•Several systemic therapies are available for metastatic uveal melanoma (UM)•The comparative efficacy of these options is unclear.•Tebentafusp is more effective than combined ICB, anti PD-1, and ...other therapies.•Tebentafusp might be the preferred first-line therapy for HLA-A*02:01-positive patients.
Distinct systemic treatments exist for metastatic uveal melanoma. Tebentafusp and combined immune checkpoint blockade (ICB) with ipilimumab plus anti-PD-1 antibodies are the most commonly used treatment options but their comparative efficacy is unclear. The aim of this study is to compare currently available systemic treatments regarding overall survival (OS) and progression-free survival (PFS) with a focus on the comparison of tebentafusp versus combined ICB.
The protocol for this study was defined a priori and registered online in the PROSPERO international prospective register of systematic reviews (CRD42022308356, date of registration: 7.2.2022). We performed a systematic literature search in Medline, Embase, and Central to identify eligible studies reporting Kaplan-Meier curves or individual-level survival data showing OS and PFS for metastatic uveal melanoma patients treated with systemic treatments. Kaplan-Meier curves were digitized using the “WebPlotDigitizer” program. Individual-level survival data were subsequently remodelled and pooled for distinct treatment groups. To compare the OS of tebentafusp versus combined ICB, we used matching-adjusted indirect comparison (MAIC), two-stage MAIC (2SMAIC), and simulated treatment comparison (STC) together with digitized individual-level survival data as population-adjusted models.
Overall, 55 independent studies were included of which 2,682 patients were evaluable for OS and 2,258 for PFS. Tebentafusp showed the highest median OS (mOS) of 22.4 months (95% confidence interval (CI): 19.9–29.6) compared to combined ICB (mOS: 15.7 months (95% CI: 14.4–17.9)), anti-PD-(L)1 antibody (mOS: 10.9 months (95% CI: 9.8–13.4)), chemotherapy (mOS: 9.95 months (95% CI: 8.9–11.2)), targeted therapies (mOS: 8.86 months (95% CI: 7.5–10.8)), and anti-CTLA-4 antibody (mOS: 7.8 months (95% CI: 6.8–9.3). The median PFS (mPFS) was similar among the treatment groups ranging from 2.7 months to 3.4 months. For the comparison of tebentafusp versus combined ICB, the hazard ratio (HR) was 0.641 (95% CI: 0.449–0.915) in the unadjusted model, whereas the population-adjusted models showed a HR of 0.386 (95% CI: 0.236–0.631) using MAIC, 0.378 (95% CI: 0.234–0.612) applying 2SMAIC and 0.284 (95% CI: 0.184–0.440) using STC.
Tebentafusp achieved the best results compared to combined ICB and other systemic treatments, although these results have to be interpreted with caution due to the approximative methodical approach and high heterogeneity of included studies.
Introduction Despite recent advancements in the treatment of metastatic uveal melanoma (UM), the availability of further treatment options remains limited and the prognosis continues to be poor in ...many cases. In addition to tebentafusp, immune checkpoint blockade (ICB, PD-1 (+/-) CTLA-4 antibodies) is commonly used for metastatic UM, in particular in HLA-A 02:01-negative patients. However, ICB comes at the cost of potentially severe immune-related adverse events (irAE). Thus, the selection of patient groups that are more likely to benefit from ICB is desirable. Methods In this analysis, 194 patients with metastatic UM undergoing ICB were included. Patients were recruited from German skin cancer sites and the ADOReg registry. To investigate the association of irAE occurrence with treatment response, progression-free survival (PFS), and overall survival (OS) two cohorts were compared: patients without irAE or grade 1/2 irAE (n=137) and patients with grade 3/4 irAE (n=57). Results In the entire population, the median OS was 16.4 months, and the median PFS was 2.8 months. Patients with grade 3/4 irAE showed more favorable survival than patients without or grade 1/2 irAE (p=0.0071). IrAE occurred in 44.7% (87/194), and severe irAE in 29.4% (57/194) of patients. Interestingly, irColitis and irHepatitis were significantly associated with longer OS (p=0.0031 and p=0.011, respectively). Conclusions This data may indicate an association between irAE and favorable survival outcomes in patients with metastatic UM undergoing ICB treatment and suggests that a reduced tolerance to tumor antigens could be linked to reduced tolerance to self-antigens.
With the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality ...rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes.
Patients who developed hem-irAE while being treated with immune checkpoint inhibitors (ICI) therapy were retrospectively identified from 18 international cancer centres.
