Clinical significance of tumour mutation burden in immunotherapy across multiple cancer types: an individual meta-analysis

2020 ◽  
Vol 50 (9) ◽  
pp. 1023-1031
Author(s):  
Zhenyu Yang ◽  
Shiyou Wei ◽  
Yulan Deng ◽  
Zihuai Wang ◽  
Lunxu Liu
Keyword(s):  
Overall Survival ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Cancer Type ◽  
Free Survival ◽  
Mutation Burden

Abstract Background Biomarkers for stratifying patients that could benefit from immune checkpoint inhibitors are necessary. Tumour mutation burden has recently become a promising biomarker in cancer, but the associations between tumour mutation burden and outcomes of immune checkpoint inhibitors treatment were not well-documented in present studies. Methods We searched PubMed, Web of Science and EMBASE databases up to 1 October 2019. Studies evaluated the association between tumour mutation burden and clinical outcomes were included. Hazard ratios and odds ratios were applied to estimate the association of tumour mutation burden score with overall survival, progression-free survival and response rate, respectively. The best cut-off value was chosen by best discriminated overall survival using Contal and O’Quigley method. Results Twenty-two studies involving 6171 patients in diverse cancers were included. The individual participant data meta-analysis demonstrated that high tumour mutation burden was associated with better overall survival (HR = 0.57, 95% CI = 0.50–0.64) and progression-free survival (HR = 0.50, 95% CI = 0.40–0.63) and higher response rate. The best cut-off values in each cancer type were 17.7/MB in non-small cell lung cancer, 7.9/MB in bladder cancer, 6.1/MB in melanoma, 12.3/MB in colorectal cancer, 6.9/MB in esophagogastric cancer, 10.5/MB in head and neck cancer. The pooled meta-analysis showed the prognosis value was robust and the sensitivity, specificity and area under the receiver operating characteristic curves in predicting response rates were 0.63, 0.71 and 0.73, respectively. Conclusions The present meta-analysis indicates tumour mutation burden is a promising predictor of immune checkpoint inhibitors therapy but the cut-off value differs in different cancers.

scholarly journals Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors

2020 ◽  
Vol 38 (27) ◽  
pp. 3088-3094 ◽  
Author(s):  
Anita Gul ◽  
Tyler F. Stewart ◽  
Charlene M. Mantia ◽  
Neil J. Shah ◽  
Emily Stern Gatof ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Free Survival ◽  
Metastatic Rcc

PURPOSE Immune checkpoint inhibitors (ICIs) are standard therapy in metastatic renal cell carcinoma (RCC). The safety and activity of the combination of ipilimumab and nivolumab in patients who have received prior ICI targeting the programmed death 1 (PD-1) pathway remains unknown. We evaluated ipilimumab and nivolumab in patients with metastatic RCC after prior treatment with anti–PD-1 pathway–targeted therapy. PATIENTS AND METHODS Patients with metastatic RCC who received prior anti–PD-1 pathway-targeted therapy and subsequently received ipilimumab and nivolumab were reviewed. Objective response rate and progression-free survival per investigator assessment were recorded. Toxicity of ipilimumab and nivolumab was also assessed. RESULTS Forty-five patients with metastatic RCC were included. All patients (100%) received prior ICIs targeting the PD-1 pathway. The median age was 62 years (range, 21-82 years). At a median follow-up of 12 months, the objective response rate to ipilimumab and nivolumab was 20%. The median progression-free survival while on ipilimumab and nivolumab was 4 months (range, 0.8-19 months). Immune-related adverse events (irAEs) of any grade with ipilimumab and nivolumab were recorded in 29 (64%) of the 45 patients; grade 3 irAEs were recorded in 6 (13%) of the 45 patients. CONCLUSION Ipilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic RCC who had prior treatment with checkpoint inhibition.

scholarly journals Results from a meta-analysis of immune checkpoint inhibitors in first-line renal cancer patients: does PD-L1 matter?

