Clinical outcome of sequential chemotherapy after immune checkpoint inhibitors in advanced ovarian cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5580-5580
Author(s):  
Luisa Bonilla ◽  
Amit M. Oza ◽  
Stephanie Lheureux ◽  
Sam Saibil ◽  
Shiyi Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Low Grade

5580 Background: Immunomodulation through check point inhibition is an important treatment strategy in many cancers. In ovarian cancer (OC) response rates with immune checkpoint inhibitors (ICI) alone are around 10%. Chemotherapy antitumoural effect is driven by cytotoxicity and immunomodulatory effect. ICI treatment reduces tumour induced immune-tolerance improving immunocompetence, essential for chemotherapy effect. We chose to investigate clinical outcomes of chemotherapy post ICI in women with OC. Methods: The Tumor Immunotherapy Program (TIP) database at the Princess Margaret Cancer Centre identified patients with OC treated with chemotherapy after ICI from 2011 to 2018. Evaluation of clinical outcomes including response rate (RR), progression free survival (PFS) and overall survival (OS) was assessed for pre ICI, ICI and post ICI. Results: 40 women with OC were treated with chemotherapy after ICI. 90% had high grade serous histology, 7.5% carcinosarcoma and 2.5% low grade serous. Median number of pre ICI treatment lines was 3 (1-8) and 2 (1-6) in the post ICI setting. Median time of ICI initiation from diagnosis was 3 years. At ICI all patients had PS 0-1 and treated in clinical trials. 2% of the patients had platinum refractory disease, 88% had platinum resistant disease and 10% platinum sensitive disease. 50% were treated with ICI single agent, 16% were treated with ICI combined with chemotherapy, 14% ICI combo and 17% ICI in combination with other agents. Patients were treated for a median of 3 cycles (1-26). 8% experienced PR, 18% SD, no CR were seen. 67% of the patients discontinued treatment due to PD, 25% due to toxicity. Last treatment in pre ICI RR was 35%. First treatment in post ICI RR was 30%. RR for each treatment used in post ICI was 9% for liposomal doxorubicin, 25% for single agent platinum, 29% for weekly paclitaxel and 67% for chemotherapy with bevacizumab. Median PFS in the last pre ICI treatment was 6.5m and 5m in the first post ICI treatment. Median PFS and OS for all the population was 53m and 54m respectively. Conclusions: ICI are associated with modest activity in OC, planned clinical trials exploring systematic sequential therapy integrating ICI, targeted agents and chemotherapy are needed.

scholarly journals Expectations and Challenges of First-Line Maintenance Therapy for Advanced Ovarian Cancer

Medicina ◽  
2021 ◽  
Vol 57 (5) ◽  
pp. 501
Author(s):  
Tadahiro Shoji ◽  
Chie Sato ◽  
Hidetoshi Tomabechi ◽  
Eriko Takatori ◽  
Yoshitaka Kaido ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Checkpoint ◽  
Clinical Studies ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Advanced Ovarian Cancer ◽  
Targeted Drugs ◽  
First Line ◽  
Double Blind ◽  
Platinum Based Chemotherapy

The incidence of ovarian cancer, which has had a poor prognosis, is increasing annually. Currently, the prognosis is expected to improve with the use of molecular-targeted drugs and immune checkpoint inhibitors as maintenance therapies after the first-line chemotherapy. The GOG218 and ICON7 studies reported the usefulness of bevacizumab and the SOLO-1 and PRIMA (A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy) studies have reported the usefulness of olaparib and niraparib, respectively. The ATHENA study investigating the usefulness of rucaparib is currently ongoing. Although clinical studies of immune checkpoint inhibitors are lagging in the field of gynecology, many clinical studies using programmed death cell-1 (PD-1) and PD-1 ligand 1 (PD-L1) antibodies are currently ongoing. Some biomarkers have been identified for molecular-targeted drugs, but none have been identified for immune checkpoint inhibitors, which is a challenge that should be addressed in the future.

