Real-World Therapy with Pembrolizumab: Outcomes and Surrogate Endpoints for Predicting Survival in Advanced Melanoma Patients in Germany

Knowledge on the real-world characteristics and outcomes of pembrolizumab-treated advanced melanoma patients in Germany and on the value of different real-world endpoints as surrogates for overall survival (OS) is limited. A sample of 664 pembrolizumab-treated patients with advanced melanoma from the German registry ADOReg was used. We examined OS, real-world progression-free survival (rwPFS), real-world time to next treatment (rwTtNT), and real-world time on treatment (rwToT). Spearman’s rank and iterative multiple imputation (IMI)-based correlation coefficients were computed between the OS and the rwPFS, rwTtNT, and rwToT and reported for the first line of therapy and the overall sample. The median OS was 30.5 (95%CI 25.0–35.4) months, the rwPFS was 3.9 months (95%CI 3.5–4.9), the rwTtNT was 10.7 months (95%CI 9.0–12.9), and the rwToT was 6.2 months (95%CI 5.1–6.8). The rwTtNT showed the highest correlation with the OS based on the IMI (rIMI = 0.83), Spearman rank correlations (rs = 0.74), followed by the rwToT (rIMI = 0.74 and rs = 0.65) and rwPFS (rIMI = 0.69 and rs = 0.56). The estimates for the outcomes and correlations were similar for the overall sample and those in first-line therapy. The median OS was higher compared to recent real-world studies, supporting the effectiveness of pembrolizumab in regular clinical practice. The rwTtNT may be a valuable OS surrogate, considering the highest correlation was observed with the OS among the investigated real-world endpoints

Real-world therapy with pembrolizumab: outcomes and surrogate endpoints for predicting survival in advanced melanoma patients in Germany

Knowledge on the real-world characteristics and outcomes of pembrolizumab-treated advanced melanoma patients in Germany and on the value of different real-world endpoints as surrogates for overall survival (OS) is limited. A sample of 664 pembrolizumab-treated patients with advanced melanoma from the German registry ADOReg was used. We examined OS, real-world progression-free survival (rwPFS), real-world time to next treatment (rwTtNT), and real-world time on treatment (rwToT). Spearman’s rank and iterative multiple imputation (IMI)-based correlation coefficients were computed between the OS and the rwPFS, rwTtNT, and rwToT and reported for the first line of therapy and the overall sample. The median OS was 30.5 (95%CI 25.0–35.4) months, the rwPFS was 3.9 months (95%CI 3.5–4.9), the rwTtNT was 10.7 months (95%CI 9.0–12.9), and the rwToT was 6.2 months (95%CI 5.1–6.8). The rwTtNT showed the highest correlation with the OS based on the IMI (rIMI = 0.83), Spearman rank correlations (rs = 0.74), followed by the rwToT (rIMI = 0.74 and rs = 0.65) and rwPFS (rIMI = 0.69 and rs = 0.56). The estimates for the outcomes and correlations were similar for the overall sample and those in first-line therapy. The median OS was higher compared to recent real-world studies, supporting the effectiveness of pembrolizumab in regular clinical practice. The rwTtNT may be a valuable OS surrogate, considering the highest correlation was observed with the OS among the investigated real-world endpoints

Long-Term Effect of Half-Fluence Photodynamic Therapy on Fundus Autofluorescence in Acute Central Serous Chorioretinopathy

Purpose. To evaluate normalized short-wavelength fundus autofluorescence (SW-FAF) imaging changes over time as a predictive parameter for the retinal pigment epithelium (RPE) function in eyes compromised by acute central serous chorioretinopathy (CSCR) after indocyanine green angiography-guided verteporfin (Visudyne®, Novartis Pharma, Basel, Switzerland) photodynamic therapy (PDT) with a half-fluence rate (25 J/cm2). Methods. Quantitative data of SW-FAF grey values (SW-FAF GV) from a 350 μm (SW-350) and 1200 μm (SW-1200) diameter circle centered on the fovea and normalized with the level of SW-FAF GV in a 30° image of 20 eyes in 11 patients initially treated for unilateral acute symptomatic CSCR were collected and retrospectively analyzed after 7 years. A 2-sided t-test was calculated to explore the differences of SW-350 and SW-1200 between one month and the long-term follow-up. Results. Mean differences (95% CI) in SW-FAF GV between 1 month and 7 years after half-fluence PDT were 0.07 ± 0.11 for SW-350 ([95% CI: −0.002; 0.14], p=0.06) and 0.11 ± 0.15 for SW-1200 ([95% CI: 0.01; 0.21], p=0.03). Mean differences in SW-FAF GV of the contralateral untreated eye were 0.06 ± 0.14 for SW-350 ([95% CI: −0.04; 0.17], p=0.22) and 0.05 ± 0.13 for SW-1200 ([95% CI: −0.04; 0.15], p=0.22). Conclusion. After 7 years, normalized SW-FAF GV were significantly lower in eyes with resolved acute CSCR treated with reduced-fluence PDT compared to the follow-up after 1 month without correlation to explicit pattern changes or structural damages. Half-fluence PDT remains a safe and considerable treatment option in acute CSCR

