Immunotherapy Moves to the Early-Stage Setting in Non-Small Cell Lung Cancer: Emerging Evidence and the Role of Biomarkers

Mielgo-Rubio, Xabier; Calvo, Virginia; Luna, J.; Remón, Jordi; Martín, M.; Berraondo, Pedro; Jarabo, José Ramón; Higuera, Oliver; Conde, Esther; Castro, Javier de; Provencio, Mariano; Trancho, Florentino Hernando; López‐Ríos, Fernando; Couñago, Felipe

doi:10.3390/cancers12113459

Cited by 10 publications

(7 citation statements)

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“…Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic scenario against advanced lung cancers and have been gradually applied for the treatment of early-stage lung cancers. 8 Preliminary small-sample studies have revealed that most high-risk GGOs in patients with stage I or advanced non-small cell lung cancer (NSCLC) have no diameter reduction after receiving ICIs. 9 10 Therefore, exploring the distribution of predictive biomarkers of immunotherapy in patients with MPLC is important to evaluate the application value of ICIs in this group of patients.…”

Section: Introductionmentioning

confidence: 99%

Genomic profiles and their associations with TMB, PD-L1 expression, and immune cell infiltration landscapes in synchronous multiple primary lung cancers

Zhao

et al. 2021

J Immunother Cancer

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BackgroundDiagnosing and treating patients with multiple primary lung cancers (MPLCs) bring challenges to the clinic, and the preliminary evidence has revealed unsatisfying outcomes after targeted therapy and immunotherapy. Therefore, we surveyed genomic profiles of MPLCs and their possible associations with tumor mutation burden (TMB), programmed death-ligand 1 (PD-L1), and the immune cell infiltration landscape.Materials and methodsA total of 112 patients with MPLCs with surgically resected 294 tumors were eligible, and 255 tumors were sequenced using a 1021-gene panel. Immunohistochemistry staining was performed to evaluate the levels of PD-L1 and the density of CD3+/CD8+ tumor-infiltrating lymphocytes (TILs), and CD68+/CD163+ tumor-associated macrophages (TAMs) at the central tumor and invasive margin, and immunotypes were generated based on those variables.ResultsMPLCs often occur simultaneously in non-smoker women younger than 60 years and manifest as ground-glass opacities, adenocarcinoma, and stage I lung lesions. The most frequently mutated genes in the 255 tumors were EGFR (56%), ERBB2 (12%), TP53 (12%), BRAF (11%), RBM10 (11%), and KRAS (9%). We found 87 (77.7%) patients with diverse genomic profiles, and 61 (54.5%) who shared at least one putative driver gene between different tumors presented more aggressive tumors. The median TMB was 1.92 mutations/Mb, and high-TMB (≥3) lesions often harbored EGFRL858R/KRASG12C/RBM10/TP53/LRP1B mutations or wild-type ERBB2. Only 8.1% of patients and 3.9% of lesions were positive for PD-L1 on tumor cells, and this positivity was more frequent in LRP1B/TP53-mutant tumors. EGFRL858R/RBM10/TP53 mutations were positively associated with specific immune cells and an inflamed immunotype, but ERBB2 mutations were negatively correlated. TMB, CD3+TILs, and CD68+/CD163+ TAMs presented with significant heterogeneity among paired tumors (all kappa <0.2), but PD-L1 and CD8 +TILs were more uniformly present in tumor pairs.ConclusionMPLCs are driven by different molecular events and often exhibit low TMB, low PD-L1, and a heterogeneous immune infiltration landscape. Specific genomic profiles are associated with TMB and the tumor immune microenvironmental landscape in MPLCs. Our findings can help to guide MPLCs diagnoses and to identify patient populations that may benefit from immunotherapy and targeted therapy.

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Section: Introductionmentioning

confidence: 99%

Genomic profiles and their associations with TMB, PD-L1 expression, and immune cell infiltration landscapes in synchronous multiple primary lung cancers

Zhao

et al. 2021

J Immunother Cancer

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“…In both cases, concurrent or sequential therapy, a consolidation with durvalumab, an immune checkpoint inhibitor (ICI), is approved according to the results of PACIFIC trial ( Antonia et al, 2017 ). ICIs are currently being evaluated as neoadjuvant/adjuvant therapy in combination with standard treatments ( Mielgo-Rubio et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

The Expression of Programmed Death Ligand 1 and Vimentin in Resected Non-Metastatic Non-Small-Cell Lung Cancer: Interplay and Prognostic Effects

Bravaccini

Bronte

Petracci

et al. 2021

Front. Cell Dev. Biol.

