The Predictive Value of Tumor Mutation Burden on Efficacy of Immune Checkpoint Inhibitors in Cancers: A Systematic Review and Meta-Analysis.
Topic: Immunotherapy


PICO
Population: Patients with cancers
Intervention: Immune checkpoint inhibitors
Comparison: Tumor mutation burden
Outcomes: Efficacy of immune checkpoint inhibitors

Included studies:
title: Phase I Dose-Escalation Study of Anti-CTLA-4 Antibody Ipilimumab and Lenalidomide in Patients with Advanced Cancers.
abstract: Preclinical data suggest that combining a checkpoint inhibition with immunomodulatory derivative can increase anticancer response. We designed a dose-escalation study using a 3 + 3 design to determine the safety, maximum tolerated dose (MTD) or recommended phase II dose (R2PD) and dose-limiting toxicities (DLT) of the anti-CTLA-4 antibody ipilimumab (1.5-3 mg/kg intravenously every 28 days × 4) and lenalidomide (10-25 mg orally daily for 21 of 28 days until disease progression or unacceptable toxicity) in advanced cancers. Total of 36 patients (Hodgkin lymphoma, 7; melanoma, 5; leiomyosarcoma, 4; renal cancer, 3; thyroid cancer, 3; other cancers, 14; median of 3 prior therapies) were enrolled. The MTD has not been reached and ipilimumab 3 mg/kg and lenalidomide 25 mg have been declared as R2PD. DLT were grade (G) 3 rash (3 patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3 thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis, and G4 hypopituitarism (all in 1 patient). Eight patients had tumor shrinkage per immune-related response criteria (-79% to -2%) including a PR (-79% for 7.2+ months) in a refractory Hodgkin lymphoma. Using comprehensive genomic profiling, a total mutation burden (mutations/Mb) was evaluated in 17 patients, with one of the patients achieving a PR demonstrated intermediate mutation burden. In conclusion, combination of ipilimumab and lenalidomide is well tolerated and demonstrated preliminary signals of activity in patients with refractory Hodgkin lymphoma and other advanced cancers. 
title: Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer.
abstract: The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability-high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein-Barr virus-positive patient achieved a durable, complete response to immunotherapy. The level of 
title: Alterations in DNA Damage Response and Repair Genes as Potential Marker of Clinical Benefit From PD-1/PD-L1 Blockade in Advanced Urothelial Cancers.
abstract: Purpose Alterations in DNA damage response and repair (DDR) genes are associated with increased mutation load and improved clinical outcomes in platinum-treated metastatic urothelial carcinoma. We examined the relationship between DDR alterations and response to PD-1/PD-L1 blockade. Methods Detailed demographic, treatment response, and long-term outcome data were collected on patients with metastatic urothelial carcinoma treated with atezolizumab or nivolumab who had targeted exon sequencing performed on pre-immunotherapy tumor specimens. Presence of DDR alterations was correlated with best objective response per Response Evaluation Criteria in Solid Tumors (RECIST) and progression-free and overall survival. Results Sixty patients with urothelial cancer enrolled in prospective trials of anti-PD-1/PD-L1 antibodies met inclusion criteria. Any DDR and known or likely deleterious DDR mutations were identified in 28 (47%) and 15 (25%) patients, respectively. The presence of any DDR alteration was associated with a higher response rate (67.9% v 18.8%; P < .001). A higher response rate was observed in patients whose tumors harbored known or likely deleterious DDR alterations (80%) compared with DDR alterations of unknown significance (54%) and in those whose tumors were wild-type for DDR genes (19%; P < .001). The correlation remained significant in multivariable analysis that included presence of visceral metastases. DDR alterations also were associated with longer progression-free and overall survival. Conclusion DDR alterations are independently associated with response to PD-1/PD-L1 blockade in patients with metastatic urothelial carcinoma. These observations warrant additional study, including prospective validation and exploration of the interaction between tumor DDR alteration and other tumor/host biomarkers of immunotherapy response.
title: [Secondary syphilis with negative serology].
title: Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden.
abstract: Nivolumab plus ipilimumab showed promising efficacy for the treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase).
title: Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer.
abstract: Nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, disrupts PD-1-mediated signaling and may restore antitumor immunity.
title: Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.
abstract: Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population.
title: Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer.
