Quantitative analysis of interstitial lung abnormalities on computed tomography to predict symptomatic radiation pneumonitis after lung stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: Symptomatic radiation pneumonitis (SRP) is a complication of thoracic stereotactic body radiotherapy (SBRT). As visual assessments pose limitations, artificial intelligence-based quantitative computed tomography image analysis software (AIQCT) may help predict SRP risk. We aimed to evaluate high-resolution computed tomography (HRCT) images with AIQCT to develop a predictive model for SRP. MATERIALS AND METHODS: AIQCT automatically labelled HRCT images of patients treated with SBRT for stage I lung cancer according to lung parenchymal pattern. Quantitative data including the volume and mean dose (Dmean) were obtained for reticulation + honeycombing (Ret + HC), consolidation + ground-glass opacities, bronchi (Br), and normal lungs (NL). After associations between AIQCT's quantified metrics and SRP were investigated, we developed a predictive model using recursive partitioning analysis (RPA) for the training cohort and assessed its reproducibility with the testing cohort. RESULTS: Overall, 26 of 207 patients developed SRP. There were significant between-group differences in the Ret + HC, Br-volume, and NL-Dmean in patients with and without SRP. RPA identified the following risk groups: NL-Dmean ≥ 6.6 Gy (high-risk, n = 8), NL-Dmean < 6.6 Gy and Br-volume ≥ 2.5 % (intermediate-risk, n = 13), and NL-Dmean < 6.6 Gy and Br-volume < 2.5 % (low-risk, n = 133). The incidences of SRP in these groups within the training cohort were 62.5, 38.4, and 7.5 %; and in the testing cohort 50.0, 27.3, and 5.0 %, respectively. CONCLUSION: AIQCT identified CT features associated with SRP. A predictive model for SRP was proposed based on AI-detected Br-volume and the NL-Dmean.

Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade.

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.

Successful treatment of lung cancer coexisting with B­cell lymphoma with pembrolizumab following rituximab­included chemotherapy: A case report.

The combined occurrence of lung cancer and B-cell lymphoma, such as mucosa-associated lymphoid tissue (MALT) lymphoma, is rare. The efficacy and safety of immune checkpoint inhibitors (ICIs) remain unknown in this population of patients, and the occurrence of ICI-induced exacerbation of lymphoma is concerning. The present study describes a case of successful treatment with pembrolizumab following rituximab-containing chemotherapy for lung cancer complicated by MALT lymphoma. The patient was a 69-year-old woman diagnosed with MALT lymphoma based on a biopsy of stomach ulcerative lesions, and advanced lung cancer based on a biopsy of a lymph node in the left pulmonary hilum. Complete remission was achieved after one cycle of rituximab and bendamustine therapy for MALT lymphoma. Pembrolizumab monotherapy was subsequently initiated, resulting in a good response for lung cancer without recurrence or exacerbation of the lymphoma. In conclusion, the present study suggested that pembrolizumab, following rituximab-containing therapy, could be a treatment option for patients with lung cancer coexisting with MALT lymphoma.

Immune checkpoint inhibitors in patients with lung cancer having chronic interstitial pneumonia.

Background: In interstitial pneumonia (IP)-associated lung cancer, immune checkpoint inhibitor pneumonitis (ICIP) is common with immune checkpoint inhibitor (ICI) treatment. The purpose of the present study was to clarify the safety and efficacy of ICI treatment for patients with lung cancer with IP. Methods: This multicentre retrospective observational study was conducted from June 2016 to December 2020 in patients with primary lung cancer with IP who received ICI treatment. Results: A total of 200 patients (median age 70 years; male/female, 176/24) were enrolled from 27 institutions. ICIP occurred in 61 patients (30.5%), pneumonitis grades 3-5 in 32 patients (15.5%) and death in nine patients (4.5%). The common computed tomography pattern of ICIP was organising pneumonia in 29 patients (47.5%). Subsequently, diffuse alveolar damage (DAD) pattern was observed in 19 patients (31.1%) who had a significantly worse prognosis than those with a non-DAD pattern (median progression-free survival (PFS) 115 days versus 226 days, p=0.042; median overall survival (OS) 334 days versus 1316 days, p<0.001). Immune-related adverse events (irAEs) occurred in approximately 50% of patients. Patients with irAEs (n=100) had a better prognosis than those without irAEs (n=100) (median PFS 200 days versus 77 days, p<0.001; median OS 597 days versus 390 days p=0.0074). The objective response rate and disease control rate were 41.3% and 68.5%, respectively. Conclusions: Although ICI treatment was effective for patients with lung cancer with IP, ICIP developed in approximately 30% of patients. Patients with irAEs had a significantly better PFS and OS than those without irAEs.

