Immune Checkpoint Inhibitors In Non-small Cell Lung Cancer Research Articles

Unveiling the influence of tumor and immune signatures on immune checkpoint therapy in advanced lung cancer.

This study investigates the variability among patients with non-small cell lung cancer (NSCLC) in their responses to immune checkpoint inhibitors (ICIs). Recognizing that patients with advanced-stage NSCLC rarely qualify for surgical interventions, it becomes crucial to identify biomarkers that influence responses to ICI therapy. We conducted an analysis of single-cell transcriptomes from 33 lung cancer biopsy samples, with a particular focus on 14 core samples taken before the initiation of palliative ICI treatment. Our objective was to link tumor and immune cell profiles with patient responses to ICI. We discovered that ICI non-responders exhibited a higher presence of CD4+ regulatory T cells, resident memory T cells, and TH17 cells. This contrasts with the diverse activated CD8+ T cells found in responders. Furthermore, tumor cells in non-responders frequently showed heightened transcriptional activity in the NF-kB and STAT3 pathways, suggesting a potential inherent resistance to ICI therapy. Through the integration of immune cell profiles and tumor molecular signatures, we achieved an discriminative power (area under the curve [AUC]) exceeding 95% in identifying patient responses to ICI treatment. These results underscore the crucial importance of the interplay between tumor and immune microenvironment, including within metastatic sites, in affecting the effectiveness of ICIs in NSCLC.

Unveiling the influence of tumor and immune signatures on immune checkpoint therapy in advanced lung cancer

This study investigates the variability among patients with non-small cell lung cancer (NSCLC) in their responses to immune checkpoint inhibitors (ICIs). Recognizing that patients with advanced-stage NSCLC rarely qualify for surgical interventions, it becomes crucial to identify biomarkers that influence responses to ICI therapy. We conducted an analysis of single-cell transcriptomes from 33 lung cancer biopsy samples, with a particular focus on 14 core samples taken before the initiation of palliative ICI treatment. Our objective was to link tumor and immune cell profiles with patient responses to ICI. We discovered that ICI non-responders exhibited a higher presence of CD4+ regulatory T cells, resident memory T cells, and TH17 cells. This contrasts with the diverse activated CD8+ T cells found in responders. Furthermore, tumor cells in non-responders frequently showed heightened transcriptional activity in the NF-kB and STAT3 pathways, suggesting a potential inherent resistance to ICI therapy. Through the integration of immune cell profiles and tumor molecular signatures, we achieved an discriminative power (area under the curve [AUC]) exceeding 95% in identifying patient responses to ICI treatment. These results underscore the crucial importance of the interplay between tumor and immune microenvironment, including within metastatic sites, in affecting the effectiveness of ICIs in NSCLC.

Immune checkpoint inhibitors in driver mutation-positive nonsmall cell lung cancer.

Immune checkpoint inhibitors (ICIs) and targeted therapies have changed the landscape of management of nonsmall cell lung cancer (NSCLC) dramatically. Whereas ICIs in NSCLC without specific driver mutations are well established it is unclear what the place of ICIs in driver mutation-positive NSCLC is. This review summarizes the current view on the use of ICIs in driver mutation-positive NSCLC. Immune checkpoint inhibition in combination with chemotherapy (and antiangiogenesis) in recurrent driver mutation-positive NSCLC after tyrosine kinase inhibitor therapy may be effective. Currently the role of immune checkpoint inhibitors in driver mutation-positive NSCLC is limited. They can in combination be applied in second and later line settings if no specific therapy is available.

Comparison of Short-term Efficacy of Neoadjuvant Immunotherapy Combined with Chemotherapy and Surgery Alone for Locally Advanced Resectable Non-small Cell Lung Cancer

