KEYNOTE-022 Part 3: Phase II randomized study of 1L dabrafenib (D) and trametinib (T) plus pembrolizumab (Pembro) or placebo (PBO) for BRAF-mutant advanced melanoma

Ascierto, Paolo A.; Ferrucci, Pier Francesco; Stephens, Rosalie; Vecchio, Michele Del; Atkinson, Victoria; Schmidt, Henrik; Schachter, Jacob; Queirolo, Paola; Long, Georgina V.; Giacomo, Anna Maria Di; Svane, Inge Marie; Lotem, Michal; Bar‐Sela, Gil; Couture, Félix; Mookerjee, Bijoyesh; Ghori, Razi; Ibrahim, Nageatte; Moreno, Blanca Homet; Ribas, Antoni

doi:10.1093/annonc/mdy289

Cited by 46 publications

(27 citation statements)

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“…Avelumab has also achieved high rates of response and was well tolerated as first-line therapy in patients with distant metastatic MCC, with a confirmed ORR of 62.1% [56]. These data are supported by results of a European expanded access programme, which has reported physician-assessed objective responses in 54.3% (n = 57) of patients and a disease control rate (DCR) of 75% [57]. Taken together, these data suggest that checkpoint inhibitors may represent a new standard of care for advanced MCC.…”

Section: Immunotherapy For Merkel Cell Carcinoma: Present and Futurementioning

confidence: 87%

Perspectives in immunotherapy: meeting report from the “Immunotherapy Bridge 2018” (28–29 November, 2018, Naples, Italy)

Ascierto

Buonaguro

Emens

et al. 2019

j. immunotherapy cancer

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Immunotherapy is now widely established as a potent and effective treatment option across several types of cancer. However, there is increasing recognition that not all patients respond to immunotherapy, focusing attention on the immune contexture of the tumor microenvironment (TME), drivers of the immune response and mechanisms of tumor resistance to immunity. The development of novel immunotherapeutics and their use in combination with checkpoint inhibitors and other standard of care and novel treatment modalities is an area of particular attention across several tumor types, including melanoma, lung, ovarian, breast, pancreatic, renal, head and neck, brain and non-melanoma skin cancers. The 4th Immunotherapy Bridge meeting (28-29 November, 2018, Naples, Italy) focused on a wide range of evolving topics and trends in the field of cancer immunotherapy and key presentations from this meeting are summarised in this report.

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Section: Immunotherapy For Merkel Cell Carcinoma: Present and Futurementioning

confidence: 87%

Perspectives in immunotherapy: meeting report from the “Immunotherapy Bridge 2018” (28–29 November, 2018, Naples, Italy)

Ascierto

Buonaguro

Emens

et al. 2019

j. immunotherapy cancer

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“…The primary outcome of PFS was 16 months for the pembrolizumab arm and 10.3 months for the placebo arm (HR 0.66), but this outcome did not reach significance for the prespecified HR goal. In addition, the triplet combination was more toxic with 58% of patients experiencing grade 3-5 adverse events (115).…”

Section: Targeted Agentsmentioning

confidence: 99%

Immunotherapy of Melanoma: Facts and Hopes

Weiss

Wolchok

Sznol

2019

Clinical Cancer Research

217

152

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Melanoma is among the most sensitive of malignancies to immune modulation. Although multiple trials conducted over decades with vaccines, cytokines, and cell therapies demonstrated meaningful responses in a small subset of patients with metastatic disease, a true increase in overall survival (OS) within a randomized phase III trial was not observed until the development of anti-CTLA-4 (ipilimumab). Further improvements in OS for metastatic disease were observed with the anti-PD-1-based therapies (nivolumab, pembrolizumab) as single agents or combined with ipilimumab. A lower bound for expected 5-year survival for metastatic melanoma is currently approximately 35% and could be as high as 50% for the nivolumab/ ipilimumab combination among patients who would meet criteria for clinical trials. Moreover, a substantial fraction of long-term survivors will likely remain progression-free without continued treatment. The hope and major challenge for the future is to understand the immunobiology of tumors with primary or acquired resistance to anti-PD-1 or anti-PD-1/anti-CTLA-4 and to develop effective immune therapies tailored to individual patient subsets not achieving long-term clinical benefit. Additional goals include optimal integration of immune therapy with nonimmune therapies, the development and validation of predictive biomarkers in the metastatic setting, improved prognostic and predictive biomarkers for the adjuvant setting, understanding mechanisms of and decreasing toxicity, and optimizing the duration of therapy.

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“…It is further supported by preclinical and translational data proving the immune-mediated anti-tumor effects and microenvironment changes of BRAF pathway inhibitors [ 107 , 108 , 109 , 110 ]. Early phase studies have demonstrated promising activity in melanoma patients with the manageable safety profile of such combinations [ 111 , 112 , 113 , 114 , 115 , 116 ]. The advanced phase studies focusing on triple combinations of anti-PD-1/anti-PD-L1 or sequential therapy are ongoing.…”

Section: Treatment Regimens Enabling the Overcoming Of Brafi/mekimentioning

confidence: 99%

Targeted Therapy in Melanoma and Mechanisms of Resistance

Czarnecka

Bartnik

Fiedorowicz

et al. 2020

IJMS

131

101

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The common mutation BRAFV600 in primary melanomas activates the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway and the introduction of proto-oncogene B-Raf (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors (BRAFi and MEKi) was a breakthrough in the treatment of these cancers. However, 15–20% of tumors harbor primary resistance to this therapy, and moreover, patients develop acquired resistance to treatment. Understanding the molecular phenomena behind resistance to BRAFi/MEKis is indispensable in order to develop novel targeted therapies. Most often, resistance develops due to either the reactivation of the MAPK/ERK pathway or the activation of alternative kinase signaling pathways including phosphatase and tensin homolog (PTEN), neurofibromin 1 (NF-1) or RAS signaling. The hyperactivation of tyrosine kinase receptors, such as the receptor of the platelet-derived growth factor β (PDFRβ), insulin-like growth factor 1 receptor (IGF-1R) and the receptor for hepatocyte growth factor (HGF), lead to the induction of the AKT/3-phosphoinositol kinase (PI3K) pathway. Another pathway resulting in BRAFi/MEKi resistance is the hyperactivation of epidermal growth factor receptor (EGFR) signaling or the deregulation of microphthalmia-associated transcription factor (MITF).

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KEYNOTE-022 Part 3: Phase II randomized study of 1L dabrafenib (D) and trametinib (T) plus pembrolizumab (Pembro) or placebo (PBO) for BRAF-mutant advanced melanoma

Cited by 46 publications

References 0 publications

Perspectives in immunotherapy: meeting report from the “Immunotherapy Bridge 2018” (28–29 November, 2018, Naples, Italy)

Perspectives in immunotherapy: meeting report from the “Immunotherapy Bridge 2018” (28–29 November, 2018, Naples, Italy)

Immunotherapy of Melanoma: Facts and Hopes

Targeted Therapy in Melanoma and Mechanisms of Resistance

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