Targeting the PD-1/PD-L1 Immune Checkpoint in EGFR-Mutated or ALK-Translocated Non-Small-Cell Lung Cancer

Bylicki, Olivier; Paleiron, Nicolas; Margery, J.; Guisier, Florian; Vergnenègre, A.; Robinet, G.; Auliac, J.B.; Gervais, Radj; Chouaïd, C.

doi:10.1007/s11523-017-0510-9

Cited by 72 publications

(77 citation statements)

References 67 publications

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“…In this context, the use of ICIs remains controversial for patients harboring EGFR mutation and resistance to TKIs. Several studies have suggested that tumors with genetic EGFR/ALK alterations respond less well to ICI therapy than tumors without genetic EGFR/ALK alterations . The present study revealed that genetic EGFR/ALK alterations were associated with RP in the univariate analysis, although this association disappeared in the multivariate analysis.…”

Section: Discussioncontrasting

confidence: 52%

Factors related to rapid progression of non‐small cell lung cancer in Chinese patients treated using single‐agent immune checkpoint inhibitor treatment

et al. 2020

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Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). While rapid progression (RP) has been proposed as a non-negligible pattern of response to ICIs, its definition and related factors remain unclear. This study aimed to develop a clinical definition of RP and to identify related factors. Methods: We retrospectively evaluated Chinese patients who had received an ICI as second-line or later treatment for locally advanced or metastatic NSCLC at a single center. We defined RP as radiological progression at the first response assessment (<2 months after starting the ICI), as well as confirmation of progressive disease or cancer-related death occurring at <3 months. The clinical outcomes were compared for patients with RP or non-RP to identify prognostic factors. Results: The study evaluated 74 eligible patients with detailed records regarding their ICI therapy, including 25 patients (33.8%) who had experienced RP. Relative to patients with non-RP, patients with RP had significantly shorter median progression-free survival (1.7 months [95% CI: 1.4-2.0 months] vs. 6.3 months [95% CI 5.2-7.3 months], P < 0.001; hazard ratio: 0.14, 95% CI: 0.08-0.25) and significantly shorter median overall survival (8.2 months [95% CI 3.0-13.4 months] vs. 22.6 months [95% CI 17.0-28.1 months], P < 0.001; hazard ratio: 0.27, 95% CI: 0.15-0.49). Multivariate analysis revealed that RP was independently predicted by the presence of ≥3 metastatic sites (P = 0.039) and a neutrophil-to-lymphocyte ratio of ≥3 (P = 0.044). Conclusions: Among NSCLC patients, RP was a common response to ICI monotherapy and was associated with dramatically reduced progression-free and overall survival. Care is needed when selecting ICI monotherapy for these patients, especially if they have ≥3 metastatic sites or a neutrophil-to-lymphocyte ratio of ≥3. Key pointsSignificant findings of the study: Patients with rapid progression after immune checkpoint inhibitor monotherapy had poor survival outcomes. The number of metastatic sites and the neutrophil-to-lymphocyte ratio may independently predict treatment response in this setting.What this study adds: This is the first study to evaluate rapid progression after second-line or later single-agent immunotherapy in a Chinese population. Our findings may help establish effective immunotherapy strategies for NSCLC.

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Section: Discussioncontrasting

confidence: 52%

Factors related to rapid progression of non‐small cell lung cancer in Chinese patients treated using single‐agent immune checkpoint inhibitor treatment

et al. 2020

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“…In our analysis, patients with EGFR mutations and/or ALK rearrangement had shorter OS. Retrospective analyses suggest lower PD‐L1 expression, and tyrosine kinase inhibitor (TKI)‐mediated inhibition of the PD‐1 axis in patients with ALK‐ and EGFR‐positive mNSCLC may lead to inferior outcomes . Additionally, these patients generally receive PD‐1 inhibitors in a later line of therapy, following progression on a TKI and chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…In our analysis, patients with EGFR mutations and/or ALK rearrangement had shorter OS. Retrospective analyses suggest lower PD-L1 expression, and tyrosine kinase inhibitor (TKI)-mediated inhibition of the PD-1 axis in patients with ALK-and EGFRpositive mNSCLC may lead to inferior outcomes [22][23][24].…”

