Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial

Luke, Jason J.; Rutkowski, Piotr; Queirolo, Paola; Vecchio, Michele Del; Mackiewicz, Jacek; Chiarion-Sileni, Vanna; Merino, Luis de la Cruz; Khattak, Muhammad A.; Schadendorf, Dirk; Long, Georgina V.; Ascierto, Paolo A.; Mandalà, Mario; Galitiis, Federica De; Haydon, Andrew; Dummer, Reinhard; Grob, Jean‐Jacques; Robert, Caroline; Carlino, Matteo S.; Mohr, Peter; Poklepovic, Andrew; Sondak, Vernon K.; Scolyer, Richard A.; Kirkwood, John M.; Chen, Ke; Diede, Scott J.; Ahsan, Sama; Ibrahim, Nageatte; Eggermont, Alexander M.M.

doi:10.1016/s0140-6736(22)00562-1

Cited by 344 publications

(240 citation statements)

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“…This provides some support for the notion that a lack of PD-1 expression by CD8+ T cells could be beneficial to primary melanoma patient outcomes. In light of ongoing clinical trials of adjuvant anti-PD-1 therapy in stage II melanoma and the recent approval by the FDA for adjuvant pembrolizumab for stage II melanoma ( 5 ), investigating these CD8+ T cell populations within the context of primary melanoma immunotherapy is of great interest.…”

Section: Discussionmentioning

confidence: 99%

“…With further validation, P1 and P2 CD8+ T cells and B cells could act independently as biomarkers for recurrence in primary melanoma. Identifying patients with a high risk of recurrence could allow these patients to be given adjuvant immunotherapy immediately following primary melanoma excision ( 5 ), which could greatly reduce their risk of recurrence.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, patients with stage IIB/C primary melanoma have a higher risk of melanoma-related death compared to patients with stage IIIA/B metastatic melanomas (87-82% vs 93-83% 5-year survival) ( 4 ). While surgery is curative for the majority of primary melanoma patients, a recent clinical trial demonstrated improved recurrence-free survival in high-risk stage II (stage IIB/C) melanoma patients receiving adjuvant anti-PD-1 therapy ( 5 ). However, a proportion of patients experienced immune-related adverse events, some irreversible.…”

Section: Introductionmentioning

confidence: 99%

“…Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia, 2 Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia, 3 Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia, 4 Centenary Institute, The University of Sydney, Sydney, NSW, Australia, 5 Westmead and Blacktown Hospitals, Sydney, NSW, Australia, 6 Royal Prince Alfred Hospital, Sydney, NSW, Australia, 7 Mater Hospital, North Sydney, NSW, Australia, 8 Royal North Shore Hospital, St Leonards, NSW, Australia, 9 NSW Health Pathology, Sydney, NSW, Australia While the tumor immune microenvironment (TIME) of metastatic melanoma has been well characterized, the primary melanoma TIME is comparatively poorly understood. Additionally, although the association of tumor-infiltrating lymphocytes with primary melanoma patient outcome has been known for decades, it is not considered in the current AJCC melanoma staging system.…”

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confidence: 99%

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Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome

et al. 2022

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While the tumor immune microenvironment (TIME) of metastatic melanoma has been well characterized, the primary melanoma TIME is comparatively poorly understood. Additionally, although the association of tumor-infiltrating lymphocytes with primary melanoma patient outcome has been known for decades, it is not considered in the current AJCC melanoma staging system. Detailed immune phenotyping of advanced melanoma has revealed multiple immune biomarkers, including the presence of CD8+ T-cells, for predicting response to immunotherapies. However, in primary melanomas, immune biomarkers are lacking and CD8+ T-cells have yet to be extensively characterized. As recent studies combining immune features and clinicopathologic characteristics have created more accurate predictive models, this study sought to characterize the TIME of primary melanomas and identify predictors of patient outcome. We first phenotyped CD8+ T cells in fresh stage II primary melanomas using flow cytometry (n = 6), identifying a CD39+ tumor-resident CD8+ T-cell subset enriched for PD-1 expression. We then performed Opal multiplex immunohistochemistry and quantitative pathology-based immune profiling of CD8+ T-cell subsets, along with B cells, NK cells, Langerhans cells and Class I MHC expression in stage II primary melanoma specimens from patients with long-term follow-up (n = 66), comparing patients based on their recurrence status at 5 years after primary diagnosis. A CD39+CD103+PD-1- CD8+ T-cell population (P2) comprised a significantly higher proportion of intratumoral and stromal CD8+ T-cells in patients with recurrence-free survival (RFS) ≥5 years vs those with RFS <5 years (p = 0.013). Similarly, intratumoral B cells (p = 0.044) and a significantly higher B cell density at the tumor/stromal interface were associated with RFS. Both P2 and B cells localized in significantly closer proximity to melanoma cells in patients who remained recurrence-free (P2 p = 0.0139, B cell p = 0.0049). Our results highlight how characterizing the TIME in primary melanomas may provide new insights into how the complex interplay of the immune system and tumor can modify the disease outcomes. Furthermore, in the context of current clinical trials of adjuvant anti-PD-1 therapies in high-risk stage II primary melanoma, assessment of B cells and P2 could identify patients at risk of recurrence and aid in long-term treatment decisions at the point of primary melanoma diagnosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome

et al. 2022

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“…According to current guidelines, these patients are treated with a curative-intent resection with additional sentinel lymph node biopsy (SLNB), subject to melanoma Breslow thickness ≥ 0.8 mm or < 0.8 mm with ulceration ( 7 ). In case of sentinel lymph node (SLN)–positive disease, adjuvant systemic treatment with a programmed cell death-1 (PD-1) monoclonal antibody (mAb) is now approved by the U.S. Food and Drug Administration (FDA) for patients with high-risk stage III melanoma and for patients with pathology-confirmed high-risk stage IIB or IIC melanoma ( 8 , 9 ). Recurrence rates in early-stage patients run as high as 16 to 30% ( 10 , 11 ), and the 10-year melanoma-specific survival can run as low as 75%, depending on risk factors such as Breslow thickness, tumor ulceration, and mitotic rate.…”

