PD-L1 expression on tumor cells as a potential predictive biomarker for patients with unresectable stage III non-small cell lung cancer treated with chemoradiotherapy followed by durvalumab

Käsmann, Lukas; Nieto, Alexander; Taugner, Julian; Manapov, Farkhad

doi:10.21037/tcr-23-52

Cited by 4 publications

(5 citation statements)

References 12 publications

(25 reference statements)

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“…The immune phenotype and contexture is important for response to immunotherapy [ 37 ], with different tumor types comprising differing proportions of inflamed, immune-excluded, and immune-desert phenotypes. In ES-SCLC, we and others have shown that PD-L1 TC expression levels are markedly low [ 17 ], relative to the expression seen in NSCLC, in which it serves as an informative biomarker [ 13 , 14 , 28 ]. Of note, our data from CASPIAN indicate that PD-L1 IC expression ≥ 1% is more prevalent in ES-SCLC (25.8%) compared to PD-L1 TC ≥ 1% (5.7%), and thus PD-L1 on immune cells or immune cells themselves could be more important in driving clinical benefit with D ± T + EP in the subset of patients with PD-L1 TC/IC ≥ 1% in CASPIAN.…”

Section: Discussionmentioning

confidence: 99%

“…Comprehensive molecular characterization of SCLC is important for providing a better understanding of disease heterogeneity and may consequently lead to identification of predictive biomarkers for current and future treatment options, including immune checkpoint inhibitor (ICI)-based therapy [ 5 , 12 ]. However, while PD-L1 expression and tumor mutational burden (TMB) have been identified as predictive biomarkers for outcomes with ICIs in other indications, including non-small-cell lung cancer (NSCLC) [ 13 , 14 ] and metastatic triple-negative breast cancer [ 15 ], there is no clear evidence from randomized phase 3 studies that PD-L1 expression or TMB predicts outcomes with immunochemotherapy in ES-SCLC. Analyses of the CASPIAN trial [ 16 ], the IMpower133 trial of atezolizumab plus EP versus EP [ 17 , 18 ], and the KEYNOTE-604 trial of pembrolizumab plus EP versus EP [ 19 ] showed that tissue TMB (tTMB) was not associated with outcomes with immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

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Molecular classification and biomarkers of outcome with immunotherapy in extensive-stage small-cell lung cancer: analyses of the CASPIAN phase 3 study

Xie,

Vuko,

Rodriguez-Canales

et al. 2024

Mol Cancer

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Background We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with durvalumab (D) + tremelimumab (T) + etoposide-platinum (EP), D + EP, or EP in the randomized phase 3 CASPIAN trial. Methods 805 treatment-naïve patients with ES-SCLC were randomized (1:1:1) to receive D + T + EP, D + EP, or EP. The primary endpoint was overall survival (OS). Patients were required to provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening, if these samples existed. After assessment for programmed cell death ligand-1 expression and tissue tumor mutational burden, residual tissue was used for additional molecular profiling including by RNA sequencing and immunohistochemistry. Results In 182 patients with transcriptional molecular subtyping, OS with D ± T + EP was numerically highest in the SCLC-inflamed subtype (n = 10, median 24.0 months). Patients derived benefit from immunotherapy across subtypes; thus, additional biomarkers were investigated. OS benefit with D ± T + EP versus EP was greater with high versus low CD8A expression/CD8 cell density by immunohistochemistry, but with no additional benefit with D + T + EP versus D + EP. OS benefit with D + T + EP versus D + EP was associated with high expression of CD4 (median 25.9 vs. 11.4 months) and antigen-presenting and processing machinery (25.9 vs. 14.6 months) and MHC I and II (23.6 vs. 17.3 months) gene signatures, and with higher MHC I expression by immunohistochemistry. Conclusions These findings demonstrate the tumor microenvironment is important in mediating better outcomes with D ± T + EP in ES-SCLC, with canonical immune markers associated with hypothesized immunotherapy mechanisms of action defining patient subsets that respond to D ± T. Trial registration ClinicalTrials.gov, NCT03043872.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular classification and biomarkers of outcome with immunotherapy in extensive-stage small-cell lung cancer: analyses of the CASPIAN phase 3 study

Xie,

Vuko,

Rodriguez-Canales

et al. 2024

Mol Cancer

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“…Furthermore, radiotherapy could kill tumor cells and expose new antigens, which may also lead to the death of immune cells in the chemoradiotherapy area and reduce blood volume exposure ( 20 - 22 ). In addition, maintaining lymph node integrity before immunotherapy may improve the efficacy of immunotherapy ( 23 , 24 ). Therefore, immunotherapy prior to or concurrent with definitive chemoradiotherapy may bring superior therapeutic benefits than may immunotherapy following definitive chemoradiotherapy.…”

Section: Discussionmentioning

confidence: 99%

A retrospective comparative cohort study: concurrent versus consolidative immunotherapy with chemoradiotherapy in EGFR- or ALK-negative unresectable stage III non-small cell lung cancer

