Merkel cell carcinoma (MCC) is an infrequent, rapidly growing skin neoplasm that carries a greater probability of regional lymph node involvement, and a grim prognosis in advanced cases. While it is ...seen predominantly in old age in sun-exposed body parts, the prevalence varies among different races and geographical regions. Merkel cell polyomavirus and UV radiation-induced mutations contribute to its etiopathogenesis. The clinical presentation of MCC lacks pathognomonic features and is rarely considered highly at the time of presentation. Histopathological examination frequently reveals hyperchromatic nuclei with high mitotic activity, but immunohistochemistry is required to confirm the diagnosis. Sentinel lymph node biopsy (SLNB) and imaging are advised for effective staging of the disease. Multimodal management including surgery, radiation therapy, and/or immunotherapy are deployed. Traditional cytotoxic chemotherapies may result in an initial response, but do not result in a significant survival benefit. Checkpoint inhibitors have dramatically improved the prognosis of patients with metastatic MCC, and are recommended first-line in advanced cases. There is a need for well-tolerated agents with good safety profiles in patients who have failed immunotherapies.
Cutaneous squamous cell carcinoma (cSCC) is a common malignancy of the skin and has an overall favorable outcome, except for patients with an advanced stage of the disease. The efficacy of checkpoint ...inhibitors (CPI) for advanced cSCC has been demonstrated in recent clinical studies, but data from real-world cohorts and trial-ineligible cSCC patients are limited. We retrospectively investigated patients with advanced cSCC who have been treated with CPI in a first-line setting at eight German skin cancer centers registered within the multicenter registry ADOReg. Clinical outcome parameters including response, progression-free (PFS) and overall survival (OS), time-to-next-treatment (TTNT), and toxicity were analyzed and have been stratified by the individual immune status. Among 39 evaluable patients, the tumor response rate (rwTRR) was 48.6%, the median PFS was 29.0 months, and the median OS was not reached. In addition, 9 patients showed an impaired immune status due to immunosuppressive medication or hematological diseases. Our data demonstrated that CPI also evoked tumor responses among immunocompromised patients (rwTRR: 48.1 vs. 50.0%), although these responses less often resulted in durable remissions. In line with this, the median PFS (11 vs. 40 months, p = 0.059), TTNT (12 months vs. NR, p = 0.016), and OS (29 months vs. NR, p < 0.001) were significantly shorter for this patient cohort. CPI therapy was well tolerated in both subcohorts with 15% discontinuing therapy due to toxicity. Our real-world data show that first-line CPI therapy produced strong and durable responses among patients with advanced cSCC. Immunocompromised patients were less likely to achieve long-term benefit from anti-PD1 treatment, despite similar tumor response rates.
The advent of BRAF/MEK inhibitors (BRAFi/MEKi) has significantly improved progression-free (PFS) and overall survival (OS) for patients with advanced BRAF-V600-mutant melanoma. Long-term survivors ...have been identified particularly among patients with a complete response (CR) to BRAF/MEK-directed targeted therapy (TT). However, it remains unclear which patients who achieved a CR maintain a durable response and whether treatment cessation might be a safe option in these patients. Therefore, this study investigated the impact of treatment cessation on the clinical course of patients with a CR upon BRAF/MEK-directed-TT. We retrospectively selected patients with BRAF-V600-mutant advanced non-resectable melanoma who had been treated with BRAFi ± MEKi therapy and achieved a CR upon treatment out of the multicentric skin cancer registry ADOReg. Data on baseline patient characteristics, duration of TT, treatment cessation, tumor progression (TP) and response to second-line treatments were collected and analyzed. Of 461 patients who received BRAF/MEK-directed TT 37 achieved a CR. TP after initial CR was observed in 22 patients (60%) mainly affecting patients who discontinued TT (n = 22/26), whereas all patients with ongoing TT (n = 11) maintained their CR. Accordingly, patients who discontinued TT had a higher risk of TP compared to patients with ongoing treatment (p < 0.001). However, our data also show that patients who received TT for more than 16 months and who discontinued TT for other reasons than TP or toxicity did not have a shorter PFS compared to patients with ongoing treatment. Response rates to second-line treatment being initiated in 21 patients, varied between 27% for immune-checkpoint inhibitors (ICI) and 60% for BRAFi/MEKi rechallenge. In summary, we identified a considerable number of patients who achieved a CR upon BRAF/MEK-directed TT in this contemporary real-world cohort of patients with BRAF-V600-mutant melanoma. Sustained PFS was not restricted to ongoing TT but was also found in patients who discontinued TT.