Lung cancer is the cancer with the highest incidence and mortality rates in China, and non-small cell lung cancer (NSCLC) accounts for 80%-85% of all malignant lung tumors. Currently, surgical treatment remains the primary treatment modality for lung cancer. In recent years, the effectiveness of immune checkpoint inhibitors for NSCLC has become a consensus, and neoadjuvant immunochemotherapy (nICT) has shown promising efficacy and safety in early to intermediate stage NSCLC. However, there are fewer studies related to nICT for locally advanced NSCLC. This study aims to evaluate the efficacy and safety of nICT therapy in locally advanced resectable NSCLC. 85 confirmed resectable stage IIIA and IIIB patients treated in the Department of Thoracic Surgery, Second Hospital of Lanzhou University, from January 2021 to April 2024, were divided into the nICT group (n=32) and the surgery alone group (n=53). Clinical baseline data, perioperative indicators, postoperative complications, imaging response rate, pathological response rate, incidence of adverse events, and quality of life were compared between the two groups. There were no statistically significant differences in clinical baseline data between the two groups (P>0.05). Incidence of choosing thoracotomy was higher in the nICT group than in the surgery alone group (P=0.002). There were no significant differences in surgical time, intraoperative blood loss, number of dissected lymph nodes, duration of chest tube placement, postoperative hospital stay, and R0 resection rate between the two groups (P>0.05). The overall incidence of postoperative complications was 31.25% in the nICT group and 22.64% in the surgery alone group, with no statistically significant difference (P=0.380). In the nICT group, the objective response rate (ORR) was 84.38%, with 5 cases of complete response (CR)(15.63%), 22 cases of partial response (PR)(68.75%), 15 cases of pathological response rate (pCR)(46.88%), and 11 cases of major pathological reaponse (MPR) (34.38%). During nICT treatment, 12 cases (37.50%) experienced grade 3 treatment-related adverse events, no death induced by adverse events or immune related adverse events. Moreover, the symptoms of the patients were improved after nICT treatment. Neoadjuvant immunochemotherapy shows promising efficacy in locally advanced resectable NSCLC, with manageable treatment-related adverse events. It is a safe and feasible neoadjuvant treatment modality for locally advanced resectable NSCLC.

Molecular Characteristics and Pretreatment Neutrophil-to-Lymphocyte Ratio as Predictors of Durable Clinical Benefit from Immune Checkpoint Inhibition in Non-Small Cell Lung Cancer

BackgroundPrior research in non-small cell lung cancer (NSCLC) has shown that tumors with specific driver mutations may be less likely to respond to immune checkpoint inhibitors (ICI). In this analysis, we evaluated the characteristics of patients with durable clinical benefit (DCB) to ICI compared to those with no durable clinical benefit (NDB), with emphasis on the role of molecular alterations in EGFR, ALK, and ROS1 and pretreatment neutrophil-to-lymphocyte ratio (NLR). MethodsWe retrospectively collected clinical characteristics and outcomes for patients who initiated ICI monotherapy for advanced NSCLC at Stanford University between April 2015 and May 2018. Patients were classified as having DCB if time on ICI therapy was greater than or equal to 180 days, or NDB if less than 180 days. Outcomes included best radiographic benefit while on ICI and survival from time of ICI initiation. ResultsOf 123 patients treated with ICI for NSCLC, 28 patients had DCB (23%), while 95 had NDB (77%). Median overall survival from initiation of ICI in the 33 patients with molecular alterations in EGFR (n = 31), ALK, or ROS1 and NLR of 5.9 or higher was 2.0 months, compared to 8.1 months in patients with these genomic alterations and NLR less than 5.9. Median overall survival in patients without alterations in EGFR, ALK, or ROS1 and NLR of 5.9 or higher was 4.3 months, compared to 12.1 months in patients with NLR less than 5.9 (P = .023). ConclusionsElevation in pretreatment NLR was associated with significantly lower overall median survival from initiation of ICI, particularly when in combination with NSCLC with alterations in EGFR, ALK, or ROS1. This finding could influence clinical practice as NLR is readily available through routine blood testing.

Combination of plasma MMPs and PD-1-binding soluble PD-L1 predicts recurrence in gastric cancer and the efficacy of immune checkpoint inhibitors in non-small cell lung cancer.

