Investigation of age and smoking in NSCLC patients with uncommon EGFR mutations.

Introduction: In addition to the two common epidermal growth factor receptor (EGFR) mutations, there are many uncommon mutations. Due to the high number of uncommon types, as well as the rarity of patients, there is lack of information regarding patient demographics, especially age distribution and smoking status. Against this background, we conducted an analysis to clarify the background of patients with uncommon EGFR mutations, especially considering their age distribution and smoking status. Materials and Methods: We retrospectively reviewed the medical records of non-small cell lung cancer (NSCLC) patients diagnosed in a multicenter clinical practice from 2002 to 2023. Patients included all cases of non-advanced and advanced NSCLC with uncommon EGFR mutations. Result: Information on 158 patients with uncommon EGFR mutation was collected. Median age was 72 years, with the age distribution showing that most patients were in their 70s. There was a significant difference between the proportion of patients aged up to 59 years and the proportion aged 75 years or older. In 88 patients with a smoking habit history, a significant correlation was found between smoking index and age. Among non-smokers, there was a peak between ages 70 and 74, which was older than the peak among smokers. Conclusions: Even in elderly patients and NSCLC patients with a history of smoking, although it is unclear whether EGFR mutation is common or uncommon, EGFR gene testing should be performed considering the possibility of these patients being EGFR-positive.

Real Clinical Practice of Combined Atezolizumab Plus Chemotherapy in Patients With Small Cell Lung Cancer.

BACKGROUND/AIM: Atezolizumab, an anti-PD-L1 antibody, has been increasingly administered in combination with chemotherapy to patients with small cell lung cancer (SCLC). This study aimed to determine how patients with extensive disease (ED) -SCLC responded to atezolizumab with chemotherapy and found factors affecting long-term response and survival. PATIENTS AND METHODS: This study focused on patients with SCLC who were treated with a combination of atezolizumab and chemotherapy in Japan between 2019 and 2023. Patient information and tumor response were analyzed, along with adverse events. We compared data and estimated survival probabilities. RESULTS: In our clinical trial, 95 patients with SCLC who received this treatment had a median progression-free survival of 6.0 months and a median overall survival of 15.0 months. Immune-related adverse events were observed in 13.7% of the patients, with grade 3 or higher in 5.3%. The efficacy and immune-related adverse events associated with this treatment regimen were comparable to those reported in previous clinical trials. Progression-free survival >2 years was observed in a small number of patients (5.3%). CONCLUSION: Our research will offer important insights for the future care of patients with extensive-stage SCLC by utilizing atezolizumab in combination with chemotherapy. Accumulation and confirmation of clinical practice results will have important implications for the future implementation of this therapy.

Novel therapeutic strategies targeting bypass pathways and mitochondrial dysfunction to combat resistance to RET inhibitors in NSCLC.

RET fusion is an oncogenic driver in 1-2 % of patients with non-small cell lung cancer (NSCLC). Although RET-positive tumors have been treated with multikinase inhibitors such as vandetanib or RET-selective inhibitors, ultimately resistance to them develops. Here we established vandetanib resistance (VR) clones from LC-2/ad cells harboring CCDC6-RET fusion and explored the molecular mechanism of the resistance. Each VR clone had a distinct phenotype, implying they had acquired resistance via different mechanisms. Consistently, whole exome-seq and RNA-seq revealed that the VR clones had unique mutational signatures and expression profiles, and shared only a few common remarkable events. AXL and IGF-1R were activated as bypass pathway in different VR clones, and sensitive to a combination of RET and AXL inhibitors or IGF-1R inhibitors, respectively. SMARCA4 loss was also found in a particular VR clone and 55 % of post-TKI lung tumor tissues, being correlated with higher sensitivity to SMARCA4/SMARCA2 dual inhibition and shorter PFS after subsequent treatments. Finally, we detected an increased number of damaged mitochondria in one VR clone, which conferred sensitivity to mitochondrial electron transfer chain inhibitors. Increased mitochondria were also observed in post-TKI biopsy specimens in 13/20 cases of NSCLC, suggesting a potential strategy targeting mitochondria to treat resistant tumors. Our data propose new promising therapeutic options to combat resistance to RET inhibitors in NSCLC.

Patient Age and EGFR-positive Non-small Cell Lung Cancer: A Multicenter Retrospective Study.

