Anti–PD-1/PD-L1 antibodies in non-small cell lung cancer: the era of immunotherapy
01 Jan 2017-Expert Review of Anticancer Therapy (Expert Rev Anticancer Ther)-Vol. 17, Iss: 1, pp 47-59
TL;DR: This article will review the outcomes of various trials of anti-PD-1/anti- PD-L1 antibodies in the treatment of NSCLC, and offer several advantages including significant antitumor activity, induction of long lasting responses, and favorable safety profile.
Abstract: Introduction: Advanced non-small cell lung cancer (NSCLC) has been conventionally treated with cytotoxic chemotherapy with short-lived responses and significant toxicities. Monoclonal antibodies to programmed death-1 receptor (PD-1) and programmed death ligand 1 (PD-L1) have shown tremendous promise in the treatment of advanced NSCLC in various clinical trials.Areas covered: In this article, we will review the outcomes of various trials of anti-PD-1/anti-PD-L1 antibodies in the treatment of NSCLC. We will also discuss their mechanism of action and toxicities.Expert commentary: Anti-PD-1/PD-L1 antibodies offer several advantages including significant antitumor activity, induction of long lasting responses, and favorable safety profile. Several trials are now being conducted to evaluate their efficacy as first line agents as well as in combination with other agents. More research is also needed to identify other biomarkers, in addition to PD-L1 expression, that could more reliably predict response t...
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TL;DR: A deeper understanding of the gut microbiome which comprises of all the genetic material within the gut microbiota and its role in respiratory disorders is likely to help in designing appropriate probiotic cocktails for therapeutic applications.
Abstract: The gut microbial community (Gut microbiota) is known to impact metabolic functions as well as immune responses in our body Diet plays an important role in determining the composition of the gut microbiota Gut microbes help in assimilating dietary nutrients which are indigestible by humans The metabolites produced by them not only modulate gastro-intestinal immunity, but also impact distal organs like lung and brain Micro-aspiration of gut bacteria or movement of sensitized immune cells through lymph or bloodstream can also influence immune response of other organs Dysbiosis in gut microbiota has been implicated in several lung diseases, including allergy, asthma and cystic fibrosis The bi-directional cross-talk between gut and lung (termed as Gut-Lung axis) is best exemplified by intestinal disturbances observed in lung diseases Some of the existing probiotics show beneficial effects on lung health A deeper understanding of the gut microbiome which comprises of all the genetic material within the gut microbiota and its role in respiratory disorders is likely to help in designing appropriate probiotic cocktails for therapeutic applications
233 citations
Cites background from "Anti–PD-1/PD-L1 antibodies in non-s..."
...Antibodies against PD-1/PD-L1 prevent this interaction, thereby leading to T cell activation and thus acting as an immunotherapy against tumor cells (Valecha et al., 2017)....
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TL;DR: Plasma sPD‐L1 levels might represent a novel biomarker for the prediction of the efficacy of nivolumab therapy against NSCLC, and this study prospectively studied the baseline plasma soluble programmed cell death ligand 1 (sPD‐ L1) levels from 39 NSCLc patients as a predictive marker of nIVolumAB therapy.
97 citations
TL;DR: The results showed that the combination of erdafitinib and anti–PD-1 drives expansion of T-cell clones and immunologic changes in the tumor microenvironment to support enhanced antitumor immunity and survival.