Section: Discussionmentioning

confidence: 99%

Real-World Outcomes of Patients with Metastatic Non-Small Cell Lung Cancer Treated with Programmed Cell Death Protein 1 Inhibitors in the Year Following U.S. Regulatory Approval

et al. 2018

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Background Evidence from cancer clinical trials has strong internal validity but can be difficult to generalize to real‐world patient populations. Here we analyzed real‐world outcomes of patients with metastatic non‐small cell lung cancer (mNSCLC) treated with programmed cell death protein 1 (PD‐1) inhibitors in the first year following U.S. regulatory approval. Materials and Methods This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in community cancer care clinics. The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease (n = 1,344) with >1 EHR‐documented visit from January 1, 2011, to March 31, 2016. Patients with a > 90‐day gap between advanced disease diagnosis and first EHR structured data entry were excluded. Results Estimated median overall survival (OS) was 8.0 months (95% confidence interval 7.4–9.0 months). Estimated median OS was 4.7 months (3.4–6.6) for patients with anaplastic lymphoma kinase rearrangement‐ and epidermal growth factor receptor mutation‐positive tumors, and 8.6 months (7.7–10.6) for patients without such mutations. Age at PD‐1 inhibitor initiation or line of therapy did not impact OS. Conclusion This analysis suggests OS in real‐world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD‐1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome. Further studies are underway in patients with comorbidities, organ dysfunction, and multiple prior therapies. Implications for Practice This study evaluated data derived from electronic health records of patients with metastatic non‐small cell lung cancer treated with programmed cell death protein 1 (PD‐1) inhibitors in the year following regulatory approval. This real‐world cohort had shorter overall survival (OS) indexed to PD‐1 inhibitor initiation than reported in clinical trials. Late‐line treatment did not influence OS, and patients aged >75 at immunotherapy initiation did not have worse outcomes than younger patients. As new therapies enter clinical practice, real‐world data can complement clinical trial evidence providing information on generalizability and helping inform clinical treatment decisions.

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“…1,2 Furthermore, it has been predicted that lung adenocarcinoma could remain a major health problem for at least the next 50 years. 5 However, as it is a highly heterogeneous disease, the efficiency of targeted therapies is easily affected by compensatory changes of tumor tissues in response to different targeted therapies. 5 However, as it is a highly heterogeneous disease, the efficiency of targeted therapies is easily affected by compensatory changes of tumor tissues in response to different targeted therapies.…”

Section: Introductionmentioning

confidence: 99%

CASTOR1 suppresses the progression of lung adenocarcinoma and predicts poor prognosis

Zhou

Cheng

Hao

et al. 2018

J of Cellular Biochemistry

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As a naturally occurring inhibitor of mammalian target of rapamycin (mTOR), accumulated evidence has confirmed that CASTOR1 plays a pivotal role in regulating the progression of human malignancies. However, the function of CASTOR1 in the development of lung adenocarcinoma is still unclear. Here we report that the expression of CASTOR1 is significantly reduced in lung adenocarcinoma cell lines as compared with that in normal lung epithelial cells. Cellular studies further revealed that ectopic CASTOR1 expression led to a significant suppression of the cellular proliferation, migration, and invasion of PC-9 cells. To further test the role of CASTOR1 in human patients with lung cancers, tumor tissues derived from lung cancer patients and paired adjacent normal lung tissues were collected for immunohistochemical, biochemical, and molecular biology analysis. Immunoblotting and real-time quantitative reverse transcription polymerase chain reaction analysis is revealed that CASTOR1 was significantly reduced in tumor tissues as compared with that in paired normal lung tissues. With immunostaining and retrospective analysis of pathological samples from lung cancer patients further revealed that expression of CASTOR1 was negatively correlated with smoking history, TNM stage, lymphnode metastasis, and distant metastasis. Furthermore, Kaplan-Meier survival analysis indicated that patients with low CASTOR1 expression levels had a significantly worse 5-year survival rate than those with high CASTOR1 expression. To further explore the molecular actions of CASTOR1 in lung cancer development, biochemical assays were performed and the results suggested that ectopic CASTOR1 expression resulted significant suppression of mTOR and downstream S6K phosphorylation, indicating that CASTOR1 might regulate the progression of lung adenocarcinoma by controlling mTOR activation. Thus, these findings demonstrated that CASTOR1 inhibits the tumorigenesis of lung adenocarcinoma cells and might serve as a potential therapeutic target or prognostic marker for human patients with lung adenocarcinoma.

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Targeting the PD-1/PD-L1 Immune Checkpoint in EGFR-Mutated or ALK-Translocated Non-Small-Cell Lung Cancer

Cited by 72 publications

References 67 publications

Factors related to rapid progression of non‐small cell lung cancer in Chinese patients treated using single‐agent immune checkpoint inhibitor treatment

Factors related to rapid progression of non‐small cell lung cancer in Chinese patients treated using single‐agent immune checkpoint inhibitor treatment

Real-World Outcomes of Patients with Metastatic Non-Small Cell Lung Cancer Treated with Programmed Cell Death Protein 1 Inhibitors in the Year Following U.S. Regulatory Approval

CASTOR1 suppresses the progression of lung adenocarcinoma and predicts poor prognosis

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