The tumor microenvironment (TME) impacts the therapeutic efficacy of immune checkpoint inhibitors (ICIs). No liquid biomarkers are available to evaluate TME heterogeneity. Here, we investigated the clinical significance of PD-1-binding soluble PD-L1 (bsPD-L1) in gastric cancer (GC) patients and non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 blockade. We examined bsPD-L1, matrix metalloproteinases (MMPs), and IFN-γ levels in plasma samples from GC patients (n = 117) prior to surgery and NSCLC patients (n = 72) prior to and 2months after ICI treatment. We also examined extracellular matrix (ECM) integrity, PD-L1 expression, and T cell infiltration in tumor tissues from 25GC patients by Elastica Masson-Goldner staining and immunohistochemical staining for PD-L1 and CD3, respectively. bsPD-L1 was detected in 17/117GC patients and 16/72 NSCLC patients. bsPD-L1 showed strong or moderate correlations with plasma MMP13 or MMP3 levels, respectively, in both GC and NSCLC patients. bsPD-L1 expression in GC was associated with IFN-γ levels and intra-tumoral T cell infiltration, whereas MMP13 levels were associated with loss of ECM integrity, allowing tumor cells to access blood vessels. Plasma MMP3 and MMP13 levels were altered during ICI treatment. Combined bsPD-L1 and MMP status had higher predictive accuracy to identify two patient groups with favorable and poor prognosis than tumor PD-L1 expression: bsPD-L1+MMP13high in GC and bsPD-L1+(MMP3 and MMP13)increased in NSCLC were associated with poor prognosis, whereas bsPD-L1+MMP13low in GC and bsPD-L1+(MMP3 or MMP13)decreased in NSCLC were associated with favorable prognosis. Plasma bsPD-L1 and MMP13 levels indicate T cell response and loss of ECM integrity, respectively, in the TME. The combination of bsPD-L1 and MMPs may represent a non-invasive tool to predict recurrence in GC and the efficacy of ICIs in NSCLC.

Abstract 1538: Impact of C-reactive protein on the efficacy of immune checkpoint inhibitors in non-small cell lung cancer

Abstract Background: Immune checkpoint inhibitors (ICIs) therapy has achieved remarkable success in the treatment of non-small cell lung cancer (NSCLC). Clinical studies have suggested a correlation between C-reactive protein (CRP) levels and treatment efficacy, but it remains unclear whether CRP can directly impact the efficacy. Therefore, we investigated the imapct of CRP on the efficacy of ICIs in NSCLC. Methods: The tumor growth model was established in CRP knockout and wildtype mice by injecting LLC cells to evaluate the effect of CRP on tumor proliferation. The frequencies and phenotypes of macrophages and T cells in mouse tumors were detected by flow cytometry. The impact of CRP on macrophage polarization was evaluated using flow cytometry and IF, while its impact on T cell chemokines CCL5, CXCL9, and CXCL10 was analyzed by ELISA and qRT-PCR. mCRP and α-PD-1 were implemented in C57/BL6 mice injected with LLC cells to evaluate the effect of mCRP on tumor immunotherapy. The frequencies of T cells in mouse tumors were detected by flow cytometry. Expression of mCRP and infiltration of immune cells in human NSCLC tissues were analyzed using IHC. Results: We found that tumor progression was enhanced and the proportion of tumor-infiltrated M1 macrophages was decreased in CRP knockout mice. Using human PBMC-derived macrophage and RAW264.7 cell lines, we demonstrated that the monomeric form of CRP, known as mCRP, induced M1 polarization of macrophages, leading to increased secretion of CCL5, CXCL9, and CXCL10. In tumor bearing mice, mCRP treatment enhanced anti-tumor immunity and suppressed tumor progression by increasing CD4+ and CD8+ T cell recruitment. Surprisingly, the combined treatment of mCRP and α-PD-1 induced more significant tumor regression than α-PD-1 treatment alone. Additionally, high level of mCRP in NSCLC tissues is correlated with a more inflamed tumor microenvironment phenotype. Conclusion: mCRP can enhance the efficacy of immune checkpoint inhibitors in NSCLC by activating anti-tumor immunity. Citation Format: Wenyuan Li, Hui Guo. Impact of C-reactive protein on the efficacy of immune checkpoint inhibitors in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1538.

Genomic and Immunophenotypic Landscape of Acquired Resistance to PD-(L)1 Blockade in Non-Small-Cell Lung Cancer.

