Reinduction of Hedgehog Inhibitors after Checkpoint Inhibition in Advanced Basal Cell Carcinoma : A Series of 12 Patients

For patients with advanced basal cell carcinoma (aBCC) first-line treatment with hedgehog inhibitors (HHIs) and second-line treatment with PD1 inhibitors (PD1i) is available, offering combination and sequencing options. Here, we focus on the efficacy and safety of HHI reinduction after PD1i failure. Retrospective data analysis was performed with 12 patients with aBCC (locally advanced (n = 8)/metastatic (n = 4)). These patients (male:female 6:6, median age 68 years) initially received HHIs, leading to complete/partial response (66%) or stable disease (33%). Median treatment duration was 20.8 (2–64.5) months until discontinuation due to progression (n = 8), adverse events (n = 3), or patient request (n = 1). Subsequent PD1 inhibition (pembrolizumab 42%, cemiplimab 58%) yielded a partial response (8%), stable disease (33%), or progression (59%). Median treatment duration was 4.1 (0.8–16.3) months until discontinuation due to progression (n = 9), adverse events (n = 1), patient request (n = 1), or missing drug approval (n = 1). HHI reinduction resulted in complete/partial response (33%), stable disease (50%), or progression (17%). Median treatment duration was 3.6 (1–29) months. Response duration in the four responding patients was 2–29+ months. Thus, a subgroup of patients with aBCC responded to reinduction of HHI following PD1i failure. Therefore, this sequential treatment represents a feasible treatment option

Identification of the Rage-dependent gene regulatory network in a mouse model of skin inflammation

<p>Abstract</p> <p>Background</p> <p>In the past, molecular mechanisms that drive the initiation of an inflammatory response have been studied intensively. However, corresponding mechanisms that sustain the expression of inflammatory response genes and hence contribute to the establishment of chronic disorders remain poorly understood. Recently, we provided genetic evidence that signaling via the receptor for advanced glycation end products (Rage) drives the strength and maintenance of an inflammatory reaction. In order to decipher the mode of Rage function on gene transcription levels during inflammation, we applied global gene expression profiling on time-resolved samples of mouse back skin, which had been treated with the phorbol ester TPA, a potent inducer of skin inflammation.</p> <p>Results</p> <p>Ranking of TPA-regulated genes according to their time average mean and peak expression and superimposition of data sets from wild-type (<it>wt</it>) and <it>Rage</it>-deficient mice revealed that Rage signaling is not essential for initial changes in TPA-induced transcription, but absolutely required for sustained alterations in transcript levels. Next, we used a data set of differentially expressed genes between TPA-treated <it>wt </it>and <it>Rage</it>-deficient skin and performed computational analysis of their proximal promoter regions. We found a highly significant enrichment for several transcription factor binding sites (TFBS) leading to the prediction that corresponding transcription factors, such as Sp1, Tcfap2, E2f, Myc and Egr, are regulated by Rage signaling. Accordingly, we could confirm aberrant expression and regulation of members of the E2f protein family in epidermal keratinocytes of Rage-deficient mice.</p> <p>Conclusions</p> <p>In summary, our data support the model that engagement of Rage converts a transient cellular stimulation into sustained cellular dysfunction and highlight a novel role of the Rb-E2f pathway in Rage-dependent inflammation during pathological conditions.</p

Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG

Background Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy.Methods Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC–V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS).Results Of 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmut patients. In BRAFwt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK.Conclusions In BRAFmut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1

The concepts of rechallenge and retreatment in melanoma: A proposal for consensus definitions

Patients with BRAF-mutant melanoma commonly develop resistance to BRAF inhibitor and MEK inhibitor (BRAF/MEKi) treatment, resulting in disease recurrence or progression. Repeated treatment after a break or an intervening therapy may provide clinical benefit. To ensure a common understanding when discussing the treatment of BRAF-mutant melanoma, we propose consensus definitions for retreatment and rechallenge. ‘Retreatment’ should be defined as ‘repeated treatment with the same therapeutic class following relapse after adjuvant treatment has ended.’ Retreatment may be an option for patients with unresectable or metastatic disease who have completed prior adjuvant therapy or discontinued adjuvant therapy early due to toxicity or patients with locoregional recurrence after adjuvant treatment who subsequently underwent resection. ‘Rechallenge’ should be defined as ‘repeated treatment with the same therapeutic class following disease progression in patients who had clinical benefit with prior treatment for unresectable or metastatic disease.’ Rechallenge may be an option for patients who had disease progression after an initial response and received an alternative intervening treatment or patients with unresectable or metastatic melanoma who had a treatment break after responding to BRAF/MEKi therapy. Clinical benefits may be possible with repeated BRAF/MEKi treatment because of the role of the MAPK pathway in melanoma oncogenesis and resistance mechanisms specific to BRAF/MEKi, which are discussed in this article. The concepts of retreatment and rechallenge may also be relevant for treatment with immune checkpoint inhibitors in patients with melanoma. Use of consistent terminology will help to stimulate and align further research in this area

