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Ipilimumab (Yervoy)

"An anti-cytotoxic T lymphocyte-associated antigen 4 antibody for treatment of metastatic melanoma and other cancers" (MeSH 2013)

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Latest Research Publications

Web Resources: Ipilimumab (6 links)

Latest Research Publications

Schaefer T, Satzger I, Gutzmer R
Clinics, prognosis and new therapeutic options in patients with mucosal melanoma: A retrospective analysis of 75 patients.
Medicine (Baltimore). 2017; 96(1):e5753 [PubMed] Free Access to Full Article Related Publications
Mucosal melanomas represent a rare entity with different risk factors and molecular features compared to cutaneous melanomas. They arise most commonly from mucosal surfaces in the head/neck region, the female genital tract (FGT) and the anorectal region. The aim of this study was to evaluate clinics, prognosis, and treatment options of patients with mucosal melanoma, in particular with regard to different primary sites.We retrospectively analyzed 75 patients with mucosal melanomas diagnosed in the years 1993 to 2015 in our department. The primary melanomas were located in the head/neck region (n = 32), the FGT (n = 24), and the anorectal region (n = 19).The median age of the patients was 66 years. At initial diagnosis the primary melanoma was not completely resectable in 11 (15%) patients, 18 (24%) patients had regional lymph node metastases, and 7 (9%) patients distant metastases. During follow-up, 22 (29%) patients suffered from a local recurrence, in particular patients with primary melanoma in the head/neck region without postoperative radiotherapy. By multivariate analysis location of the primary melanoma in the head/neck area or anorectal region and presence of metastases at time of diagnosis represented poor prognostic factors for recurrence-free survival. In 62 tested individuals 7 KIT mutations were found, 2 BRAF mutations in 57 tested patients. Four patients received targeted therapies, 14 checkpoint inhibitors, 4 (1/1 on vemurafenib, 1/7 on ipilimumab, and 2/7 on PD-1 inhibitors) patients showed responses of more than 100 days duration.Mucosal melanomas are often locally advanced or metastatic at initial diagnosis, thus they require extensive staging procedures. The high rate of local recurrences in the head/neck region can be significantly reduced by postoperative radiotherapy. For the potential use of medical treatment a mutation analysis for KIT and BRAF genes should be performed. The use of new immunologic and targeted therapies has to be further evaluated.

Kroeze SG, Fritz C, Hoyer M, et al.
Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: A systematic review.
Cancer Treat Rev. 2017; 53:25-37 [PubMed] Related Publications
BACKGROUND AND PURPOSE: Both stereotactic radiotherapy (SRT) and immune- or targeted therapy play an increasingly important role in personalized treatment of metastatic disease. Concurrent application of both therapies is rapidly expanding in daily clinical practice. In this systematic review we summarize severe toxicity observed after concurrent treatment.
MATERIAL AND METHODS: PubMed and EMBASE databases were searched for English literature published up to April 2016 using keywords "radiosurgery", "local ablative therapy", "gamma knife" and "stereotactic", combined with "bevacizumab", "cetuximab", "crizotinib", "erlotinib", "gefitinib", "ipilimumab", "lapatinib", "sorafenib", "sunitinib", "trastuzumab", "vemurafenib", "PLX4032", "panitumumab", "nivolumab", "pembrolizumab", "alectinib", "ceritinib", "dabrafenib", "trametinib", "BRAF", "TKI", "MEK", "PD1", "EGFR", "CTLA-4" or "ALK". Studies performing SRT during or within 30days of targeted/immunotherapy, reporting severe (⩾Grade 3) toxicity were included.
RESULTS: Concurrent treatment is mostly well tolerated in cranial SRT, but high rates of severe toxicity were observed for the combination with BRAF-inhibitors. The relatively scarce literature on extra-cranial SRT shows a potential risk of increased toxicity when SRT is combined with EGFR-targeting tyrosine kinase inhibitors and bevacizumab, which was not observed for cranial SRT.
CONCLUSIONS: This review gives a best-possible overview of current knowledge and its limitations and underlines the need for a timely generation of stronger evidence in this rapidly expanding field.

Chou S, Hwang SJ, Carlos G, et al.
Histologic Assessment of Lichenoid Dermatitis Observed in Patients With Advanced Malignancies on Antiprogramed Cell Death-1 (anti-PD-1) Therapy With or Without Ipilimumab.
Am J Dermatopathol. 2017; 39(1):23-27 [PubMed] Related Publications
Lichenoid drug reaction is a common adverse reaction in patients taking immune-modulatory agents such as antiprogramed cell death (PD-1) and cytotoxic T lymphocyte antigen-4 agents. The authors describe the clinical and histologic features of lichenoid drug reaction in 20 biopsies from 15 patients on anti-PD-1 agents and 9 biopsies from 7 patients on anti-PD-1 plus ipilimumab therapy. Clinically, all except 2 patients presented with discrete, violaceous exanthematous papules to plaques. The lichenoid inflammation in the majority (18 of 29 biopsies) was florid although histology was quite heterogeneous. Nevertheless, there was frequent involvement of the superficial follicular epithelium and acrosyringium, and also a propensity to blister that occurred in approximately 20% of the biopsies. Occasional patients had disease closely resembling lichen planus, although all of these biopsies had some atypical features for lichen planus such as parakeratosis. Dermal eosinophils were common particularly in those with mild inflammation. The lichenoid reaction was responsive to topical steroid or oral systemic treatment in general, and the anti-PD-1 agent had to be ceased in only one patient.