Although immune checkpoint inhibitors (ICI) have extended survival in patients with non-small-cell lung cancer (NSCLC), acquired resistance (AR) to ICI frequently develops after an initial benefit. However, the mechanisms of AR to ICI in NSCLC are largely unknown. Comprehensive tumor genomic profiling, machine learning-based assessment of tumor-infiltrating lymphocytes, multiplexed immunofluorescence, and/or HLA-I immunohistochemistry (IHC) were performed on matched pre- and post-ICI tumor biopsies from patients with NSCLC treated with ICI at the Dana-Farber Cancer Institute who developed AR to ICI. Two additional cohorts of patients with intervening chemotherapy or targeted therapies between biopsies were included as controls. We performed comprehensive genomic profiling and immunophenotypic characterization on samples from 82 patients with NSCLC and matched pre- and post-ICI biopsies and compared findings with a control cohort of patients with non-ICI intervening therapies between biopsies (chemotherapy, N = 32; targeted therapies, N = 89; both, N = 17). Putative resistance mutations were identified in 27.8% of immunotherapy-treated cases and included acquired loss-of-function mutations in STK11, B2M, APC, MTOR, KEAP1, and JAK1/2; these acquired alterations were not observed in the control groups. Immunophenotyping of matched pre- and post-ICI samples demonstrated significant decreases in intratumoral lymphocytes, CD3e+ and CD8a+ T cells, and PD-L1-PD1 engagement, as well as increased distance between tumor cells and CD8+PD-1+ T cells. There was a significant decrease in HLA class I expression in the immunotherapy cohort at the time of AR compared with the chemotherapy (P = .005) and the targeted therapy (P = .01) cohorts. These findings highlight the genomic and immunophenotypic heterogeneity of ICI resistance in NSCLC, which will need to be considered when developing novel therapeutic strategies aimed at overcoming resistance.

Increased interleukin-6/C-reactive protein levels are associated with the upregulation of the adenosine pathway and serve as potential markers of therapeutic resistance to immune checkpoint inhibitor-based therapies in non-small cell lung cancer

BackgroundSystemic immune activation, hallmarked by C-reactive protein (CRP) and interleukin-6 (IL-6), can modulate antitumor immune responses. In this study, we evaluated the role of IL-6 and CRP in the stratification...

Prognostic factors affecting survival in patients with non-small cell lung cancer treated with salvage surgery after drug therapy: a multi-institutional retrospective study

BackgroundThe prevalence of salvage surgeries after drug therapy for non-small cell lung cancer (NSCLC) has risen, mainly due to recent progress in molecular-targeted drugs and immune checkpoint inhibitors for NSCLC. While the safety and effectiveness of salvage surgery after drug therapy for NSCLC have been studied, its indications remain unclear. We aimed to identify the prognostic factors affecting survival in patients with advanced-stage (stages III–IV) NSCLC treated with salvage surgery after drug therapy.MethodsA retrospective investigation was conducted on patients who received salvage surgery after drug therapy at four hospitals between 2007 and 2020. Salvage surgery was defined as surgery after drug therapy for local progression, tumor conversion to resectable status, and discontinuation of prior drug therapy owing to serious complications.ResultsThirty-two patients received cytotoxic agents alone (n = 12 [38%]), tyrosine kinase inhibitors (TKIs; n = 16 [50%]), or immune checkpoint inhibitors (n = 4 [13%]) as prior drug therapy. In 11 (34%) and 21 (66%) patients, the clinical stage before treatment was III or IV, respectively. The median initial and preoperative serum carcinoembryonic antigen (CEA) levels were 10.2 (range, 0.5–1024) ng/mL and 4.2 (range, 0.6–92.5) ng/mL, respectively. Among the patients, 28 (88%) underwent lobectomy, 2 (6%) underwent segmentectomy, and 2 (6%) underwent wedge resection. Complete resection of the primary lesion was accomplished in 28 (88%) patients. Postoperative complications were documented in six (19%) patients. Mortality rates were 0% at 30 days and 3% at 90 days post-operation. The 5-year overall survival rate stood at 66%, while the 5-year progression-free survival rate was 21%. Multivariate analyses showed that prior TKI therapy and preoperative serum CEA level < 5 ng/mL were prognostic factors influencing overall survival (hazard ratio [95% confidence interval]: 0.06 [0.006–0.68] and 0.03 [0.002–0.41], respectively). The 5-year overall survival in the 11 patients with both favorable prognosticators was 100%.ConclusionsIn this study, prior TKI therapy and preoperative serum CEA level < 5 ng/mL were favorable prognostic factors for overall survival in patients with NSCLC treated with salvage surgery. Patients with these prognostic factors are considered good candidates for salvage surgery after drug therapy.

