Evaluation of the clinical benefits of immune checkpoint inhibitors in patients with advanced melanoma.

194 Background: Immune checkpoint inhibitors selection in advanced melanoma is complicated further, with choices among anti-CTLA4 or anti-PD-1 therapeutic antibodies options. We aimed to evaluate the clinical benefits of immune checkpoint inhibitors for discussing evidence-based treatment strategies by a meta-analysis of randomized clinical trials (RCTs) data. Methods: We searched for RCTs investigating immune checkpoint inhibitors in patients with advanced melanoma until September 2017. Hazard ratios (HRs) was estimated for overall survival (OS) and progression-free survival (PFS). The quality of the evidence was evaluated with the GRADE framework. Results: Overall, 18 RCTs including a total of 8,917 patients were identified. Immune checkpoint inhibitors versus placebo or observation prolonged PFS (HR = 0.59, 95% confidence interval (CI) 0.44 to 0.78, P < 0.0001) and OS (HR = 0.77, 95% CI 0.72 to 0.84, P < 0.0001). The combination immunotherapy had significantly higher benefit than monotherapy for PFS (HR = 0.75, 95% CI 0.61 to 0.92, P = 0.005) and OS (HR = 0.70, 95% CI 0.61 to 0.79, P < 0.0001). Treatment with anti-PD-1 monoclonal antibody was associated with improved PFS (HR = 0.61, 95% CI 0.59 to 0.69, P < 0.0001) and OS (HR = 0.66, 95% CI 0.58 to 0.77, P < 0.0001) compared with anti-CTLA-4 monoclonal antibody. According to BRAF status analysis, there was a PFS benefit of immune checkpoint inhibitors versus placebo or observation (mutant, HR = 0.58, 95% CI 0.35 to 0.96, P = 0.035; wild–type, HR = 0.52, 95% CI 0.43 to 0.69, P = 0.001), anti-PD-1 outperformed anti-CTLA-4 checkpoint inhibitor (mutant, PFS HR = 0.64, 95% CI 0.51 to 0.79, P < 0.0001; wild–type, PFS HR = 0.58, 95% CI 0.47 to 0.71, P < 0.0001); and combination compared with single-agent immunotherapy (mutant, HR = 0.38, 95% CI 0.15 to 0.98, P = 0.046; wild–type, HR = 0.40, 95% CI 0.23 to 0.69, P = 0.001). Conclusions: This analysis provides an evidence that immune checkpoint inhibitors enhanced OS and PFS in patients with advanced melanoma, as well as combination immunotherapy and anti-PD-1 monoclonal antibody appear to be clinically beneficial option preference.

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Combination of biomarker and clinicopathologic characters to circle out beneficiaries through second-line immunotherapy: A meta analyse.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e14535 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e14535-e14535

Author(s):

C Zhang ◽

Wenzhao Zhong ◽

Zhong yi Dong ◽

Yi-Long Wu

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Smoking Status ◽

Single Agent ◽

Egfr Mutations ◽

Second Line ◽

Wild Type ◽

Second Line Therapy ◽

Line Therapy

e14535 Background: Programmed cell death ligand 1 (PD-L1) expression had been proposed as predictive biomarker to immune-checkpoint inhibitors. Yet treatment responses are not always consistent with this single agent in the second-line therapy of non-small cell lung cancer (NSCLC). Whether combination of PD-L1 and clinicopathologic characters could circle out optimal beneficiaries are still unknown. Methods: We performed a meta-analysis of randomized control trials that compared immune-checkpoint inhibitors against chemotherapy in second-line therapy. Data including smoking status, EGFR status, KRAS status and histology were extracted as subgroup analyse to estimate the potential predictor of efficacy for anti PD-1/L1. Results: Five clinical trials that compared immune-checkpoint inhibitors against chemotherapy for second-line therapy were included. Both PD-L1 positive (HR = 0.64, 95%CI = 0.56-0.73, P < 0.00001) and PD-L1 negative (HR = 0.88, 95%CI = 0.78-1.00, P = 0.05) favored anti PD-1/L1. Subgroup analyse indicated that adenocarcinoma (ADC) as well as squamous cell carcinoma (SCC) preferred anti PD-1/L1. Never smokers may not benefit from anti PD-1/L1 but current/ever smokers did (HR = 0.70, 95%CI = 0.63-0.79, P < 0.00001). Patients with EGFR mutation could not gain benefit from anti PD-1/L1 while the EGFR wild type could (HR = 0.67, 95%CI = 0.60-0.76, P < 0.00001). Both KRAS mutation (HR = 0.60, 95%CI = 0.39-0.92, P = 0.02) and wild type/unknown (HR = 0.81, 95%CI = 0.67-0.97, P = 0.02) were apt to anti PD-1/L1. Conclusions: Regardless of PD-L1 status, immune-checkpoint inhibitors could achieve better efficacy than chemotherapy in second-line therapy. Current/ever smokers without EGFR mutations may benefit more from anti PD-1/L1. Combination of PD-L1 and strongly relevant clinicopathologic characters should be considered to tailor optimal patients for anti PD-1/L1.

