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The Effectiveness and Safety of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer Patients With Stage III/IV: A Multicenter Study.

ABSTRACT: Immune checkpoint inhibitors (ICIs) have been approved to treat patients with various cancer types, including lung cancer, in many countries. This study aims to investigate the effectiveness and safety of ICIs under different treatment conditions of non-small cell lung cancer patients. A population-based retrospective cohort study was conducted using the electronic health records of three medical centers in Taiwan. From January 01, 2016, to November 30, 2018, a total of 91 ICIs and 300 traditional chemotherapy users who had undergone stage III and IV lung cancer treatment were included in the study. We performed the randomized matched pair design by selecting a Chemotherapy subject for each ICI patient in the sample population. All subjects were monitored from the date of taking ICIs or chemotherapy drugs until the event of death, loss to follow-up, or were occurred with any defined adverse events. Kaplan-Meier estimators and cox proportional hazard regression models were used to compute the overall survival, efficacy, and safety of the ICIs group. The median overall survival (OS) in the ICI and Chemo groups after matching was 11.2 months and 10.5 months, respectively. However, the results showed no significant OS differences between ICIs and chemo groups for both before and after matching (HR,1.30; 95%CI, 0.68-2.46; p=0.428 before matching and HR,0.96; 95CI%, 0.64-1.44; p=0.838 after matching). We observed that with the higher amount of PD-L1, the length of the patients' overall survival was (positive vs. negative PD-L1, HR,0.21; 95%CI, 0.05-0.80; p=0.022). The incidences of serious adverse drug events above grade 3 in the ICIs and traditional chemo groups were 12.7% and 21.5%, respectively. We also found that the number of AEs was less in ICIs than in the Chemo group, and the AEs that occurred after treatments were observed earlier in the ICIs compared to the Chemo group. ICIs drugs were observed to be safer than traditional chemotherapy as they had a lower risk of serious adverse drug events. It is necessary to pay attention to immune-related side effects and provide appropriate treatment. Furthermore, the patient's physical status and PD-L1 test can be used to evaluate the clinical effectiveness of ICIs.

SUBMITTER: Hsu JC

PROVIDER: S-EPMC8293991 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundFor clinical decision making, it is crucial to identify patients with stage IV non-small cell lung cancer (NSCLC) who may benefit from tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). In this study, a deep learning-based system was designed and validated using pre-therapy computed tomography (CT) images to predict the survival benefits of EGFR-TKIs and ICIs in stage IV NSCLC patients.MethodsThis retrospective study collected data from 570 patients with stage IV EGFR-mutant NSCLC treated with EGFR-TKIs at five institutions between 2010 and 2021 (data of 314 patients were from a previously registered study), and 129 patients with stage IV NSCLC treated with ICIs at three institutions between 2017 and 2021 to build the ICI test dataset. Five-fold cross-validation was applied to divide the EGFR-TKI-treated patients from four institutions into training and internal validation datasets randomly in a ratio of 80%:20%, and the data from another institution was used as an external test dataset. An EfficientNetV2-based survival benefit prognosis (ESBP) system was developed with pre-therapy CT images as the input and the probability score as the output to identify which patients would receive additional survival benefit longer than the median PFS. Its prognostic performance was validated on the ICI test dataset. For diagnosing which patient would receive additional survival benefit, the accuracy of ESBP was compared with the estimations of three radiologists and three oncologists with varying degrees of expertise (two, five, and ten years). Improvements in the clinicians' diagnostic accuracy with ESBP assistance were then quantified.FindingsESBP achieved positive predictive values of 80·40%, 75·40%, and 77·43% for additional EGFR-TKI survival benefit prediction using the probability score of 0·2 as the threshold on the training, internal validation, and external test datasets, respectively. The higher ESBP score (>0·2) indicated a better prognosis for progression-free survival (hazard ratio: 0·36, 95% CI: 0·19-0·68, p<0·0001) in patients on the external test dataset. Patients with scores >0·2 in the ICI test dataset also showed better survival benefit (hazard ratio: 0·33, 95% CI: 0·18-0·55, p<0·0001). This suggests the potential of ESBP to identify the two subgroups of benefiting patients by decoding the commonalities from pre-therapy CT images (stage IV EGFR-mutant NSCLC patients receiving additional survival benefit from EGFR-TKIs and stage IV NSCLC patients receiving additional survival benefit from ICIs). ESBP assistance improved the diagnostic accuracy of the clinicians with two years of experience from 47·91% to 66·32%, and the clinicians with five years of experience from 53·12% to 61·41%.InterpretationThis study developed and externally validated a preoperative CT image-based deep learning model to predict the survival benefits of EGFR-TKI and ICI therapies in stage IV NSCLC patients, which will facilitate optimized and individualized treatment strategies.FundingThis study received funding from the National Natural Science Foundation of China (82001904, 81930053, and 62027901), and Key-Area Research and Development Program of Guangdong Province (2021B0101420005).