Wu,

Guo,

Meng

et al. 2023

Transl Lung Cancer Res

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Background The treatment of stage III non-small cell lung cancer (NSCLC) is very challenging because it is a heterogeneous group of diseases. This study was to investigative whether concurrent immunotherapy with chemoradiotherapy was associated with improved outcomes compared to consolidative immunotherapy following chemoradiotherapy in patients with unresectable stage III NSCLC, which may provide evidence-based medical evidence for the treatment of stage III NSCLC. Methods A total of 78 epidermal growth factor receptor or anaplastic lymphoma kinase (EGFR/ALK) negative patients from the clinical database of the shanghai pulmonary hospital with locally advanced unresectable NSCLC and we evaluated them for baseline clinical factors, follow-up. Patients underwent concurrent immunotherapy with chemoradiotherapy or consolidative immunotherapy after chemoradiotherapy. Patients were classified based on initial site of progression (primary versus non-primary site). The study endpoints were progression-free survival (PFS) and time to death or distant metastasis (TDDM). Cox proportional hazards analysis was used to assess the factors affecting PFS and TDDM. Results The median follow-up time for both groups was 26 months, and there was no significant difference in baseline clinical characteristics (P>0.05). The patients receiving concurrent immunotherapy (n=36) had a longer PFS than those receiving consolidative immunotherapy (n=42) (median 32.4 vs. 15.5 months; P<0.01). The TDDM was also longer in patients with concurrent immunotherapy than those with consolidative immunotherapy (median 57.3 vs. 31.0 months; P=0.01). Furthermore, in a subset of patients with initial site of progression at a non-primary-site, patients undergoing concurrent immunotherapy had longer PFS than those undergoing consolidative immunotherapy (median 22.7 vs. 11.9 months; P=0.03). Conclusions Concurrent immunotherapy with chemoradiotherapy may be associated with improved disease progression outcomes as compared to consolidative immunotherapy following chemoradiotherapy.

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“…[6][7][8][9] As a key point of PD-1/PD-L1 inhibition therapy, the level of PD-L1 expression has been found to influence therapeutic outcomes. [42][43][44][45][46] For instance, the evidence indicates that tumors exhibiting higher levels of PD-L1 expression tend to exhibit a more favorable response to PD-1/PD-L1 inhibition therapy. This underscores the significance of PD-L1 expression as a predictive biomarker for the effectiveness of PD-1/PD-L1 inhibitors.…”

Section: Circrnasmentioning

confidence: 99%

“…This underscores the significance of PD-L1 expression as a predictive biomarker for the effectiveness of PD-1/PD-L1 inhibitors. [42][43][44][45][46] Consequently, in certain scenarios, the identification of tumors with low PD-L1 expression and subsequent efforts to elevate its expression may potentially broaden the population of patients who can benefit from PD-1/PD-L1 inhibitor treatment. 33,47 Furthermore, bolstering the immune system's positive regulation can expedite the therapeutic impact of PD-1/PD-L1 inhibitors.…”

Section: Circrnasmentioning

confidence: 99%

Synergistic Immunoregulation: harnessing CircRNAs and PiRNAs to Amplify PD-1/PD-L1 Inhibition Therapy

Han,

Rao,

Zhou

et al. 2024

IJN

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The utilization of PD-1/PD-L1 inhibitors marks a significant advancement in cancer therapy. However, the efficacy of monotherapy is still disappointing in a substantial subset of patients, necessitating the exploration of combinational strategies. Emerging from the promising results of the KEYNOTE-942 trial, RNA-based therapies, particularly circRNAs and piRNAs, have distinguished themselves as innovative sensitizers to immune checkpoint inhibitors (ICIs). These non-coding RNAs, notable for their stability and specificity, were once underrecognized but are now known for their crucial roles in regulating PD-L1 expression and bolstering anti-cancer immunity. Our manuscript offers a comprehensive analysis of selected circRNAs and piRNAs, elucidating their immunomodulatory effects and mechanisms, thus underscoring their potential as ICIs enhancers. In conjunction with the recent Nobel Prize-awarded advancements in mRNA vaccine technology, our review highlights the transformative implications of these findings for cancer treatment. We also discuss the prospects of circRNAs and piRNAs in future therapeutic applications and research. This study pioneers the synergistic application of circRNAs and piRNAs as novel sensitizers to augment PD-1/PD-L1 inhibition therapy, demonstrating their unique roles in regulating PD-L1 expression and modulating immune responses. Our findings offer a groundbreaking approach for enhancing the efficacy of cancer immunotherapy, opening new avenues for treatment strategies. This abstract aims to encapsulate the essence of our research and the burgeoning role of these non-coding RNAs in enhancing PD-1/ PD-L1 inhibition therapy, encouraging further investigation into this promising field.

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PD-L1 expression on tumor cells as a potential predictive biomarker for patients with unresectable stage III non-small cell lung cancer treated with chemoradiotherapy followed by durvalumab

Abstract: PD-L1 expression on tumor cells as a potential predictive biomarker for patients with unresectable stage III non-small cell lung cancer treated with chemoradiotherapy followed by durvalumab maintenance treatment. Transl Cancer Res 2023.

Cited by 4 publications

References 12 publications

Molecular classification and biomarkers of outcome with immunotherapy in extensive-stage small-cell lung cancer: analyses of the CASPIAN phase 3 study

Molecular classification and biomarkers of outcome with immunotherapy in extensive-stage small-cell lung cancer: analyses of the CASPIAN phase 3 study

A retrospective comparative cohort study: concurrent versus consolidative immunotherapy with chemoradiotherapy in EGFR- or ALK-negative unresectable stage III non-small cell lung cancer

Synergistic Immunoregulation: harnessing CircRNAs and PiRNAs to Amplify PD-1/PD-L1 Inhibition Therapy

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