Nguyen AH, Detty SQ, Agrawal DK
Clinical Implications of High-mobility Group Box-1 (HMGB1) and the Receptor for Advanced Glycation End-products (RAGE) in Cutaneous Malignancy: A Systematic Review.
Anticancer Res. 2017; 37(1):1-7 [PubMed] Related Publications
Inflammation and the immune system play a role in the development and progression of melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). The pro-inflammatory and tumor-promoting effects of the high-mobility group box-1 (HMGB1) protein and the receptor for advanced glycation end products (RAGE) have been investigated in these cutaneous malignancies. The clinical implication of these molecules is not fully described. The National Library of Medicine database was searched for articles addressing the clinical relevance of HMGB1 and RAGE in melanoma, BCC, and SCC. This systematic review includes nine articles, with six summarizing RAGE in cutaneous malignancies and three involving HMGB1. RAGE has been found to be up-regulated in SCC lesions, as well as melanoma. Levels of RAGE were highest in stage IV melanomas. Lower levels of soluble RAGE have been associated with poor overall survival in melanoma. Sporadic extracellular expression of HMGB1 was evident in BCC and SCC lesions, which could be released by necrotic tumor cells. HMGB1 was found to be a prognostic marker in melanoma, and HMGB1 levels were elevated in patients who were non-responders to ipilimumab treatment. HMGB1 and RAGE could serve as potential prognostic markers or therapeutic targets in treating melanoma, BCC, and SCC, but further research regarding the clinical utility of the HMGB1-RAGE axis in cutaneous malignancies is warranted.

O'Donnell JS, Long GV, Scolyer RA, et al.
Resistance to PD1/PDL1 checkpoint inhibition.
Cancer Treat Rev. 2017; 52:71-81 [PubMed] Related Publications
For the first time in decades, patients with difficult-to-treat cancers such as advanced stage metastatic melanoma are being offered a glimpse of hope in the form of immunotherapies. By targeting factors that foster the development and maintenance of an immunosuppressive microenvironment within tumors, these therapies release the brakes on the host's own immune system; allowing cure of disease. Indeed, phase III clinical trials have revealed that therapies such as ipilimumab and pembrolizumab which target the CTLA4 and PD-1 immune checkpoints, respectively, have raised the three-year survival of patients with melanoma to ∼70%, and overall survival (>5years) to ∼30%. Despite this unprecedented efficacy, many patients fail to respond, and more concerning, some patients who demonstrate encouraging initial responses to immunotherapy, can acquire resistance over time. There is now an urgent need to identify mechanisms of resistance, to predict outcome and to identify targets for combination therapy. Here, with the aim of guiding future combination trials that target specific resistance mechanisms to immunotherapies, we have summarised and discussed the current understanding of mechanisms promoting resistance to anti-PD1/PDL1 therapies, and how combination strategies which target these pathways might yield better outcomes for patients.

Letendre P, Monga V, Milhem M, Zakharia Y
Ipilimumab: from preclinical development to future clinical perspectives in melanoma.
Future Oncol. 2017; 13(7):625-636 [PubMed] Related Publications
The arsenal for the treatment of metastatic melanoma is limited. A new approach to therapy using checkpoint blockade has improved overall survival in this patient population. Ipilimumab a CTLA-4 monoclonal antibody is a first in class drug that has pioneered this revolution. In this review, the authors provide an account of the different stages that led to the development of ipilimumab, its approval in the clinical setting for the treatment of advanced melanoma and ongoing investigations of combinatorial immune therapy.

