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Immunotherapy with Checkpoint Inhibitors for Non-small Cell Lung Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 March 2025) | Viewed by 22177

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Dr. Alessandro Inno

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Unità Operativa di Oncologia, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar di Valpolicella (VR), Italy
Interests: immunotherapy; lung cancer; cardio-oncology; immune-related adverse events
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Dr. Diego Signorelli

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Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
Interests: lung cancer; immunotherapy; malignant pleural mesothelioma; thymic malignancies
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Immune checkpoint inhibitors (ICIs) have deeply changed the landscape of treatment for non-small cell lung cancer, in both early- and advanced-stage disease. However, several challenging questions remain, such as how to optimize neoadjuvant/adjuvant ICI-based treatment, how to add novel ICIs under investigation to the current standard of care, how to integrate ICIs with other immunotherapy approaches, how to improve combinations of ICIs with other systemic therapies, how to overcome primary and acquired resistance to ICIs, how to improve the selection of potentially responsive patients through the development of reliable predictive biomarkers, and how to use ICIs in special populations (i.e., those with brain metastases, oncogene-addicted tumors, pre-existing autoimmune disease, interstitial lung disease or idiopathic fibrosis, those who develop severe immune-related adverse events, etc.).

This Special Issue of Cancers encompasses new research articles and timely reviews on all aspects of immune checkpoint blockade in non-small cell lung cancer.

Dr. Alessandro Inno
Dr. Diego Signorelli
Guest Editors

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Keywords

immune-checkpoint inhibitors
non-small cell lung cancer
neoadjuvant therapy
adjuvant therapy
primary resistance
acquired resistance
biomarkers
immune-related adverse events

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Published Papers (9 papers)

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Research

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14 pages, 2035 KiB

Open AccessArticle

Correlation Between Body Mass Index and Immunotherapy Response in Advanced NSCLC

by Walid Shalata, Itamar Gothelf, Yulia Dudnik, Ahron Yehonatan Cohen, Ashraf Abu Jama, Tom Liba, Ofir Dan, Lena Tourkey, Sondos Shalata, Abed Agbarya, Amichay Meirovitz and Alexander Yakobson

Cancers 2025, 17(7), 1149; https://doi.org/10.3390/cancers17071149 - 29 Mar 2025

Viewed by 524

Abstract

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced non-small cell lung cancer (NSCLC). Emerging evidence suggests a potential association between elevated body mass index (BMI) and enhanced ICI efficacy, yet this relationship remains inconclusive and warrants further investigation. This study aims to evaluate the impact of BMI on treatment efficacy and survival outcomes in advanced NSCLC patients treated with first-line ICI therapy. Methods: A retrospective study was conducted at a multi-center registry to evaluate the impact of baseline BMI on overall survival (OS) and progression-free survival (PFS) in patients with stage IV NSCLC who received first-line ICI therapies. Treatment regimens included pembrolizumab or the combination of ipilimumab and nivolumab, administered either as monotherapy or in combination with chemotherapy, at the oncology department between January 2018 and December 2023. BMI was categorized according to the World Health Organization (WHO) classification, and OS and PFS were evaluated using Kaplan–Meier survival analysis and the Cox proportional hazards regression model. Results: Among 346 patients, 12.72% were underweight, 45.38% normal weight, 29.19% overweight, and 12.72% obese. Overweight and obese patients were more likely to receive pembrolizumab (p = 0.039) and less likely to undergo chemotherapy (p = 0.012). No significant differences in median overall survival (OS, log-rank: p = 0.155) or progression-free survival (PFS, log-rank: p = 0.370) were observed across BMI categories. However, differences emerged upon further analysis of PD-L1 levels (OS, log-rank: p = 0.029; PFS, log-rank: p = 0.044), additional chemotherapy (OS, log-rank: p = 0.009; PFS, log-rank: p = 0.021), type of immune checkpoint inhibitor (OS, log-rank: p < 0.001; PFS, log-rank: p < 0.001), and histologic diagnosis (OS, log-rank: p = 0.011; PFS, log-rank: p = 0.003). Conclusions: BMI was not an independent predictor of survival outcomes in advanced NSCLC treated with ICI. Incorporating BMI with other patient-specific factors into personalized immunotherapy strategies highlights the importance of tailored approaches to improve patient care and clinical outcomes. Full article

(This article belongs to the Special Issue Immunotherapy with Checkpoint Inhibitors for Non-small Cell Lung Cancer)

