Efficacy of anti-PD-1 antibodies in NSCLC patients with an EGFR mutation and high PD-L1 expression

Masuda, Ken; Horinouchi, Hidehito; Tanaka, Midori; Higashiyama, Ryoko; Shinno, Yuki; Sato, Jun; Matsumoto, Yuji; Okuma, Yusuke; Yoshida, Tatsuya; Goto, Yasushi; Yamamoto, Noboru; Ohe, Yuichiro

doi:10.1007/s00432-020-03329-0

Cited by 53 publications

(41 citation statements)

References 20 publications

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“…Our data indicate that EGFR mutation status is associated with high TIL density and high PD-1/PD-L1 expression (cluster 1) and with low TIL density and low PD-1/PD-L1 expression (cluster 2). This result is in contrast with previous reports stating that NSCLC patients with EGFR mutations have high PD-L1 expression ( 23 ). We further evaluated the prognostic value of immune cells in gene-mutated patients and wild-type patients, and the results indicate that only CD8 levels relative to FOXP3 levels have prognostic value in a wild-type subgroup of patients ( Supplementary Figures S4A-G ), underlying the crucial prognostic value of the CD8/FOXP3 ratio.…”

Section: Resultscontrasting

confidence: 99%

Combined Consideration of Tumor-Associated Immune Cell Density and Immune Checkpoint Expression in the Peritumoral Microenvironment for Prognostic Stratification of Non-Small-Cell Lung Cancer Patients

Yang

Wang

et al. 2022

Front. Immunol.

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Given the complexity and highly heterogeneous nature of the microenvironment and its effects on antitumor immunity and cancer immune evasion, the prognostic value of a single immune marker is limited. Here, we show how the integration of immune checkpoint molecule expression and tumor-associated immune cell distribution patterns can influence prognosis prediction in non-small-cell lung cancer (NSCLC) patients. We analyzed tissue microarray (TMA) data derived from multiplex immunohistochemistry results and measured the densities of tumor-infiltrating CD8+ and FOXP3+ immune cells and tumor cells (PanCK+), as well as the densities of programmed cell death 1 (PD-1)+ and programmed cell death ligand 1 (PD-L1)+ cells in the peritumor and intratumor subregions. We found a higher density of infiltrating CD8+ and FOXP3+ immune cells in the peritumoral compartment than in the intratumoral compartment. In addition, unsupervised hierarchical clustering analysis of these markers revealed that the combination of high CD8/FOXP3 expression, low PD-1 and PD-L1 immune checkpoint expression, and lack of epidermal growth factor receptor (EGFR) mutation could be a favorable predictive marker. On the other hand, based on the clustering analysis, low CD8/FOXP3 and immune checkpoint (PD-1 and PD-L1) expression might be a marker for patients who are likely to respond to strategies targeting regulatory T (Treg) cells. Furthermore, an immune risk score model was established based on multivariate Cox regression, and the risk score was determined to be an independent prognostic factor for NSCLC patients. These results indicate that the immune context is heterogeneous because of the complex interactions of different components and that using multiple factors in combination might be promising for predicting the prognosis of and stratifying NSCLC patients.

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Section: Resultscontrasting

confidence: 99%

Combined Consideration of Tumor-Associated Immune Cell Density and Immune Checkpoint Expression in the Peritumoral Microenvironment for Prognostic Stratification of Non-Small-Cell Lung Cancer Patients

Yang

Wang

et al. 2022

Front. Immunol.

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“…Chemotherapy and immunotherapy could diminish much further the clinical and subclinical tumor by activing anti-tumor immunity. Our patient with EGFR-TKI resistance responded well to IO combination therapy, which was consistent with the previous study ( 5 ). Thus, PD-L1 TPS 50% or higher may function a predictive role in immunotherapy efficacy after the kinase inhibitor resistance.…”

Section: Discussionsupporting

confidence: 93%

“…Patients with a co-occurrence of high PD-L1 (>50%) and EGFR aberrations were disclosed less than 10% in NSCLC ( 4 ). A Japanese retrospective study found PD-1 inhibitors were more beneficial as second-line or later treatment for EGFR-TKI resistant NSCLC patients with high PD-L1 expression (TPS>50%) than patients with low PD-L1 expression ( 5 ). At the time of resistance to gefitinib, we offered the intervening treatment immunity-combined chemo-radiotherapy to our patient.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Re-Sensitization to Gefitinib in Lung Adenocarcinoma Harboring EGFR Mutation and High PD-L1 Expression After Immunotherapy Resistance, Which Finally Transform Into Small Cell Carcinoma