Forschner A, Eichner F, Amaral T, et al.
Improvement of overall survival in stage IV melanoma patients during 2011-2014: analysis of real-world data in 441 patients of the German Central Malignant Melanoma Registry (CMMR).
J Cancer Res Clin Oncol. 2017; 143(3):533-540 [PubMed] Related Publications
BACKGROUND: During 2011 and 2014, new treatment modalities like tyrosine kinase inhibitors and checkpoint inhibitors were introduced into the therapy of metastatic melanoma. This study addresses the question whether overall survival (OS) of metastatic melanoma patients has already been improved in 441 patients diagnosed with metastatic melanoma between 2011 and 2014 in the real-world setting at the University Hospital Tuebingen.
METHODS: All patients were documented with their different therapies by the CMMR and followed up until March 2016. Survival probabilities were calculated by Kaplan-Meier estimators, and log-rank tests were used to evaluate significances. Hazard ratios were estimated by Cox regression analysis for survival probabilities and prognostic factors in stage IV melanoma.
RESULTS: Best OS was observed in patients (n = 93) treated by metastasectomy as primary treatment with the intention to completely excise all metastases (3-year OS 61%). OS for patients with first-line systemic treatment (n = 258) was unfavorable in general (3-year OS 23%). Of those, the most favorable outcome was observed in patients without brain metastasis and treated with immunotherapy (mostly ipilimumab), as first-line treatment (median OS 35 months, 3-year OS 43%). In case of brain metastases, patients with targeted therapy had a better OS (median 14 months) than patients with ipilimumab treatment (median 7 months). Among all patients with first-line systemic treatment, outcome of patients diagnosed in the years 2013/2014, compared to 2011 and 2012, showed an improved survival. Three-year OS for patients that entered stage IV in 2013/2014 was 37% compared to those that entered stage IV in 2011 (18%) and 2012 (20%).
CONCLUSION: The analysis of real-world data of treatment of metastatic melanoma showed an improvement of OS with both immunotherapy and targeted therapy. In case of cerebral metastasis, patients treated with targeted therapy showed a longer median OS than patients treated with ipilimumab.

Kim C, Gao J, Shannon VR, Siefker-Radtke A
Systemic sarcoidosis first manifesting in a tattoo in the setting of immune checkpoint inhibition.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
The use of immune checkpoint inhibitors is revolutionising the treatment of cancer. However, their unique toxicity profile is substantially different from what has been observed with traditional chemotherapy, resulting in a novel learning curve for medical oncologists. Early recognition of these toxicities can make a substantial impact in ameliorating these side effects in the oncological and medical-surgical fields. Here, we present a case of Lofgren syndrome sarcoidosis, which first manifested in a tattoo in a patient with metastatic urothelial cancer on therapy with anti-CTLA-4 (ipilimumab) and anti-PD1 (nivolumab).

Okano Y, Satoh T, Horiguchi K, et al.
Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma.
Endocr J. 2016; 63(10):905-912 [PubMed] Related Publications
The anti-programmed cell death-1 monoclonal antibody (mab), nivolumab has recently been approved for the treatment of unresectable or metastatic malignant melanoma and non-small-cell lung cancers in Japan. Ipilimumab, an anti-cytotoxic T lymphocyte antigen-4 mab for malignant melanoma that was approved earlier than nivolumab in Western countries, is known to frequently cause endocrine immune-related adverse events such as hypophysitis and thyroid dysfunction. We herein report a patient with advanced melanoma who appeared to develop hypophysitis as a consequence of the inhibition of PD-1 by nivolumab. One week after the 6(th) administration of nivolumab, the patient developed progressive fatigue and appetite loss. Laboratory data on admission for the 7(th) administration of nivolumab showed eosinophilia and hyponatremia. Since ACTH and cortisol levels were low, nivolumab was discontinued and a large dose of hydrocortisone (100 mg/d) was promptly administered intravenously. A magnetic resonance imaging scan revealed the mild enlargement of the anterior pituitary gland and thickening of the stalk with homogenous contrast. A detailed assessment of anterior pituitary functions with hypothalamic hormone challenges showed that hormonal secretions other than ACTH and TSH were normal. With a replacement dose of hydrocortisone (20 mg/d), the 7(th) administration of nivolumab was completed without exacerbating the patient's general condition. The present report provides the first detailed endocrinological presentation of nivolumab-induced hypophysitis showing the enlargement of the pituitary gland and stalk in a malignant melanoma patient in Japan. Oncologists and endocrinologists need to be familiar with potentially life-threatening hypophysitis induced by immune-checkpoint inhibitors.

Morales-Barrera R, Suárez C, de Castro AM, et al.
Targeting fibroblast growth factor receptors and immune checkpoint inhibitors for the treatment of advanced bladder cancer: New direction and New Hope.
Cancer Treat Rev. 2016; 50:208-216 [PubMed] Related Publications
Bladder cancer is one of the leading causes of death in Europe and the United States. About 25% of patients with bladder cancer have advanced disease (muscle-invasive or metastatic disease) at presentation and are candidates for systemic chemotherapy. In the setting of metastatic disease, use of cisplatin-based regimens improves survival. However, despite initial high response rates, the responses are typically not durable leading to recurrence and death in the vast majority of these patients with median overall survival of 15months and a 5-year survival rate of ⩽10%. Furthermore, unfit patients for cisplatin have no standard of care for first line therapy in advance disease Most second-line chemotherapeutic agents tested have been disappointing. Newer targeted drugs and immunotherapies are being studied in the metastatic setting, their usefulness in the neoadjuvant and adjuvant settings is also an intriguing area of ongoing research. Thus, new treatment strategies are clearly needed. The comprehensive evaluation of multiple molecular pathways characterized by The Cancer Genome Atlas project has shed light on potential therapeutic targets for bladder urothelial carcinomas. We have focused especially on emerging therapies in locally advanced and metastatic urothelial carcinoma with an emphasis on immune checkpoints inhibitors and FGFR targeted therapies, which have shown great promise in early clinical studies.

