A Synopsis of Serum Biomarkers in Cutaneous Melanoma Patients

Many serum biomarkers have been evaluated in melanoma but their clinical significance remains a matter of debate. In this paper, a review of the serum biomarkers for melanoma will be detailed and will be discussed from the point of view of their practical usefulness. The expression of biomarkers can be detected intracellularly or on the cell membrane of melanoma cells or noncancer cells in association with the melanoma. Some of these molecules can then be released extracellularly and be found in body fluids such as the serum. Actually, with the emergence of new targeted therapies for cancer and the increasing range of therapeutic options, the challenge for the clinician is to assess the unique risk/response ratio and the prognosis for each patient. New serum biomarkers of melanoma progression and metastatic disease are still awaited in order to provide efficient rationale for followup and treatment choices. LDH as well as S100B levels have been correlated with poor prognosis in AJCC stage III/IV melanoma patients. However, the poor sensitivity and specificity of those markers and many other molecules are serious limitations for their routine use in both early (AJCC stage I and II) and advanced stages of melanoma (AJCC stage III and IV). Microarray technology and proteomic research will surely provide new candidates in the near future allowing more accurate definition of the individual prognosis and prediction of the therapeutic outcome and select patients for early adjuvant strategies

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma

Background: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. Methods: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. Results: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. Conclusions: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.)

Cost-effectiveness analysis in melanoma detection: a transition model applied to dermoscopy

Abstract Aim: The main aim of this study is to demonstrate how our melanoma disease model (MDM) can be used for cost-effectiveness analyses (CEAs) in the melanoma detection field. In particular, we used the data of two cohorts of Belgian melanoma patients to investigate the cost-effectiveness of dermoscopy. Methods: A MDM, previously constructed to calculate the melanoma burden, was slightly modified to be suitable for CEAs. Two cohorts of patients entered into the model to calculate morbidity, mortality and costs. These cohorts were constituted by melanoma patients diagnosed by dermatologists adequately, or not adequately, trained in dermoscopy. Effectiveness and costs were calculated for each cohort and compared. Effectiveness was expressed in quality-adjusted life years (QALYs), a composite measure depending on melanoma-related morbidity and mortality. Costs included costs of treatment and follow-up as well as costs of detection in non-melanoma patients and costs of excision and pathology of benign lesions excised to rule out melanoma. Results: The result of our analysis concluded that melanoma diagnosis by dermatologists adequately trained in dermoscopy resulted in both a gain of QALYs (less morbidity and/or mortality) and a reduction in costs. Conclusion: This study demonstrates how our MDM can be used in CEAs in the melanoma detection field. The model and the methodology suggested in this paper were applied to two cohorts of Belgian melanoma patients. Their analysis concluded that adequate dermoscopy training is cost-effective. The results should be confirmed by a large-scale randomised study

Tisotumab Vedotin in Combination with Carboplatin, Pembrolizumab, or Bevacizumab in Recurrent or Metastatic Cervical Cancer:Results from the innovaTV 205/GOG-3024/ENGOT-cx8 Study

PURPOSE Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC). METHODS This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR). RESULTS A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E).CONCLUSION TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC.</p

Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma

Background Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. Methods We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no doselimiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. Results Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab–dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab–dacarbazine group. Conclusions Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.

Interim Analysis of Phase 2 Results for Cemiplimab in Patients with Metastatic Basal Cell Carcinoma (mBCC) who Progressed on or are Intolerant to Hedgehog Inhibitors (HHIs)

Abstract not available

Importante immunité anti-tumorale et évolution clinique très favorable chez deux patients ayant reçu un vaccin autologue

Thèse de doctorat en sciences biomédicales (MIGE) -- UCL, 200

Importante immunité anti-tumorale et évolution clinique très favorable chez deux patients ayant reçu un vaccin autologue [Important antitumoral immunity and a favorable clinical outcome in two patients receiving an autologous vaccine]