Background
Adjuvant therapy with immune-checkpoint inhibitors (CPI) or BRAF/MEK-directed targeted therapy (TT) improves recurrence-free survival (RFS) for patients with advanced,
BRAF
V600-mutant (
...BRAF
mut) resected melanoma. However, 40% of these patients will develop distant metastases (DM) within 5 years, which require systemic therapy. Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM. This study evaluated the efficacy of subsequent treatments following tumor recurrence upon upfront adjuvant therapy.
Methods
For this multicenter cohort study, we identified 515
BRAF
mut patients with resected stage III melanoma who were treated with PD-1 inhibitors (anti-PD1) or TT in the adjuvant setting. Disease characteristics, treatment regimens, details on tumor recurrence, subsequent treatment management, and survival outcomes were collected within the prospective, real-world skin cancer registry ADOReg. Primary endpoints included progression-free survival (PFS) following DM and best tumor response to first-line (1L) treatments.
Results
Among 515 eligible patients, 273 patients received adjuvant anti-PD1 and 242 adjuvant TT. At a median follow-up of 21 months, 54.6% of anti-PD1 patients and 36.4% of TT patients recurred, while 39.6% (anti-PD1) and 29.3% (TT) developed DM. Risk of recurrence was significantly reduced in patients treated with TT compared with anti-PD1 (adjusted HR 0.52; 95% CI 0.40 to 0.68, p<0.001). Likewise, median RFS was significantly longer in TT-treated patients (31 vs 17 months, p<0.001). Patients who received TT as second adjuvant treatment upon locoregional recurrence had a longer RFS2 as compared with adjuvant CPI (41 vs 6 months, p=0.009). Patients who recurred at distant sites following adjuvant TT showed favorable response rates (42.9%) after switching to 1L ipilimumab+nivolumab (ipi+nivo). Patients with DM during adjuvant anti-PD1 achieved response rates of 58.7% after switching to 1L TT and 35.3% for 1L ipi+nivo. Overall, median PFS was significantly longer in patients who switched treatments for stage IV disease (median PFS 9 vs 5 months, p=0.004).
Conclusions
BRAF
mut melanoma patients who developed DM upon upfront adjuvant therapy achieve favorable tumor control and prolonged PFS after switching treatment modalities in the first-line setting of stage IV disease. Patients with locoregional recurrence benefit from complete resection of recurrence followed by a second adjuvant treatment with TT.
Background Immune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%–46%. However, irMyocarditis can be asymptomatic. Thus, ...improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management. Methods Patients with cardiac irAEs from the SERIO registry ( www.serio-registry.org ) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases ( n = 12) were analyzed by Nanostring and compared to healthy heart muscle ( n = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients ( n = 4 baseline and n = 8 during irAE) in comparison to patients without toxicity under ICI-therapy ( n = 4 baseline and n = 7 during ICI-therapy) using flow cytometry. Results A total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and –if required–second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4–1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis. Conclusion Interestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity.
Side effects due to allergic reactions to vaccine antigen or to additives such as chicken protein or gelatin have been known for some time. Recent findings regarding reactions mediated via the ...carbohydrate epitope galactose-alpha-1,3-galactose (alpha-gal), a constituent of animal gelatin, broaden the spectrum of gelatin-related allergies. This case series presents four patients who developed anaphylactic reactions following rabies vaccination using the vaccine Rabipur®. After appropriate allergy testing by skin prick testing and the determination of specific IgE to allergens in the vaccine, triggering by alpha-gal could be excluded and an allergy to gelatin was detected. The absence of allergic symptoms following the consumption of gelatin could potentially be explained through intestinal hydrolysis resulting in a loss of allergenic potency. Further implications related to the use of gelatin-containing infusions in emergency medicine are discussed.
Heterodimeric β2 integrin surface receptors (CD11a-d/CD18) are specifically expressed by leukocytes that contribute to pathogen uptake, cell migration, immunological synapse formation and cell ...signaling. In humans, the loss of CD18 expression results in leukocyte adhesion deficiency syndrome (LAD-)1, largely characterized by recurrent severe infections. All available mouse models display the constitutive and ubiquitous knockout of either α or the common β2 (CD18) subunit, which hampers the analysis of the cell type-specific role of β2 integrins in vivo. To overcome this limitation, we generated a CD18 gene floxed mouse strain. Offspring generated from crossing with CD11c-Cre mice displayed the efficient knockdown of β2 integrins, specifically in dendritic cells (DCs). Stimulated β2-integrin-deficient splenic DCs showed enhanced cytokine production and the concomitantly elevated activity of signal transducers and activators of transcription (STAT) 1, 3 and 5, as well as the impaired expression of suppressor of cytokine signaling (SOCS) 2–6 as assessed in bone marrow-derived (BM) DCs. Paradoxically, these BMDCs also showed the attenuated expression of genes involved in inflammatory signaling. In line, in experimental autoimmune encephalomyelitis mice with a conditional DC-specific β2 integrin knockdown presented with a delayed onset and milder course of disease, associated with lower frequencies of T helper cell populations (Th)1/Th17 in the inflamed spinal cord. Altogether, our mouse model may prove to be a valuable tool to study the leukocyte-specific functions of β2 integrins in vivo.