Current status of clinical trial research and application of immune checkpoint inhibitors for non-small cell lung cancer.

Immunotherapy has emerged as a hot topic in the treatment of non-small cell lung cancer (NSCLC) with remarkable success. Compared to chemotherapy patients, the 5-year survival rate for immunotherapy patients is 3-fold higher, approximately 4%-5% versus 15%-16%, respectively. Immunotherapies include chimeric antigen receptor T-cell (CAR-T) therapy, tumor vaccines, immune checkpoint inhibitors, and so forth. Among them, immune checkpoint inhibitors are in the spotlight. Common immune checkpoint inhibitors (ICIs) currently in clinical use include programmed death receptor-1(PD-1)/programmed death ligand-1(PD-L1) and cytotoxic T lymphocyte-associated antigen 4(CTLA-4). This article focuses on monotherapy and combination therapy of CTLA-4 and PD-1/PD-L1 immune checkpoint inhibitors. In particular, the combination therapy of ICIs includes the combination of ICIs and chemotherapy, the combination therapy of dual ICIs, the combination of ICIs and anti-angiogenic drugs, the combination of ICIs and radiotherapy, and the combination of ICIs inhibitors and tumor vaccines and so forth. This article focuses on the combination therapy of ICIs with chemotherapy, the combination therapy of dual ICIs, and the combination therapy of ICIs with anti-angiogenic drugs. The efficacy and safety of ICIs as single agents in NSCLC have been demonstrated in many trials. However, ICIs plus chemotherapy regimens offer significant advantages in the treatment of NSCLC with little to no dramatic increase in toxicity, while combined dual ICIs significantly reduce the adverse effects (AEs) of chemotherapy. ICIs plus anti-angiogenic agents regimen improves anti-tumor activity and safety and is expected to be the new paradigm for the treatment of advanced NSCLC. Despite some limitations, these agents have achieved better overall survival rates. In this article, we review the current status and progress of research on ICIs in NSCLC in recent years, aiming to better guide the individualized treatment of NSCLC patients.

Dynamic evaluation of blood immune cells predictive of response to immune checkpoint inhibitors in NSCLC by multicolor spectrum flow cytometry.

Immune checkpoint inhibitors (ICIs) only benefit a subset of cancer patients, underlining the need for predictive biomarkers for patient selection. Given the limitations of tumor tissue availability, flow cytometry of peripheral blood mononuclear cells (PBMCs) is considered a noninvasive method for immune monitoring. This study explores the use of spectrum flow cytometry, which allows a more comprehensive analysis of a greater number of markers using fewer immune cells, to identify potential blood immune biomarkers and monitor ICI treatment in non-small-cell lung cancer (NSCLC) patients. PBMCs were collected from 14 non-small-cell lung cancer (NSCLC) patients before and after ICI treatment and 4 healthy human donors. Using spectrum flow cytometry, 24 immune cell markers were simultaneously monitored using only 1 million PBMCs. The results were also compared with those from clinical flow cytometry and bulk RNA sequencing analysis. Our findings showed that the measurement of CD4+ and CD8+ T cells by spectrum flow cytometry matched well with those by clinical flow cytometry (Pearson R ranging from 0.75 to 0.95) and bulk RNA sequencing analysis (R=0.80, P=1.3 x 10-4). A lower frequency of CD4+ central memory cells before treatment was associated with a longer median progression-free survival (PFS) [Not reached (NR) vs. 5 months; hazard ratio (HR)=8.1, 95% confidence interval (CI) 1.5-42, P=0.01]. A higher frequency of CD4-CD8- double-negative (DN) T cells was associated with a longer PFS (NR vs. 4.45 months; HR=11.1, 95% CI 2.2-55.0, P=0.003). ICIs significantly changed the frequency of cytotoxic CD8+PD1+ T cells, DN T cells, CD16+CD56dim and CD16+CD56- natural killer (NK) cells, and CD14+HLDRhigh and CD11c+HLADR + monocytes. Of these immune cell subtypes, an increase in the frequency of CD16+CD56dim NK cells and CD14+HLADRhigh monocytes after treatment compared to before treatment were associated with a longer PFS (NR vs. 5 months, HR=5.4, 95% CI 1.1-25.7, P=0.03; 7.8 vs. 3.8 months, HR=5.7, 95% CI 169 1.0-31.7, P=0.04), respectively. Our preliminary findings suggest that the use of multicolor spectrum flow cytometry helps identify potential blood immune biomarkers for ICI treatment, which warrants further validation.