Abstract: The success of targeted or immune therapies is often hampered by the emergence of resistance and/or clinical benefit in only a subset of patients. We hypothesized that combining targeted therapy with immune modulation would show enhanced antitumor responses. Here, we explored the combination potential of erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor under clinical development, with PD-1 blockade in an autochthonous FGFR2K660N/p53mut lung cancer mouse model. Erdafitinib monotherapy treatment resulted in substantial tumor control but no significant survival benefit. Although anti-PD-1 alone was ineffective, the erdafitinib and anti-PD-1 combination induced significant tumor regression and improved survival. For both erdafitinib monotherapy and combination treatments, tumor control was accompanied by tumor-intrinsic, FGFR pathway inhibition, increased T-cell infiltration, decreased regulatory T cells, and downregulation of PD-L1 expression on tumor cells. These effects were not observed in a KRASG12C-mutant genetically engineered mouse model, which is insensitive to FGFR inhibition, indicating that the immune changes mediated by erdafitinib may be initiated as a consequence of tumor cell killing. A decreased fraction of tumor-associated macrophages also occurred but only in combination-treated tumors. Treatment with erdafitinib decreased T-cell receptor (TCR) clonality, reflecting a broadening of the TCR repertoire induced by tumor cell death, whereas combination with anti-PD-1 led to increased TCR clonality, suggesting a more focused antitumor T-cell response. Our results showed that the combination of erdafitinib and anti-PD-1 drives expansion of T-cell clones and immunologic changes in the tumor microenvironment to support enhanced antitumor immunity and survival.
96 citations
Cites background from "Anti–PD-1/PD-L1 antibodies in non-s..."
...In contrast, immunotherapy agents, such as those targeting the PD-1 pathway, have demonstrated clinical activity in patients by reactivating preexisting antitumor immune responses (38) but only benefit a subset of patients....
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TL;DR: Thyroid dysfunction during PD-1 blockade is associated with treatment response and could provide supplementary information for immune monitoring in patients with advanced NSCLC.
Abstract: Purpose: Drugs that blockade interaction between programmed cell-death protein 1 (PD-1) and its ligand (PD-L1) are promising. Immune-related adverse events (irAEs) might be associated with favorable clinical outcomes, and thyroid dysfunction is one of the most common irAE. We evaluated the association of thyroid dysfunction during PD-1 blockade with the treatment efficacy in patients with non-small cell lung cancer (NSCLC). Experimental Design: A total 58 patients with stage IV NSCLC treated with PD-1 blockade were enrolled. Patients were categorized into thyroid dysfunction and euthyroid groups. Overall survival (OS) and progression-free survival (PFS) of the two groups were compared. Patients, tumor, and medication factors were adjusted using Cox proportional hazard modeling. Objective response rate (RR) and durable control rate were assessed according to the severity of thyroid dysfunction. Results: OS [median 118.0 (73.0-267.0) vs. 71.0 (28.0-160.0) days, log-rank P = 0.025] and PFS [118.0 (73.0-267.0) vs. 61.0 (28.0-130.0), log-rank P = 0.014] were longer in the thyroid dysfunction group. After adjustment, thyroid dysfunction was an independent predictive factor for favorable outcome [adjusted HR = 0.11 (95% CI) 0.01-0.92 for overall death; 0.38 (0.17-0.85) for disease progression]. The severity of thyroid dysfunction was associated with durable control rate (P for trend = 0.008). Conclusions: Thyroid dysfunction during PD-1 blockade is associated with treatment response and could provide supplementary information for immune monitoring in patients with advanced NSCLC.
85 citations
Cites background from "Anti–PD-1/PD-L1 antibodies in non-s..."
...Immune checkpoint inhibitors are currently in the spotlight as promising therapeutics for advanced non-small cell lung cancer (NSCLC).(1,2) Among these drugs, nivolumab and pembrolizumab, which are classified as blockade for programmed celldeath protein 1 (PD-1) were recently approved as standard drugs for subsequent treatment of NSCLC patients by FDA....
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TL;DR: A mini-review of the latest understanding of TGF-β signaling pathway and cancer immunity is summarized and the synergistic effect of T GF-β blockade and ICIs is highlighted.