BackgroundAdjuvant therapy with immune-checkpoint inhibitors (CPI) or BRAF/MEK-directed targeted therapy (TT) improves recurrence-free survival (RFS) for patients with advanced, BRAFV600-mutant ...(BRAFmut) resected melanoma.1–6 However, 40% of these patients will develop distant metastasis (DM) within 5 years, which require systemic treatments.2 5 Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM.7 8 This study evaluated the efficacy of subsequent treatments following recurrence upon upfront adjuvant therapy.MethodsFor this multicenter cohort study, we identified 515 BRAFmut patients with resected stage III melanoma who were treated with PD-1 inhibitors (anti-PD1) or TT in the adjuvant setting (figure 1). Disease characteristics, treatment regimens, details on recurrence, subsequent management and survival outcomes were collected within the prospective, real-world registry ADOReg. Primary endpoints included progression-free survival (PFS) following DM and best tumor response to subsequent treatments.ResultsAmong 515 eligible patients, 273 patients received adjuvant anti-PD1 and 242 adjuvant TT. At a median follow-up of 21.0 months, 54.6% of anti-PD1 patients and 36.4% of TT patients recurred, while 39.6% (anti-PD1) and 29.3% (TT) developed DM. Risk of recurrence was significantly reduced in patients treated with TT compared to anti-PD1 (Hazard ratio adjusted for age, gender and baseline AJCC stage: 0.52; 95% CI: 0.40–0.68, p<0.001). Likewise, median RFS was significantly longer in TT-treated patients (31.0 vs 17.0 months, p<0.001) (figure 2). Patients who received TT as second adjuvant treatment following resection of locoregional recurrence had a longer RFS2 as compared to adjuvant CPI (median RFS2: 41.0 vs 6 months, p=0.009). Patients who recurred at distant sites following adjuvant TT showed favorable response rates (42.9%) after switching to first-line treatment (1L) with Ipilimumab+Nivolumab (IPI+Nivo) (table 1). By contrast, patients with DM during adjuvant anti-PD1 achieved response rates of 58.7% after switching to 1L TT and 35.3% for 1L IPI+Nivo (table 2). Overall, median PFS was significantly longer for patients who switched treatments for metastatic disease (median PFS 9 vs 5 months, p=0.004) (figure 3).ConclusionsIn this real-world cohort study we demonstrate that BRAFmut melanoma patients who developed DM upon adjuvant therapy achieve favorable tumor control and prolonged PFS after switching treatment modalities in the first-line setting of stage IV disease. Patients with locoregional recurrence benefit from complete resection followed by second adjuvant treatment with TT. Upfront adjuvant TT significantly reduced the risk of recurrence compared to adjuvant anti-PD1 therapy.References1. Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. New England Journal of Medicine. 2018;378(19):1789–801.2. Eggermont Alexander MM, Kicinski M, Blank Christian U, Mandala M, Long Georgina V, Atkinson V, et al. Five-Year analysis of adjuvant pembrolizumab or placebo in stage III melanoma. NEJM Evidence. 2022;1(11):EVIDoa2200214.3. Weber J, Del Vecchio M, Mandala M, Gogas H, Arance A, Dalle S, et al. Adjuvant nivolumab (NIVO) versus ipilimumab (IPI) in resected stage III/IV melanoma: 3-year efficacy and biomarker results from the phase III CheckMate 238 trial. Annals of Oncology. 2019;30:v533–v4.4. Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824–35.5. Dummer R, Brase JC, Garrett J, Campbell CD, Gasal E, Squires M, et al. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. The Lancet Oncology. 2020;21(3):358–72.6. Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. New England Journal of Medicine. 2017;377(19):1813–23.7. Owen CN, Shoushtari AN, Chauhan D, Palmieri DJ, Lee B, Rohaan MW, et al. Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy. Annals of Oncology. 2020;31(8):1075–82.8. Bhave P, Pallan L, Long GV, Menzies AM, Atkinson V, Cohen JV, et al. Melanoma recurrence patterns and management after adjuvant targeted therapy: a multicentre analysis. British Journal of Cancer. 2021;124(3):574–80.Abstract 459 Table 1Response to first-line treatments following distant metastasis after adjuvant anti-PD1 therapyAbstract 459 Table 2Response to first line treatments following distant metastasis after adjuvant TTAbstract 459 Figure 1CONSORT diagram for patients investigated in the study. In this study we investigated treatment outcomes following recurrence following adjuvant melanoma therapy (primary study cohort), as well as efficacy of upfront adjuvant melanoma in general (secondary study cohort). Overall, 242 patients that received adjuvant BRAF/MEKi therapy or adju- vant anti-PD1 therapy (n=273). Among patients receiving BRAF/MEKi therapy 154 did not show any tumor recurrence in the observation period, while