Combination Therapy with EGFR Tyrosine Kinase Inhibitors and TEAD Inhibitor Increases Tumor Suppression Effects in EGFR Mutation-positive Lung Cancer.

EGFR-tyrosine kinase inhibitors (TKI) are the first-line therapies for EGFR mutation-positive lung cancer. EGFR-TKIs have favorable therapeutic effects. However, a large proportion of patients with EGFR mutation-positive lung cancer subsequently relapse. Some cancer cells survive the initial treatment with EGFR-TKIs, and this initial survival may be associated with subsequent recurrence. Therefore, we aimed to overcome the initial survival against EGFR-TKIs. We hypothesized that yes-associated protein 1 (YAP1) is involved in the initial survival against EGFR-TKIs, and we confirmed the combined effect of EGFR-TKIs and a YAP1-TEAD pathway inhibitor. The KTOR27 (EGFR kinase domain duplication) lung cancer cell lines established from a patient with EGFR mutation-positive lung cancer and commercially available PC-9 and HCC827 (EGFR exon 19 deletions) lung cancer cell lines were used. These cells were used to evaluate the in vitro and in vivo effects of VT104, a TEAD inhibitor. In addition, YAP1 involvement was investigated in pathologic specimens. YAP1 was activated by short-term EGFR-TKI treatment in EGFR mutation-positive lung cancer cells. In addition, inhibiting YAP1 function using siRNA increased the sensitivity to EGFR-TKIs. Combination therapy with VT104 and EGFR-TKIs showed better tumor-suppressive effects than EGFR-TKIs alone, in vitro and in vivo. Moreover, the combined effect of VT104 and EGFR-TKIs was observed regardless of the localization status of YAP1 before EGFR-TKI exposure. These results suggest that combination therapy with the TEAD inhibitor and EGFR-TKIs may improve the prognosis of patients with EGFR mutation-positive lung cancer.

CD47 polymorphism for predicting nivolumab benefit in patients with advanced non­small­cell lung cancer.

Immune checkpoint inhibitors (ICIs), such as nivolumab, play an essential role in non-small-cell lung cancer (NSCLC) treatment. Programmed death ligand-1 has been used as a predictive biomarker for the efficacy of ICI treatment in patients with NSCLC; however, its predictive value is considered insufficient. Therefore, there is an urgent need for better predictive biomarkers. The present study focused on the CD47 molecule, which is associated with macrophages and tumor immunity. The study aimed to investigate the association between CD47 single nucleotide polymorphism (SNP) and the therapeutic effect of nivolumab in patients with NSCLC. The CD47 SNP genotypes and clinical outcomes were retrospectively analyzed in 164 patients with NSCLC treated with nivolumab at Kyoto University Hospital (Kyoto, Japan). Patients with the G/G genotype of the CD47 SNP rs3804639 had significantly longer progression-free survival than those with the G/T or T/T genotypes [2.6 months vs. 2.1 months, hazard ratio (HR), 0.70; P=0.026]. Moreover, the G/G genotype of the CD47 SNP rs3804639 was associated with a significantly longer median overall survival than the G/T or T/T genotypes of the CD47 SNP rs3804639 (24.8 months vs. 12.0 months, HR, 0.64; P=0.021). In conclusion, CD47 polymorphism may be a novel predictive biomarker of nivolumab efficacy in patients with advanced NSCLC.

Outcomes of immune checkpoint inhibitors for postoperative recurrence of non-small cell lung cancer.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are effective treatment options for patients with advanced non-small cell lung cancer (NSCLC); however, there is a dearth of data on outcomes of patients receiving ICIs for postoperative recurrence. The objective of this study was to investigate the short- and long-term outcomes of patients who received ICIs for postoperative recurrence. METHODS: A retrospective chart review was performed to identify consecutive patients who received ICIs for postoperative recurrence of NSCLC. We investigated therapeutic responses, adverse events, progression-free survival (PFS), and overall survival (OS). Survival outcomes were estimated using the Kaplan-Meier method. Univariable and multivariable analyses were performed using the Cox proportional hazards model. RESULTS: Eighty-seven patients, with a median age of 72 years were identified between 2015 and 2022. The median follow-up period after ICI initiation was 13.1 months. Adverse events of grade ≥ 3 were observed in 29 (33.3%) patients, including 17 (19.5%) patients with immune-related adverse events. The median PFS and OS of the whole cohort were 3.2 and 17.5 months, respectively. Limited to those receiving ICIs as first-line therapy, the median PFS and OS were 6.3 and 25.0 months, respectively. On multivariable analysis, smoking history (HR: 0.29, 95% CI 0.10-0.83) and non-squamous cell histology (HR: 0.25, 95% CI 0.11-0.57) were associated with more favorable PFS in patients receiving ICIs as first-line treatment. CONCLUSIONS: Outcomes in patients receiving ICIs as first-line treatment appear acceptable. A multi-institutional study is required to confirm our findings.