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19 pages, 1401 KiB

Open AccessArticle

Site-Specific Response and Resistance Patterns in Patients with Advanced Non-Small-Cell Lung Cancer Treated with First-Line Systemic Therapy

by Lauren Julia Brown, Julie Ahn, Bo Gao, Harriet Gee, Adnan Nagrial, Eric Hau and Inês Pires da Silva

Cancers 2024, 16(11), 2136; https://doi.org/10.3390/cancers16112136 - 4 Jun 2024

Cited by 2 | Viewed by 2068

Abstract

Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy. In NSCLC, the impact of the distribution of metastatic sites and the response to systemic therapy combinations remain poorly understood. In a retrospective cohort study of patients with unresectable stage III/IV NSCLC who received first-line systemic therapy, we sought to assess the association between the site of metastases with patterns of response and progression. Data regarding demographics, tumour characteristics (including site, size, and volume of metastases), treatment, and outcomes were examined at two cancer care centres. The endpoints included organ site-specific response rate, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Two-hundred and eighty-five patients were included in the analysis. In a multivariate analysis, patients with bone metastases had a reduced ORR, PFS, and OS. Primary resistance was also more likely in patients with bone metastases. Patients with bone or liver metastases had a shorter OS when receiving ICIs with or without chemotherapy, but not with chemotherapy alone, suggesting an immunological basis for therapeutic resistance. A directed assessment of the tumour microenvironment in these locations and a deeper understanding of the drivers of organ-specific resistance to immunotherapy are critical to optimise novel combination therapies and sequencing in these patients. Full article

(This article belongs to the Special Issue Immunotherapy with Checkpoint Inhibitors for Non-small Cell Lung Cancer)

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14 pages, 1692 KiB

Open AccessArticle

First-Line Chemoimmunotherapy versus Sequential Platinum-Based Chemotherapy Followed by Immunotherapy in Patients with Non-Small Cell Lung Cancer with ≤49% Programmed Death-Ligand 1 Expression: A Real-World Multicenter Retrospective Study

by Keiko Tanimura, Takayuki Takeda, Nobutaka Kataoka, Akihiro Yoshimura, Kentaro Nakanishi, Yuta Yamanaka, Hiroshige Yoshioka, Ryoichi Honda, Kiyoaki Uryu, Mototaka Fukui, Yusuke Chihara, Shota Takei, Hayato Kawachi, Tadaaki Yamada, Nobuyo Tamiya, Naoko Okura, Takahiro Yamada, Junji Murai, Shinsuke Shiotsu, Takayasu Kurata and Koichi Takayama Show full author list Hide full author list

Cancers 2023, 15(20), 4988; https://doi.org/10.3390/cancers15204988 - 14 Oct 2023

Cited by 1 | Viewed by 2025

Abstract

Background: The long overall survival (OS) observed among patients with non-small cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression in chemoimmunotherapy (CIT) groups in previous phase III trials suggests the limited efficacy of CIT among the subgroup with ≤49% PD-L1 expression on tumor cells. Hence, sequential treatment with first-line platinum-based chemotherapy followed by second-line immune checkpoint inhibitor treatment (SEQ) is an option. This study examined whether first-line CIT would provide better outcomes than SEQ in patients with advanced NSCLC with ≤49% PD-L1 expression. Methods: This retrospective study evaluated patients with untreated NSCLC who received first-line CIT or SEQ at nine hospitals in Japan. OS, progression-free survival (PFS), PFS-2 (the time from first-line treatment to progression to second-line treatment or death), and other related outcomes were evaluated between the CIT and SEQ groups. Results: Among the 305 enrolled patients, 234 eligible patients were analyzed: 165 in the CIT group and 69 in the SEQ group. The COX proportional hazards model suggested a significant interaction between PD-L1 expression and OS (p = 0.006). OS in the CIT group was significantly longer than that in the SEQ group in the 1–49% PD-L1 expression subgroup but not in the <1% PD-L1 expression subgroup. Among the subgroup with 1–49% PD-L1 expression, the CIT group exhibited longer median PFS than the SEQ group (CIT: 9.3 months (95% CI: 6.7–14.8) vs. SEQ:5.5 months (95% CI: 4.5–6.1); p < 0.001), while the median PFS in the CIT group was not statistically longer than the median PFS-2 in the SEQ group (p = 0.586). There was no significant difference between the median PFS in the CIT and SEQ groups among the <1% PD-L1 expression subgroup (p = 0.883); the median PFS-2 in the SEQ group was significantly longer than the median PFS in the CIT group (10.5 months (95% CI: 5.9–15.3) vs. 6.4 months (95% CI: 4.9–7.5); p = 0.024). Conclusions: CIT is recommended for patients with NSCLC with 1–49% PD-L1 expression because it significantly improved OS and PFS compared to SEQ. CIT had limited benefits in patients with <1% PD-L1 expression, and the median PFS-2 in the SEQ group was significantly longer than the median PFS in the CIT group. These findings will help physicians select the most suitable treatment option for patients with NSCLC, considering PD-L1 expressions. Full article

