Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial

Ascierto, Paolo A.; Vecchio, Michele Del; Robert, Caroline; Maćkiewicz, Andrzej; Chiarion-Sileni, Vanna; Arance, Ana; Lebbe, Célèste; Bastholt, Lars; Hamid, Omid; Rutkowski, Piotr; McNeil, Catriona M.; Garbe, Claus; Loquai, Carmen; Dréno, Brigitte; Thomas, Luc; Grob, Jean Jacques; Liszkay, Gabriella; Nyakas, Marta; Gutzmer, Ralf; Pikiel, Joanna; Grange, Florent; Höeller, Christoph; Ferraresi, Virginia; Smylie, Michael; Schadendorf, Dirk; Mortier, Laurent; Svane, Inge Marie; Hennicken, Delphine; Qureshi, Anila; Maio, Michele

doi:10.1016/s1470-2045(17)30231-0

Cited by 440 publications

(357 citation statements)

References 22 publications

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“…Furthermore, recent data from a 3 mg/kg versus 10 mg/kg phase III study of ipilimumab demonstrated no difference in objective response rates, though the higher dose of ipilimumab was associated with improved survival. [12] The addition of temozolomide represents a different maneuver than the addition of dacarbazine to ipilimumab. Temozolomide demonstrates a preferentially cytotoxic effect to regulatory T cells (Treg) rather than effector T cells (Teff).…”

Section: Discussionmentioning

confidence: 99%

A phase II study of ipilimumab plus temozolomide in patients with metastatic melanoma

Patel

Kim

Bassett

et al. 2017

Cancer Immunol Immunother

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Checkpoint blockade has revolutionized the treatment of melanoma; however, it benefits only the minority of patients. Several agents have been combined with immunotherapy to improve T-cell activation and persistence including growth factor, chemotherapy, and radiation. Preclinical data suggest temozolomide, which metabolizes to the same active compound as dacarbazine, selectively depletes regulatory T cells. This potential immunomodulatory effect of temozolomide provides rationale for combination with ipilimumab. We performed an open-label single-arm phase II study of ipilimumab plus temozolomide in the frontline setting for patients with metastatic melanoma and LDH <=2x upper limit of normal. Ipilimumab was given at 10 mg/kg on day 1 and temozolomide 200 mg/m2 orally days 1–4 every three weeks for four doses followed by maintenance ipilimumab every 12 weeks plus temozolomide every four weeks. The primary objective of the study was 6-month PFS. A total of 64 patients were enrolled and the 6-month PFS was 45% with median OS of 24·5 months. There were 10 (15·6%) confirmed partial responses and 10 (15·6%) confirmed complete responses. Duration of response amongst responders is 35 months with 10 patients demonstrating an ongoing response at median follow-up of 20 months. There were no deaths or unexpected toxicities on study. The most common gastrointestinal side effects were nausea and constipation rather than diarrhea or colitis. These results suggest that the combination of induction ipilimumab plus temozolomide could potentially be an effective strategy to enhance antitumor activity with a manageable toxicity profile. These findings warrant further evaluation in a large prospective study.

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Section: Discussionmentioning

confidence: 99%

A phase II study of ipilimumab plus temozolomide in patients with metastatic melanoma

Patel

Kim

Bassett

et al. 2017

Cancer Immunol Immunother

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“…In the absence of obvious differences in efficacy emerged in indirect comparison of clinical trials, we do not know which is the best treatment choice. Other issues that are not completely answered by the evidence produced in clinical trials are the dose-response relationship (recent evidence in melanoma with ipilimumab suggests that higher dose is associated with higher efficacy [55]) and the optimal duration of treatment (continuous until disease progression or with planned “stop-and-go”).…”

Section: Discussionmentioning

confidence: 99%

Immunotherapy for Patients with Advanced Urothelial Cancer: Current Evidence and Future Perspectives

Zichi

Tucci

Leone

et al. 2017

BioMed Research International

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In recent years, immunotherapy has produced encouraging results in a rapidly increasing number of solid tumors. The responsiveness of bladder cancer to immunotherapy was first established in nonmuscle invasive disease in 1976 with intravesical instillations of bacillus Calmette-Guérin (BCG). Very recently immune checkpoint inhibitors demonstrated good activity and significant efficacy in metastatic disease. In particular the best results were obtained with programmed death-ligand-1 (PD-L1) and programmed death-1 (PD-1) inhibitors, but many other immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibodies, are currently under investigation in several trials. Simultaneously other therapeutic strategies which recruit an adaptive immune response against tumoral antigens or employ externally manipulated tumor infiltrating lymphocytes might change the natural history of bladder cancer in the near future. This review describes the rationale for the use of immunotherapy in bladder cancer and discusses recent and ongoing clinical trials with checkpoint inhibitors and other novel immunotherapy agents.

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“…Data from the Italian ipilimumab expanded access programme clearly showed no difference in term of overall survival (OS) between patients who harbored the BRAF mutation and those who were BRAF wild-type [8]. However, results from two recent clinical trials, the CA184-169 study of ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg [2] and the CheckMate 067 trial of ipilimumab plus nivolumab versus ipilimumab or nivolumab monotherapy [9], showed better outcomes with, respectively, ipilimumab 10 mg/kg and the combined ipilimumab plus nivolumab regimen in BRAF-mutated patients. Whilst it is possible that could simply be attributed to the limitations of subgroup analyses with imbalance between the groups, we speculate that new biological data in NSCLC coupled with recently published data from melanoma provide a plausible explanation.…”

Section: Mutational Statusmentioning

confidence: 99%

“…chemotherapy, targeted therapy, radiation). Most recently, research has shown that I-O therapy can be used as adjuvant therapy [1], outcomes may be influenced by dose [2], and that clinical activity is observed in patients with brain metastases [3]. …”

Section: Introductionmentioning

confidence: 99%

Checkpoint inhibitors in melanoma and early phase development in solid tumors: what’s the future?

Ascierto

McArthur

2017

J Transl Med

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Anti-programmed death (PD)-1 and PD-ligand (L)-1 checkpoint inhibitors have revolutionized the therapy of several cancers. Immunotherapy of cancer can offer long-term durable benefit to patients, is active regardless of tumour histology, has a unique immune-related safety profile, and can be used in combination with other cancer treatments. In addition, recent research has shown that immune-based therapy can be used as adjuvant therapy, that outcomes may be influenced by dose, and that clinical activity is observed in patients with brain metastases. Despite our increased understanding of these agents, there are still several important questions that need to be answered. These include strategies to overcome primary and acquired resistance, the influence of mutational status on treatment outcomes, the optimal duration of treatment, and the need to identify novel combination regimens that offer increased anti-tumour potency and/or reduced toxicity. Here we review recent developments in these areas, with particular focus on new data reported at the 2017 ASCO Annual Meeting.

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Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial

Cited by 440 publications

References 22 publications

A phase II study of ipilimumab plus temozolomide in patients with metastatic melanoma

A phase II study of ipilimumab plus temozolomide in patients with metastatic melanoma

Immunotherapy for Patients with Advanced Urothelial Cancer: Current Evidence and Future Perspectives

Checkpoint inhibitors in melanoma and early phase development in solid tumors: what’s the future?

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