Eosinophil count and immune-related adverse events (irAEs) as predictive biomarkers of survival in patients with NSCLC treated with ICIs.

e21144 Background: Immune Checkpoint Inhibitors (ICIs) changed the algorithm of treatment for Non-Small Cell Lung Cancer (NSCLC). Consequently, an increased incidence of specific immune-related adverse events (irAEs) were reported, although a clear relationship between toxicity and response to ICIs was not identified. To date no strong predictive factor of response to ICIs are univocally recognized in NSCLC. Methods: This is an observational, retro-prospective, monocentric study aimed to evaluate, in patients (pts) with NSCLC treated with ICIs, the predictive impact of selected blood biomarkers and the occurrence of irAEs on survival. Differential cells count, and specifically the Absolute Eosinophil Count (AEC, N°/μL), were registered at baseline to evaluate their impact on response to ICIs. Patients were divided in two groups: those with high AEC ( &gt; 190/µL, group A), and those with low basal AEC ( &lt; 190/µL, group B). Results: We enrolled 48 pts, median age was 70 years. All pts were treated with an ICI as single-agent: 5 (10%) with Nivolumab (N), 37 (77%) with Pembrolizumab (P), and 5 pts received Atezolizumab (A). Thirty-seven pts were treated in first-line setting, 9 pts in second-line, and 2 pts in successive lines. Of total, 63% pts (30/48) developed at least one irAE: an endocrine event occurred in 11 pts (23%), gastrointestinal toxicity in 10 pts (21%), dermatological events in 19 pts (40%), while a pulmonary irAE in 6 pts (13%). Progression free survival (PFS) was higher in group A than in group B (16 vs 9.5, p = 0.041) with a trend for a superior median Overall Survival (mOS) (median not reached vs 23 months, p = 0.07, respectively). At a median follow-up of 18 months (mos), pts who developed at least one irAE had a significant benefit in PFS (15mos vs 8mos, p = 0.027), reporting a trend for better PFS for pts with endocrine toxicities (p = 0.057) and GI- toxicities (p = 0.051) vs no toxicities. Pulmonary irAEs are significantly related to a better PFS: median not reached vs 12 mos, p = 0.025. Conclusions: In this real-life experience we observed that baseline AEC values correlates with PFS in pts with NSCLC treated with ICIs. Additional analyses are ongoing to identify appropriate cut-offs of AEC to better stratify patients. Moreover, our study underlines that the development of toxicities, in particular pulmonary ones, could be considered as a predictive indicator of response to ICIs in NSCLC. With all the limitations of being a small analysis, our real-life experience is innovative and explored prospectively the potential role of differential cell count and irAEs as predictive biomarkers of survival in NSCLC patients treated with ICIs.

Improved survival on morning pembrolizumab with or without chemotherapy during initial treatment for stage IV non-small cell lung cancer.