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

2020 ◽  
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.

scholarly journals Efficacy of immune checkpoint inhibitors for in-transit melanoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000440 ◽  
Author(s):  
Emilia Nan Tie ◽  
Julia Lai-Kwon ◽  
Michael Alexander Rtshiladze ◽  
Lumine Na ◽  
James Bozzi ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Progression Free Survival ◽  
Distant Metastases ◽  
Mek Inhibitor ◽  
Disease Recurrence ◽  
In Transit

BackgroundThe efficacy of immune checkpoint inhibitors (ICI) in metastatic melanoma is well established. However, there are limited data regarding their efficacy in in-transit melanoma (ITM). This study assessed the efficacy of ICI in patients with ITM.MethodsA retrospective review of patients with ITM commenced on an ICI between March 2013 and February 2018 at three tertiary centers in Australia. Patients were excluded if they had previous or synchronous distant metastases. Overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were based on a composite of radiological and clinical assessments.ResultsFifty-four patients were included: 27 (50%) female; median age 75 (range 26–94); 12 (22%) stage IIIB, 40 (74%) stage IIIC and 2 (4%) stage IIID; 10 (19%) BRAF mutant. Forty (74%) received single-agent anti-PD-1 (pembrolizumab or nivolumab), 8 (15%) single agent anti-CTLA-4 (ipilimumab), 5 (9%) combination anti-PD-1/anti-CTLA-4 (ipilimumab and nivolumab or pembrolizumab) and 1 (2%) combination anti-PD-L1 (atezolizumab) and MEK inhibitor (cobimetinib). The median follow-up was 15 months (2–46).ORR to ICI was 54%: 14 (26%) complete responses; 15 (28%) partial responses; 9 (17%) stable disease; 16 (30%) progressive disease. Thirteen (46%) responders had only one ITM lesion. ORR was 58% for single-agent anti-PD-1, 38% for single-agent anti-CTLA4 and 40% for anti-PD-1/anti-CTLA-4. The median PFS was 11.7 months (6.6-not reached). 1-year and 2-year PFS were 48% and 39%, respectively,. Fourteen progressed locoregionally and 11 progressed distantly. The median OS was not reached. 1-year and 2-year OS were 85% and 63%, respectively. No clinicopathological features were associated with ORR.Conclusions and relevanceICI produce objective responses in ITM and should be considered in patients with unresectable ITM or disease recurrence.

scholarly journals Clinical Benefits of Immune Checkpoint Inhibitors and Predictive Value of Tumor Mutation Burden in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

2022 ◽  
Author(s):  
Jiaxi Zheng ◽  
◽  
Haihua Yang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Advanced Hepatocellular Carcinoma ◽  
Tumor Mutation Burden ◽  
Mutation Burden

Review question / Objective: Is immunotherapy associated with beneficial clinical outcomes for hepatocellular carcinoma (HCC) and how can combination immunotherapy be deployed to produce the best benefit? Is tumor mutation burden (TMB) a predictive biomarker for immune‐checkpoint inhibitors? Condition being studied: To this date, about 50 single-arm clinical trials and several randomized control trials (RCTs) presented final or interim results of investigations on the efficacy of PD-1/PD-L1 inhibitors for advanced HCC. In the CheckMate 459, IMbrave 050, and ORIENT-32, immunotherapies were found to significantly improve progression-free survival (PFS) and overall survival (OS) compared with sorafenib (a tyrosine-kinase inhibitor, as standard systemic treatment) in patients with advanced hepatocellular carcinoma. However, these clinical trials were different on clinical phases, sample size, and response evaluation criteria, and inconsistent clinical outcomes were shown in several trials.

Re-introducing immunotherapy in patients surviving immune checkpoint inhibitors-mediated myocarditis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15228-e15228
Author(s):  
Shira Peleg Hasson ◽  
Michal laufer-Perl ◽  
Ido Wolf ◽  
Ayelet Sivan
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Case Reports ◽  
Single Agent ◽  
Low Grade ◽  
Reduced Ejection Fraction ◽  
Cardiac Symptoms ◽  
The One ◽  
Grade Iii

e15228 Background: Immune checkpoint inhibitors (ICI) have transformed the standard care in cancer treatment. Recent case reports describe ICI-mediated myocarditis with an atypical presentation and fatal potential which lead to permanent interruption of immunotherapy. We aim to characterize ICI-mediated myocarditis and re-introduction to immunotherapy. Methods: We retrospectively evaluated the presentation, severity, and prognosis of patients diagnosed with ICI-mediated myocarditis during 2019, and presented the clinical course and outcomes of patients that were chosen for re-introduction. Results: Among seven patients, only one patient had a history of cardiac disease. The majority were diagnosed with lung adenocarcinoma and treated with anti-programmed death-1 antibody (57%). All patients were treated with single agent ICI. Most patients presented with cardiac symptoms, elevated troponin and typical magnetic resonance imaging; however only 43% had reduced ejection fraction. Five patients were defined as grade I-II and two as grade III-IV. Overall, three patients were chosen for re-introduction with concomitant low dose steroids and weekly troponin follow-up. Two patients diagnosed with grade I/II renewed therapy successfully with no recurrence of symptoms and improvement in disease burden, while the one patient diagnosed with grade III developed worsening of cardiac symptoms after the 1st cycle and therefore therapy was interrupted permanently. Overall, survival was higher among the re-introduction patients (67% vs. 25%). Conclusions: ICI-mediated myocarditis is potentially fatal and leads to permanent interruption of life saving cancer therapy. We imply that re-introduction may be considered in low grade patients; however, better definition of the diagnosis and grading is needed.

