Recent breakthroughs in targeted therapy and immunotherapy have revolutionized the treatment of lung cancer, the leading cause of cancer-related deaths in the United States and worldwide. Here we ...provide an overview of recent progress in immune checkpoint blockade therapy for treatment of non-small cell lung cancer (NSCLC), and discuss biomarkers associated with the treatment responses, mechanisms underlying resistance and strategies to overcome resistance. The success of immune checkpoint blockade therapies is driven by immunogenicity of tumor cells, which is associated with mutation burden and neoantigen burden in cancers. Lymphocyte infiltration in cancer tissues and interferon-γ-induced PD-L1 expression in tumor microenvironments may serve as surrogate biomarkers for adaptive immune resistance and likelihood of responses to immune checkpoint blockade therapy. In contrast, weak immunogenicity of, and/or impaired antigen presentation in, tumor cells are primary causes of resistance to these therapies. Thus, approaches that increase immunogenicity of cancer cells and/or enhance immune cell recruitment to cancer sites will likely overcome resistance to immunotherapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The germline mutation landscape in Chinese lung cancer patients has not been well defined. In this study, sequencing data of 1,021 cancer genes of 1,794 Chinese lung cancer patients was analyzed. A ...total of 111 pathogenic or likely pathogenic germline mutations were identified, significantly higher than non-cancer individuals (111/1794 vs. 84/10,588, p < 2.2e-16). BRCA1/2 germline mutations are associated with earlier onset age (median 52.5 vs 60 years-old, p = 0.008). Among 29 cancer disposition genes with germline mutations detected in Chinese cohort and/or TCGA lung cancer cohort, Only 11 from 29 genes are identified in both cohorts and BRCA2 mutations are significantly more common in Chinese cohort (p = 0.015). Chinese patients with germline mutations have different prevalence of somatic KRAS, MET exon 14 skipping and TP53 mutations compared to those without. Our findings suggest potential ethnic and etiologic differences between Western and Asian lung cancer patients.
Background About 10% of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are harbored as uncommon mutations. This study aimed to explore the efficacy ...and safety of dacomitinib, a second-generation EGFR tyrosine kinase inhibitor (EGFR-TKIs), in treating uncommon EGFR-mutated advanced NSCLC. Methods Treatment-naïve advanced NSCLC patients treated with dacomitinib at Hunan Cancer Hospital with uncommon EGFR mutations were evaluated. The primary endpoint was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Result Between December 2019 and December 2021, a total of 16 patients was included. Median PFS was 14.0 (95% CI 4.32-23.7) months, and median OS was not reached. ORR was 68.8% (95% CI 41.3 to 89.0%) and DCR was 93.8% (95%CI 69.8 to 99.8%), including three achieving complete remission (CR) and eight achieving partial remission (PR). Median PFS for patients with brain metastasis was 9.0 (95%CI 6.9 to 11.1) months. Intracranial ORR was 100%, including 2 CR and 4 PR. Major treatment-related adverse events (TRAEs) included rash (87.5%), paronychia (62.5%), oral ulcers (50.0%), and diarrhea (50.0%), none of which were greater than or equal to grade 3 TRAEs. Conclusions Dacomitinib showed good activity and manageable toxicity in NSCLC patients with uncommon EGFR mutations. Keywords: Uncommon EGFR mutation, Non-small cell lung cancer, Dacomitinib, Efficacy, Safety
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background:
Selecting patients who potentially benefit from immune checkpoint inhibitors (ICIs) is critical. Programmed death ligand-1 (PD-L1) protein immunohistochemical expression on cancer cells ...or immune cells and next-generation sequencing-based tumor mutational burden (TMB) are hot spots in studies on ICIs, but there is still confusion in the testing methods. Because blood samples are much easier for clinical application, many potential peripheral biomarkers have been proposed. This study identified blood parameters associated with the outcome of non-small cell lung cancer (NSCLC) patients with ICI monotherapy.
Materials and Methods:
Data from 76 NSCLC patients were analyzed retrospectively. To assess the connection between survival and peripheral blood markers measured before the first and fifth doses of ICI treatment, we utilized Cox regression model survival analysis and receiver operating characteristic (ROC) curve analysis to assess the markers.
Results:
In the nivolumab cohort, the optimal cutoffs for predicting 11-month overall survival (OS) were 168.13 and 43 g/L for platelet-to-lymphocyte ratio (PLR) and albumin, respectively. When patients were grouped with PLR and albumin, a significant difference in SD-PR vs. PD rate was found between the high and low groups, which was not found when the patients were grouped by PD-L1 expression. Patients with high PLR (>168.13) or low albumin ( ≤ 43 g/L) before ICI had a significantly increased hazard of progression, separately (for PLR,
P
= 0.006; for albumin,
P
= 0.033), and of death (for PLR,
P
= 0.014; for albumin,
P
= 0.009) compared with those patients who had low PLR or albumin levels. More importantly, we found that a higher PLR (>168.13) before the fifth dose of ICIs was also a prognostic biomarker, which significantly correlated with shorter OS in both the nivolumab (
P
= 0.046) and durvalumab cohorts (
P
= 0.028).