Section: Introductionmentioning

confidence: 99%

Local delivery of low-dose anti–CTLA-4 to the melanoma lymphatic basin leads to systemic T _reg reduction and effector T cell activation

et al. 2022

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Preclinical studies show that locoregional CTLA-4 blockade is equally effective in inducing tumor eradication as systemic delivery, without the added risk of immune-related side effects. This efficacy is related to access of the CTLA-4 blocking antibodies to tumor-draining lymph nodes (TDLNs). Local delivery of anti–CTLA-4 after surgical removal of primary melanoma, before sentinel lymph node biopsy (SLNB), provides a unique setting to clinically assess the role of TDLN in the biological efficacy of locoregional CTLA-4 blockade. Here, we have evaluated the safety, tolerability, and immunomodulatory effects in the SLN and peripheral blood of a single dose of tremelimumab [a fully human immunoglobulin gamma-2 (IgG2) mAb directed against CTLA-4] in a dose range of 2 to 20 mg, injected intradermally at the tumor excision site 1 week before SLNB in 13 patients with early-stage melanoma (phase 1 trial; NCT04274816). Intradermal delivery was safe and well tolerated and induced activation of migratory dendritic cell (DC) subsets in the SLN. It also induced profound and durable decreases in regulatory T cell (T reg ) frequencies and activation of effector T cells in both SLN and peripheral blood. Moreover, systemic T cell responses against NY-ESO-1 or MART-1 were primed or boosted ( N = 7), in association with T cell activation and central memory T cell differentiation. These findings indicate that local administration of anti–CTLA-4 may offer a safe and promising adjuvant treatment strategy for patients with early-stage melanoma. Moreover, our data demonstrate a central role for TDLN in the biological efficacy of CTLA-4 blockade and support TDLN-targeted delivery methods.

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Stage-Specific Risk of Recurrence and Death From Melanoma in Denmark, 2008-2021

Helvind,

Brinch-Møller Weitemeyer,

Chakera

et al. 2023

JAMA Dermatol

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ImportanceTo ensure optimal treatment and surveillance of patients with melanoma, knowledge of the clinical stage-specific risk of recurrence, mortality, and recurrence patterns across the American Joint Committee on Cancer Eighth Edition (AJCC8) substages is needed.ObjectiveTo estimate stage-specific recurrence and melanoma-specific mortality rates, assess absolute stage-specific risks of recurrence and mortality, and describe stage-specific recurrence patterns, including conditional rates.DesignRetrospective cohort study of prospectively collected nationwide population-based registry data.SettingNationwide, population-based cohort study.ParticipantsThe 25 720 Danish patients, 18 years or older, diagnosed with first-time stage IA to IV cutaneous melanoma between January 1, 2008, and December 31, 2019, were included and followed up from time of primary treatment until December 31, 2021.ExposuresFirst diagnosis of stage IA to IV cutaneous melanoma.Main OutcomesStage-specific cumulative incidence of recurrence and melanoma-specific mortality, melanoma-specific recurrence-free survival, and assessed absolute stage-specific risks of recurrence and melanoma-specific mortality. Secondary outcomes were stage-specific recurrence patterns, including conditional rates, and melanoma-specific survival.ResultsWe followed up 25 720 patients for a median of 5.9 years (95% CI, 58.9-59.3 years). Mean age was 59.1 years (95% CI, 58.9-59.3 years). Patients with stage IIB to IIC melanoma were older, had more comorbidities at diagnosis, and had the lowest rate of pathologic staging by sentinel node biopsy (81.6%-87.4%). A total of 10.6% of patients developed recurrence; first recurrence included distant recurrence, alone or with synchronous locoregional recurrence, in 56.6% of patients. We found a comparable risk of recurrence in stages IIIA and IIB (29.7% vs 33.2%) and in stages IIIB and IIC (35.9% vs 36.8%), respectively. Melanoma-specific mortality was comparable between stages IIIA and IIA (13.0% vs 13.6%) and between stages IIIB and IIB (18.4% vs 22.0%), respectively. These risk patterns persisted in cause-specific hazards models.Conclusions and RelevanceThis nationwide, population-based cohort study found that the increasing stages of the current AJCC8 staging system do not accurately reflect an increasing risk of recurrence and mortality in melanoma. The high proportion of distant recurrences suggests that hematogenous spread is a more common metastatic pathway than previously assumed, and surveillance with routine functional/cross-sectional imaging should be considered for stages IIB to IV. Future efforts should be put toward developing new tools for risk stratification and determining the survival effect of routine imaging in surveillance.

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Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial

Cited by 344 publications

References 19 publications

Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome

Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome

Local delivery of low-dose anti–CTLA-4 to the melanoma lymphatic basin leads to systemic T _reg reduction and effector T cell activation

Stage-Specific Risk of Recurrence and Death From Melanoma in Denmark, 2008-2021

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Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial

Cited by 344 publications

References 19 publications

Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome

Detailed spatial immunophenotyping of primary melanomas reveals immune cell subpopulations associated with patient outcome

Local delivery of low-dose anti–CTLA-4 to the melanoma lymphatic basin leads to systemic T reg reduction and effector T cell activation

Stage-Specific Risk of Recurrence and Death From Melanoma in Denmark, 2008-2021

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Local delivery of low-dose anti–CTLA-4 to the melanoma lymphatic basin leads to systemic T _reg reduction and effector T cell activation