BACKGROUND/AIM: The median age of subjects in many clinical trials of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor conducted to date has been approximately 60 years. However, it is not uncommon to encounter EGFR gene-positive patients in their 70s or 80s. Based on information obtained from these clinical trials, EGFR gene-positive non-small cell lung cancer (NSCLC) patients are considered to be younger than EGFR-negative patients. In this study, we analyzed clinical data to identify whether this assumption is true. PATIENTS AND METHODS: We retrospectively reviewed the medical records of NSCLC patients diagnosed in a multicenter clinical practice from 2009 to 2023. Patients included all cases of non-advanced and advanced NSCLC. RESULTS: Information on 2,540 patients, including 605 EGFR gene-positive patients, was collected. The median age of EGFR-positive and EGFR-negative patients was 72 years and 71 years, respectively, and there was no significant difference in the age of patients between these two groups (p=0.7887). The most common age in these two groups was 70 years. Among the EGFR gene subtypes, the frequency of exon 19 deletion decreased with age, whereas that of EGFR L858R increased. CONCLUSION: Patients in their 70s and 80s with non-small cell lung cancer were relatively frequently EGFR gene-positive. To avoid missing out on treatment opportunities, EGFR gene testing should also be performed on patients in this age group.

Extended ICI treatment after first-line chemoimmunotherapy could predict the clinical benefit of ramucirumab plus docetaxel in advanced non-small lung cancer: Post hoc analysis from NEJ051 (REACTIVE study).

BACKGROUND: The factors that predict the clinical response to ramucirumab plus docetaxel (RD) after first-line chemoimmunotherapy are unresolved. We explored whether the therapeutic efficacy of prior chemoimmunotherapy could predict the outcome of RD as sequential therapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Our study comprised 288 patients with advanced NSCLC who received RD as the second-line treatment after first-line chemoimmunotherapy at 62 Japanese institutions. Chemoimmunotherapy consisted of a platinum-based regimen and immune checkpoint inhibitors (ICIs). The association between several variables and the therapeutic outcome of RD was determined via logistic regression analysis. RESULTS: Of the 288 patients, 225 (78.1%) received maintenance therapy and 108 (37.5%) received both ICI treatment for >180 days and maintenance therapy. All of 108 patients having ICIs for >180 days received maintenance therapy. Univariate analysis identified performance status, histology (adenocarcinoma), maintenance therapy, and ICI treatment >180 days as significant predictors of better progression-free survival (PFS) and overall survival (OS) after RD administration. Multivariate analysis confirmed that these factors independently predicted favorable PFS and OS. The therapeutic response and PD-L1 expression were not closely associated with outcome after RD treatment. In particular, maintenance therapy >4 cycles was more predictive of the better prognosis for RD treatment. CONCLUSION: Extended ICI treatment after chemoimmunotherapy and maintenance therapy enhanced the efficacy of second-line RD treatment in patients with advanced NSCLC.

Atezolizumab for EGFR-mutated Non-small Cell Lung Cancer Patients: An Observation Study in Ibaraki Group (ATTENTION-IBARAKI).

BACKGROUND/AIM: Atezolizumab, an anti-programed death-ligand 1 monoclonal antibody, targets programed death-ligand 1 expressed on cancer cells and antigen-presenting cells and is now commonly used in combination with chemotherapy. We conducted a study to clarify the efficacy of atezolizumab in epidermal growth factor receptor (EGFR)-mutated patients who are considered less responsive to immune checkpoint inhibitors. PATIENTS AND METHODS: A retrospective review of patients with advanced non-small cell lung cancer (NSCLC) who received atezolizumab-containing therapy at 11 hospitals from April 2018 to March 2023 was performed. RESULTS: Median progression-free survival and overall survival in 33 EGFR-mutated patients treated with atezolizumab monotherapy were 2.0 and 9.0 months, respectively, and those in 19 patients who received combined atezolizumab plus chemotherapy were 12.0 and 17.0 months, respectively. When comparing EGFR-mutated and EGFR-negative patients after propensity score matching, there were no significant differences in progression-free survival and overall survival between the two groups, whether atezolizumab monotherapy or combined atezolizumab plus chemotherapy. Among EGFR-mutated patients, being male was a significant favorable factor in both atezolizumab treatment groups. None of the EGFR-mutated patients had grade 5 immune-related adverse events. CONCLUSION: Efficacy of atezolizumab in EGFR-mutated NSCLC patients could be comparable to that for EGFR-negative patients. To prolong the survival of EGFR-mutated NSCLC patients, appropriate selection and sequencing of EGFR for tyrosine kinase inhibitors, as well as immune checkpoint inhibitors, anti-tumor agents, and anti-angiogenic agents are important.

Atezolizumab Monotherapy for Non-small Cell Lung Cancer Patients: An Observational Study in Ibaraki Group (ATTENTION-IBARAKI).