Adaptive resistance to lorlatinib via EGFR signaling in ALK-rearranged lung cancer.

Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors rarely elicit complete responses in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC), as a small population of tumor cells survives due to adaptive resistance. Therefore, we focused on the mechanisms underlying adaptive resistance to lorlatinib and therapeutic strategies required to overcome them. We found that epidermal growth factor receptor (EGFR) signaling was involved in the adaptive resistance to lorlatinib in ALK-rearranged NSCLC, activation of which was induced by heparin-binding EGF-like growth factor production via c-Jun activation. EGFR inhibition halted ALK-rearranged lung cancer cell proliferation by enhancing ALK inhibition-induced apoptosis via suppression of Bcl-xL. Xenograft models showed that the combination of EGFR inhibitor and lorlatinib considerably suppressed tumor regrowth following cessation of these treatments. This study provides new insights regarding tumor evolution due to EGFR signaling after lorlatinib treatment and the development of combined therapeutic strategies for ALK-rearranged lung cancer.

Recurrence patterns and progression-free survival after chemoradiotherapy with or without consolidation durvalumab for stage III non-small cell lung cancer.

Chemoradiotherapy followed by consolidation durvalumab (CCRT+D) improves survival in patients with stage III non-small-cell lung cancer (NSCLC). We compared recurrence patterns and survival in the CCRT+D and CCRT cohorts. We conducted a multicenter, retrospective study in Japan. Patients who received CCRT for stage III NSCLC were included in this study. Of 178 eligible patients, 136 were in the CCRT+D and 42 were in the CCRT cohorts. Locoregional recurrence (LR), LR plus distant metastases (DM), and DM were observed in 20.6%, 8.8%, 27.9% of the CCRT+D, and 26.2%, 16.7% and 33.3% of the CCRT cohorts, respectively. In-field recurrence was the most common LR pattern in both cohorts. Squamous cell carcinoma and PD-L1 expression < 1%, and female sex and EGFR mutations were significantly associated with an increased risk of LR and DM. In patients with any risk factors for LR, the incidence of LR was similar in the CCRT+D and CCRT (39.5% vs 45.5%). The 24 month progression-free survival (PFS) and overall survival (OS) were 40.3% and 69.4% in the CCRT+D and 24.7% and 61.0% in the CCRT cohorts, respectively. Poor performance status and no consolidation durvalumab were significantly associated with shorter PFS. There was a significant difference in PFS between the CCRT+D and CCRT in the propensity score-matched cohort (HR = 0.51, P = 0.005). In conclusion, consolidation durvalumab decreased both LR and DM, and significantly improved PFS. However, in-field recurrence was still a major problem, as well as DM.

Yes-associated protein 1 mediates initial cell survival during lorlatinib treatment through AKT signaling in ROS1-rearranged lung cancer.

Tyrosine kinase inhibitors (TKIs) that target the ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) gene have shown dramatic therapeutic effects in patients with ROS1-rearranged non-small-cell lung cancer (NSCLC). Nevertheless, advanced ROS1-rearranged NSCLC is rarely cured as a portion of the tumor cells can survive the initial stages of ROS1-TKI treatment, even after maximum tumor shrinkage. Therefore, understanding the mechanisms underlying initial cell survival during ROS1-TKI treatment is necessary to prevent cell survival and achieve a cure for ROS1-rearranged NSCLC. In this study, we clarified the initial survival mechanisms during treatment with lorlatinib, a ROS1 TKI. First, we established a patient-derived ezrin gene-ROS1-rearranged NSCLC cell line (KTOR71). Then, following proteomic analysis, we focused on yes-associated protein 1 (YAP1), which is a major mediator of the Hippo pathway, as a candidate factor involved in cell survival during early lorlatinib treatment. Yes-associated protein 1 was activated by short-term lorlatinib treatment both in vitro and in vivo. Genetic inhibition of YAP1 using siRNA, or pharmacological inhibition of YAP1 function by the YAP1-inhibitor verteporfin, enhanced the sensitivity of KTOR71 cells to lorlatinib. In addition, the prosurvival effect of YAP1 was exerted through the reactivation of AKT. Finally, combined therapy with verteporfin and lorlatinib was found to achieve significantly sustained tumor remission compared with lorlatinib monotherapy in vivo. These results suggest that YAP1 could mediate initial cell resistance to lorlatinib in KTOR71 cells. Thus, combined therapy targeting both YAP1 and ROS1 could potentially improve the outcome of ROS1-rearranged NSCLC.