In total, more than 7626 patients treated with ICI were screened, and 50 patients with hem-irAE identified. The calculated incidence amounts to 0.6% and median onset was 6 weeks after the ICI initiation (range 1–128 weeks). Thrombocytopenia and leucopaenia were the most frequent hem-irAE with 34% (17/50) and 34% (17/50), respectively, followed by anaemia 28% (14/50), hemophagocytic lymphohistiocytosis (4% (2/50)), aplastic anaemia (2% (1/50)), acquired haemophilia A (2% (1/50)) and coagulation deficiency (2% (1/50)). Simultaneous thrombocytopenia and neutropenia occurred in two patients, concurrent anaemia and thrombocytopenia in one patient. Other than cessation of ICI (in 60%) and corticosteroids (in 78%), treatment included second-line immunosuppression in 24% of cases. Events resolved in 78% (39/50), while 18% (9/50) had persistent changes, and 2% (1/50) had fatal outcomes (agranulocytosis).
Hem-irAE can affect all haematopoietic blood cell lineages and may persist or even be fatal. Management may require immunosuppression beyond corticosteroids. Although these irAE are rare, treating physicians should be aware, monitor blood counts regularly and promptly act upon detection.
•Haematological immune-related adverse events are rare and initially asymptomatic.•Anaemia, thrombocytopenia and neutropenia comprised ~1/3 of cases each.•Regular blood count and prompt management are crucial as hem-irAE can be fatal.•Management may require immunosuppression beyond corticosteroids.
Reducing symptoms of depression is an important target in the treatment of borderline personality disorder (BPD). Although current treatments for BPD are effective in reducing depression, the average ...post-treatment level of depression remains high.
To test whether experiential avoidance (EA) impedes the reduction of depression during treatment for BPD.
EA and depression were assessed in 81 clients at baseline and 4-month intervals during 1 year of therapy. Simple correlations, hierarchical linear modeling, and latent difference score models were used to investigate the association between self-reports of EA and both self-reports and observer-based ratings of depression.
EA was positively associated with greater severity of depression at all points of assessment, and changes in EA were positively associated with changes in depression. Moreover, EA significantly predicted less subsequent reduction in depression whereas no such effect was found for depression on subsequent EA.
The findings are consistent with the hypothesis that EA impedes the reduction of depression in the treatment of BPD and should thus be considered an important treatment target.
Actinic keratoses (AK) are common lesions of the skin caused by cumulative sun exposure. Since AK may progress to invasive cutaneous squamous cell carcinoma (cSCC), guidelines uniformly recommend ...early and consequent treatment. A variety of interventions are available; however, most randomized controlled trials, meta-analyses, and guidelines focus on outcomes that are usually evaluated 8–12 weeks after the end of treatment. Importantly, these assessments can capture the short-term, transient outcomes, but do not allow any conclusions about long-term results to be drawn and do not reflect the probability of transition towards cSCC. Until now, few studies have assessed the long-term results of interventions for AK. Indeed, finding the most appropriate end-point and adjunct time point for determining the long-term results of interventions for AK remains a challenge. Here, we provide an overview of the different ways of measuring the efficacy of AK treatments, such as using recurrence rates or sustained clearance rates, and discuss methodological aspects. Furthermore, we highlight the importance of evidence from post-marketing surveillance trials for the detection of efficacy values and safety signals. Additionally, we emphasize that a follow-up period of 12 months might not be sufficient to reflect the long-term results and stress the urgent need for a longer follow-up period and regular risk-stratified surveillance.
In the emerging era of digitalization and electronic health, skin cancer-related apps represent useful tools to support dermatologic consultation and examination. Yet, little is known about how ...patients perceive the value of such apps.
The aim of this study was to investigate patient attitudes and their awareness toward skin cancer-related apps.
A cross-sectional study including 200 patients from the oncological outpatient unit was conducted at the University Hospital (LMU Munich, Germany) between September and December 2018. Patients were asked to complete a self-administered questionnaire on the popularity and usefulness of health-related and skin cancer-related apps. A descriptive analysis was performed with the expression of categorical variables as frequencies and percentages. For continuous variables, the median and range were indicated. Contingency tables and chi-square tests were performed to investigate associations between sociodemographic data and selected items of the questionnaire.
A total of 98.9% (195/197) of patients had never used skin cancer-related apps or could not remember. In 49.7% (93/187) of cases, patients were unsure about the usefulness of skin cancer apps, whereas 42.6% (78/183) thought that skin cancer apps could supplement or support the professional skin examination performed by a physician. However, 47.9% (90/188) were interested in acquiring more information by their dermatologists about skin cancer apps. Young age (P=.002), male gender (P=.02), a previous history of melanoma (P=.004), and higher educational level (P=.002) were significantly associated with a positive attitude. Nevertheless, 55.9% (105/188) preferred a printed patient brochure on skin cancer to downloading and using an app.
The experience and knowledge of skin cancer-related apps was surprisingly low in this population, although there was a high general interest in more information about such apps. Printed patient brochures were the preferred information source.
Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first ...analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A,
= 52) versus those who received only one treatment line of ICB (cohort B,
= 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (
= 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1-23.8) versus 9.4 months (cohort B, 95% CI: 6.1-14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities.
Effective treatment options are limited for patients with advanced melanoma who have progressed on immune checkpoint inhibitors (ICI) and targeted therapies (TT). Preclinical models support the ...combination of ICI with TT; however, clinical trials evaluating the efficacy of triplet combinations in first-line setting showed limited advantage compared to TT only.
We conducted a retrospective, multicenter study, that included patients with advanced melanoma who were treated with BRAF/MEK inhibitors in combination with an anti-PD-(L)1 antibody (triplet therapy) after failure of at least one anti-PD-(L)1-based therapy and one TT in seven major melanoma centers between February 2016 and July 2022.
A total of 48 patients were included, of which 32 patients, 66.7% had brain metastases, 37 patients (77.1%) had three or more metastatic organs and 21 patients (43.8%) had three or more treatment lines. The median follow-up time was 31.4 months (IQR, 22.27–40.45 months). The treatment with triplet therapy resulted in an ORR of 35.4% (n = 17) and a DCR of 47.9% (n = 23). The median DOR was 5.9 months (range, 3.39–14.27 months). Patients treated with BRAF/MEK inhibitors as the last treatment line showed a slightly lower ORR (29.6%) compared to patients who received ICI or chemotherapy last (ORR: 42.9%). Grade 3–4 treatment-related adverse events occurred in 25% of patients (n = 12), with seven patients (14.6%) requiring discontinuation of treatment with both or either drug.
Triplet therapy has shown activity in heavily pretreated patients with advanced melanoma and may represent a potential treatment regimen after failure of ICI and TT.
•Unmet need for advanced melanoma after failure of immune- and targeted therapy (TT)•Combination of BRAF/MEK inhibitors plus anti-PD-(L)1 as so-called triplet therapy•Triplet therapy showed efficacy after failure of anti-PD-1-based therapy and TT•Triplet therapy as a viable regimen after failure of immune- and targeted therapy
TPS9600
Background: There are no approved therapies for pts with MCC for whom an anti PD-1/L1 agent has failed. The high rate of non-responsive disease after anti PD-1/L1 therapy together with high ...mortality rate and the absence of a standard of care in this setting highlight the urgent unmet need for effective novel therapies. Approximately 80% of MCC tumors carry the oncogenic Merkel cell polyoma virus (MCPyV) and most cases are TP53
WT
. Oncoproteins from MCPyV inhibit p53 tumor suppressor functions by activating MDM2. Navtemadlin, a potent, selective, orally available MDM2i, overcomes MDM2 dysregulation by restoring p53 activity and inducing apoptosis of TP53
WT
MCC tumors. Navtemadlin is the first targeted therapy to show single-agent activity in pts with metastatic MCC for whom anti-PD-1/L1 has failed (Wong ASCO 2022). In the dose finding study, evaluable pts (n=8) receiving the recommended phase 2 dose of navtemadlin (180 mg QD on Day 1-5/28-day cycle) demonstrated a 25% confirmed objective response rate (ORR), 38% unconfirmed + confirmed ORR, and 63% disease control rate. The median duration of response was not reached (range, 6-16.2+ months mos) and median time to treatment response was 4.1 mos (range, 1.2-7). Responses to navtemadlin were highest in those pts with no prior chemotherapy (chemo; Wong ASCO oral 2022). In pts receiving navtemadlin at doses of ≥180 mg, an ORR of 40% was reported with no prior chemo (n=15) versus 14% in those who received prior chemo (n=14, Wong ASCO oral 2022). Navtemadlin demonstrated an acceptable safety profile with the most common treatment emergent adverse events (TEAEs) cytopenias, nausea, vomiting, diarrhea, and fatigue. Grade 3/4 TEAEs were 32% anemia, 32% lymphopenia, and 19% thrombocytopenia (Wong 2022). Based on this encouraging data, the NOTOS study (navtemadlin induces p53-driven apoptosis in Merkel cell carcinoma) will evaluate the safety and efficacy of navtemadlin in two post PD-1/L1 treated cohorts: chemo-naive pts and chemo treated pts. Methods: Adults with MCC for whom anti PD-1/L1 therapy has failed, who have ≥1 measurable lesion per RECIST v1.1, ECOG PS 0-1 and TP53
WT
MCC by central testing will receive 180 mg QD on days 1-5 of a 28-day cycle until disease progression, unacceptable toxicity, death or withdrawal of consent. The primary endpoint is ORR per RECIST v1.1 by blinded independent review. Secondary endpoints include ORR per investigator, duration of response, progression-free survival, overall survival, clinical benefit rate (including stable disease for ≥10 wk, partial response or complete response), and safety. The NOTOS trial is currently enrolling (NCT03787602). Clinical trial information: NCT03787602 .
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