e21055 Background: Seven retrospective studies have shown that a greater proportion of infusions of immune checkpoint inhibitors (ICIs) in the morning or at early daytime improved survival in patients (pts) with stage IV cancers. Pembrolizumab (Pembro) binds to PD-1 receptors and targets T(CD8) and other immune cells, whose functions and trafficking are regulated by the circadian timing system. Since 4 courses are needed to reach Pembro steady-state plasma levels, we questioned whether Pembro timing would predict survival outcomes. Methods: Non-small-cell lung cancer (NSCLC) pts received Pembro alone or with chemotherapy (CT) according to PD-L1 status q3 weeks. Infusion timeslots were allocated by the day-hospital coordinators and recorded. The study population was split into two groups according to the median timing of the initial four Pembro infusions. The ‘morning’ group received 2 to 4 infusions starting before this median timing, whilst the ‘afternoon’ group received 0 or 1 infusion before it. Progression-free survival (PFS), and overall survival (OS) were analyzed according to timing group. Results: 97 consecutive pts with stage IV NSCLC (M/F, 68/29; PS 0-1, 97%; 37-87 y.o.) received Pembro as 1st line for 86% of the pts or 2nd-3rd line for 14%. Pembro was administered as a single agent to 41 pts (42%) or with CT to 56 pts (58%). Tumor PD-L1 expression was not assessed for 5 pts, &lt; 1% for 18 pts, 1-49% for 20 pts, and ≥ 50% for 54 pts. Main metastatic sites were bone (43% of the pts), pleura (26%), brain (29%), liver (20%), and adrenal gland (14%). The median infusion time of the initial 4 courses was at 11:45. Pts were retrospectively allocated to the ‘morning’ group (48 pts) or the ‘afternoon’ group (49 pts). Pembro+CT was given to 77 % of the ‘morning’ group pts and to 39% of the ‘afternoon’ group pts (p &lt; 0.001), as expected from the longer infusional Pembro+CT duration. All other pt characteristics were similar between both groups. Pts receiving single-agent Pembro or Pembro+CT displayed non-significant differences in PFS (HR = 0.58, p = 0.08) or OS (HR = 0.81, p = 0.57). PFS did not differ significantly between timing groups (HR = 0.64, p = 0.145). In contrast, OS was significantly longer in the ‘morning’ as compared to the ‘afternoon’ group (HR = 0.41 [95%CI, 0.20-0.82], P = 0.012), with respective 2-year survival rates of 65% and 38% (p = 0.010). Multivariable analysis confirmed that morning dosing of 2-4 of the initial 4 Pembro courses predicted longer OS (HR = 0.28 [0.13-0.64], p = 0.003) irrespective of combination with CT, PD-L1 status, and other clinical features. Conclusions: Pembro was largely more effective on OS in those NSCLC pts receiving 2 to 4 infusions before 11:45 over the initial 3 treatment months. Randomized trials and translational studies are now needed to recommend morning timing for Pembro and possibly other ICIs in NSCLC in order to optimize survival benefits from immunotherapy.

Immunotherapy through the Lens of Non-Small Cell Lung Cancer.

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.

Incorporating risk preferences of patients in the valuation of immune checkpoint inhibitors for non-small cell lung cancer.

Immunotherapy offers a distinctive mechanism of action compared to traditional treatments, arising from additional value dimensions that may not be captured in standard health technology assessments. Cancer patients may have the expectation that immunotherapy provides durable, long-term survival gains. Moreover, some patients may be willing to take a 'risk' to undergo immunotherapy to achieve better survival outcomes. We reviewed quantitative methods that explored patients' risk preferences in their non-small cell lung cancer (NSCLC) treatment choices, in PubMed (MEDLINE), from January 1, 2015, until July 1, 2022. The consideration of a value dimension ('hope') based on patients' risk-seeking preferences is specifically addressed for the valuation of immune checkpoint inhibitors in NSCLC. We reported that the quantitative methods that aim to measure patients' risk preferences or 'hope' empirically are emerging. Value assessments should not only comprise survival improvements for the mean or median patient but also consider methods that reflect durable, long-term overall survival gains for risk-seeking patients. However, the published evidence for incorporating 'hope' based on patients' stated preferences for uncertain treatment profiles is not strong, and future research could strengthen this evidence base. We encourage further research on the development and validation of quantification methods to incorporate 'hope' and risk preferences of patients treated with immunotherapy for NSCLC and beyond.

Hypoxia and acidity regulate immune checkpoint molecule and IFN-β expression in non-small cell lung cancer cell lines

Purpose Non-small cell lung cancer (NSCLC) is one of the most lethal tumors in humans. Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the treatment of patients with advanced diseases. Tumor microenvironment conditions like hypoxia and low pH may compromise the efficacy of ICIs. Materials and methods We report the effect of hypoxia and acidity on the expression levels of the major checkpoint molecules, namely PD-L1, CD80, and CD47, in the A549 and H1299 NSCLC cell lines. Results Hypoxia induces PD-L1 protein and mRNA expression, represses CD80 mRNA levels, and enhances IFNβ protein expression. An opposite effect was noticed when cells were exposed to acidic conditions. Hypoxia-induced the CD47 molecule at protein and mRNA levels. It is concluded that hypoxia and acidity are important regulators of the expression of PD-L1 and CD80 immune checkpoint molecules. Acidity contributes to the suppression of the interferon type I pathway. Conclusions These findings suggest that hypoxia and acidity assist cancer cells in the escape from immune surveillance through direct effects on cancer cells’ ability to present immune checkpoint molecules and release type I interferons. Targeting hypoxia and acidity may enhance the activity of ICIs in NSCLC.