(This article belongs to the Special Issue Immunotherapy with Checkpoint Inhibitors for Non-small Cell Lung Cancer)

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18 pages, 1431 KiB

Open AccessArticle

Gene Expressions and High Lymphocyte Count May Predict Durable Clinical Benefits in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Immune Checkpoint Inhibitors

by Mette T. Mouritzen, Morten Ladekarl, Henrik Hager, Trine B. Mattesen, Julie B. Lippert, Malene S. Frank, Anne K. Nøhr, Ida B. Egendal and Andreas Carus

Cancers 2023, 15(18), 4480; https://doi.org/10.3390/cancers15184480 - 8 Sep 2023

Cited by 3 | Viewed by 1721

Abstract

Background: Not all patients with advanced non-small cell lung cancer (NSCLC) benefit from immune checkpoint inhibitors (ICIs). Therefore, we aimed to assess the predictive potential of gene expression profiling (GEP), peripheral immune cell counts, and clinical characteristics. Methods: The primary endpoint of this prospective, observational study was a durable clinical benefit (DCB) defined as progression-free survival >6 months. In a subgroup with histological biopsies of sufficient quality (n = 25), GEP was performed using the nCounter^® PanCancer IO 360 panel. Results: DCB was observed in 49% of 123 included patients. High absolute lymphocyte count (ALC) and absence of liver metastases were associated with DCB (OR = 1.95, p = 0.038 and OR = 0.36, p = 0.046, respectively). GEP showed clustering of differentially expressed genes according to DCB, and a strong association between PD-L1 assessed by GEP (CD274) and immunohistochemistry (IHC) was observed (p = 0.00013). The TGF-β, dendritic cell, and myeloid signature scores were higher for patients without DCB, whereas the JAK/STAT loss signature scores were higher for patients with DCB (unadjusted p-values < 0.05). Conclusions: ALC above 1.01 × 10⁹/L and absence of liver metastases were significantly associated with DCB in ICI-treated patients with NSCLC. GEP was only feasible in 20% of the patients. GEP-derived signatures may be associated with clinical outcomes, and PD-L1 could be assessed by GEP rather than IHC. Full article

(This article belongs to the Special Issue Immunotherapy with Checkpoint Inhibitors for Non-small Cell Lung Cancer)

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Review

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33 pages, 3441 KiB

Open AccessReview

CD47: The Next Frontier in Immune Checkpoint Blockade for Non-Small Cell Lung Cancer

by Asa P. Y. Lau, Sharon S. Khavkine Binstock and Kelsie L. Thu

Cancers 2023, 15(21), 5229; https://doi.org/10.3390/cancers15215229 - 31 Oct 2023

Cited by 8 | Viewed by 5093

Abstract

The success of PD-1/PD-L1-targeted therapy in lung cancer has resulted in great enthusiasm for additional immunotherapies in development to elicit similar survival benefits, particularly in patients who do not respond to or are ineligible for PD-1 blockade. CD47 is an immunosuppressive molecule that binds SIRPα on antigen-presenting cells to regulate an innate immune checkpoint that blocks phagocytosis and subsequent activation of adaptive tumor immunity. In lung cancer, CD47 expression is associated with poor survival and tumors with EGFR mutations, which do not typically respond to PD-1 blockade. Given its prognostic relevance, its role in facilitating immune escape, and the number of agents currently in clinical development, CD47 blockade represents a promising next-generation immunotherapy for lung cancer. In this review, we briefly summarize how tumors disrupt the cancer immunity cycle to facilitate immune evasion and their exploitation of immune checkpoints like the CD47–SIRPα axis. We also discuss approved immune checkpoint inhibitors and strategies for targeting CD47 that are currently being investigated. Finally, we review the literature supporting CD47 as a promising immunotherapeutic target in lung cancer and offer our perspective on key obstacles that must be overcome to establish CD47 blockade as the next standard of care for lung cancer therapy. Full article