Combination bezafibrate and nivolumab treatment of patients with advanced non-small cell lung cancer.

Despite the success of cancer immunotherapies such as programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) inhibitors, patients often develop resistance. New combination therapies with PD-1/PD-L1 inhibitors are needed to overcome this issue. Bezafibrate, a ligand of peroxisome proliferator-activated receptor-γ coactivator 1α/peroxisome proliferator-activated receptor complexes, has shown a synergistic antitumor effect with PD-1 blockade in mice that is mediated by activation of mitochondria in T cells. We have therefore now performed a phase 1 trial (UMIN000017854) of bezafibrate with nivolumab in previously treated patients with advanced non-small cell lung cancer. The primary end point was the percentage of patients who experience dose-limiting toxicity, and this combination regimen was found to be well tolerated. Preplanned comprehensive analysis of plasma metabolites and gene expression in peripheral cytotoxic T cells indicated that bezafibrate promoted T cell function through up-regulation of mitochondrial metabolism including fatty acid oxidation and may thereby have prolonged the duration of response. This combination strategy targeting T cell metabolism thus has the potential to maintain antitumor activity of immune checkpoint inhibitors and warrants further validation.

Sarcomatoid malignant pleural mesothelioma treated with nivolumab: A case series.

Immune checkpoint therapy (ICT) with nivolumab has been widely used to treat malignant pleural mesothelioma (MPM) since clinical trials confirmed its efficacy. However, only a few clinical trials have been conducted for the treatment of sarcomatoid MPM, which is a rare histological type of MPM. Additionally, clinical reports of sarcomatoid MPM are scarce. Therefore, the benefits and risks of nivolumab treatment for sarcomatoid MPM remain unclear. The present report describes the treatment of 3 cases of sarcomatoid MPM (all 3 were men) with nivolumab monotherapy. In all three cases, nivolumab was effective despite variations in the duration of treatment, although side effects were observed in 2 patients. Programmed death ligand 1 (PD-L1) expression was positive in all 3 cases. In particular, the patient with the highest PD-L1 expression had the most rapid response of the 3 patients, and the effect lasted as long as those of the other 2, despite receiving the smallest number of doses of nivolumab. It has been reported that sarcomatoid MPM tends to respond poorly to chemotherapy and express higher levels of PD-L1 than epithelial MPM; thus, ICT may be necessary in these cases. This case series suggests that ICT with nivolumab is a promising treatment option for sarcomatoid MPM.

Usefulness of pro-gastrin-releasing peptide as a predictor of the incidence of brain metastasis and effect of prophylactic cranial irradiation in patients with limited-stage small-cell lung cancer.

Prophylactic cranial irradiation (PCI) is recommended for patients with limited-stage small-cell lung cancer (LS-SCLC) who respond well to initial treatment. However, PCI is often omitted because of its potential neurotoxicity in the era of modern diagnostic imaging devices. In the present study, we aimed to investigate the risk factors for brain metastasis (BM) in patients eligible for PCI and who may benefit more from it. Patients with LS-SCLC who responded well to definitive thoracic chemoradiotherapy were included in the present study. Competing risk regression was used to identify factors associated with BM, and the Kaplan-Meier method was used to assess overall survival (OS). Between 2004 and 2017, 62 patients were eligible for PCI and were analyzed. Of these, 38 (61.3%) underwent PCI. Overall, 17 patients (27.4%) developed BM, with a 2-year cumulative incidence of 22.8%. Multivariate analysis (MVA) revealed that pretreatment elevated pro-gastrin-releasing peptide (ProGRP) levels were associated with an increased risk for BM (HR, 7.96, P = 0.0091). PCI tended to reduce the risk of BM (HR, 0.33; P = 0.051). The use of PCI was associated with improved OS in patients with ProGRP levels > 410 pg/mL (P = 0.008), but not in those with ProGRP ≤ 410 pg/mL (P = 0.9). Pretreatment ProGRP levels may be useful in predicting the development of BM in patients with LS-SCLC who achieved a good response to initial therapy and to determine which patients should undergo PCI.

