The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial ...to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma.
Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated.
At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% 95% confidence interval {CI}, 71.3 to 78.9 vs. 61.0% 95% CI, 56.5 to 65.1; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% 95% CI, 72.7 to 80.9 in the pembrolizumab group and 62.6% 95% CI, 57.7 to 67.0 in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group.
As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).
Melanoma Schadendorf, Dirk; van Akkooi, Alexander C J; Berking, Carola ...
The Lancet (British edition),
09/2018, Letnik:
392, Številka:
10151
Journal Article
Recenzirano
Cutaneous melanoma causes 55 500 deaths annually. The incidence and mortality rates of the disease differ widely across the globe depending on access to early detection and primary care. Once ...melanoma has spread, this type of cancer rapidly becomes life-threatening. For more than 40 years, few treatment options were available, and clinical trials during that time were all unsuccessful. Over the past 10 years, increased biological understanding and access to innovative therapeutic substances have transformed advanced melanoma into a new oncological model for treating solid cancers. Treatments that target B-Raf proto-oncogene serine/threonine-kinase (BRAF)V600 (Val600) mutations using selected BRAF inhibitors combined with mitogen-activated protein kinase inhibitors have significantly improved response and overall survival. Furthermore, advanced cutaneous melanoma has developed into a prototype for testing checkpoint-modulating agents, which has increased hope for long-term tumour containment and a potential cure. These expectations have been sustained by clinical success with targeted agents and antibodies that block programmed cell-death protein 1 in locoregional disease, which induces prolongation of relapse-free, distant-metastasis-free, and overall survival times.
The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six ...clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%, P < 0.001) and OS (pCR 2-year OS 95% versus no pCR 83%, P = 0.027). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma.
A unique collaboration of multidisciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO), and the European Organization of Research and ...Treatment of Cancer (EORTC) was formed to make recommendations on cutaneous melanoma diagnosis and treatment, based on the systematic literature reviews and the experts' experience. Cutaneous melanomas are excised with one to 2-cm safety margins. Sentinel lymph node dissection shall be performed as a staging procedure in patients with tumor thickness ≥1.0 mm or ≥0.8 mm with additional histological risk factors, although there is as yet no clear survival benefit for this approach. Therapeutic decisions in stage III/IV patients should be primarily made by an interdisciplinary oncology team (“tumor board”). Adjuvant therapies can be proposed in stage III/completely resected stage IV patients and are primarily anti-PD-1, independent of mutational status, or alternatively dabrafenib plus trametinib for BRAF mutant patients. In distant metastases (stage IV), either resected or not, systemic treatment is always indicated. For first-line treatment particularly in BRAF wild-type patients, immunotherapy with PD-1 antibodies alone or in combination with CTLA-4 antibodies shall be considered. In stage IV melanoma with a BRAF-V600 E/K mutation, first-line therapy with BRAF/MEK inhibitors can be offered as an alternative to immunotherapy. In patients with primary resistance to immunotherapy and harboring a BRAF-V600 E/K mutation, this therapy shall be offered as second-line therapy. Systemic therapy in stage III/IV melanoma is a rapidly changing landscape, and it is likely that these recommendations may change in the near future.
Tumor immune cell compositions play a major role in response to immunotherapy, but the heterogeneity and dynamics of immune infiltrates in human cancer lesions remain poorly characterized. Here, we ...identify conserved intratumoral CD4 and CD8 T cell behaviors in scRNA-seq data from 25 melanoma patients. We discover a large population of CD8 T cells showing continuous progression from an early effector “transitional” into a dysfunctional T cell state. CD8 T cells that express a complete cytotoxic gene set are rare, and TCR sharing data suggest their independence from the transitional and dysfunctional cell states. Notably, we demonstrate that dysfunctional T cells are the major intratumoral proliferating immune cell compartment and that the intensity of the dysfunctional signature is associated with tumor reactivity. Our data demonstrate that CD8 T cells previously defined as exhausted are in fact a highly proliferating, clonal, and dynamically differentiating cell population within the human tumor microenvironment.
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•scRNA-seq and TCR analysis in melanoma identifies a gradient of T cell dysfunction•Cytotoxic T cells are unconnected to the dysfunctional gradient•Proliferation in CD8 T cells is most profound during early stages of dysfunction•The abundance of dysfunctional CD8 T cells is associated with tumor recognition
Single-cell analysis of melanoma tumor immune infiltrates reveals a separation between bystander cytotoxic T cells and a population that displays a continuous progression from a transitional toward a dysfunctional state that is associated with active proliferation and tumor reactivity.
Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumor and causes 90% of skin cancer mortality. A unique collaboration of multi-disciplinary experts from the European ...Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization for Research and Treatment of Cancer (EORTC) was formed to make recommendations on CM diagnosis and treatment, based on systematic literature reviews and the experts' experience. The diagnosis of melanoma can be made clinically and shall always be confirmed with dermatoscopy. If a melanoma is suspected, a histopathological examination is always required. Sequential digital dermatoscopy and full body photography can be used in high-risk patients to improve the detection of early melanoma. Where available, confocal reflectance microscopy can also improve clinical diagnosis in special cases. Melanoma shall be classified according to the 8th version of the American Joint Committee on Cancer classification. Thin melanomas up to 0.8 mm tumor thickness do not require further imaging diagnostics. From stage IB onwards, examinations with lymph node sonography are recommended, but no further imaging examinations. From stage IIC onwards whole-body examinations with computed tomography (CT) or positron emission tomography CT (PET-CT) in combination with brain magnetic resonance imaging are recommended. From stage III and higher, mutation testing is recommended, particularly for BRAF V600 mutation. It is important to provide a structured follow-up to detect relapses and secondary primary melanomas as early as possible. There is no evidence to define the frequency and extent of examinations. A stage-based follow-up scheme is proposed which, according to the experience of the guideline group, covers the optimal requirements, but further studies may be considered. This guideline is valid until the end of 2024.
Talimogene laherparepvec (T‐VEC) is a modified herpes simplex virus, type 1 (HSV‐1), which can be administered intralesionally in patients with stage IIIB/C‐IVM1a unresectable melanoma (EMA label). ...The phase 3 OPTiM registration study showed an overall response rate (ORR) of 26%. Since December 2016, 48 eligible patients started treatment at the Netherlands Cancer Institute. We included 26 patients in this study with a follow up time ≥6 months, reporting Overall Response Rate (ORR), Disease Control Rate (DCR), Adverse Events (AE), prior treatment for melanoma and baseline characteristics, documented in a prospectively maintained database. In house developed treatment protocol consists of clinical evaluation, periodic PET‐CT and histological biopsies for response evaluation. Median follow‐up was 12.5 months. Of 26 patients, 16 (61.5%) had a Complete Response (CR) as their best response. Seven (26.9%) patients had a Partial Response (PR) as their best response, 1 (3.8%) patient Stable Disease (SD) and 2 (7.7%) patients Progressive Disease (PD). Best ORR was 88.5%. DCR was 92.3%. Grade 1–2 AEs occurred in all patients. Mostly, these consisted of fatigue, influenza‐like symptoms and injection site erythema. All patients underwent prior treatment. Prior treatment did not influence response or toxicity of T‐VEC. Best ORR for T‐VEC monotherapy at our institute was 88.5% with 61.5% achieving a CR. This prospective study for T‐VEC in early metastatic (stage IIIB/C‐IVM1a) melanoma demonstrated superior results to the phase 3 OPTiM study and confirms the role of oncolytic immunotherapy for melanoma.
What's new?
Talimogene laherparepvec (T‐VEC) is a modified herpes simplex virus, type 1 (HSV‐1), which is registered for the treatment of stage IIIB/C‐IVM1a unresectable locally advanced melanoma. Here the authors evaluated the response to this drug in 26 patients with a follow up longer than 6 months. They demonstrate promising response rates, with 61.5% of their treated patients achieving a CR. This indicates a strong potential of this novel drug in the rapidly developing field of immunotherapeutic treatment of melanoma.
Background
Immune checkpoint inhibitor treatment of patients with metastatic Merkel cell carcinoma (mMCC) has shown high response rates, ranging from 33% to 73%. The ideal duration of treatment, ...however, is currently unknown. The aim of this study was to evaluate if avelumab treatment for mMCC can be safely stopped after 1 year of treatment and a complete response (CR) confirmed by fluorodeoxyglucose positron emission tomography/computed tomography (FDG‐PET/CT) imaging.
Methods
Patients who received more than one dose of avelumab treatment for mMCC between November 2017 and February 2022 were included in this study. Treatment was discontinued in case of a FDG‐PET/CT confirmed CR after 1 year (26 cycles) of avelumab or a CR and unacceptable toxicity earlier. The primary end point was recurrence‐free survival (RFS).
Results
Sixty‐five patients were included: 25 (38%) had a FDG‐PET/CT–confirmed CR at discontinuation of avelumab. In those 25 patients, reasons for discontinuation of treatment were completion of 1 year of treatment in 13 (52%), toxicity in five (20%), and patient preference in seven (28%). Median duration of treatment in this group was 11 months (interquartile range, 6.1–11.7). Median follow‐up was 27 months (interquartile range, 15.8–33.8). The 12‐month RFS was 88% (95% CI, 0.74–1) and median RFS was not reached. Two patients (8%) had a recurrence at 4 and 7 months after discontinuation of treatment.
Conclusions
Patients with mMCC who acquire a CR on PET/CT imaging appear to have durable responses after discontinuation of treatment after 1 year.
The optimal duration of avelumab treatment for metastatic Merkel cell carcinoma is unknown. Here, we show that avelumab treatment can be safely stopped after 1 year and a positron emission tomography/computed tomography–confirmed complete response.
Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells. However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to ...immunotherapy. Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cytotoxic T cells and observe strong enrichment of a pre-existing NGFR
population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRAF + MEK inhibitors. NGFR
cells induce the neurotrophic factor BDNF, which contributes to T cell resistance, as does NGFR. In melanoma patients, a tumor-intrinsic NGFR signature predicts anti-PD-1 therapy resistance, and NGFR
tumor fractions are associated with immune exclusion. Lastly, pharmacologic NGFR inhibition restores tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFR
multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention.
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