Seven-Year Visual and Anatomical Outcomes of Intravitreal Vascular Endothelial Growth Factor Inhibition for Neovascular Age-Related Macular Degeneration

Purpose. To evaluate 7-year visual and anatomical outcomes of intravitreal injections (IVI) with antivascular endothelial growth factor (anti-VEGF) for neovascular age-related macular degeneration (nAMD) based on a personalized pro re nata (PRN) regimen. Methods. Anonymized data of 124 consecutive eyes in 121 patients with treatment-naïve nAMD were initially collected in 2010. Of those, 45 received anti-VEGF IVI at least every 6months until 2017 in one single center in Austria and hence were retrospectively analyzed. All eyes had been initiated on a loading dose of 3 monthly IVI with different anti-VEGF agents followed by a PRN regimen in the first year. At year 2, monitoring as well as therapeutic intervention could be prolonged every 2weeks up to intervals of 3months without capping treatment. Primary outcome measure was the change of visual acuity (VA) assessed by Early Treatment Diabetic Retinopathy Study charts at 4 meters (ETDRS) in letters—counting every correctly read letter—and converted to Snellen. Secondary outcome measures were number of injections and change of central retinal thickness (CMT) from baseline. Results. Mean baseline VA was 20/63 + 1 (0.63 ± 0.26 ETDRS) and declined to 20/100 + 2 (0.45 ± 0.33) with an overall loss of 9 letters ETDRS after 7years (p = 0.001). An average of 3.5 ± 1.9 IVI was given per year and eye. Mean CMT at baseline was 322 ± 95 μm, decreased by 52 μm to 270 ± 70 μm within the first year, and remained below baseline at year 7 (271 ± 106 μm; p<0.001). Conclusions. Our data confirm an absolute vision loss in eyes compromised by nAMD after 7 years of continuous VEGF inhibition. The visual decline was significantly related to baseline VA as well as the number of injections. We suggest following patients thoroughly independent of the initial VA and a greater incentive for the physician to treat

The Diagnostic Capability of Swept Source OCT Angiography in Treatment-Naive Exudative Neovascular Age-Related Macular Degeneration

Purpose. To evaluate the capability of swept source-optical coherence tomography angiography (SS-OCTA) in the detection and localization of treatment-naive macular neovascularization (MNV) secondary to exudative neovascular age-related macular degeneration (nAMD). Methods. In this prospective, observational case series, 158 eyes of 142 patients were diagnosed with exudative nAMD using fluorescein (FA) and indocyanine green angiography (ICGA) and evaluated by SS-OCTA in a tertiary retina center (Rudolf Foundation Hospital Vienna, Austria). The main outcome measure was the sensitivity of SS-OCTA compared to the standard multimodal imaging approach. Secondary outcome measure was the anatomic analysis of MNV in relation to the retinal pigment epithelium. Results. En-face SS-OCTA confirmed a MNV in 126 eyes (sensitivity: 79.8%), leaving 32 eyes (20.2%) undetected. In 23 of these 32 eyes (71.9%), abnormal flow in cross-sectional SS-OCTA B-scans was identified, giving an overall SS-OCTA sensitivity of 94.3%. Eyes with a pigment epithelium detachment (PED) ≥ 300 μm had a smaller probability for correct MNV detection (p=0.015). Type 1 MNV showed a trend (p=0.051) towards smaller probability for the correct detection compared to all other subtypes. Other relevant factors for the nondetection of MNV in SS-OCTA were image artifacts present in 3 of 32 eyes (9.4%). SS-OCTA confirmed the anatomic localization of 93 in 126 MNVs as compared to FA (sensitivity: 73.8%). There was no influence of age, gender, pseudophakia, visual acuity, central foveal thickness, or subfoveal choroidal thickness on the detection rate of MNV. Conclusions. SS-OCTA remains inferior to dye-based angiography in the detection rate of exudative nAMD consistent with type 1 MNV and a PED ≥300 µm. The capability to combine imaging modalities and distinguish the respective MNV subtype improves its diagnostic value

Overcoming Intrinsic Multidrug Resistance in Melanoma by Blocking the Mitochondrial Respiratory Chain of Slow-Cycling JARID1Bhigh Cells

Despite success with BRAFV600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. We identified a mechanism of intrinsic multidrug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (oxidative phosphorylation) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1B(high) subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anticancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation