Pembrolizumab Plus Ipilimumab Following Anti-PD-1/L1 Failure in Melanoma

Olson, Daniel J.; Eroglu, Zeynep; Brockstein, Bruce; Poklepovic, Andrew; Bajaj, Madhuri; Babu, Sunil; Hallmeyer, Sigrun; Velasco, M; Lutzky, Jose; Higgs, Emily; Bao, Riyue; Carll, Timothy; Labadie, Brian; Krausz, Thomas; Zha, Yuanyuan; Karrison, Theodore; Sondak, Vernon K.; Gajewski, Thomas F.; Khushalani, Nikhil I.; Luke, Jason J.

doi:10.1200/jco.21.00079

Cited by 105 publications

(105 citation statements)

References 27 publications

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“…42 In a small prospective study of pembrolizumab plus low-dose ipilimumab (1 mg/kg), the ORR was 29% in all enrolled patients. 43 In our study, the DCRs at week 18 were comparable in patients treated with ipilimumab and ipilimumab plus nivolumab. Notably, the elapsed time interval between the last dose of anti-PD-1 monotherapy and the study drug was short in both arms: 6 weeks (range 3–55 weeks) in patients treated with ipilimumab arm and 4.3 (range 2–36 weeks) in patients treated with ipilimumab plus nivolumab.…”

Section: Discussionsupporting

confidence: 53%

Ipilimumab alone or in combination with nivolumab in patients with advanced melanoma who have progressed or relapsed on PD-1 blockade: clinical outcomes and translational biomarker analyses

Friedman¹,

Spencer

Cabanski

et al. 2022

J Immunother Cancer

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BackgroundThere are no validated biomarkers that can aid clinicians in selecting who would best benefit from anticytotoxic T lymphocyte-associated antigen 4 monotherapy versus combination checkpoint blockade in patients with advanced melanoma who have progressive disease after programmed death 1 (PD-1) blockade.MethodsWe conducted a randomized multicenter phase II trial in patients with advanced melanoma. Patients were randomly assigned to receive either 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab or 3 mg/kg of ipilimumab every 3 weeks for up to four doses. Patients were stratified by histological subtype and prior response to PD-1 therapy. The primary clinical objective was overall response rate by week 18. Translational biomarker analyses were conducted in patients with blood and tissue samples.ResultsObjective responses were seen in 5 of 9 patients in the ipilimumab arm and 2 of 10 patients in the ipilimumab+nivolumab arm; disease control rates (DCRs) (66.7% vs 60.0%) and rates of grade 3–4 adverse events (56% vs 50%) were comparable between arms. In a pooled analysis, patients with clinical benefit (CB), defined as Response Evaluation Criteria in Solid Tumors response or progression-free for 6 months, showed increased circulating CD4+ T cells with higher polyfunctionality and interferon gamma production following treatment. Tumor profiling revealed enrichment of NRAS mutations and activation of transcriptional programs associated with innate and adaptive immunity in patients with CB.ConclusionsIn patients with advanced melanoma that previously progressed on PD-1 blockade, objective responses were seen in both arms, with comparable DCRs. Findings from biomarker analyses provided hypothesis-generating signals for validation in future studies of larger patient cohorts.Trial registration numberNCT02731729.

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Section: Discussionsupporting

confidence: 53%

Ipilimumab alone or in combination with nivolumab in patients with advanced melanoma who have progressed or relapsed on PD-1 blockade: clinical outcomes and translational biomarker analyses

Friedman¹,

Spencer

Cabanski

et al. 2022

J Immunother Cancer

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“… 551 Of note, improved antitumor response and tolerable safety are seen in anti-PD-1/PD-L1-refractory melanoma patients with pembrolizumab plus low-dose ipilimumab. 552 The treatment of other types of melanoma excluding cutaneous melanoma is of great challenge for their relatively insensitive response to existing therapies. The combination of nivolumab and ipilimumab has been subsequently evaluated in non-cutaneous melanoma including acral, mucosal, and uveal melanoma, and the combination regimen shows sustained and improved response compared with either single agent, although with elevated toxicity but manageable safety profile.…”

Section: Present Advances In Therapies Targeting Tumor Immunology and Ongoing Clinical Trialsmentioning

confidence: 99%

Signal pathways of melanoma and targeted therapy

Guo

Wang

2021

Sig Transduct Target Ther

134

119

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Melanoma is the most lethal skin cancer that originates from the malignant transformation of melanocytes. Although melanoma has long been regarded as a cancerous malignancy with few therapeutic options, increased biological understanding and unprecedented innovations in therapies targeting mutated driver genes and immune checkpoints have substantially improved the prognosis of patients. However, the low response rate and inevitable occurrence of resistance to currently available targeted therapies have posed the obstacle in the path of melanoma management to obtain further amelioration. Therefore, it is necessary to understand the mechanisms underlying melanoma pathogenesis more comprehensively, which might lead to more substantial progress in therapeutic approaches and expand clinical options for melanoma therapy. In this review, we firstly make a brief introduction to melanoma epidemiology, clinical subtypes, risk factors, and current therapies. Then, the signal pathways orchestrating melanoma pathogenesis, including genetic mutations, key transcriptional regulators, epigenetic dysregulations, metabolic reprogramming, crucial metastasis-related signals, tumor-promoting inflammatory pathways, and pro-angiogenic factors, have been systemically reviewed and discussed. Subsequently, we outline current progresses in therapies targeting mutated driver genes and immune checkpoints, as well as the mechanisms underlying the treatment resistance. Finally, the prospects and challenges in the development of melanoma therapy, especially immunotherapy and related ongoing clinical trials, are summarized and discussed.

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“…This combination approach has become the most intensively studied as well as the most widely used immune combination regimen (103). Daniel et al (104) evaluated the efficacy of Pembrolizumab plus Ipilimumab in melanoma patients after failure of anti-PD-1/PD-L1 therapy and showed that 29% of patients achieved a confirmed response (including 21.4% partial responses and 7.2% complete responses). This demonstrates the significant antitumor activity of the combination.…”

Section: Ctla-4 Inhibitorsmentioning

confidence: 99%

Various Uses of PD1/PD-L1 Inhibitor in Oncology: Opportunities and Challenges

Sun

Cheng

et al. 2021

Front. Oncol.

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The occurrence and development of cancer are closely related to the immune escape of tumor cells and immune tolerance. Unlike previous surgical, chemotherapy, radiotherapy and targeted therapy, tumor immunotherapy is a therapeutic strategy that uses various means to stimulate and enhance the immune function of the body, and ultimately achieves the goal of controlling tumor cells.With the in-depth understanding of tumor immune escape mechanism and tumor microenvironment, and the in-depth study of tumor immunotherapy, immune checkpoint inhibitors represented by Programmed Death 1/Programmed cell Death-Ligand 1(PD-1/PD-L1) inhibitors are becoming increasingly significant in cancer medication treatment. employ a variety of ways to avoid detection by the immune system, a single strategy is not more effective in overcoming tumor immune evasion and metastasis. Combining different immune agents or other drugs can effectively address situations where immunotherapy is not efficacious, thereby increasing the chances of success and alternative access to alternative immunotherapy. Immune combination therapies for cancer have become a hot topic in cancer treatment today. In this paper, several combination therapeutic modalities of PD1/PD-L1 inhibitors are systematically reviewed. Finally, an analysis and outlook are provided in the context of the recent advances in combination therapy with PD1/PD-L1 inhibitors and the pressing issues in this field.

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Pembrolizumab Plus Ipilimumab Following Anti-PD-1/L1 Failure in Melanoma

Cited by 105 publications

References 27 publications

Ipilimumab alone or in combination with nivolumab in patients with advanced melanoma who have progressed or relapsed on PD-1 blockade: clinical outcomes and translational biomarker analyses

Ipilimumab alone or in combination with nivolumab in patients with advanced melanoma who have progressed or relapsed on PD-1 blockade: clinical outcomes and translational biomarker analyses

Signal pathways of melanoma and targeted therapy

Various Uses of PD1/PD-L1 Inhibitor in Oncology: Opportunities and Challenges

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