2019 ◽  
Vol 11 ◽  
pp. 175883591986190 ◽  
Author(s):  
Giandomenico Roviello ◽  
Silvia Paola Corona ◽  
Gabriella Nesi ◽  
Enrico Mini
Keyword(s):  
Overall Survival ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Pooled Analysis ◽  
First Line

Background: The aim of this study was to perform a literature-based meta-analysis to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in first-line metastatic renal cell carcinoma (RCC), focusing on the predictive role of PD-L1 expression. Methods: The primary outcome was overall survival, and secondary outcomes were progression-free survival (PFS) and objective response. We planned a subgroup analysis for overall survival according to PD-L1 status. Results: Five studies were included in the analysis for a total of 4063 cases. Overall survival was greater in PD-L1 positive tumours (HR = 0.49, 95% CI: 0.36–0.67; p < 0.001). The pooled analysis of the unselected cases showed a statistically significative improvement in PFS with the use of ICIs (HR = 0.85, 95% CI: 0.72–0.99; p = 0.04) and we found a greater PFS benefit (HR = 0.65, 95% CI: 0.57–0.74; p < 0.001) in patients with PD-L1 positive tumours. Conclusions: This study supports the efficacy of ICIs and, although a significant clinical benefit has been reported in PD-L1 negative patients, a greater efficacy of ICIs was observed in PD-L1 positive patients. More prospective randomized studies are needed to clarify the role of PDL-1 status in metastatic RCC treated with ICIs.

Efficacy of immune checkpoint inhibitors in cancer patients of different ages: a meta-analysis

2019 ◽  
Vol 15 (31) ◽  
pp. 3633-3646 ◽  
Author(s):  
Jing Li ◽  
Jian Gu
Keyword(s):  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Age Groups ◽  
Progression Free Survival ◽  
Systematic Evaluation ◽  
Free Survival ◽  
Older Cancer Patients

Aim: We conducted an up-to-date meta-analysis of randomized controlled trials (RCTs) to compare the immune checkpoint inhibitors (ICIs) in different age groups. Methods: The relevant RCTs in cancer patients receiving ICIs were searched and the systematic evaluation was performed. PubMed, MEDLINE and EMBASE were searched for studies published till January 2019. Results: A total of 27 RCTs included 17,546 patients were available for this meta-analysis. ICIs significantly improved overall survival (OS) and progression-free survival (PFS) in both of the younger (<65 years) and the older cancer patients (≥65 years). No significantly prolonged OS and PFS was observed among patients older than 75 years. Conclusion: ICIs could not significantly improve OS and PFS compared with controls in cancer patients aged over 75 years.

scholarly journals The efficacy and safety of immune checkpoints inhibitors plus radiotherapy as a combination therapy for advanced non-small cell lung carcinoma: a meta-analysis

2020 ◽  
Author(s):  
Dan Yang ◽  
DaiRong Li ◽  
LuLu Wang ◽  
LuMi Huang ◽  
JianLin Long ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
Radiotherapy Group

Abstract BackgroundImmune checkpoint inhibitors have showed good efficacy in advanced non-small-cell lung cancer(NSCLC). This meta-analysis was conducted to explore the therapeutic efficacy and safety of immune checkpoint inhibitors combined with radiotherapy for patients with advanced NSCLC.MethodsWe used many proper keywords to perform a systematic search in databases and performed a meta-analysis of trials that conducted immune checkpoint inhibitors plus radiotherapy as a treatment for advanced non-small-cell lung cancer. The outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events. A fixed-effect or random-effects model was adopted depending on between-study heterogeneity.ResultsTen trials were finally included in this meta-analysis. The combined ORR and DCR was 34% (19%-49%) and 72% (65%-79%). The combined six-month progression-free survival rates (PFSR6m) and one-year overall survival rate(OSR1y) were 50.0% (29.4%-72.8%) and 59.0% (48%-69%). Immune checkpoint inhibitors plus radiotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.64; 95% CI 0.46–0.90; P = 0.01), OS (HR, 0.62; 95% CI 0.46–0.85; P = 0.003). In subgroup analyses, the combined ORR was 31.5% (16.4%-46.6%), combined DCR was 72.1% (63.3%-80.9%), combined PFS6m was 50.0% (20.6%-79.5%) and combined OSR1y was 59.7% (48.1%-71.2%) for anti-PD-1/PD-L1 antibody plus radiotherapy. The combined ORR was 19.5% (9.1%-29.8%) for anti-CTLA4 antibody plus radiotherapy. The combined PFS6m and OSR1y were 58.9% (26.2%-91.7%) and 59.7% (29.7%-89.8%) respectively for the concurrent therapy group. And the combined PFS6m and OS1y were 55.2% (41.6%-68.8%) and 55.7% (42.1%-69.3%) for sequential therapy. For the low-dose radiotherapy group. The combined PFS6m and OS1y were 45.9% (27.0%-64.8%) and 51.6% (37.5%-65.6%). The combined PFS6m and OS1y were 71.1% (37.9%-104.4%) and 67.4% (29.2%-105.6%) separately for high-dose radiotherapy group. When using as first-line therapy. The combined ORR was 53.8% (23.6%-84.1%) and combined ORR was 76.5% (65.0%-88.1%). While as subsequent therapy, the combined ORR and DCR were 25.9% (14.7%-37.2%) and 69.9% (60.9%-78.9%). The combined PFS6m and OS1y were 51.1% (40.3%-61.9%) and 51.8% (40.9%-62.7%).ConclusionsImmune checkpoint inhibitors plus radiotherapy might be an effective and tolerable option as a treatment for advanced NSCLC.