La réponse immunitaire anti-tumorale de deux patients a été étudiée. La première patiente est en vie quinze and après le diagnostic d’un mélanome cutané, et ce malgré des métastases uniques récidivantes. Elle reçoit une vaccination autologue. Le deuxième patient est toujours en vie dix ans après le diagnostic d’un cancer du poumon, et bénéficie également d’une vaccination autologue. La réponse immunitaire de ces deux malades est principalement dirigée contre un seul antigène parfaitement spécifique de la tumeur. Ces réponses importantes sont facilement détectables par un nouvel outil : des complexes solubles HLA-peptides. A chaque dois, ils ‘agit d’une réponse oligoclonale, où un clone est largement majoritaire. De plus, il existe des éléments suggérant que ces réponses aient pu influer sur l’évolution clinique favorable de ces deux malade

Espérance pour les patients atteints d’un cancer grâce à l’immunothérapie et à l’avènement de nouvelles therapies ciblées

Les avancées en oncologie médicale sont encore nombreuses en 2016. Nous avons décidé de mettre en lumière quelques-unes de ces avancées. Tout d’abord, une nouvelle classe thérapeutique, les inhibiteurs CDK4/6 (palbociclib, ribociclib), suscite l’engouement. Lorsqu’ils sont associés à une hormonothérapie, la survie des patientes atteintes d’un cancer du sein métastatique exprimant des récepteurs aux oestrogènes est augmentée de plusieurs mois. Deuxièmement, les inhibiteurs PARP (niraparib) qui bloquent un des deux mécanismes de réparation de l’ADN, sont actifs chez toutes les patientes récidivant d’un cancer de l’ovaire ayant répondu à une chimiothérapie à base de sel de platine. Finalement, l’immunothérapie est devenue une thérapeutique essentielle pour le traitement des cancers et certaines courbes de survie suggèrent que probablement certains patients pourraient être guéris. L’ipilimumab, un anticorps anti CTLA-4, augmente la survie des mélanomes stade III opérés et à haut risque de rechute. La combinaison d’anticorps anti-PD1 et anti-CTLA-4 est plus efficace que les monothérapies dans le mélanome métastatique. Les anticorps anti-PD1 deviennent un standard dans le traitement du cancer tête et cou, du rein et du poumon. L’administration de ces anticorps est associée à une toxicité bien spécifique, une toxicité auto-immune qui peut être redoutable voire fatale si elle n’est pas reconnue et prise en charge rapidement. Tous ces traitements sont disponibles à l’Institut Roi Albert II.[Hope for cancer patients due to immunotherapy and the advent of new targeted therapies] Major advances in medical oncology were observed in 2016. This article highlights some of these advances. Firstly, a new therapeutic class, the CDK4/6 inhibitors (palbociclib, ribociclib), was discovered, arousing major interest. When combined with hormonotherapy, these inhibitors were shown to increase overall survival of ER-positive metastatic breast cancer patients by several months. Secondly, PARP inhibitors (niraparib) that block one of the two DNA repair mechanisms were shown active in all relapsing ovarian cancer patients with a response to platinum-based chemotherapy. Finally, immunotherapy is now generally regarded as an essential therapeutic modality in the treatment of cancer, with shapes of some survival curves suggesting that some patients could be definitely cured. Ipilimumab, an anti-CTL-4 antibody, was shown able to increase the global survival of resected Stage III melanoma patients at high risk of relapse. The combination of anti-PD1 and CTLA-4 antibodies proved superior to the respective monotherapies in the treatment of metastatic melanoma. Anti-PD1 antibodies currently represent the standard of care in the treatment of metastatic head and neck cancers, kidney cancers, and lung cancers. The administration of these antibodies was associated with a very specific, autoimmune toxicity, which was at times severe or even fatal if not recognized and treated early. All these treatments are presently accessible at the King Albert II Cancer Institute