistically significant (p > 0.05 for all). Liver metastases were present in 54 patients (17.7%), and the distribution was similar across vitamin D groups (p = 0.92). Median PFS was shortest in patients with severe vitamin D deficiency (3.4 months), intermediate in the 10–20 ng/mL group (5.2 months), and longest in patients with sufficient levels (8.1 months). Median OS ranged from 8.6 months in the < 10 ng/mL group to 15.8 months in the ≥ 20 ng/mL group. Patients with liver metastases had significantly shorter OS compared to those without (median OS 9.8 vs. 13.6 months, HR 1.48, p = 0.006). Vitamin D deficiency was associated with significantly worse PFS and OS on univariate analysis. In multivariable analysis, vitamin D levels < 20 ng/mL remained independently associated with poorer OS. ORR was numerically higher in patients with sufficient vitamin D levels (30% vs. 14%). Lower baseline vitamin D levels were associated with inferior clinical outcomes in advanced NSCLC patients treated with nivolumab. Patients with vitamin D levels ≥ 20 ng/mL demonstrated longer PFS and OS and a trend toward higher response rates. These findings support a prognostic role for vitamin D status in immunotherapy-treated NSCLC; however, prospective studies are required to determine whether vitamin D optimization can causally enhance immunotherapy efficacy.

Background: Vandetanib and cabozantinib are the approved first-line antiangiogenic multikinase inhibitors (aaMKIs) for metastatic medullary thyroid carcinoma (MTC); however, real-world data on their comparative efficacy, optimal sequencing, and outcomes beyond the first-line setting remain limited. We report multicenter real-world outcomes from a large Turkish cohort. Methods: In this retrospective multicenter cohort study, we analyzed data from 24 oncology referral centers across Türkiye. Patients with histologically confirmed metastatic MTC who received systemic therapy between December 2011 and December 2024 were included. The primary endpoint was progression-free survival (PFS), assessed separately for first-line (PFS1) and second-line (PFS2) therapy. Overall survival (OS) and prognostic factors were evaluated using Kaplan–Meier and Cox proportional hazards analyses. Results: A total of 115 patients were included (median age 47.4 years; 63.5% male). In the first-line setting, vandetanib (47.8%) and cabozantinib (30.4%) were the most frequently used agents. Median PFS1 was 40.8 months with vandetanib and was not reached with cabozantinib; both were significantly superior to chemotherapy (median PFS1 4.9 months; log-rank p < 0.001). In the second-line setting, median PFS2 was not reached with cabozantinib and was 32.5 months with vandetanib. Sequential use of cabozantinib and vandetanib across the first two lines was associated with a median time to second progression of 114 months, compared with 39 months in patients receiving any other TKI combination (p = 0.003). Second-line use of cabozantinib or vandetanib was independently associated with improved OS (HR 0.40, 95% CI 0.16–0.98; p = 0.046). On multivariate analysis, younger age (HR 0.16, 95% CI 0.03–0.72; p = 0.017) and bone metastasis (HR 0.29, 95% CI 0.11–0.73; p = 0.009) were independent prognostic factors for OS. Conclusions: In this real-world cohort of patients with metastatic MTC, cabozantinib and vandetanib demonstrated durable efficacy across treatment lines, substantially outperforming alternative TKIs and chemotherapy. Sequential use of both approved aaMKIs was associated with prolonged disease control. These findings suggest a potential association between access to both agents and improved outcomes. They are consistent with their central role in treatment sequencing, particularly in settings with limited access to selective RET inhibitors. Given the retrospective design and small subgroup sizes, these results should be interpreted as exploratory and hypothesis-generating.

Background: Patient‐reported outcomes (PROs) for cemiplimab monotherapy versus chemotherapy from the EMPOWER‐Lung 1 phase 3 clinical trial (ClinicalTrials.gov identifier NCT03088540) in patients who had advanced non‐small cell lung cancer with programmed cell death‐ligand 1 expression ≥50% were previously reported. Methods: This review article characterizes PRO findings for cemiplimab monotherapy versus chemotherapy overall and in prespecified subgroups of patients from the EMPOWER‐Lung 1 clinical trial. Patients were randomly assigned 1:1 to receive either cemiplimab 350 mg every 3 weeks or platinum‐doublet chemotherapy, and multiple PROs, including the European Organization for Research and Treatment of Cancer Quality of Life–Core 30 questionnaire, were administered in the EMPOWER‐Lung 1 trial. PRO analyses using mixed model for repeated measures analysis to estimate least‐squares mean changes in PRO scores from baseline and Cox proportional hazards models for the time to deterioration using a 10‐point threshold have been reported and are summarized herein. Results: Generally, the mixed model for repeated measures analysis of global health status/quality of life (GHS/QoL) significantly favored cemiplimab versus chemotherapy in the overall study population and in prespecified subgroup populations. Statistically significant differences in the overall change from baseline in GHS/QoL favoring cemiplimab versus chemotherapy were observed overall and in multiple subgroups, including patients who had brain metastasis ( p = .0110), an Eastern Cooperative Oncology Group performance status of 1 ( p = .0017), squamous ( p = .0247) and nonsquamous ( p = .0073) histology, and patients aged 65 years and older ( p = .0069). Statistically significant delays in the time to deterioration favoring cemiplimab were observed in GHS/QoL for the subgroup with programmed cell death‐ligand 1 expression ≥90% ( p = .0152) and the subgroup younger than 65 years ( p = .0195). Conclusions: Collectively, the current data support the GHS/QoL benefit of first‐line cemiplimab monotherapy versus chemotherapy overall and in multiple subpopulations of patients with programmed cell death‐ligand 1 expression ≥50% advanced non‐small cell lung cancer.