Expression of Neural Crest Markers GLDC and ERRFI1 is Correlated with Melanoma Prognosis

Regulation of particular genes during the formation of neural crest (NC) cells is also described during progression of malignant melanoma. In this context, it is of paramount importance to develop neural crest models allowing the identification of candidate genes, which could be used as biomarkers for melanoma prognosis. Here, we used a human induced Pluripotent Stem Cells (iPSC)-based approach to present novel NC-associated genes, expression of which was upregulated in melanoma. A list of 8 candidate genes, based on highest upregulation, was tested for prognostic value in a tissue microarray analysis containing samples from advanced melanoma (good versus bad prognosis) as well as from high-risk primary melanomas (early metastasizing versus non or late-metastasizing). CD271, GLDC, and ERRFI1 showed significantly higher expression in metastatic patients who died early than the ones who survived at least 30 months. In addition, GLDC and TWIST showed a significantly higher immunohistochemistry (IHC) score in primary melanomas from patients who developed metastases within 12 months versus those who did not develop metastases in 30 months. In conclusion, our iPSC-based study reveals a significant association of NC marker GLDC protein expression with melanoma prognosis

Combination of Immune Checkpoint Inhibitors and Liver-Specific Therapies in Liver-Metastatic Uveal Melanoma: Can We Thus Overcome Its High Resistance?

Uveal Melanoma (UM) is a rare disease; however, it is the most common primary intraocular malignant tumor in adults. Hematogenous metastasis, occurring in up to 50% of cases, mainly to the liver (90%), is associated with poor clinical course and treatment failure. In contrast to dramatic benefits of immunotherapy in many tumor entities, as seen in cutaneous melanoma, immune checkpoint inhibitors (ICI) do not achieve comparable results in Metastatic UM (MUM). The aim of this study was to investigate whether the combination of ICI with liver-directed therapies provides a potential survival benefit for those affected. This retrospective, single-center study, including n = 45 patients with MUM, compared the effect of combining ICI with liver-directed therapy (&ldquo;Cohort 1&rdquo;) with respect to standard therapies (&ldquo;Cohort 2&rdquo;) on overall survival (OS). Our results revealed a significant survival difference between Cohort 1 (median OS 22.5 months) and Cohort 2 (median OS 11.4 months), indicating that this combination may enhance the efficacy of immunotherapy and thus provide a survival benefit. There is an urgent need for randomized, prospective trials addressing the combination of liver-directed therapies and various strategies of immunotherapy (such as ICI; IMCgp100; personalized vaccines) in order to establish regimens which finally improve the prognosis of patients with MUM

Long-Term Management of Advanced Basal Cell Carcinoma: Current Challenges and Future Perspectives

The first-line therapy for locally advanced basal cell carcinoma (laBCC) is Hedgehog pathway inhibitors (HHIs), as they achieve good efficacy and duration of response. However, toxicity in the course of long-term treatment may lead to a decrease in the quality of life, and consequently to interruption or even discontinuation of therapy. As HHI therapy is a balancing act between effectiveness, adverse events, quality of life, and adherence, numerous successful treatment strategies have evolved, such as dose reduction and dose interruptions with on-off treatment schedules or interruptions with re-challenge after progression. As a small percentage of patients show primary or acquired resistance to HHIs, the inhibition of programmed cell death protein 1 (PD-1) has been approved as a second-line therapy, which may also be accompanied by immune-related toxicities and non-response. Thus, optimization of current treatment schedules, novel agents, and combination strategies are urgently needed for laBCC. Here, we narratively model the treatment sequence for patients with laBCC and summarize the current state of approved treatment regimens and therapeutic strategies to optimize the long-term management of laBCC