scholarly journals 191. The impact of antibiotic use on clinical outcomes in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S101-S101
Author(s):  
Maria Tsikala Vafea ◽  
Neel Belani ◽  
Kendra Vieira ◽  
Dimitrios Farmakiotis
Keyword(s):  
Cancer Patients ◽  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Antibiotic Use ◽  
Experimental Models ◽  
The Impact

Abstract Background Observational studies and experimental models suggest that use of antibiotics close to the administration of immune checkpoint inhibitors (ICI) can negatively affect tumor response and patient survival. This observation may be attributed to microbiome dysbiosis and the resultant suppression of host immune response against neoplastic cells. Methods We conducted a systematic search of PUBMED and EMBASE databases and references of articles retrieved. We included studies published between 1/1/17 and 2/1/20, which evaluated the association between antibiotic use and clinical outcomes in cancer patients treated with ICI. Primary endpoints were overall survival (OS), progression free survival (PFS), response rate (RR) and progressive disease (PD) rate. We performed a study-level random-effects meta-analysis with pooling of hazards ratios (HR) for OS, PFS, and odds ratios (OR) for RR and PD (PROSPERO ID: CRD42020166473). Results We included 41 studies with a total of 10,857 patients. The most common malignancies were lung cancer (59.7%), melanoma (23.1%), renal cell and urothelial carcinomas (8.1%). OS and PFS were shorter, RR lower, and PD higher in patients receiving antibiotics, both in univariate analyses and after adjustment for other confounders. Heterogeneity was significant for all outcomes, less so for adjusted OS and PFS (Table). To our knowledge, this is the largest meta-analysis on the association between antibiotic use and efficacy of ICI, and the only one to address RR and PD to-date. Association between antibiotics and clinical outcomes. Conclusion We demonstrated a significant association between antibiotic use and unfavorable clinical outcomes in patients with cancer receiving ICI. Such patients may be an important target group for antibiotic stewardship interventions. The high heterogeneity across all outcomes underscores the need for more detailed, patient-level studies with stratification by host, antibacterial and cancer treatment factors. Disclosures All Authors: No reported disclosures

Impact of corticosteroids use on efficacy of immune checkpoint inhibitors in cancer patients: A meta-analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15234-e15234
Author(s):  
Jiarui Li ◽  
Kaili Yang ◽  
Lin Zhao ◽  
Chunmei Bai ◽  
Zhao Sun
Keyword(s):  
Cancer Patients ◽  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Study Selection ◽  
The Impact ◽  
Detrimental Impact

e15234 Background: Corticosteroids are commonly used for management of cancer-related symptoms or immune-related adverse events (irAEs) in cancer patients treated with immune checkpoint inhibitors (ICIs). However, given the inhibitory effects of corticosteroids on a broad range of immune responses, it is presumed that the use of these agents may affect the clinical outcomes of ICIs. This meta-analysis aims to explore the impact of corticosteroids use on the efficacy of ICIs in cancer patients. Methods: We conducted a search covering electronic databases (MEDLINE, EMBASE, and CENTRAL), conference abstracts (ASCO and ESMO) and reference lists to identify relevant studies. Studies that reported clinical outcomes of patients with corticosteroids administration before and/or after the initiation of ICIs treatment were eligible for evaluation. The primary outcomes included progression-free survival (PFS) and overall survival (OS). The random-effects model was utilized to synthesize the effect sizes of individual studies. Results: The initial literature search identified 1,900 records. After study selection, a total of 15 studies with 14,123 patients were included in the quantitative analysis. Corticosteroids use significantly reduced PFS (HR = 1.84; 95% CI: 1.30–2.61; P = 0.001) and OS (HR = 1.41; 95% CI: 1.18–1.68; P < 0.001) in cancer patients treated with ICIs. In subgroup analysis, corticosteroids use for cancer-related symptoms was associated with a shorter PFS (HR = 1.98; 95% CI: 1.40–2.78; P < 0.001) and OS (HR = 1.88; 95% CI: 1.25–2.83; P = 0.003), but their use for irAEs did not show a detrimental impact on OS (HR = 1.05; 95% CI: 0.77–1.44; P = 0.740). Conclusions: This meta-analysis indicated that corticosteroids use might hinder the efficacy of ICIs in cancer patients. The indications of corticosteroids use should be strictly controlled during the course of immunotherapy.