Project description:BACKGROUND:Since 2012, several immune checkpoint inhibitors have been approved by the Taiwan FDA for various types of cancer treatment. However, none of them are covered by Taiwan National Health Insurance due to the fact that they are expensive, and there is a lack of clinical evidence as to their effectiveness. OBJECTIVES:This study was aimed toward an exploration of clinical experiences with use of immune checkpoint inhibitors, including indications, prescription types, drug effectiveness, adverse drug event types, and incidence, all of which shall serve as references for future clinical drug use. METHODS:This is a retrospective study focusing on three immune checkpoint inhibitors (ipilimumab, nivolumab, and pembrolizumab), which are available for cancer treatment in Taiwan. We collected data from medical records for the period from January 1st, 2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a medical center in southern Taiwan, and recorded these cases until May 31st, 2017. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed using a chi-square analysis. RESULTS:The 50 patients under consideration in this study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS for all immunotherapies was 4.9 months. The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For NSCLC patients, the OS and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months, respectively. The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials. CONCLUSIONS:The histological subtype, the intensity of the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic results. It is recommended that clinical tests be conducted in order to enhance therapeutic effectiveness. It is expected that more testing, observation-based studies, and research results will validate their efficacy and the tolerance levels of patients.

Project description:There has been no improvement in outcome for patients with unresectable locally advanced (stage III) non-small cell lung cancer (NSCLC) for more than 10 years. The standard treatment for these patients is definitive concurrent chemotherapy and radiation (CCRT). Although the goal of treatment in this setting is to achieve a cure, most patients progress and their prognosis is poor, with a 5-year survival rate of 15-30%. There is thus an urgent need for the development of novel anticancer treatments in this patient population. Recent advances in cancer immunotherapy have led to a marked improvement in clinical outcome for advanced NSCLC. Such immunotherapy mainly consists of the administration of immune checkpoint inhibitors (ICIs) such as antibodies to cytotoxic T lymphocyte-associated protein-4 (CTLA-4) or to either programmed cell death-1 (PD-1) or its ligand PD-L1. Durvalumab (MEDI4736) is a high-affinity human immunoglobulin G1 monoclonal antibody that blocks the binding of PD-L1 on tumor cells or antigen-presenting cells to PD-1 on T cells. The PACIFIC study recently evaluated consolidation immunotherapy with durvalumab versus placebo administered after concurrent chemoradiotherapy (CCRT) in patients with unresectable stage III NSCLC. It revealed a significant improvement in both progression-free and overall survival with durvalumab, and this improvement was associated with a favorable safety profile. This achievement has made durvalumab a standard of care for consolidation after CCRT in patients with unresectable stage III NSCLC, and it has now been approved in this setting by regulatory agencies in the United States, Canada, Japan, Australia, Switzerland, Malaysia, Singapore, India, and the United Arab Emirates. In this review, we briefly summarize the results of the PACIFIC trial, including those of post hoc analysis, and we address possible molecular mechanisms, perspectives, and remaining questions related to combined treatment with CCRT and ICIs in this patient population.

Project description:BACKGROUND:The PACIFIC study has defined a new standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC) in the form of immune checkpoint inhibitor (ICI) consolidation therapy. However, there is little specific data pertaining to the safety and efficacy of this approach in Chinese NSCLC patients. METHODS:This was a prospective multicenter cohort study. Between September 2018 and January 2020, patients with unresectable stage III NSCLC that had undergone chemoradiation therapy (CRT) and ICI consolidation treatment were enrolled in this study. The short-term safety, tolerability, and efficacy of ICI combination with CRT were evaluated in these patients. RESULTS:Of the 20 Chinese patients eligible for inclusion, 17 (85.0%) underwent concurrent CRT treatment. In these patients, a median period of 40.5?days (range: 1-85?days) passed between the end of CRT and initiation of consolidation therapy. Pneumonitis occurred in 80.0% of patients, with seven (35.0%) being diagnosed with grade 1 pneumonitis and nine (45.0%) with grade 2 pneumonitis. No patients experienced grade 3 or higher pneumonitis or other ICI-related toxicities. Lung V20???20% was associated with higher grade 2 pneumonitis (77.8%; ?20% vs. 18.2%; <20%, P = 0.027). The overall response rate (ORR) in these patients was 95.0%. Over a median follow-up period of 11.3 months (range: 6.2-21.8 months), 12-month PFS of these patients were 89.5% (95% CI: 76.7-100.0%), and 12 months OS was 100.0%. CONCLUSIONS:These data indicate that ICI consolidation therapy can achieve favorable short-term efficacy, while exhibiting good safety and acceptable toxicity profiles in Chinese patients with unresectable stage III NSCLC. KEY POINTS:Significant findings of the study This is the first report evaluating the safety and efficacy of ICI consolidation therapy after chemoradiotherapy in China. Our results indicate that ICI consolidation is associated with favorable efficacy and no severe pneumonitis incidence in Chinese patients undergoing both anti-PD-1 and anti-PD-L1 monoclonal antibody consolidation. What this study adds Post-hoc analysis of the Japanese subgroup in the PACIFIC study suggested that consolidation therapy may be associated with increased pneumonitis incidence in Asian patients. However, our findings indicate that consolidation therapy is safe and tolerable in Chinese patients with unresectable stage III NSCLC.

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The Effectiveness and Safety of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer Patients With Stage III/IV: A Multicenter Study.

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