Eggermont AM, Chiarion-Sileni V, Grob JJ, et al.
Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy.
N Engl J Med. 2016; 375(19):1845-1855 [PubMed] Related Publications
Background On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma. Methods After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety. Results At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events. Conclusions As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168 , and EudraCT number, 2007-001974-10 .).

Gao J, Shi LZ, Zhao H, et al.
Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy.
Cell. 2016; 167(2):397-404.e9 [PubMed] Article available free on PMC after 06/10/2017 Related Publications
Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in a subset of patients with metastatic melanoma. Anti-CTLA-4 enhances T cell responses, including production of IFN-γ, which is a critical cytokine for host immune responses. However, the role of IFN-γ signaling in tumor cells in the setting of anti-CTLA-4 therapy remains unknown. Here, we demonstrate that patients identified as non-responders to anti-CTLA-4 (ipilimumab) have tumors with genomic defects in IFN-γ pathway genes. Furthermore, mice bearing melanoma tumors with knockdown of IFN-γ receptor 1 (IFNGR1) have impaired tumor rejection upon anti-CTLA-4 therapy. These data highlight that loss of the IFN-γ signaling pathway is associated with primary resistance to anti-CTLA-4 therapy. Our findings demonstrate the importance of tumor genomic data, especially IFN-γ related genes, as prognostic information for patients selected to receive treatment with immune checkpoint therapy.

Basnet A, Saad N, Benjamin S
A Case of Vanishing Brain Metastasis in a Melanoma Patient on Nivolumab.
Anticancer Res. 2016; 36(9):4795-8 [PubMed] Related Publications
BACKGROUND: Melanoma is among the top three cancers to present with brain metastasis. The risk of brain metastases in advanced melanoma increases with disease duration. Cytotoxic chemotherapy does not have a significant role in the management of melanoma patients with brain metastases, neither alone nor in conjunction with radiation therapy.
PATIENTS AND METHODS: We herein discuss a case of a 66-year-old male diagnosed initially with stage III-B melanoma and underwent a wide local excision with a split thickness graft and sentinel lymph node biopsy, followed by adjuvant treatment with high-dose interferon.
RESULTS: On subsequent follow up he was found to have a brain lesion, which later on resolved after starting ipilumumab. Five to twenty percent of patients with melanoma of any stage develop cerebral metastases.
CONCLUSION: Immunotherapy modalities, ipilimumab has been shown to have activity against brain metastases.

Santabarbara G, Maione P, Rossi A, et al.
Novel immunotherapy in the treatment of advanced non-small cell lung cancer.
Expert Rev Clin Pharmacol. 2016; 9(12):1571-1581 [PubMed] Related Publications
INTRODUCTION: Lung cancers remain the principal cause of death cancer-related worldwide with a poor survival rate at five years from diagnosis. In patients with NSCLC harboring specific genetic alterations the anti EGFR TKIs and the ALK TKIs have improved the response rate and the quality of life compared to standard platinum-based chemotherapy. New approaches possibly applicable at the major of patients are needed. Areas covered: The discovery that the immune system plays a fundamental role in the fight against cancer. The cancer cells use mechanisms able to avoid the immune control has led to the development of drugs able to overcome this escape route. The best known checkpoint pathways are the CTLA-4 and PD-1/PD-L1; they suppress T-cell activity in different ways: CTLA-4 regulates T-cell activity at an early stage whereas PD-1 regulates later effector T-cell activity within tissue and tumors. The best characterized checkpoint inhibitors in advanced NSCLC setting are ipilimumab and tremelimumab, (anti-CTLA-4 antibodies), nivolumab and pembrolizumab (anti-PD-1 antibodies), atezolizumab and durvalumab (anti-PD-L1 antibodies). Nivolumab and pembrolizumab have received the FDA and EMA approval for the treatment of NSCLC in second-line setting. Expert commentary: The role played by tumor microenvironment may be the next area of research to overcome the resistance at the checkpoint inhibitors as well as the identification of biomarkers to better select patients. In addition checkpoint inhibitors are investigate in combination with other agent involved in immune control with promising results in solid tumors.