Response to salvage chemotherapy after progression on immune checkpoint inhibitors in patients with advanced urothelial carcinoma.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 519-519
Author(s):  
Seung-Hoon Beom ◽  
Sun Young Rha ◽  
Joong Bae Ahn ◽  
Sang Joon Shin
Keyword(s):  
Overall Survival ◽  
Urothelial Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Salvage Chemotherapy ◽  
Free Survival ◽  
Platinum Based Chemotherapy ◽  
Advanced Urothelial Carcinoma

519 Background: Immune checkpoint inhibitors (ICI) are active in patients with advanced urothelial carcinoma which progressed to platinum-based chemotherapy. Recent data suggest that exposure to ICI improves response to salvage chemotherapy (SCT) in several cancer types. Here we evaluated whether PD-1/PD-L1 inhibitors affect the antitumor effects of SCT after ICI in patients with urothelial carcinoma. Methods: A retrospective study was conducted at Yonsei Cancer Center. Eligibility criteria were patients who received at least one SCT as 3rd-line or beyond, following progression after platinum-based chemotherapy and ICI and for whom efficacy data were available between January 2017 and September 2019. We evaluated efficacy outcomes to each therapy, including ORR by RECIST version 1.1, progression-free survival (PFS), and overall survival (OS). Results: In total, 35 patients met the inclusion criteria and were included in the analyses. ICIs were given as monotherapy and they were administrated as second-line in 48% and as later line in 52%. Twenty-six patients (74%) received a anti-PD-L1 inhibitor and 9 (26%) did a anti-PD-1 inhibitor. SCT included single paclitaxel (60%), MVAC (26%), gemcitabine/platinum combination (9%), and pemetrexed (6%). The ORR to SCT was 26%. Among 9 patients who received MVAC, 5 (55.5%) achieved a partial response. Median progression-free survival was 2.5 months and median overall survival was 7.8 months. A number of prior chemotherapy regimens was associated with response to SCT on univariate analysis. Conclusions: In urothelial cancer patients, the confirmed ORR (26%) to SCT after ICI exposure was higher as compared to historical data from the pre-ICI era. These data indicate that anti–PD-1/PD-L1 inhibitors could make tumors more vulnerable to subsequent chemotherapy.

190 Timing of steroid doses and response rates to immune-checkpoint inhibitors in metastatic cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A204-A204
Author(s):  
Karine Tawagi ◽  
Diana Maslov ◽  
Victoria Simenson ◽  
Helen Yuan ◽  
Cameron Parent ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Metastatic Cancer ◽  
Progression Free Survival ◽  
Response Rates ◽  
Free Survival ◽  
Treatment Type