Conclusions:
PLR and albumin may help in the stratification of high progression and death risk groups in advanced NSCLC patients treated with nivolumab and durvalumab monotherapy.
Background
Biomarkers that predict the efficacy of first-line tyrosine kinase inhibitors (TKIs) are pivotal in epidermal growth factor receptor (EGFR) mutant advanced lung adenocarcinoma. ...Imaging-based biomarkers have attracted much attention in anticancer therapy. This study aims to use the machine learning method to distinguish EGFR mutation status and further explores the predictive role of EGFR mutation-related radiomics features in response to first-line TKIs.
Methods
We retrospectively analyzed pretreatment CT images and clinical information from a cohort of lung adenocarcinomas. We entered the top-ranked features into a support vector machine (SVM) classifier to establish a radiomics signature that predicted EGFR mutation status. Furthermore, we identified the best response-related features based on EGFR mutant-related features in first-line TKI therapy patients. Then we test and validate the predictive effect of the best response-related features for progression-free survival (PFS).
Results
Six hundred ninety-two patients were enrolled in building radiomics signatures. The 13 top-ranked features were input into an SVM classifier to establish the radiomics signature of the training cohort (n = 514), and the predictive score of the radiomics signature was assessed on an independent validation group with 178 patients and obtained an area under the curve (AUC) of 74.13%, an F1 score of 68.29%, a specificity of 79.55%, an accuracy of 70.79%, and a sensitivity of 62.22%. More importantly, the skewness-Low (≤0.882) or 10th percentile-Low group (≤21.132) had a superior partial response (PR) rate than the skewness-High or 10th percentile-High group (
p
< 0.01). Higher skewness (hazard ratio (HR) = 1.722,
p
= 0.001) was also found to be significantly associated with worse PFS.
Conclusions
The radiomics signature can be used to predict EGFR mutation status. Skewness may contribute to the stratification of disease progression in lung cancer patients treated with first-line TKIs.
Background
The impact of neoadjuvant chemoimmunotherapy on pulmonary resection and related outcomes had been poorly reported in previous studies. The present study aims to clarify the efficacy and ...safety of neoadjuvant chemoimmunotherapy, and intraoperative difficulty in the following surgery, in comparison with chemotherapy alone in non‐small cell lung cancer (NSCLC).
Methods
Patients with newly diagnosed clinical stages IB–IIIB(T3‐4N2) NSCLC, received neoadjuvant chemotherapy + PD‐1 inhibitors (PD‐1 + Chemo group) or chemotherapy alone (Chemo group) followed by surgery between December 2018 and December 2020 were included. The clinicopathological characteristics were retrospectively reviewed and analyzed.
Results
There were 69 NSCLC patients in the PD‐1 + Chemo group and 121 in the Chemo group. The major pathological response (MPR) rate in the PD‐1 + Chemo group was 49.3%, higher than that of 19.0% in the Chemo group (p < 0.001). The 2‐year disease‐free survival (DFS) rate was 79.3% and 60.2%, respectively, in the two groups (p = 0.048). Multivariate analysis identified surgical radicality (hazard ratio (HR), 2.954, 95% confidence interval (CI), 1.527–5.714, p = 0.001), and pathological response (MPR(CR) vs. SD(PD), HR, 0.248, 95% CI, 0.107–0.572, p = 0.001) to be independent prognostic factors for DFS. Lobectomy was performed in 73.9% and 66.1% of patients, respectively, and bronchial sleeve resection/bronchoplasty rate was also comparable (43.4% vs. 40.5%, p = 0.688). More patients in the PD‐1 + Chemo group received vascular sleeve resection/angioplasty (15.9% vs. 6.6%, p = 0.039) and pericardial resection (10.1% vs. 2.5%, p = 0.038). After propensity score matching analysis, pericardial resection rate was still slightly higher in the PD‐1 + Chemo group (9.4% vs. 1.6%, p = 0.05). Perioperative morbidities within 30 days and mortality in 90 days were comparable between groups (p > 0.05).
Conclusions
Neoadjuvant chemoimmunotherapy for NSCLC is safe and feasible, with higher MPR rates, as well as favorable DFS than chemotherapy alone. Surgical complexity might be increased in certain patients, with comparable perioperative morbidity and mortality.
This real‐world study confirmed that neoadjuvant chemoimmunotherapy is safe and feasible, with higher MPR and pCR rates, as well as favorable DFS compared with chemotherapy alone. Surgical complexity might be increased in certain patients, with comparable perioperative morbidity and mortality. This large‐scale real‐word study has provided a solid evidence for the use of neoadjuvant chemoimmunotherapy for NSCLC in the future. Our results may help improve the perioperative management and surgical techniques in pulmonary resections following neoadjuvant chemoimmunotherapy.