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Predictable clinical benefits without synergy in trials of combination therapies with immune checkpoint inhibitors

10.21203/rs.3.rs-253936/v1 ◽

2021 ◽

Author(s):

Adam (C.) Palmer ◽

Benjamin Izar ◽

Haeun Hwangbo ◽

Peter Sorger

Keyword(s):

Survival Data ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Progression Free Survival ◽

Phase Iii ◽

Cancer Therapies ◽

Immune Priming ◽

Clinical Benefits

Abstract Hundreds of clinical trials are currently underway testing combinations of Immune Checkpoint Inhibitors (ICIs) with other cancer therapies in the hope that drug combinations will be more effective than monotherapy. Enhanced efficacy is proposed to result from drug additivity or synergy involving mechanisms such as immune priming. In this paper we re-analyze progression free survival data from thirteen recent Phase III trials of ICI combinations and find that observed benefits are fully and accurately accounted for by an increased chance that each patient will respond to a single-agent, consistent with the predictions of drug independence, with no requirement for additive or synergistic efficacy. Thus, the likely anti-tumor efficacy of new ICI combinations can be reliably predicted from monotherapy data (Pearson r=0.98, P < 5×10-9, n = 4173 patients and 8 types of cancer), although predicting adverse effects is not yet possible. Realizing the clinical potential of drug additivity or synergy is likely to require biomarkers that identify patients in whom multiple constituents of a drug combination are active.

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Clinical outcome of immune related hepatitis (IrHep) in patients with advanced melanoma (AM) treated with single agent or combination immune checkpoint inhibitors (ICIs)

Annals of Oncology ◽

10.1093/annonc/mdy288.093 ◽

2018 ◽

Vol 29 ◽

pp. viii433-viii434 ◽

Cited By ~ 1

Author(s):

N. Shah ◽

J. Puthiamadathil ◽

M.T. Serzan ◽

A. Belouali ◽

W.J. Kelly ◽

...

Keyword(s):

Clinical Outcome ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Advanced Melanoma

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ESDR289 - The effect of immune checkpoint Inhibitors on the CD4+ T-cell population by patients with advanced melanoma and the role of these cells in immune related adverse events

10.26226/morressier.61081ff8bc981037240fe4ae ◽

2021 ◽

Author(s):

Tereza Jakovljevicova

Keyword(s):

T Cell ◽

Adverse Events ◽

Cell Population ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Advanced Melanoma ◽

Cd4 T Cell

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RNF43 mutations to predict survival from treatment with immune checkpoint inhibitors and are associated with a high tumor mutation burden in bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16528 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16528-e16528

Author(s):

Liping Li ◽

Mengmei Yang ◽

Mengli Huang

Keyword(s):

Bladder Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Negative Regulator ◽

Wilcoxon Test ◽

Wild Type ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

The Impact

e16528 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1/L1 have been approved as first-line treatment for cisplatin-ineligible patients and as second-line therapy for patients with metastatic urothelial carcinoma of the bladder. Biomarkers can help select patients who are more likely to response to ICIs. RNF43 is an E3 ubiquitin ligase that acts as a negative regulator of Wnt/β-catenin signaling pathway. In colorectal cancer (CRC) patients treated with immune checkpoint inhibitors (ICIs), RNF43 mutations predicted longer overall survival (OS). The impact of RNF43 mutations on the efficiency of ICIs in bladder cancer(BLC) remains to be explored. Methods: We downloaded the mutation and clinical data of 211 BLC patients treated with ICIs from the immunotherapeutic cohort published by Samstein et al. (2019). OS analyses were conducted using Kaplan-Meier curves and log-rank tests. Wilcoxon test was used for the comparison of TMB. We also downloaded a TCGA cohort for prognostic analysis. The correlations between RNF43 and immune infiltrates were analyzed in the TIMER2.0 database. Statistical significance was set at p = 0.05. Results: RNF43 mutations were identified in 4.3%(9/211) and 3%(13/438) BLC patients in the immunotherapeutic and TCGA cohort, respectively. In the immunotherapeutic cohort, patients with RNF43 mutations had significantly longer OS (25 months vs 8 months; p = 0.015) and higher tumor mutation burden(TMB, 42.3 vs 7.9; p = 3.15E-06) than RNF43-wild-type patients. Different from this, no significant difference was found in OS between RNF43-mutant and RNF43-wild-type BLC patients with standard treatment in the TCGA cohort (p = 0.696). These results indicated that RNF43 was not a prognostic factor but a predictive biomarker of survival in BLC treated with ICIs. No difference was observed in subsets of immune cells between RNF43-mutant and the RNF43-wide-type BLC patients, including neutrophils, macrophages, CD8+ T cells, Tregs, B cells and NK cells. Conclusions: RNF43 mutations may be a predictor of survival benefit from ICIs in bladder cancer and correlated with higher TMB. Further studies in other ICI-treated cohorts are needed to confirm these results.

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Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors

10.1101/2020.01.31.20019604 ◽

2020 ◽

Cited By ~ 1

Author(s):

Adam C. Palmer ◽

Benjamin Izar ◽

Peter K. Sorger

Keyword(s):

Clinical Trials ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Combination Therapies ◽

Anti Tumor Activity

ABSTRACTHundreds of clinical trials are testing whether combination therapies can increase the anti-tumor activity of Immune Checkpoint Inhibitors (ICIs). We find that the benefits of recently reported and approved combinations involving ICIs are fully accounted for by increasing the chance of a single-agent response (drug independence), with no requirement for additive or synergistic efficacy. Thus, the degree of success of combinations involving ICIs with other therapies is largely predictable.

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