scholarly journals Immune checkpoint inhibitors in advanced or metastatic mucosal melanoma: a systematic review

2020 ◽  
Vol 12 ◽  
pp. 175883592092202 ◽  
Author(s):  
Jiarui Li ◽  
Haoxuan Kan ◽  
Lin Zhao ◽  
Zhao Sun ◽  
Chunmei Bai
Keyword(s):  
Systematic Review ◽  
Monoclonal Antibodies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Single Agent ◽  
Progression Free Survival ◽  
Mucosal Melanoma ◽  
One Year

Background: Conventional cytotoxic chemotherapy offers minor benefit to patients with mucosal melanoma (MM). Although immune checkpoint inhibitors (ICIs) have become the preferred approach in patients with advanced or metastatic cutaneous melanoma, the evidence of their clinical use for MM is still limited. This systematic review aims to summarize the efficacy and safety of ICIs in advanced or metastatic MM. Methods: We searched electronic databases, conference abstracts, clinical trial registers and reference lists for relevant studies. The primary outcomes included the overall response rate (ORR), median progression-free survival (PFS), median overall survival (OS), one-year PFS rate, and one-year OS rate. Results: This review identified 13 studies assessing anti-CTLA-4 monotherapy, 22 studies assessing anti-PD-1 monotherapy, two studies assessing anti-CTLA-4 and anti-PD-1 combination therapy, one study assessing anti-PD-1 antibodies combined with axitinib, and three studies assessing anti-PD-1 antibodies combined with radiotherapy. For most patients who received ipilimumab monotherapy, the ORR ranged from 0% to 17%, the median PFS was less than 5 months, and the median OS was less than 10 months. For patients who received nivolumab or pembrolizumab monotherapy, most studies showed an ORR of more than 15% and a median OS of more than 11 months. The combined administration of anti-CTLA-4 and anti-PD-1 agents showed benefits over single-agent therapy with an ORR of more than 33.3%. In a phase Ib trial of toripalimab in combination with axitinib, approximately half of patients had complete or partial responses. Three retrospective studies that investigated anti-PD-1 antibodies combined with radiotherapy showed an ORR of more than 50%, which was higher than each single modality treatment. Conclusions: Immune checkpoint inhibitors, especially anti-PD-1 monoclonal antibodies alone and in combination with anti-CTLA-4 monoclonal antibodies or other modalities, are promising treatment options for advanced or metastatic MM. However, high-level evidence is still needed to support the clinical application.

scholarly journals Correlation Between Immune-Related Adverse Events and Prognosis in Hepatocellular Carcinoma Patients Treated With Immune Checkpoint Inhibitors

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuo Xu ◽  
Ruixue Lai ◽  
Qian Zhao ◽  
Pandong Zhao ◽  
Ruili Zhao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Low Grade ◽  
Better Than

BackgroundImmune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) were associated with clinical benefit in cancer patients of melanoma, a lung cancer. In the present study, we investigated the correlation between irAE and ICI efficacy in hepatocellular carcinoma (HCC) patients.MethodsWe divided the HCC patients who received the anti-PD-1 antibody into two groups as irAE group and non-irAE group according to the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.03. The treatment efficacy of ICIs was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).ResultOf the 65 HCC patients who received the anti-PD-1 antibody (monotherapy or combined with targeted medicine), median PFS in the irAE group was superior to that in the non-irAE group (302 days vs. 148 days, p = 0.004). Median OS in the irAE group was also better than that in the non-irAE group (374 days vs. 279 days, p = 0.038). Although the statistical difference for DCR in the irAE group and non-irAE group was not reached, the DCR of the irAE displayed a trend better than that of the non-irAE group (41.20% vs. 20.80%, p = 0.118). Multivariate analysis also demonstrated that the non-irAE group (HR = 6.410, 95% CI: 1.404 to 29.275) was associated independently with the poor prognosis.ConclusionsDevelopment of irAEs was associated with clinical benefit for HCC patients who were treated with immune checkpoint inhibitors; irAE, particularly low-grade irAE, was a predictable marker for better ICI treatment efficiency in HCC patients.

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

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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