Aya F, Gaba L, Victoria I, et al.
Ipilimumab after progression on anti-PD-1 treatment in advanced melanoma.
Future Oncol. 2016; 12(23):2683-2688 [PubMed] Related Publications
AIM: While both efficacy and safety of anti-PD-1 agents seem to be independent of previous treatment with anti-CTLA-4, limited data exist of efficacy and toxicity of ipilimumab after progression on anti-PD-1 therapy. This retrospective analysis describes the efficacy and safety of sequential therapy with ipilimumab in patients with metastatic melanoma who progressed on anti-PD-1 antibody.
METHODS: Nine patients who progressed on anti-PD-1 therapy received four cycles of ipilimumab 3 mg/kg every 3 weeks.
RESULTS: Two out of nine patients (2/9; 22.2%) showed a partial response, and seven patients (7/9; 77.8%) experienced disease progression. Median progression-free survival was 3.14 months (95% CI: 2.56-3.71), and the median overall survival since the start of anti-PD-1 therapy was 16.8 months (95% CI: 8.1-25.4). Five (5/9; 55.6%) patients experienced grade 3 immune-related adverse events. No grade 4 or 5 adverse events were reported.
CONCLUSION: In this small retrospective series of cases, the efficacy of ipilimumab post-anti-PD-1 was similar to that described in the previous reports on ipilimumab.

Franceschini D, Franzese C, Navarria P, et al.
Radiotherapy and immunotherapy: Can this combination change the prognosis of patients with melanoma brain metastases?
Cancer Treat Rev. 2016; 50:1-8 [PubMed] Related Publications
Brain metastases are a common occurrence in patients with melanoma. Prognosis is poor. Radiotherapy is the main local treatment for brain metastases. Recently, immunotherapy (i.e. immune checkpoints inhibitors) showed a significant impact on the prognosis of patients with metastatic melanoma, also in the setting of patients with brain metastases. Despite various possible treatments, survival of patients with melanoma brain metastases is still unsatisfactory; new treatment modalities or combination of therapies need to be explored. Being immunotherapy and radiotherapy alone both efficient in the treatment of melanoma brain metastases, the combination of these two therapies seems logical. Moreover radiotherapy can improve the efficacy of immunotherapy and the immune system plays a relevant role in the action of radiotherapy. Preclinical data support this combination. Clinical data are more contradictory. In this review, we will discuss available therapies for melanoma brain metastases, focusing on the preclinical and clinical available data supporting the possible synergism between radiotherapy and immunotherapy.

Hsieh AH, Ferman M, Brown MP, Andrews JM
Vedolizumab: a novel treatment for ipilimumab-induced colitis.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
Use of the immune checkpoint inhibitors, ipilimumab and nivolumab, has revolutionised treatment in patients with metastatic melanoma. However, these drugs can cause an autoimmune enterocolitis, with diarrhoea as the presenting symptom. This is conventionally managed by prompt institution of corticosteroid therapy if moderate diarrhoea (3-6 times/day; grade 2) is present for >5 days or if diarrhoea is severe (>6 times/day; grade 3). We report a case of steroid-dependent ipilimumab-induced colitis successfully treated with vedolizumab (an inhibitor of memory T-cell trafficking to the gut), after which complete withdrawal of corticosteroid was achieved. Hence, vedolizumab warrants further evaluation as a potential novel treatment of ipilimumab-induced colitis.

Davids MS, Kim HT, Bachireddy P, et al.
Ipilimumab for Patients with Relapse after Allogeneic Transplantation.
N Engl J Med. 2016; 375(2):143-53 [PubMed] Article available free on PMC after 06/10/2017 Related Publications
BACKGROUND: Loss of donor-mediated immune antitumor activity after allogeneic hematopoietic stem-cell transplantation (HSCT) permits relapse of hematologic cancers. We hypothesized that immune checkpoint blockade established by targeting cytotoxic T-lymphocyte-associated protein 4 with ipilimumab could restore antitumor reactivity through a graft-versus-tumor effect.
METHODS: We conducted a phase 1/1b multicenter, investigator-initiated study to determine the safety and efficacy of ipilimumab in patients with relapsed hematologic cancer after allogeneic HSCT. Patients received induction therapy with ipilimumab at a dose of 3 or 10 mg per kilogram of body weight every 3 weeks for a total of 4 doses, with additional doses every 12 weeks for up to 60 weeks in patients who had a clinical benefit.
RESULTS: A total of 28 patients were enrolled. Immune-related adverse events, including one death, were observed in 6 patients (21%), and graft-versus-host disease (GVHD) that precluded further administration of ipilimumab was observed in 4 patients (14%). No responses that met formal response criteria occurred in patients who received a dose of 3 mg per kilogram. Among 22 patients who received a dose of 10 mg per kilogram, 5 (23%) had a complete response, 2 (9%) had a partial response, and 6 (27%) had decreased tumor burden. Complete responses occurred in 4 patients with extramedullary acute myeloid leukemia and 1 patient with the myelodysplastic syndrome developing into acute myeloid leukemia. Four patients had a durable response for more than 1 year. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells in the blood.
CONCLUSIONS: Our early-phase data showed that administration of ipilimumab was feasible in patients with recurrent hematologic cancers after allogeneic HSCT, although immune-mediated toxic effects and GVHD occurred. Durable responses were observed in association with several histologic subtypes of these cancers, including extramedullary acute myeloid leukemia. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01822509.).