abstract: Durable responses and encouraging survival have been demonstrated with immune checkpoint inhibitors in small-cell lung cancer (SCLC), but predictive markers are unknown. We used whole exome sequencing to evaluate the impact of tumor mutational burden on efficacy of nivolumab monotherapy or combined with ipilimumab in patients with SCLC from the nonrandomized or randomized cohorts of CheckMate 032. Patients received nivolumab (3 mg/kg every 2 weeks) or nivolumab plus ipilimumab (1 mg/kg plus 3 mg/kg every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks). Efficacy of nivolumab ± ipilimumab was enhanced in patients with high tumor mutational burden. Nivolumab plus ipilimumab appeared to provide a greater clinical benefit than nivolumab monotherapy in the high tumor mutational burden tertile.
title: Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab.
abstract: Although programmed death-ligand 1-programmed death 1 (PD-L1-PD-1) inhibitors are broadly efficacious, improved outcomes have been observed in patients with high PD-L1 expression or high tumor mutational burden (TMB). PD-L1 testing is required for checkpoint inhibitor monotherapy in front-line non-small-cell lung cancer (NSCLC). However, obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging. Thus, an unmet medical need exists for diagnostic approaches that do not require tissue to identify patients who may benefit from immunotherapy. Here, we describe a novel, technically robust, blood-based assay to measure TMB in plasma (bTMB) that is distinct from tissue-based approaches. Using a retrospective analysis of two large randomized trials as test and validation studies, we show that bTMB reproducibly identifies patients who derive clinically significant improvements in progression-free survival from atezolizumab (an anti-PD-L1) in second-line and higher NSCLC. Collectively, our data show that high bTMB is a clinically actionable biomarker for atezolizumab in NSCLC.
title: [Use of antibiotic combinations].
title: Hashimoto's thyroiditis and polyarthritis: a possible subset of seronegative polyarthritis.
abstract: Fifteen patients presenting with inflammatory polyarthritis who had Hashimoto's thyroiditis were investigated. Only 2/15 had frank myxoedema, 8/15 had incipient hypothyroidism (raised levels of thyrotropin or early symptoms of mild hypothyroidism), and 5/15 were euthyroid (thyrotropin levels normal). The presence or absence of rheumatoid factor (RF) distinguished two subgroups with different severity of synovitis. Nine out of 15 (group A) who remained RF negative throughout their follow-up had mild polyarthritis, lacked nodules or erosions on x-ray, and required, in addition to thyroid replacement, non-steroidal anti-inflammatory drugs for control of synovitis. Six out of 15 who remained RF positive (group B) had more severe synovitis, nodules, and erosive x-ray changes, and some required remittive drug treatment to control their disease. HLA-DR2 was present in 67% of group A and 13% of group B patients, while HLA-DR4 was present in 67% of group B and 33% of group A. Group A patients may represent a subset of patients with Hashimoto's thyroiditis and seronegative inflammatory polyarthritis, while group B patients appear to have features suggesting the coexistence of both rheumatoid arthritis and Hashimoto's thyroiditis.
title: Association of Tumor Microenvironment T-cell Repertoire and Mutational Load with Clinical Outcome after Sequential Checkpoint Blockade in Melanoma.
abstract: To understand prognostic factors for outcome between differentially sequenced nivolumab and ipilimumab in a randomized phase II trial, we measured T-cell infiltration and PD-L1 by IHC, T-cell repertoire metrics, and mutational load within the tumor. We used next-generation sequencing (NGS) and assessed the association of those parameters with response and overall survival. Immunosequencing of the T-cell receptor β-chain locus (TCRβ) from DNA of 91 pretreatment tumor samples and an additional 22 pairs of matched pre- and posttreatment samples from patients who received nivolumab followed by ipilimumab (nivo/ipi), or the reverse (ipi/nivo), was performed to measure T-cell clonality and fraction. Mutational and neoantigen load were also assessed by NGS in 82 of the 91 patients. Tumors were stained using IHC for PD-L1
title: Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade.
abstract: The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, but the prevalence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown.
title: The presence of leishmania antibodies in some inhabitants in Assiut Governorate, upper Egypt.
title: Correlation between patients' age and cancer immunotherapy efficacy.
title: Optimizing panel-based tumor mutational burden (TMB) measurement.
abstract: Panel sequencing based estimates of tumor mutational burden (psTMB) are increasingly replacing whole exome sequencing (WES) tumor mutational burden as predictive biomarker of immune checkpoint blockade (ICB).
title: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.
abstract: Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma.
title: Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.
abstract: Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.
title: Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.
abstract: Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options.
title: Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.
abstract: The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.