Nivolumab in Previously Untreated Melanoma without<i>BRAF</i>Mutation

Robert, Caroline; Long, Georgina V.; Brady, Benjamin; Dutriaux, Caroline; Maio, Michele; Mortier, Laurent; Hassel, Jessica C.; Rutkowski, Piotr; McNeil, Catriona M.; Kalinka, Ewa; Savage, Kerry J.; Hernberg, Micaela; Lebbe, Célèste; Charles, J.; Mihalcioiu, Catalin; Chiarion-Sileni, Vanna; Mauch, Cornelia; Cognetti, Francesco; Arance, Ana; Schmidt, Henrik; Schadendorf, Dirk; Gogas, Helen; Lundgren-Eriksson, L; Horak, Christine E.; Sharkey, Brian J.; Waxman, Ian M.; Atkinson, Victoria; Ascierto, Paolo A.

doi:10.1056/nejmoa1412082

Cited by 4,789 publications

(3,742 citation statements)

References 23 publications

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“…1–10 Given the ubiquitous use of corticosteroids in the medical management of cancer patients and their immunosuppressive effects, this study primarily sought to determine whether responses mediated by anti-PD-1 therapy are influenced by corticosteroids in a preclinical setting. Utilizing well-established in vivo tumor models that are sensitive to PD-1 blockade, this study examined whether dexamethasone’s impact was dependent on its timing, duration, and tumor location within or outside the CNS.…”

Section: Discussionmentioning

confidence: 99%

“…1–10 As the list of approvals and clinical trials investigating its efficacy in other tumor types continues to grow, it is paramount to determine factors, both tumor-intrinsic and extrinsic, that influence responses to anti-PD-1 therapy. 11 An important concern to address is how iatrogenic immunosuppression caused by conventional therapies such as chemotherapy, fractionated radiotherapy, and corticosteroids may potentially impact the efficacy of anti-PD-1 as well as other immunotherapy strategies.…”

Section: Introductionmentioning

confidence: 99%

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Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

et al. 2018

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Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

et al. 2018

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“…However, as novel agents extend patient survival times, it becomes increasingly difficult to conduct long clinical trials in order to measure OS [75,76]. Although the use of ICBs has improved survival in melanoma over standard chemotherapy, with some patients experiencing OS of 3 to 5 years [77,78], when the follow-up is less than 1 year, median OS is usually not reached [22,23,39,43]. Therefore, there is an interest in validating surrogate endpoints that can accurately predict survival benefit in clinical trials of immunotherapy and using these surrogate endpoints for drug approval [75].…”

Section: Endpoints To Assess Clinical Outcomes Associated With Icbsmentioning

confidence: 99%

“…Some studies investigating ICBs in NSCLC, RCC, HNSCC, and UC have demonstrated increased OS in the absence of a PFS benefit [27,28,31,42,47,57], whereas other trials in melanoma and NSCLC have demonstrated increased OS, as well as ORR and PFS, compared with standard of care (Table 2) [23,43].…”

Section: Endpoints To Assess Clinical Outcomes Associated With Icbsmentioning

confidence: 99%

“…Generally, ICBs have been shown to significantly improve ORR when compared with standard therapies, for example in patients with melanoma [22,23,39], RCC [28], and NSCLC with high PD-L1 expression [43] (Table 2). ICBs have also been shown to prolong duration of response (DOR) when compared with standard therapies (Table 2) [22,23,25,39,42,43,46].…”

Section: Endpoints To Assess Clinical Outcomes Associated With Icbsmentioning

confidence: 99%

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Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

et al. 2018

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Immune checkpoint blockers have revolutionized cancer treatment in recent years. These agents are now approved for the treatment of several malignancies, including melanoma, squamous and non-squamous non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and head and neck squamous cell carcinoma. Studies have demonstrated the significant impact of immunotherapy versus standard of care on patient outcomes, including durable response and extended survival. The use of immunotherapy-based combination therapy has been shown to further extend duration of response and survival. Immunotherapies function through modulation of the immune system, which can lead to immune-mediated adverse events (imAEs). These include a range of dermatologic, gastrointestinal, endocrine, and hepatic toxicities, as well as other less common inflammatory events. ImAEs are typically low grade and manageable when identified early and treated with appropriate measures. Identifying the right patient for the right therapy will become more important as new immunotherapies and immunotherapy-based combinations are approved and costs of cancer care continue to rise.

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Ipilimumab Plus Sargramostim vs Ipilimumab Alone for Treatment of Metastatic Melanoma

Hodi

Lee

McDermott

et al. 2014

JAMA

313

249

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Importance Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockade with ipilimumab prolongs survival in metastatic melanoma patients. CTLA-4 blockade and granulocyte-macrophage colony stimulating factor (GM-CSF) secreting tumor vaccine combinations demonstrate therapeutic synergy in pre-clinical models. A key issue is whether systemic GM-CSF synergizes with CTLA-4 blockade. Objective To compare the effect of sargramostim plus ipilimumab vs ipilimumab alone on overall survival in patients with metastatic melanoma. Design, Setting, and Participants A phase II randomized clinical trial was conducted in the United States by Eastern Cooperative Oncology Group between December 28, 2010 and July 28, 2011. Patients with unresectable stage III or IV melanoma, ≥one prior therapy, no CNS metastases, and ECOG performance status 0/1 were eligible. Interventions Patients were randomized to ipilimumab 10 mg/kilogram intravenously day 1 plus sargramostim 250 μg subcutaneously days 1-14 of 21 day cycles versus ipilimumab alone. Ipilimumab treatment included induction for four cycles followed by maintenance every fourth cycle. Main Outcomes and Measures Primary was comparison of the length of overall survival. Secondary was progression-free survival, response rate, safety, and tolerability. Results A total of 245 patients were treated. Median follow-up was 13.3 months (range; .03-19.9). Median overall survival for sargramostim plus ipilimumab was 17.5 months (95% CI; 14.9, not reached) compared to 12.7 months (95% CI; 10.0, not reached) for ipilimumab. One-year survival rate for sargramostim was 68.9% (95% CI; 60.6%, 85.5%) compared to 52.9% (95% CI; 43.6%, 62.2%) with ipilimumab (stratified logrank one-sided P=.01; mortality hazard ratio .64, one-sided 90% repeated CI (not applicable, .90)). A planned interim analysis was conducted at 69.8% (104 observed/ 149 planned deaths) information time. O'Brien-Fleming boundary was crossed for improvement in overall survival. There was no difference in progression-free survival. Median progression free survival for ipilimumab+sargramostim was 3.1 months (95% CI; 2.9, 4.6) and for ipilimumab was 3.1 months (95% CI; 2.9, 4.0). Grade 3-5 adverse events occurred in 44.9% (95% CI; 35.8%, 54.4%) of sargramostim plus ipilimumab and 58.3% (95% CI; 49.0%, 67.2%) of ipilimumab alone (two-sided P=.04). Conclusion and Relevance Among patients with unresectable stage III or IV melanoma, treatment with sargramostim plus ipilimumab, compared to ipilimumab alone, resulted in longer overall survival and lower toxicity, but no difference in progression free survival. These findings require confirmation in larger sample sizes and longer follow up.

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Nivolumab in Previously Untreated Melanoma withoutBRAFMutation

Cited by 4,789 publications

References 23 publications

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

Ipilimumab Plus Sargramostim vs Ipilimumab Alone for Treatment of Metastatic Melanoma

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