BackgroundCorticosteroids (CS) are the mainstay of immune-related adverse effect (irAE) management, as well as for other indications in cancer treatment. Previous studies evaluating whether CS affect immune checkpoint inhibitor (CPI) efficacy compared patients receiving steroids vs. no steroids.1 This comparison may be confounded by different rates of irAEs, which are known to be associated with higher response rates to CPIs. Preclinically CS have been shown to diminish naïve T-cell proliferation and differentiation,2 though there is a paucity of clinical data evaluating how the timing of concomitant CS affects CPI efficacy.MethodsWe retrospectively collected data from patients treated with CPIs alone, who received CS during their CPI treatment at a single institution. Patients were allocated into two cohorts based on timing of initiation of CS (> 2 months vs. < 2 months after initiating CPI). Patient characteristics, irAEs, cancer type, treatment type, treatment response/progression per RECIST v1.1, and survival data were collected. Kaplan Meier and Cox proportional hazard regression methods were used to estimate hazard ratios (HR) for the primary endpoint of progression free survival (PFS) along with overall survival (OS).ResultsWe identified 247 patients with metastatic cancer who received CS concurrently with CPIs alone. The majority of patients had non-small cell lung cancer (n=98), followed by renal cell carcinoma (n=43), and melanoma (n=30). 242 patients were on PD-1 inhibitor monotherapy, while 45 patients received CPI in combination with anti-CTLA-4 ipilimumab (table 1). The median time on steroids for all patients was 1.8 months. After adjusting for differences in rates of treatment type, tumor type, brain metastases and irAEs, patients who were treated with CS > 2 months after starting CPI had a statistically significant longer progression free survival (PFS) [HR of 0.33, p≤0.0001], and overall survival (OS) [HR of 0.36, p≤0.0001] than those who received steroids < 2 months after starting CPI. Rates of irAEs in each group were not significantly different (p = 0.15). Objective response rate (ORR) for patients on CS > 2 months was 39.8%, vs. ORR for patients <2 months was 14.7% (p-value = <0.001).Abstract 190 Table 1Cancer subtypes and drug types in the study population (n=247)ConclusionsAfter adjusting for possible confounding factors such as rates of irAEs, our results suggest that early use of steroids during CPI treatment significantly hinders CPI efficacy. These data need to be validated prospectively. Future studies should focus on the immune mechanisms by which CS affect T-cell function early in CPI treatment course.ReferencesGarant A, Guilbault C, Ekmekjian T, Greenwald Z, Murgoi P, & Vuong T. ( 2017). Concomitant use of corticosteroids and immune checkpoint inhibitors in patients with hematologic or solid neoplasms: a systematic review. Critical reviews in oncology/hematology120, 86–92.Giles AJ, Hutchinson MKN, Sonnemann HM, Jung J, Fecci PE, Ratnam NM,. .. & Reid CM. Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. Journal for immunotherapy of cancer 2018;6(1):1–13.

Evaluation of the impact of thyroiditis development in patients receiving immunotherapy with programmed cell death-1 inhibitors

2019 ◽  
Vol 25 (6) ◽  
pp. 1402-1411 ◽  
Author(s):  
Matthew Lei ◽  
Angela Michael ◽  
Seema Patel ◽  
Ding Wang
Keyword(s):  
Immune Checkpoint ◽  
Objective Response Rate ◽  
Immune Checkpoint Inhibitors ◽  
Tumor Response ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Free Survival ◽  
Tumor Types

Purpose We evaluated if the development of thyroiditis in patients who received treatment with immune checkpoint inhibitors across various tumor types was associated with tumor response. Methods In this retrospective, single-center, cross-sectional study, patients with various tumor types who received treatment with nivolumab or pembrolizumab as standard of care were evaluated. The primary endpoint was to evaluate the objective response rate in patients who developed thyroiditis compared with patients who did not develop thyroiditis. Secondary endpoints included disease control rate, progression-free survival, and overall survival. Results One hundred and three patients were included for analysis with a median follow-up duration of 12.8 months (range, 4.0–21.6). The data cutoff was 31 December 2016. The objective response rate was 38.2% among the 34 patients in the thyroiditis group and 17.4% in the 69 patients in the non-thyroiditis group (p = 0.028). Progression-free survival was longer in the thyroiditis group than in the non-thyroiditis group. The median progression-free survival was 10.1 months (95% CI, 1.6–18.5) in the thyroiditis group and 3.7 months (95% CI, 2.5–4.9) in the non-thyroiditis group (hazard ratio, 0.45; 95% CI, 0.27–0.76; p = 0.002). Conclusion Patients with various tumor types who received treatment with immune checkpoint inhibitors and developed thyroiditis had a higher objective response rate than those who did not develop thyroiditis. The development of thyroiditis should be investigated further in the context of prospective randomized trials as a surrogate marker for tumor response to treatment with immune checkpoint inhibitor therapies.

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