Abstract: During malignant transformation, a growing body of mutations accumulate in cancer cells which not only drive cancer progression but also endow cancer cells with high immunogenicity. However, because one or multiple steps in cancer-immunity cycle are impaired, anti-cancer immune response is too weak to effectively clear cancer cells. Therefore, how to restore robust immune response to malignant cells is a hot research topic in cancer therapeutics field. In the last decade, based on the deeper understanding of cancer immunity, great signs of progress have been made in cancer immunotherapies especially immune checkpoint inhibitors (ICIs). ICIs could block negative immune co-stimulatory pathways and reactivate tumor-infiltrating lymphocytes (TILs) from exhausted status. ICIs exhibit potent anti-cancer effect and have been approved for the treatment of numerous cancer types. Parallel with durable and effective tumor control, the actual response rate of ICIs is unsatisfactory. Although a subset of patients benefit from ICIs treatment, a large proportion of patients show primary or acquired resistance. Previously intensive studies indicated that the efficacy of ICIs was determined by a series of factors including tumor mutation burden, programmed death ligand-1 (PD-L1) expression, and TILs status. Recently, it was reported that transforming growth factor-beta (TGF-β) signaling pathway participated in cancer immune escape and ICI resistance. Concurrent TGF-β blockade might be a feasible strategy to enhance the efficacy of immunotherapy and relieve ICI resistance. In this mini-review, we summarized the latest understanding of TGF-β signaling pathway and cancer immunity. Besides, we highlighted the synergistic effect of TGF-β blockade and ICIs.
81 citations
References
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TL;DR: Overall cancer incidence trends are stable in women, but declining by 3.1% per year in men, much of which is because of recent rapid declines in prostate cancer diagnoses, and brain cancer has surpassed leukemia as the leading cause of cancer death among children and adolescents.
Abstract: Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2016, 1,685,210 new cancer cases and 595,690 cancer deaths are projected to occur in the United States. Overall cancer incidence trends (13 oldest SEER registries) are stable in women, but declining by 3.1% per year in men (from 2009-2012), much of which is because of recent rapid declines in prostate cancer diagnoses. The cancer death rate has dropped by 23% since 1991, translating to more than 1.7 million deaths averted through 2012. Despite this progress, death rates are increasing for cancers of the liver, pancreas, and uterine corpus, and cancer is now the leading cause of death in 21 states, primarily due to exceptionally large reductions in death from heart disease. Among children and adolescents (aged birth-19 years), brain cancer has surpassed leukemia as the leading cause of cancer death because of the dramatic therapeutic advances against leukemia. Accelerating progress against cancer requires both increased national investment in cancer research and the application of existing cancer control knowledge across all segments of the population.
14,664 citations
TL;DR: Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.
Abstract: Background Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. Methods We enrolled patients with advanced melanoma, non–small-cell lung cancer, castrationresistant prostate cancer, or renal-cell or colorectal cancer to receive anti–PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. Results A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drugrelated adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non–small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1–PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1–negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = 0.006). Conclusions Anti–PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.)
10,674 citations
TL;DR: Nivolumab was associated with even greater efficacy than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression (≥1, ≥5%, and ≥10%) of the PD-1 ligand.
Abstract: BackgroundNivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, disrupts PD-1–mediated signaling and may restore antitumor immunity. MethodsIn this randomized, open-label, international phase 3 study, we assigned patients with nonsquamous non–small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. ResultsOverall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab ve...
7,474 citations
Johns Hopkins University1, City of Hope National Medical Center2, Netherlands Cancer Institute3, University of Duisburg-Essen4, Russian Academy5, University of South Florida6, University of Chicago7, Duke University8, Harvard University9, Charles University in Prague10, Bristol-Myers Squibb11, Sarah Cannon Research Institute12, Erasmus University Rotterdam13, Autonomous University of Madrid14
TL;DR: Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level.
Abstract: BackgroundPatients 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. MethodsWe randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. ResultsThe median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 3...
6,869 citations
TL;DR: Antibody-mediated blockade of PD-L1 induced durable tumor regression and prolonged stabilization of disease in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer.
Abstract: Background Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. Methods In this multicenter phase 1 trial, we administered intravenous anti–PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti–PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. Results As of February 24, 2012, a total of 207 patients — 75 with non–small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer — had received anti–PD-L1 antibody. The media...
6,812 citations