Petrelli F, Coinu A, Cabiddu M, et al.
Early analysis of surrogate endpoints for metastatic melanoma in immune checkpoint inhibitor trials.
Medicine (Baltimore). 2016; 95(26):e3997 [PubMed] Article available free on PMC after 06/10/2017 Related Publications
Recent major phase III trials led to the approval of immune checkpoint inhibitors (ipilimumab, pembrolizumab, and nivolumab) in metastatic malignant melanoma (MM). We aim to assess whether median progression-free survival, and 1 and 2-year overall survival (OS) rates are reliable surrogate endpoints for median OS through a meta-analysis of published trials involving immunotherapy. A systematic literature search in PubMed, EMBASE, Web of Science, and SCOPUS of published phase II to III trials with immunotherapy as the treatment for MM was conducted. Adjusted weighted linear regression was used to calculate Pearson correlations (R) between surrogates and median OS, and between treatment effects on surrogates and median OS. A total of 13 studies involving 3373 patients with MM were identified. The correlation of progression-free survival with OS was not significant (R = 0.45, P = .11). Conversely, the correlation between 1-year OS and median OS was very strong (R = 0.93, 95% confidence interval [CI] 0.84-0.96, P < .00001), as was the correlation between 2-year OS and OS (R = 0.79, 95% CI 0.51-0.91, P = .0001). The correlation between the treatment effects on 1-year OS and OS was also significant (R = -0.86, 95% CI -0.3 to 0.97, P = .01). Similar results were obtained for 2-year OS. According to the available study data, 1-year OS rate could be regarded as a potential surrogate for median OS in novel immunotherapy trials of metastatic MM. Waiting for ongoing studies (e.g., pembrolizumab), we suggest that this intermediate endpoint could be considered as a potential primary endpoint in future clinical trials.

D'Angelo SP
Manipulating the Immune System With Checkpoint Inhibitors for Patients With Metastatic Sarcoma.
Am Soc Clin Oncol Educ Book. 2016; 35:e558-64 [PubMed] Related Publications
Sarcomas are a rare group of malignant tumors of mesenchymal origin that comprise 1% of all adult cancers. Despite initial surgery, distant metastatic disease will develop in approximately 25% of patients, and standard chemotherapy has limited durable efficacy. There is a dire need for more effective and less toxic therapies for the treatment of metastatic sarcoma. The immune system plays a major role in cancer control and progression. There have been tremendous breakthroughs in other malignancies by manipulating the immune system with checkpoint inhibitors. These agents, either alone or in combination with other approaches such as radiation, chemotherapy, targeted agents, or immunotherapeutics, have generally led to improved efficacy in selected malignancies thus far. Although promising, these drugs can cause specific immune-related adverse events that require prompt recognition and treatment. In addition, characterizing response and progression radiographically has become somewhat more challenging. Identifying predictive biomarkers of benefit will be essential. There remains optimism and hope that the strides made in other cancers will be emulated in sarcoma.

van Akkooi AC, Atkins MB, Agarwala SS, Lorigan P
Surgical Management and Adjuvant Therapy for High-Risk and Metastatic Melanoma.
Am Soc Clin Oncol Educ Book. 2016; 35:e505-14 [PubMed] Related Publications
Wide local excision is considered routine therapy after initial diagnosis of primary melanoma to reduce local recurrences, but it does not impact survival. Sentinel node staging is recommended for melanomas of intermediate thickness, but it has also not demonstrated any indisputable therapeutic effect on survival. The prognostic value of sentinel node staging has been long established and is therefore considered routine, especially in light of the eligibility criteria for adjuvant therapy (trials). Whether completion lymph node dissection after a positive sentinel node biopsy improves survival is the question of current trials. The MSLT-2 study is best powered to show a potential benefit, but it has not yet reported any data. Another study, the German DECOG study, presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting did not show any benefit but is criticized for the underpowered design and insufficient follow-up. There is no consensus on the use of adjuvant interferon in melanoma. This topic has been the focus of many studies with different regimens (low-, intermediate-, or high-dose and/or short- or long-term treatment). Adjuvant interferon has been shown to improve relapse-free survival but failed to improve overall survival. More recently, adjuvant ipilimumab has also demonstrated an improved relapse-free survival. Overall survival data have not yet been reported due to insufficient follow-up. Currently, studies are ongoing to analyze the use of adjuvant anti-PD-1 and molecular targeted therapies (vemurafenib, dabrafenib, and trametinib). In the absence of unambiguously positive approved agents, clinical trial participation remains a priority. This could change in the near future.

Agarwala SS
The Role of Intralesional Therapies in Melanoma.
Oncology (Williston Park). 2016; 30(5):436-41 [PubMed] Related Publications
The US Food and Drug Administration has been rapidly approving new checkpoint inhibitors and targeted therapies for melanoma and other tumors. Recently, it approved the first intralesional therapy, talimogene laherparepvec (T-VEC), for the treatment of metastatic melanoma lesions in the skin and lymph nodes. Several other intralesional therapies (PV-10, interleukin-12 electroporation, coxsackievirus A21 [CVA21]) are entering later-stage testing. Locally injected agents have clearly shown their ability to produce local responses that can be durable. The possibility that they also stimulate a regional and even systemic immune response is exciting, as this potential effect may have utility in combination regimens; such regimens are an area of active research. Favorable responses with minimal toxicities in monotherapy trials have led to the first melanoma studies of T-VEC in combination with the cytotoxic T-lymphocyte-associated antigen 4 inhibitor ipilimumab and, separately, with the programmed death 1-blocking antibody pembrolizumab. Studies of PV-10 with pembrolizumab and of CVA21 with pembrolizumab are also being initiated. Preliminary analyses of the results of the first combination trials, which show higher response rates than with either agent alone, offer some optimism that these locoregional therapies will find application--as treatment for patients who cannot tolerate systemic immunotherapies, to alleviate locoregional morbidity, and perhaps even to "prime" the immune system.

Lee D, Porter J, Hertel N, et al.
Modelling Comparative Efficacy of Drugs with Different Survival Profiles: Ipilimumab, Vemurafenib and Dacarbazine in Advanced Melanoma.
BioDrugs. 2016; 30(4):307-19 [PubMed] Related Publications
BACKGROUND: In the absence of head-to-head data, a common method for modelling comparative survival for cost-effectiveness analysis is estimating hazard ratios from trial publications. This assumes that the hazards of mortality are proportional between treatments and that outcomes are not polluted by subsequent therapy use. Newer techniques that compare treatments where the proportional hazards assumption is violated and adjust for use of subsequent therapies often require patient-level data, which are rarely available for all treatments.
OBJECTIVE: The objective of this study was to provide a comparison of overall survival data for ipilimumab, vemurafenib and dacarbazine using data from three trials lacking a common comparator arm and confounded by the use of subsequent treatment.
METHODS: We compared three estimated overall survival curves for vemurafenib and the difference compared to ipilimumab and dacarbazine. We performed a naïve comparison and adjusted it for heterogeneity between the ipilimumab and vemurafenib trials, including differences in prognostic characteristics and subsequent therapy using a published hazard function for the impact of prognostic characteristics in melanoma and trial data on the impact of second-line use of ipilimumab.
RESULTS: The mean incremental life-years gained for patients receiving ipilimumab compared with vemurafenib were 0.34 (95 % confidence interval [CI] -0.24 to 0.84) using the naïve comparison and 0.51 (95 % CI -0.08 to 0.99) using the covariate-adjusted survival curve.
CONCLUSIONS: The analyses estimated the comparative efficacy of ipilimumab and vemurafenib in the absence of head-to-head patient-level data for all trials and proportional hazards in overall survival.

Gozzo L, Navarria A, Drago V, et al.
Linking the Price of Cancer Drug Treatments to Their Clinical Value.
Clin Drug Investig. 2016; 36(7):579-89 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: Appropriate pricing of medications is one of the ultimate goals for decision makers, but reliable data on the risk/benefit ratio are often lacking when a Marketing Authorization Application is submitted. Here we propose a method to consistently evaluate price adequacy, which we applied to six anticancer medications approved in Italy in recent years.
METHODS: We obtained ratios of cost per survival per day (cost/survival/day) by dividing the total costs of evaluated medications for the median survival gain in days. Each cost/survival/day corresponds to a crude score, with 0 assigned to a cost/survival/day ≥€586. The maximum price considered as adequate was €91 cost/survival/day (score 75) while a score of 100 corresponded to a cost/survival/day ≤€11, based on the thresholds set by the British National Health System (NHS) and the "willingness-to-pay" of the Italian NHS. Crude scores were then adjusted using correction factors for efficacy, safety, quality of life, and prevalence of disease.
RESULTS: None of the analyzed medications (abiraterone, afatinib, aflibercept, bevacizumab, dabrafenib, and ipilimumab) achieved a final score of 75, corresponding to adequate pricing. The final score for afatinib was the highest with 55 points. Prices of all the other drugs resulted in being inadequate, with negative final scores for bevacizumab, dabrafenib, and ipilimumab.
CONCLUSIONS: This method may be considered a tool for the evaluation of appropriateness of price proposed at negotiation and could represent a reliable resource for decision-making. Furthermore, this analysis suggests that most recently approved cancer drugs in Italy do not fulfill price adequacy.

Ribas A, Hamid O, Daud A, et al.
Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma.
JAMA. 2016; 315(15):1600-9 [PubMed] Related Publications
IMPORTANCE: The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab.
OBJECTIVE: To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma.
DESIGN, SETTINGS, AND PARTICIPANTS: Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses.
EXPOSURES: Pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity, or investigator decision.
MAIN OUTCOMES AND MEASURES: The primary end point was confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival.
RESULTS: Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33% [95% CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45% [95% CI, 36% to 54%]). Overall, 74% (152/205) of responses were ongoing at the time of data cutoff; 44% (90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35% (95% CI, 31%-39%) in the total population and 52% (95% CI, 43%-60%) among treatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66% (95% CI, 62%-69%) and a 24-month survival rate of 49% (95% CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95% CI, 24 to not reached) with a 12-month survival rate of 73% (95% CI, 65%-79%) and a 24-month survival rate of 60% (95% CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths.
CONCLUSIONS AND RELEVANCE: Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01295827.

