Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609

Tarhini, Ahmad A.; Lee, Sandra J.; Hodi, F. Stephen; Rao, Uma; Cohen, Gary I.; Hamid, Omid; Hutchins, Laura F.; Sosman, Jeffrey A.; Kluger, H.; Eroglu, Zeynep; Koon, Henry; Lawrence, Donald P.; Kendra, Kari; Minor, David R.; Lee, Carrie B.; Albertini, Mark R.; Flaherty, Lawrence E.; Petrella, Teresa M.; Streicher, Howard; Sondak, Vernon K.; Kirkwood, John M.

doi:10.1200/jco.19.01381

Cited by 136 publications

(118 citation statements)

References 22 publications

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“…This is in contrast to findings in the metastatic setting showing improved efficacy with higher doses of ipilimumab [11]. Compared to adju-vant IFN, ipi 3 mg/kg was shown to significantly improve OS (HR 0.78; 95.6% CI 0.61-0.99; p-value: 0.044), and achieved a trend towards improved RFS (p-value: 0.065) [10]. In light of the effective new treatment options presented within this article, IFN is increasingly considered outdated as an adjuvant treatment option for melanoma.…”

Section: Adjuvant Immunotherapycontrasting

confidence: 78%

“…Most recently, results of a double-blind randomized trial comparing high dose IFN with two different doses (3 mg/kg and 10 mg/kg) of the first "modern" immunotherapy-the cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) antibody ipilimumab (ipi)-were published [10]. Interestingly, efficacy of the two ipilimumab dose regimens investigated in this trial was similar, while toxicity was significantly higher with the 10 mg/kg dose (rate of treatmentrelated adverse events (AEs) CTC grade 3 and higher: 57 vs. 38%).…”

Section: Adjuvant Immunotherapymentioning

confidence: 99%

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Adjuvant and neoadjuvant treatment of melanoma

Koelblinger

2020

memo

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For years, interferon alpha was the sole option in the adjuvant treatment of patients with completely resected melanoma with lymph node metastases and a high risk of disease recurrence, albeit being associated with a relatively low efficacy combined with significant toxicities. After the advent of immunotherapy and targeted therapy in locally advanced or metastatic melanoma at the beginning of the last decade, these therapeutic approaches have meanwhile also shown superior efficacy compared to previously used treatments or observation in the context of adjuvant therapy. Hence, adjuvant targeted or anti-PD1-antibody-based immunotherapy was incorporated into routine clinical practice to reduce the risk of tumor recurrence in affected patients in early 2018. Moreover, modern melanoma therapies are increasingly being investigated in a neoadjuvant setting in analogy to other solid malignancies. Considering the promising results reported so far, neoadjuvant immunotherapy might potentially become the treatment of choice in high-risk melanoma patients with macrometastatic disease in the near future.

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Section: Adjuvant Immunotherapycontrasting

confidence: 78%

Section: Adjuvant Immunotherapymentioning

confidence: 99%

Adjuvant and neoadjuvant treatment of melanoma

Koelblinger

2020

memo

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“…We envisage that one of the central clinical applications of a prognostic GEP might be to identify those patients with stage II melanoma who may be at higher risk of relapse or death and for whom adjuvant systemic therapies may be considered. In order to compare our data with the registration adjuvant melanoma trials conducted in resected stage III melanoma survival (4-7), we measured the absolute risk of death at 5 years (calculated as the proportion of patients who died due to melanoma within 5-years from diagnosis).…”

Section: Resultsmentioning

confidence: 99%

“…Patients with resected AJCC stage III melanoma are now eligible for adjuvant immune checkpoint inhibitors as well as BRAF targeted therapies, based on randomised trials confirming reduction in risk of relapse and improved overall survival (4-7). Clinical trials are underway to evaluate similar therapies in resected stage IIB/C patients (8), whose outcomes reflect that of stage IIIA/B melanoma, untreated (9).…”

Section: Introductionmentioning

confidence: 99%

Tumour gene expression signature in primary melanoma predicts long-term outcomes: A prospective multicentre study

Garg

Couturier

Nsengimana

et al. 2020

Preprint

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PurposePredicting outcomes after resection of primary melanoma remains crude, primarily based on tumour thickness. We explored gene expression signatures for their ability to better predict outcomes.MethodsDifferential expression analysis of 194 primary melanomas resected from patients who either developed distant metastasis (n=89) or did not (n=105) was performed. We identified 121 metastasis-associated genes that were included in our prognostic signature, “Cam_121”. Several machine learning classification models were trained using nested leave- one-out cross validation (LOOCV) to test the signature’s capacity to predict metastases, as well as regression models to predict survival. The prognostic accuracy was externally validated in two independent datasets.ResultsCam_121 performed significantly better in predicting distant metastases than any of the models trained with the clinical covariates alone (pAccuracy=4.92×10−3), as well as those trained with two published prognostic signatures. Cam_121 expression score was strongly associated with progression-free survival (HR=1.7, p=3.44×10−6), overall survival (HR=1.73, p=7.71×10−6) and melanoma-specific survival (HR=1.59, p=0.02). Cam_121 expression score also negatively correlated with measures of immune cell infiltration (ρ=−0.73, p<2.2×10−16), with a higher score representing reduced tumour lymphocytic infiltration and a higher absolute 5-year risk of death in stage II melanoma.ConclusionsThe Cam_121 primary melanoma gene expression signature outperformed currently available alternatives in predicting the risk of distant recurrence. The signature confirmed (using unbiased approaches) the central prognostic importance of immune cell infiltration in long-term patient outcomes and could be used to identify stage II melanoma patients at highest risk of metastases and poor survival who might benefit most from adjuvant therapies.Translational relevancePredicting outcomes after resection of primary melanoma is currently based on traditional histopathological staging, however survival outcomes within these disease stages varies markedly. Since adjuvant systemic therapies are now being used routinely, accurate prognostic information is needed to better risk stratify patients and avoid unnecessary use of high cost, potentially harmful drugs, as well as to inform future adjuvant strategies. The Cam_121 gene expression signature appears to have this capability and warrants evaluation in prospective clinical trials.

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“…Combined PD-1 and CTLA4 blockade with nivolumab and ipilimumab has been shown to be more effective than single-agent ipilimumab in advanced melanoma, however, toxicity is more significant. 41,49,50 As the majority of reported treatment-related adverse events in immunotherapy studies are due to ipilimumab, especially at higher doses, 51…”

Section: Checkmate-032mentioning

confidence: 99%

Checkpoint blockade in esophagogastric cancer

Cohen

Strong

Janjigian

2018

Journal of Surgical Oncology

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There are few effective treatment options for metastatic esophagogastric adenocarcinomas after progression on second-line chemotherapy. Immune checkpoint blockade therapy is a promising treatment strategy for selected advanced esophagogastric cancer, and the PD-1 inhibitor pembrolizumab has recently been approved for metastatic or recurrent gastric or gastroesophageal junction cancer that has progressed beyond second-line systemic therapy. We review the current data supporting immune checkpoint blockade therapy in advanced esophagogastric adenocarcinoma.

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Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609

Cited by 136 publications

References 22 publications

Adjuvant and neoadjuvant treatment of melanoma

Adjuvant and neoadjuvant treatment of melanoma

Tumour gene expression signature in primary melanoma predicts long-term outcomes: A prospective multicentre study

Checkpoint blockade in esophagogastric cancer

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