Reflections on immune checkpoint inhibition in non-small cell lung cancer.
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ABSTRACT:
SUBMITTER: Leventakos K
PROVIDER: S-EPMC4367678 | biostudies-literature | 2014 Dec
REPOSITORIES: biostudies-literature
Publications
Reflections on immune checkpoint inhibition in non-small cell lung cancer.
Leventakos Konstantinos K Mansfield Aaron S AS
Translational lung cancer research 20141201 6
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Project description:KRAS is the most frequent oncogene in non-small cell lung cancer (NSCLC), a molecular subset characterized by historical disappointments in targeted treatment approaches such as farnesyl transferase inhibition, downstream MEK inhibition, and synthetic lethality screens. Unlike other important mutational subtypes of NSCLC, preclinical work supports the hypothesis that KRAS mutations may be vulnerable to immunotherapy approaches, an efficacy associated in particular with TP53 co-mutation. In this review we detail reasons for previous failures in KRAS-mutant NSCLC, evidence to suggest that KRAS mutation is a genetic marker of benefit from immune checkpoint inhibition, and emerging direct inhibitors of K-Ras which will soon be combined with immunotherapy during clinical development. With signs of real progress in this subgroup of unmet need, we anticipate that KRAS mutant NSCLC will be the most important molecular subset of cancer to evaluate the combination of small molecules and immune checkpoint inhibitors (CPI).
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Project description:BackgroundThe development of immune checkpoint inhibitors (ICIs) is a revolutionary milestone in the field of immune-oncology. However, the low response rate is the major problem of ICI treatment. The recent studies showed that response rate to single-agent programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibition in unselected non-small cell lung cancer (NSCLC) patients is 25% so that researchers defined several biomarkers to predict the response of immunotherapy in ICIs treatment. Common biomarkers like tumor mutational burden (TMB) and PD-L1 expression have several limitations, such as low accuracy and inadequately validated cutoff value.MethodsTwo published and an unpublished ICIs treatment NSCLC cohorts with 129 patients were collected and divided into a training cohort (n = 53), a validation cohort (n = 22), and two independent test cohorts (n = 34 and n = 20). We identified six immune-related pathways whose mutational status was significantly associated with overall survival after ICIs treatment. Then these pathways mutational status combined with TMB, PD-L1 expression and intratumor heterogeneity were incorporated to build a Bayesian-regularization neural networks (BRNN) model to predict the ICIs treatment response.ResultsWe firstly proved that TMB, PD-L1, and mutant-allele tumor heterogeneity (MATH) were independent biomarkers. The survival analysis of six immune-related pathways revealed the mutational status could distinguish overall survival after ICIs treatment. When predicting immunotherapy efficacy, the overall accuracy of area under curve (AUC) in validation cohort reaches 0.85, outperforming previous predictors in either sensitivity or specificity. And the AUC in two independent test cohorts reach 0.74 and 0.80.ConclusionWe developed a pathway-model that could predict the efficacy of ICIs in NSCLC patients. Our study made a significant contribution to solving the low prediction accuracy of immunotherapy of single biomarker. With the accumulation of larger data sets, further studies are warranted to refine the predictive performance of the approach.
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Project description:Immunotherapy has evolved at a phenomenal pace in cancer therapeutics. This has primarily been fueled by the much perceived necessity to procure an alternative to current standard of care chemotherapy agents, owing to several concerns such as treatment-related toxicity and poor long-term survival associated with the same. The knowledge of various mechanisms involved in regulation of immune response to cancer cells has served a fundamental role in identifying key molecules through which immune cell activity may be modulated. This in-turn led to the development of immune-checkpoint inhibitors. Presently, lung cancer is among the most enthusiastically investigated targets for treatment with immune-checkpoint inhibitors. Encouraging results with initial trials have now translated to attempts directed at further enhancement of outcomes through various strategies. Herein, we shall present a critical assessment of data from pivotal trials that led to the Food and Drug Administration (FDA) approval of various immune-checkpoint inhibitors and also discuss novel strategies that may potentially yield outcomes superior to standard of care chemotherapy in patients diagnosed with advanced non-small cell lung cancer (NSCLC).