among the 71 patients that progressed to stage IV and received subsequent systemic treat- ments 28 patients achieved disease control without disease progression at the time of data cut-off. By contrast, among all patients that received adjuvant anti-PD1 treatment, 124 patients did not show a tumor recurrence. Among patients that progressed to metastatic stage IV upon adjuvant anti-PD1 treatment (n=108) 43 achieved disease control without disease progression at the time of data cut-off. Patients who progressed to metastatic stage IV and who did not receive CPI or TT either received best-supportive care (BSC) including locoregional treatments such as surgery or TVEC or deceased prior to initiation of systemic treatments. Abbreviations: 1L = first-line treatment for metastatic stage IV disease; CPI =check- point inhibitor therapy; BSC = best supportiv care; CTX = chemotherapy; TT = BRAF/MEK-directed targeted therapyAbstract 459 Figure 2Survival outcomes for patients with resected stage III melanoma that were treated outside of clini- cal trials stratified by upfront adjuvant therapy. (A) Median recurrence-free survival was significantly longer for patients given adjuvant TT as compared to adjuvant anti-PD1 (31.0 months, 95% CI: 26.0–36.0 vs 17.0 months, 95% CI: 11.9–22.1, p<0.001) as assessed by log-rank test. (B) Forest plot illustrating results of multivariable Cox-re- gression for relapse-free survival and corresponding HR. (C) Cox-adjusted Kaplan-Meier curves for recurrence-free survival (bottom, left) and time-point differences in adjusted RFS between patients treated with upfront adjuvant an- ti-PD1 vs upfront adjuvant TT. Abbreviations: TT BRAF/MEK-directed targeted therapy; HR = hazard ratio.Abstract 459 Figure 3Kaplan Meier survival plots comparing survival outcomes stratified by treatment regimen (A, C) and individual first-line treat- ments (B,C), as well as tumor response rates of first-line treatments following adjuvant treatment failure (E,F). Results show that switching treatment modalities between adjuvant therapy and first metastatic treatment particularly results in longer median PFS (9 months, 95% CI: 5.2–12.8 vs 5 months, 95% CI: 1.3–8.7, p=0.004), although median OS (35.0 months vs NR, p=0.079) was not significantly different between the two treatment re- gimens (C). More specifically we observed that patients with a re-challenge of 1L BRAF/MEKi after failure of adjuvant TT showed the least favorable survival data. These patients presented with a median PFS of 3.0 months (95% CI: 0–6.2) as compared to 8.0 months (95% CI. 1.3–14.7) for patients switching to 1L CPI after previous TT-failure. By conrrast, patients who recurred at distant sites followign adjuvant anti-PD1 and received CPI in the 1L setting achieved a median PFS of 6.0 months (95% CI: 1.5–10.5) and 11.0 months (95% CI: 5.5–16.5) for patients switching from adjuvant anti-PD1 to 1L BRAF/MEKI. Also, median OS was significantly shorter for patients who received BRAF/MEKI both in the adjuvant setting and following distant me- tastasis (median OS: 21.0 months, 95% CI: 14.5–45.5), while median OS was not reached for all other subgroups (p=0.004). In line, tumor responses were strongest for patients that switched treatments following adjuvant treatment failure (E, F). Abbreviations: 1L = first-line treatment for metastastic stage IV disease; BRAF/MEKI = BRAF/MEK-directed targeted therapy; IPI+Nivo = Ipilimumab plus Nivolumab; CPI mono = single-agent checkpoint inhibitor therapy; Tx = treatment; TT = BRAF/MEK-directed targeted therapy. ‘p-value<0.05, ns = not significant.
The approval of immune-checkpoint inhibitors (CPI) and mitogen activated protein kinase inhibitors (MAPKi) in recent years significantly improved the treatment management and survival of patients ...with advanced malignant melanoma. CPI aim to counter-act receptor-mediated inhibitory effects of tumor cells and immunomodulatory cell types on effector T cells, whereas MAPKi are intended to inhibit tumor cell survival. In agreement with these complementary modes of action preclinical data indicated that the combined application of CPI and MAPKi or their optimal sequencing might provide additional clinical benefit. In this review the rationale and preclinical evidence that support the combined application of MAPKi and CPI either in concurrent or consecutive regimens are presented. Further, we will discuss the results from clinical trials investigating the sequential or combined application of MAPKi and CPI for advanced melanoma patients and their implications for clinical practice. Finally, we outline mechanisms of MAPKi and CPI cross-resistance which limit the efficacy of currently available treatments, as well as combination regimens.
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