Combining STAT3-Targeting Agents with Immune Checkpoint Inhibitors in NSCLC.

Despite recent therapeutic advances, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor (TF) with multiple tumor-promoting effects in NSCLC, including proliferation, anti-apoptosis, angiogenesis, invasion, metastasis, immunosuppression, and drug resistance. Recent studies suggest that STAT3 activation contributes to resistance to immune checkpoint inhibitors. Thus, STAT3 represents an attractive target whose pharmacological modulation in NSCLC may assist in enhancing the efficacy of or overcoming resistance to immune checkpoint inhibitors. In this review, we discuss the biological mechanisms through which STAT3 inhibition synergizes with or overcomes resistance to immune checkpoint inhibitors and highlight the therapeutic strategy of using drugs that target STAT3 as potential combination partners for immune checkpoint inhibitors in the management of NSCLC patients.

Immune checkpoint inhibitors as first-line therapy for non-small cell lung cancer: A systematic evaluation and meta-analysis

ABSTRACT Recently, immune checkpoint inhibitors (ICIs) present promising application prospects in treating non-small cell lung cancer (NSCLC). This study aimed to investigate optimal treatment strategy by comparing the first-line treatment strategies with ICIs in NSCLC. We retrieved relevant studies on first-line therapy of NSCLC with ICIs. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were treatment-related serious adverse events (tr-SAEs) with grade 3 or higher and objective response rate (ORR). We also conducted a Bayesian network meta-analysis. We included 14 studies involving 7,823 patients and compared seven different interventions. In PD-L1 nonselective NSCLC, nivolumab+ipilimumab had good PFS and ORR, pembrolizumab significantly prolonged OS, and nivolumab had the fewest adverse events (AEs). For PD-L1-positive patients, nivolumab remarkably prolonged OS. For those with negative PD-L1, nivolumab+ipilimumab also showed an advantage. In addition, nivolumab+ipilimumab significantly prolonged the PFS in both PD-L1-negative and -positive patients. For patients with PD-L1 tumor proportion score (TPS) within 1–49%, atezolizumab+chemotherapy remarkably prolonged PFS and OS. For those with PD-L1 TPS ≥50%, pembrolizumab prolonged OS and atezolizumab+chemotherapy significantly prolonged PFS. Nivolumab combined with ipilimumab showed advantages in OS, PFS and ORR in most patients. Nivolumab+ipilimumab may be the optimal first-line therapy for NSCLC.

Choosing the optimal immunotherapeutic strategies for non-small cell lung cancer based on clinical factors.

The treatment landscape of advanced non-small cell lung cancer (NSCLC) has changed dramatically since the emergence of immune checkpoint inhibitors (ICIs). Although some patients achieve long survival with relatively mild toxicities, not all patients experience such benefits from ICI treatment. There are several ways to use ICIs in NSCLC patients, including monotherapy, combination immunotherapy, and combination chemoimmunotherapy. Decision-making in the selection of an ICI treatment regimen for NSCLC is complicated partly because of the absence of head-to-head prospective comparisons. Programmed death-ligand 1 (PD-L1) expression is currently considered a standard biomarker for predicting the efficacy of ICIs, although some limitations exist. In addition to the PD-L1 tumor proportion score, many other clinical factors should also be considered to determine the optimal treatment strategy for each patient, including age, performance status, histological subtypes, comorbidities, status of oncogenic driver mutation, and metastatic sites. Nevertheless, evidence of the efficacy and safety of ICIs with some specific conditions of these factors is insufficient. Indeed, patients with poor performance status, oncogenic driver mutations, or interstitial lung disease have frequently been set as ineligible in randomized clinical trials of NSCLC. ICI use in these patients is controversial and remains to be discussed. It is important to select patients for whom ICIs can benefit the most from these populations. In this article, we review previous reports of clinical trials or experience in using ICIs in NSCLC, focusing on several clinical factors that are associated with treatment outcomes, and then discuss the optimal ICI treatment strategies for NSCLC.