et al. 2021

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The treatment sequence of immunotherapy (IO) and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is of great importance for the survival of non-small cell lung cancer (NSCLC) patients with EGFR sensitive mutation. Here, we reported an advanced lung adenocarcinoma case concurrent with EGFR sensitive mutation and high PD-L1 expression (>50%) that was administrated with gefitinib firstly, and then became resistant to EGFR-TKI. He received the strategy of immunity-combined chemo-radiotherapy and responded significantly. However, the disease re-progressed after 10 months. Surprisingly, the tumor re-sensitized to gefitinib for 13 months. At final, following the treatment pressure of TKI-IO combination therapy-TKI strategy, tumor clone eventually transformed into small cell lung carcinoma (SCLC). For one thing, our study provided novel approach and extended the treatment spectra of overcoming immunotherapy resistance after EGFR resistance in driver oncogene-mutated NSCLC. For another thing, our case is the first time to report that SCLC transformation can be achieved after gefitinib–pembrolizumab–gefitinib resistance in EGFR sensitive mutation NSCLC, providing a new condition for SCLC transformation.

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“…Some studies have found that the status of PD-L1 expression could not be used to screen out ICI responders in EGFR-mutant NSCLC patients ( 42 ). On the contrary, other studies demonstrated that ICIs can also be used for EGFR-mutant NSCLC patients who have high PD-L1 expression ( 43 ). In cohort 1 (n=111) of the ALTLANTIC study ( 44 ), durvalumab was used as the third or later line treatment for advanced EGFR/ALK-positive NSCLC patients.…”

Section: Discussionmentioning

confidence: 99%

Front-Line ICI-Based Combination Therapy Post-TKI Resistance May Improve Survival in NSCLC Patients With EGFR Mutation

Tian

et al. 2021

Front. Oncol.

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BackgroundData on the use of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation are limited. The current study aimed to assess the efficacy of ICIs in EGFR-mutant advanced NSCLC and explore the relevant influential factors.Materials and MethodsRelevant clinical data of EGFR-mutant NSCLC patients who had received ICIs were collected from multiple hospitals. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), and relevant influential factors.ResultsA total of 122 advanced EGFR-mutant NSCLC patients were included in the final analysis. The total cohort had an objective response rate (ORR) of 32.0%, a median progression-free survival (mPFS) of 5.0 months, and a median overall survival (mOS) of 14.4 months. Among 96 patients with common EGFR mutations (19Del, 52 patients; L858R, 44 patients), those who were administered front-line ICI exhibited better survival benefits than those who received later-line ICI after disease progression on tyrosine kinase inhibitors (TKIs) treatment (mPFS: 7.2 months vs. 3.4 months, respectively, P < 0.0001; mOS: 15.1 months vs. 8.4 months, respectively, P <0.0001). Moreover, the efficacy of ICI-based combination therapy was better than that of ICI monotherapy (mPFS: 5.0 months vs. 2.2 months, respectively, P = 0.002; mOS: 14.4 months vs. 7.0 months, respectively, P = 0.001). Multivariate analysis showed that ICI-based combination therapy and front-line ICI administration after progression on EGFR-TKI were associated with significant improvements in both PFS and OS (P < 0.05). A high PD-L1 expression (tumor proportion score, TPS≥50%) and the EGFR L858R mutation were only significantly associated with a better PFS (P <0.05). A better Eastern Cooperative Oncology Group (ECOG) status was independently associated with a favorable OS (P <0.05).ConclusionsTaken together, combination immunotherapy in front-line was associated with improvement of survival in EGFR-mutant NSCLC patients post-TKI resistance. Further prospective studies with large sample sizes are required to identify the optimal combinatorial treatment strategy.

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Efficacy of anti-PD-1 antibodies in NSCLC patients with an EGFR mutation and high PD-L1 expression

Cited by 53 publications

References 20 publications

Combined Consideration of Tumor-Associated Immune Cell Density and Immune Checkpoint Expression in the Peritumoral Microenvironment for Prognostic Stratification of Non-Small-Cell Lung Cancer Patients

Combined Consideration of Tumor-Associated Immune Cell Density and Immune Checkpoint Expression in the Peritumoral Microenvironment for Prognostic Stratification of Non-Small-Cell Lung Cancer Patients

Case Report: Re-Sensitization to Gefitinib in Lung Adenocarcinoma Harboring EGFR Mutation and High PD-L1 Expression After Immunotherapy Resistance, Which Finally Transform Into Small Cell Carcinoma

Front-Line ICI-Based Combination Therapy Post-TKI Resistance May Improve Survival in NSCLC Patients With EGFR Mutation

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