Survival impact of treatment for chronic obstructive pulmonary disease in patients with advanced non-small-cell lung cancer.

Chronic obstructive pulmonary disease (COPD) may coexist with lung cancer, but the impact on prognosis is uncertain. Moreover, it is unclear whether pharmacological treatment for COPD improves the patient's prognosis. We retrospectively investigated patients with advanced non-small-cell lung cancer (NSCLC) who had received chemotherapy at Kyoto University Hospital. Coexisting COPD was diagnosed by spirometry, and the association between pharmacological treatment for COPD and overall survival (OS) was assessed. Of the 550 patients who underwent chemotherapy for advanced NSCLC between 2007 and 2014, 347 patients who underwent spirometry were analyzed. Coexisting COPD was revealed in 103 patients (COPD group). The median OS was shorter in the COPD group than the non-COPD group (10.6 vs. 16.8 months). Thirty-seven patients had received COPD treatment, and they had a significantly longer median OS than those without treatment (16.7 vs. 8.2 months). Multivariate Cox regression analysis confirmed the positive prognostic impact of COPD treatment. Additional validation analysis revealed similar results in patients treated with immune checkpoint inhibitors (ICIs). Coexisting COPD had a significant association with poor prognosis in advanced NSCLC patients if they did not have pharmacological treatment for COPD. Treatment for coexisting COPD has the potential to salvage the prognosis.

PD-L1 polymorphisms predict survival outcomes in advanced non-small-cell lung cancer patients treated with PD-1 blockade.

BACKGROUND: We previously reported that PD-L1 polymorphisms are associated with the efficacy and immune-related adverse events of PD-1 blockade with nivolumab. However, the association between PD-L1 polymorphisms and survival outcomes under PD-1/PD-L1 blockade is still uncertain. Here, we aimed to investigate whether PD-L1 polymorphisms are associated with survival outcomes in advanced non-small-cell lung cancer (NSCLC) patients treated with nivolumab. METHODS: PD-1/PD-L1 polymorphisms and survival outcomes were retrospectively analysed in two independent cohorts (133 patients treated with nivolumab and 96 patients with no treatment history of an immune checkpoint inhibitor (ICI) (the non-ICI cohort)) with advanced NSCLC. RESULTS: Among the 7 studied single-nucleotide polymorphisms, PD-L1 rs822339 and rs1411262 were associated with overall survival (OS) in patients treated with nivolumab. Patients with the A/A genotype of rs822339 had a significantly longer OS than those with A/G or G/G genotypes (not reached versus 12.0 months; hazard ratio (HR), 0.35; 95% confidence interval (CI), 0.18-0.64; p = 0.0008). A similar survival benefit with the A/A genotype was observed regardless of driver mutation status. In multivariate analysis, performance status (PS) and PD-L1 rs822339 genotype were independent prognostic factors for OS. In the non-ICI cohort, the PD-L1 rs822339 genotype did not correlate with OS (HR, 0.77; 95% CI, 0.31-1.70; p = 0.55). The T/T genotype of rs1411262 also showed a significant prolongation of OS compared to that with the C/T or C/C genotypes in patients treated with nivolumab. CONCLUSIONS: PD-L1 polymorphisms are associated with favourable OS in nivolumab-treated NSCLC patients and may be useful predictive biomarkers, regardless of driver mutation status.

A Randomized Phase II Study of Maintenance Bevacizumab, Pemetrexed or Bevacizumab Plus Pemetrexed for Advanced Non-squamous Non-small Cell Lung Cancer.

BACKGROUND/AIM: Continuation maintenance therapy is standard for advanced nonsquamous non-small cell lung cancer; however, the optimal maintenance strategy has yet to be determined. PATIENTS AND METHODS: Patients without disease progression after four cycles of carboplatin (CBDCA)+ pemetrexed (PEM)+ bevacizumab (BEV) were randomized to maintenance therapy with BEV, PEM, or BEV+PEM. The primary endpoint was 1-year progression-free survival (PFS) rate. RESULTS: Of the 90 patients enrolled, 64 were randomly assigned to maintenance therapy. The 1-year PFS rate was 9.1% in the BEV arm, 19.1% in the PEM arm, and 19.1% in the BEV+PEM arm. The median PFS and overall survival (OS) were 4.0 and 43.1 months in the BEV arm, 4.5 and 32.0 months in the PEM arm, and 6.4 and 41.8 months in the BEV+PEM arm. CONCLUSION: The median PFS was numerically better in the BEV+PEM arm, but the median OS was not significantly different among the three arms.