McMillen B, Dhillon MS, Yong-Yow S
A rare case of thyroid storm.
BMJ Case Rep. 2016; 2016:10.1136/bcr-2016-214603 [PubMed] Related Publications
Thyroid storm is a rare and life-threatening state of thyroid hormone excess. Rapid recognition of thyroid storm is key to decreasing the morbidity and mortality of this condition. Clinical manifestations of thyroid storm include unexplained weight loss, hyperactivity and irritability. The most common causes of thyrotoxicosis are Graves' disease, toxic multinodular goitre and toxic adenoma. We present a rare case of thyroid storm induced by dual nivolumab and ipilimumab immunotherapy in a patient receiving treatment for advanced melanoma. In this case, our patient was admitted for thyroid storm 1 month after initiating treatment with nivolumab and ipilimumab immunotherapy. The patient was treated with β-blockers, antithyroid medications and systemic steroids resulting in an improvement in thyroid function testing and symptoms.

Thomas S, Prendergast GC
Cancer Vaccines: A Brief Overview.
Methods Mol Biol. 2016; 1403:755-61 [PubMed] Related Publications
Vaccine approaches for cancer differ from traditional vaccine approaches for infectious disease in tending to focus on clearing active disease rather than preventing disease. In this review, we provide a brief overview of different types of vaccines and adjuvants that have been investigated for the purpose of controlling cancer burdens in patients, some of which are approved for clinical use or in late-stage clinical trials, such as the personalized dendritic cell vaccine sipuleucel-T (Provenge) and the recombinant viral prostate cancer vaccine PSA-TRICOM (Prostvac-VF). Vaccines against human viruses implicated in the development and progression of certain cancers, such as human papillomavirus in cervical cancer, are not considered here. Cancers express "altered self" antigens that tend to induce weaker responses than the "foreign" antigens expressed by infectious agents. Thus, immune stimulants and adjuvant approaches have been explored widely. Vaccine types considered include autologous patient-derived immune cell vaccines, tumor antigen-expressing recombinant virus vaccines, peptide vaccines, DNA vaccines, and heterologous whole-cell vaccines derived from established human tumor cell lines. Opportunities to develop effective cancer vaccines may benefit from seminal recent advances in understanding how immunosuppressive barricades are erected by tumors to mediate immune escape. In particular, targeted ablation of these barricades with novel agents, such as the immune checkpoint drug ipilimumab (anti-CTLA-4) approved recently for clinical use, may offer significant leverage to vaccinologists seeking to control and prevent malignancy.

Coit DG, Thompson JA, Algazi A, et al.
Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology.
J Natl Compr Canc Netw. 2016; 14(4):450-73 [PubMed] Related Publications
This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted re-assessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections.

Maul LV, Weichenthal M, Kähler KC, Hauschild A
Successful Anti-PD-1 Antibody Treatment in a Metastatic Melanoma Patient With Known Severe Autoimmune Disease.
J Immunother. 2016; 39(4):188-90 [PubMed] Related Publications
Pembrolizumab, an anti-programmed death-1 monoclonal antibody, has been approved by the Food and Drug Administration in 2014 on the basis of improved progression-free and overall survival in metastatic melanoma. We report for the first time a successful treatment with a programmed death-1 antibody in a 69-year-old metastastic melanoma patient with a Churg-Strauss lung vasculitis and a prior ipilimumab-induced autoimmune colitis. This case report suggests that pembrolizumab can be given with caution to patients with underlying autoimmune disease. As the use of checkpoint inhibitors expands, knowledge about their safety in patients with underlying autoimmune diseases will become increasingly important, in particular because these patients are typically excluded from clinical trials with immune-checkpoint inhibitors.

Seetharamu N, Budman DR, Sullivan KM
Immune checkpoint inhibitors in lung cancer: past, present and future.
Future Oncol. 2016; 12(9):1151-63 [PubMed] Related Publications
Inhibitory ligands on tumor cells and their corresponding receptors on T cells are collectively called immune checkpoint molecules and have emerged as druggable targets that harness endogenous immunity to fight cancer. Immune checkpoint inhibitors targeting CTLA-4, PD-1 and PD-L1 have been developed for the treatment of patients with non-small-cell lung cancer and other malignancies, with impressive clinical activity, durable responses and a favorable toxicity profile. This article reviews the development, current status and future directions for some of these agents. The efficacy and safety data for drugs such as ipilimumab, nivolumab, pembrolizumab, atezolizumab and durvalumab are reviewed, along with combination strategies and response evaluation criteria. The toxicity profiles and predictive biomarkers of response are also discussed.

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