The treatment of cancer of unknown primary (CUP) is a huge challenge for clinicians. Gene expression profiling can help identify the tissue origin of tumors by detecting the expression levels of ...specific genes in tumor tissues. Herein, we report four CUP cases. All of them have been successfully identified with the corresponding primary tumor sites through gene expression profiling analysis. Then all patients received accurate treatment, providing reference to guide therapeutic decisions to treat CUP tumors in the future.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) show great efficacy on advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. But whether adjuvant treatment ...with EGFR-TKI could improve the outcomes of patients with fully resected NSCLC remains unknown. Some studies show a trend toward improvement in disease free survival (DFS) among individuals with resected stage I-III lung adenocarcinomas harboring mutations in EGFR exons 19 or 21 who received EGFR-TKIs as adjuvant therapy. In other exploratory clinical trials, the patients treated with EGFR-TKIs as adjuvant therapy did not show any survival benefit. To date, there are different research results of adjuvant EGFR-TKIs treatment on NSCLC patients because of patients selection, EGFR-TKIs duration and drug resistance. There are several ongoing prospective clinical trials of adjuvant therapy with EGFR-TKIs on patients with resected stage II-III A NSCLC harboring EGFR mutations and the results are worth expecting. Till no
Background
Clinical evidence of immune checkpoint inhibitors combined with antiangiogenic drugs in patients with advanced non‐small cell lung cancer (NSCLC) was limited. Recombinant human endostatin ...(rh‐endostatin), an antiangiogenic drug, and camrelizumab, an anti‐PD‐1 antibody, have been approved for the treatment of advanced NSCLC in China. This study aimed to investigate the efficacy and safety of rh‐endostatin plus camrelizumab and chemotherapy in the treatment of advanced NSCLC.
Methods
Eligible patients were enrolled and received camrelizumab (200 mg, day 1) every 3 weeks and continuous intravenous infusion of rh‐endostatin (70 mg/day, days 1–3) and cisplatin combined with pemetrexed (for adenocarcinoma) or paclitaxel (for NSCLC other than adenocarcinoma) every 3 weeks. Primary endpoint was progression‐free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profiles.
Results
Overall, 27 patients were included, and 25 patients were eligible for efficacy evaluation. For these 25 patients, ORR was 48.15% (13/27) and DCR was 85.19% (23/27). With a median follow‐up of 10.37 months, the median PFS was 8.9 (95% CI: 4.23–13.57) months. Median OS was not reached. Overall, 96.3% of patients experienced at least one treatment‐related adverse event, and grade 3 TRAEs occurred in 9 (33.3%) patients. No unexpected AEs were observed.
Conclusion
Rh‐endostatin plus camrelizumab and chemotherapy showed favorable efficacy and safety profile in patients with advanced NSCLC, representing a promising treatment regimen for these patients.
Rh‐endostatin combined with camrelizumab plus chemotherapy treating advanced NSCLC showed ORR of 48.15% and DCR of 85.19%, with a median PFS of 8.9 months. The safety profile was comparable with former studies, representing Rh‐endostatin combined with camrelizumab and chemotherapy as a promising treatment regimen in advanced‐stage NSCLC patients.
Germline alterations in the breast cancer susceptibility genes type 1 and 2,
and
, predispose individuals to hereditary cancers, including breast, ovarian, prostate, pancreatic, and stomach cancers. ...Accumulating evidence suggests inherited genetic susceptibility to lung cancer. The present study aimed to survey the prevalence of pathogenic germline
mutations (
) and explore the potential association between
and disease onset in Chinese advanced non-small cell lung cancer (NSCLC) patients.
A total of 6,220 NSCLC patients were screened using capture-based ultra-deep targeted sequencing to identify patients harboring germline
/
mutations.
Out of the 6,220 patients screened, 1.03% (64/6,220) of the patients harbored the pathogenic
, with
mutations being the most pr edominant mutations (49/64, 76.5%). Patients who developed NSCLC before 50 years of age were more likely to carry
(
= 0.036). Among the patients harboring classic lung cancer driver mutations, those with concurrent
were significantly younger than those harboring the wild-type
(
= 0.029). By contrast, the age of patients with or without concurrent
was comparable to those of patients without the driver mutations (
= 0.972). In addition, we identified
-mutant patients with concurrent g
who showed comparable progression-free survival but significantly longer overall survival (
= 0.002) compared to
-mutant patients with wild-type germline
.
Overall, our study is the largest survey of the prevalence of pathogenic
in advanced Chinese NSCLC patients. Results suggested a lack of association between germline
status and treatment outcome of EGFR-TKI. In addition, results showed a positive correlation between pathogenic
and an early onset of NSCLC.
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