(This article belongs to the Special Issue Immunotherapy with Checkpoint Inhibitors for Non-small Cell Lung Cancer)

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23 pages, 756 KiB

Open AccessReview

Immunotherapy through the Lens of Non-Small Cell Lung Cancer

by Robyn Stanley, Saoirse Flanagan, David O’ Reilly, Ella Kearney, Jarushka Naidoo and Catríona M. Dowling

Cancers 2023, 15(11), 2996; https://doi.org/10.3390/cancers15112996 - 30 May 2023

Cited by 4 | Viewed by 4178

Abstract

Immunotherapy has revolutionised anti-cancer treatment in solid organ malignancies. Specifically, the discovery of CTLA-4 followed by PD-1 in the early 2000s led to the practice-changing clinical development of immune checkpoint inhibitors (ICI). Patients with lung cancer, including both small cell (SCLC) and non-small cell lung cancer (NSCLC), benefit from the most commonly used form of immunotherapy in immune checkpoint inhibitors (ICI), resulting in increased survival and quality of life. In NSCLC, the benefit of ICIs has now extended from advanced NSCLC to earlier stages of disease, resulting in durable benefits and the even the emergence of the word ‘cure’ in long term responders. However, not all patients respond to immunotherapy, and few patients achieve long-term survival. Patients may also develop immune-related toxicity, a small percentage of which is associated with significant mortality and morbidity. This review article highlights the various types of immunotherapeutic strategies, their modes of action, and the practice-changing clinical trials that have led to the widespread use of immunotherapy, with a focus on ICIs in NSCLC and the current challenges associated with advancing the field of immunotherapy. Full article

(This article belongs to the Special Issue Immunotherapy with Checkpoint Inhibitors for Non-small Cell Lung Cancer)

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12 pages, 2315 KiB

Open AccessSystematic Review

Surgical Outcomes After Neoadjuvant Chemo-Immunotherapy for Stage III NSCLC: A Systematic Review and Meta-Analysis

by Claudia Bardoni, Matteo Chiari, Luca Bertolaccini, Cristina Diotti, Alessia De Fabiani, Giuseppe Nicolosi, Antonio Mazzella, Monica Casiraghi and Lorenzo Spaggiari

Cancers 2025, 17(9), 1426; https://doi.org/10.3390/cancers17091426 - 24 Apr 2025

Viewed by 284

Abstract

Background. To comprehensively assess surgical safety, we conducted a meta-analysis on neoadjuvant chemo-immunotherapy for NSCLC. Methods. This systematic review and meta-analysis followed PRISMA guidelines (PROSPERO: CRD42023470682). A literature search and data extraction were performed independently by two reviewers. Primary outcomes included surgical feasibility and safety. Pooled prevalence proportions with 95% confidence intervals (CIs) were calculated. A random-effects model was applied if heterogeneity was significant (I² ≥ 50% or p ≥ 0.10). Sensitivity analysis assessed robustness and publication bias was examined using funnel plots and Egger’s test (p < 0.05 significant). Results. Fifteen studies were included, analyzing different immune checkpoint inhibitors with 2–3 cycles of neoadjuvant therapy. Surgery occurred 10–45 days post-treatment. The pooled surgical resection rate was 98.96% (95% CI: 98.93–98.98, I² = 0%). The conversion to thoracotomy rate was 16.49% (95% CI: 12.95–20.03, I² = 89.74%). Minimally invasive surgery was performed in 53.62% (95% CI: 49.53–57.72, I² = 95.92%). The median surgical delay was 28.53 days (95% CI: 23.66–33.41, I² = 0%). Surgical time averaged 165.27 min (95% CI: 112.32–218.22, I² = 0%), with mean blood loss of 182.0 mL (95% CI: 134.0–230.0, I² = 0%). Conclusions. Surgical intervention following neoadjuvant chemo-immunotherapy for NSCLC is feasible and safe, with a high resection rate (98.96%). Variability in minimally invasive surgery and conversion rates suggests differences in surgical approaches, while surgical time, blood loss, and delay showed consistency. These findings highlight the need for a multidisciplinary approach to optimize patient outcomes. Full article

(This article belongs to the Special Issue Immunotherapy with Checkpoint Inhibitors for Non-small Cell Lung Cancer)