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Project description:Historically, lung cancer was long considered a poorly immunogenic malignancy. In recent years, however, immune checkpoint inhibitors have emerged as promising therapeutic agents in non-small cell lung cancer (NSCLC). To date, the best characterized and most therapeutically relevant immune checkpoints have been cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein-1 (PD-1) pathway. In early studies, PD-1/programmed cell death ligand-1 (PD-L1) inhibitors demonstrated promising antitumor activity and durable clinical responses in a subset of patients. Based on these encouraging results, multiple different PD-1/PD-L1 inhibitors have entered clinical development, and two agents (nivolumab and pembrolizumab) have gained regulatory approval in the United States for the treatment of NSCLC. In several large, randomized studies, PD-1/PD-L1 inhibitors have produced significant improvements in overall survival compared with single-agent docetaxel delivered in the second-line setting, effectively establishing a new standard of care in NSCLC. In the present report, we provide an overview of the rationale for checkpoint inhibitors in lung cancer, recent clinical trial data, and the need for predictive biomarkers.The oncologist2017;22:81-88 IMPLICATIONS FOR PRACTICE: Strategies targeting negative regulators (i.e., checkpoints) of the immune system have demonstrated significant antitumor activity across a range of solid tumors. In non-small cell lung cancer (NSCLC), programmed cell death protein-1 (PD-1) pathway inhibitors have entered routine clinical use because of the results from recent randomized studies demonstrating superiority against single-agent chemotherapy in previously treated patients. The present report provides an overview of immune checkpoint inhibitors in lung cancer for the practicing clinician, focusing on the rationale for immunotherapy, recent clinical trial data, and future directions.
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Project description:Patients with oncogene-driven lung cancer have limited therapeutic options after progressing on their targeted tyrosine kinase inhibitor (TKI) therapy. Given the growing role of immune checkpoint inhibitor (ICI) therapy in the treatment of lung cancer, oncogene-driven cancer has warranted further evaluation regarding ICI therapy. However, initial ICI studies have suggested that ICI monotherapy is not only lacking in efficacy, but that it may be less tolerable in oncogene-driven non-small-cell lung cancer (NSCLC). We performed a detailed review of the literature using Pubmed, and present the current and impactful findings here. Studies evaluating the use of concurrent ICI therapy and TKI therapy have also suggested increased toxicity and lack of increased activity in these patients. Larger studies have suggested that the sequence of ICI therapy and TKI, such as utilizing ICI therapy after TKI as opposed to before TKI, may play a role in reducing toxicity (hepatotoxicity, pneumonitis); however, these studies are limited in number. Novel methods of patient selection, including low tumor mutational burden, inflamed phenotyping, and high CD8 + tumor infiltrating lymphocytes, may aid in determining ideal patients to give ICI therapy. Novel therapeutic combinations including the addition of anti-VEGF (vascular endothelial growth factor) therapy or radiotherapy show promising findings for these patients. Given the growing unmet need for therapeutic options in patients with oncogene-driven NSCLC who have failed TKI therapy, further research is warranted.
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Project description:Background Radiation pneumonitis and immune-related pneumonitis have been studied independently, but little information has emerged on the interactions between radiation therapy (RT) and immune checkpoint inhibition (ICI). We examine whether RT and ICI are synergistic in causing pneumonitis. Methods A retrospective cohort was assembled using the Surveillance, Epidemiology, and End Results-Medicare database, including Medicare beneficiaries diagnosed with American Joint Committee on Cancer 7th ed. (AJCC) stages IIIB–IV NSCLC between 2013–2017. Exposures to RT and ICI were determined by evaluating for treatment within 12 months of diagnosis (RT group and ICI group) and for a second exposure (e.g., ICI after RT) within 3 months after the first exposure (RT + ICI group). Untreated controls were matched to treated patients who were diagnosed in the same three-month window. A validated algorithm for identifying cases of pneumonitis in claims data was used to evaluate for the outcome within 6 months after treatment. The primary outcome was the relative excess risk due to interaction (RERI), a quantitative measure of additive interaction between two treatments. Results There were 18,780 patients included in the analysis with 9,345 (49.8%), 7,533 (40.2%), 1,332 (7.1%), and 550 (2.9%) in the control, RT, ICI, and RT + ICI groups, respectively. Relative to controls, the hazards ratios of pneumonitis were 11.5 (95% CI: 7.9 to 17.0), 6.2 (95% CI: 3.8 to 10.3), and 10.7 (95% CI: 6.0 to 19.2) in the RT, ICI, and RT-ICI groups, respectively. The RERIs were −6.1 (95% CI: −13.1 to −0.6, P=0.97) and −4.0 (95% CI: −10.7 to 1.5, P=0.91) in the unadjusted and adjusted analyses, respectively, consistent with no evidence of additive interaction (RERI ≤0) between RT and ICI. Conclusions In this study of Medicare beneficiaries with advanced NSCLC, RT and ICI were, at most, additive rather than synergistic in causing pneumonitis. Pneumonitis risk in patients treated with RT and ICI is not more than could be expected from each therapy alone.
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Project description:Surgery is the standard treatment for resectable non-small cell lung cancer (NSCLC). Neoadjuvant and adjuvant therapy have been widely used for preventing recurrence and metastasis. Immune checkpoint inhibitors (ICIs) have brought long-term survival benefits in advanced NSCLC and showed higher downstage rates and pathological remission in the neoadjuvant setting. Predictive biomarkers are of great significance to identify the beneficiaries of neoadjuvant ICIs. At present, the biomarkers are still inconclusive. We summarized the clinical trials of neoadjuvant immune checkpoint inhibitors that have been disclosed so far, and reviewed the progress of the biomarkers associated with those trials.
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