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Programmed death ligand 1 (PD-L1) is an immune checkpoint with a role in cancer-related immune evasion. It is a target for cancer immunotherapy and its expression is detected for the use of some immune checkpoint inhibitors in advanced non-small cell lung cancer patients (NSCLC). Vimentin is a key component of the epithelial-to-mesenchymal transition phenotype. Its expression has negative prognostic effects in NSCLC. In this study, we retrospectively evaluated PD-L1 and vimentin expression in tumor cells, immune infiltrate and PD-L1 positive immune infiltrate via immunohistochemistry in tissue samples from resected non-metastatic NSCLC patients. We explored the interplay between PD-L1 and vimentin expression through Spearman’s correlation test. We performed univariate analysis through the Cox models for demographic and clinico-pathological variables, and also for dichotomized biomarkers, i.e., PD-L1 and vimentin in tumor cells, both with 1 and 50% cutoffs. We used Kaplan-Meier method to estimate the overall survival, comparing both vimentin and PD-L1 positive patients with all the others. We found a weak positive correlation between PD-L1 and vimentin expressions in tumor cells (r = 0.25; p = 0.001). We also observed a statistically not significant trend towards a shorter overall survival in patients with both PD-L1 and vimentin expression >1% (HR = 1.36; 95% CI: 0.96–1.93, p = 0.087). In conclusion, these findings suggest that interplay between PD-L1 and vimentin may exist in non-metastatic NSCLC patients and the positivity of both markers in tumor tissue is associated with a trend towards a worse prognosis.

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“…Thus, it is urgently needed to explore novel treatment strategies to reduce the tumor burden and improve the pCR rate, and prolong the survival of LSqCC patients whose tumors are potentially unresectable. Emerging data from clinical trials have demonstrated that immunotherapy substantially improves the survival of patients with late-stage NSCLC, including advanced LSqCC (5,6,26), and has also clinical promise in early-stage NSCLC (27). However, in the real-world setting, studies specifically investigating neoadjuvant immunotherapy followed by surgery for locally-advanced and surgically difficult LSqCC are lacking.…”

Section: Discussionmentioning

confidence: 99%

Neoadjuvant immunotherapy facilitates resection of surgically-challenging lung squamous cell cancer

Xu¹,

Yang²,

Ma³

et al. 2021

J Thorac Dis

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Background: Locally-advanced lung squamous cell carcinoma represents a special subset that is challenging to resect completely with surgery alone. Immunotherapy has achieved great success in treating late-stage lung cancer. However, whether neoadjuvant immunotherapy can facilitate resection of initially locally-advanced and surgically-difficult locally-advanced lung squamous cell carcinoma remains to be investigated. Methods:We retrospectively collected clinical records of locally-advanced lung squamous cell carcinoma patients who received neoadjuvant immunotherapy followed by surgery between 2018 and 2020 at a large academic thoracic cancer center.Results: A total of 23 patients (22 males, 1 female) with locally-advanced locally-advanced lung squamous cell carcinoma were included, initially clinically staged at IIIA (16, 69.6%), IIIB (n=4, 17.4%), IIB (n=2, 8.7%) and IIIC (n=1, 4.3%). The median interval between final treatment to surgery was 36 days (range, 25-93 days), without treatment-related delay in surgery. The neoadjuvant treatment resulted in a high rate of radical resection (n=20, 87.0%). The final histopathological examination demonstrated 6 (26.1%) cases with pathological complete response and 8 (34.8%) with pathological major response. Comparing with the computed tomography scan-based response, we observed a very low consistency (weighted kappa =0.122, P=0.315) between the computed tomography scan-based and final pathological evaluation. The median follow-up time was 510 days (range, 217-920 days). At the end of the follow-up, 1 patient died.Conclusions: Our findings showed the clinical promise of neoadjuvant immunotherapy plus surgery for locally-advanced lung squamous cell carcinoma. Computed tomography scan displays a poor role in assessing the resectability after neoadjuvant immunotherapy.

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Immunotherapy Moves to the Early-Stage Setting in Non-Small Cell Lung Cancer: Emerging Evidence and the Role of Biomarkers

Cited by 10 publications

References 117 publications

Genomic profiles and their associations with TMB, PD-L1 expression, and immune cell infiltration landscapes in synchronous multiple primary lung cancers

Genomic profiles and their associations with TMB, PD-L1 expression, and immune cell infiltration landscapes in synchronous multiple primary lung cancers

The Expression of Programmed Death Ligand 1 and Vimentin in Resected Non-Metastatic Non-Small-Cell Lung Cancer: Interplay and Prognostic Effects

Neoadjuvant immunotherapy facilitates resection of surgically-challenging lung squamous cell cancer

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