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15 pages, 1816 KiB

Open AccessSystematic Review

Progress in Serial Imaging for Prognostic Stratification of Lung Cancer Patients Receiving Immunotherapy: A Systematic Review and Meta-Analysis

by Hwa-Yen Chiu, Ting-Wei Wang, Ming-Sheng Hsu, Heng-Shen Chao, Chien-Yi Liao, Chia-Feng Lu, Yu-Te Wu and Yuh-Ming Chen

Cancers 2024, 16(3), 615; https://doi.org/10.3390/cancers16030615 - 31 Jan 2024

Cited by 1 | Viewed by 2063

Abstract

Immunotherapy, particularly with checkpoint inhibitors, has revolutionized non-small cell lung cancer treatment. Enhancing the selection of potential responders is crucial, and researchers are exploring predictive biomarkers. Delta radiomics, a derivative of radiomics, holds promise in this regard. For this study, a meta-analysis was conducted that adhered to PRISMA guidelines, searching PubMed, Embase, Web of Science, and the Cochrane Library for studies on the use of delta radiomics in stratifying lung cancer patients receiving immunotherapy. Out of 223 initially collected studies, 10 were included for qualitative synthesis. Stratifying patients using radiomic models, the pooled analysis reveals a predictive power with an area under the curve of 0.81 (95% CI 0.76–0.86, p < 0.001) for 6-month response, a pooled hazard ratio of 4.77 (95% CI 2.70–8.43, p < 0.001) for progression-free survival, and 2.15 (95% CI 1.73–2.66, p < 0.001) for overall survival at 6 months. Radiomics emerges as a potential prognostic predictor for lung cancer, but further research is needed to compare traditional radiomics and deep-learning radiomics. Full article

(This article belongs to the Special Issue Immunotherapy with Checkpoint Inhibitors for Non-small Cell Lung Cancer)

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14 pages, 3992 KiB

Open AccessSystematic Review

PD-1/PD-L1 Inhibitors plus Chemotherapy Versus Chemotherapy Alone for Resectable Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

by Eric Pasqualotto, Francisco Cezar Aquino de Moraes, Matheus Pedrotti Chavez, Maria Eduarda Cavalcanti Souza, Anna Luíza Soares de Oliveira Rodrigues, Rafael Oliva Morgado Ferreira, Lucca Moreira Lopes, Artur Menegaz de Almeida, Marianne Rodrigues Fernandes and Ney Pereira Carneiro dos Santos

Cancers 2023, 15(21), 5143; https://doi.org/10.3390/cancers15215143 - 26 Oct 2023

Cited by 15 | Viewed by 3241

Abstract

Background: The benefit of adding programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors to the treatment of early-stage non-small cell lung cancer (NSCLC), both neoadjuvant therapy (NAT) and adjuvant therapy (AT), is not yet fully elucidated. Methods: We searched PubMed, Embase, and Cochrane databases for randomized controlled trials (RCT) that investigated PD-1/PD-L1 inhibitors plus chemotherapy for resectable stage NSCLC. We computed hazard ratios (HRs) or odds ratios (ORs) for binary endpoints, with 95% confidence intervals (CIs). Results: A total of seven RCTs comprising 3915 patients with resectable stage NSCLC were randomized to chemotherapy with or without PD-1/PD-L1 inhibitors as NAT or AT. As NAT, the PD-1/PD-L1 inhibitors plus chemotherapy group demonstrated significantly improved overall survival (HR 0.66; 95% CI 0.51–0.86) and event-free survival (HR 0.53; 95% CI 0.43–0.67) compared with the chemotherapy alone group. There was a significant increase in favor of the PD-1/PD-L1 inhibitors plus chemotherapy group for major pathological response (OR 6.40; 95% CI 3.86–10.61) and pathological complete response (OR 8.82; 95% CI 4.51–17.26). Meanwhile, as AT, disease-free survival was significant in favor of the PD-1/PD-L1 inhibitors plus chemotherapy group (HR 0.78; 95% CI 0.69–0.90). Conclusions: In this comprehensive systematic review and meta-analysis of RCTs, the incorporation of PD-1/PD-L1 inhibitors alongside chemotherapy offers a promising prospect for reshaping the established treatment paradigms for patients diagnosed with resectable stages of NSCLC. Moreover, our analyses support that neoadjuvant administration with these agents should be encouraged, in light of the fact that it was associated with an increased survival and pathological response, at the expense of a manageable safety profile. Full article

(This article belongs to the Special Issue Immunotherapy with Checkpoint Inhibitors for Non-small Cell Lung Cancer)

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