BACKGROUND/AIM: Atezolizumab is a monoclonal antibody that targets programmed death-ligand 1 (PD-L1) expressed on cancer cells derived from various organs and antigen-presenting cells and is currently commonly used in combination with chemotherapy. We conducted a study to clarify the current status of response to atezolizumab monotherapy in clinical practice and clarify the factors that contribute to long-term response and survival. PATIENTS AND METHODS: We conducted a retrospective review of patients with advanced non-small cell lung cancer (NSCLC) treated with atezolizumab monotherapy from April 2018 to March 2023 at 11 Hospitals. RESULTS: The 147 patients evaluated had a progression-free survival (PFS) of 3.0 months and an overall survival of 7.0 months. Immune-related adverse events of any grade were observed in 13 patients (8.8%), grade 3 or higher in nine patients (6.1%), and grade 5 with pulmonary toxicity in one patient (0.7%). Favorable factors related to PFS were 'types of NSCLC other than adenocarcinoma'. Favorable factors for overall survival were 'performance status 0-1' and 'treatment lines up to 3'. There were 16 patients (10.9%) with PFS >1 year. No characteristic clinical findings were found in these 16 patients compared to the remaining 131 patients. CONCLUSION: Efficacy and immune-related adverse events of NSCLC patients associated with atezolizumab monotherapy were comparable to those of previous clinical trial results. Knowledge of characteristics of patients who are most likely to benefit from atezolizumab monotherapy is a crucial step towards implementing appropriate prescribing.

Long-term Progression-free Survival With Pemetrexed Plus Bevacizumab in NSCLC Patients.

BACKGROUND/AIM: Pemetrexed (PEM) and bevacizumab (BEV) are commonly used in combination as second or subsequent line regimens and maintenance therapy after platinum + PEM + BEV therapy for advanced non-small cell lung cancer (NSCLC). Median progression-free survival (PFS) for PEM + BEV has been reported to be less than six months in both clinical trials and clinical practice, but in clinical practice, we found that some patients demonstrate long-term PFS. Furthermore, there is a paucity of clinical practice data on whether long-term administration of PEM + BEV causes renal dysfunction. This study aimed to clarify these aspects in clinical practice. PATIENTS AND METHODS: A retrospective review of patients with advanced NSCLC treated with PEM + BEV between September 2011 and June 2022 at four hospitals was conducted. Long-term PFS in PEM + BEV therapy was defined as ≥12 months. RESULTS: During the study period, 109 patients received PEM + BEV treatment. Of them, 42 (38.5%) achieved long-term PFS ≥12 months. No significant differences in patient characteristics were found between patients with PFS ≥12 months and <12 months, except for 'relapse after resection'. Univariate and multivariate analysis showed that the favorable factor for PFS was 'relapse after resection'. With regard to influence on renal function of PEM + BEV therapy, no significant difference was found before and after PEM+BEV therapy between these two groups. CONCLUSION: NSCLC patients commonly achieved long-term PFS with PEM + BEV therapy with no observed effects on renal function.

Discontinuation of Immune Checkpoint Inhibitor due to irAEs in NSCLC Patients With EGFR Mutation.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) have revolutionized advanced non-small cell lung cancer (NSCLC) treatment. Even patients with epidermal growth factor receptor (EGFR)-mutated NSCLC may choose an ICI after failure of EGFR-tyrosine kinase inhibitor treatment. ICI-mediated immune-related adverse events (irAEs) may prompt NSCLC patients to discontinue their treatment. This study evaluated the effect of ICI treatment discontinuation on the prognosis of patients with EGFR-mutated NSCLC. PATIENTS AND METHODS: We performed a retrospective study that reviewed the clinical courses of patients with EGFR-mutated NSCLC treated with ICI therapy from February 2016 to February 2022. 'Discontinuation' was defined as failure to receive at least two treatment courses of ICI due to grade 2 irAEs (grade 1 in the lung) or higher in patients responding to ICI. RESULTS: During the study period, 13 of 31 patients discontinued ICI therapy due to irAEs. Survival from the initiation of ICI therapy was significantly longer in patients who discontinued ICI therapy compared with those who did not discontinue. In uni- and multivariate analyses, 'discontinuation' was a favourable factor. There was no significant difference in survival from ICI initiation between patients with grade 3 or higher irAEs and those with grade 2 or lower irAEs. CONCLUSION: In this patient cohort, discontinuation of ICI therapy due to irAEs did not adversely affect prognosis in patients with EGFR-mutant NSCLC. Our results suggest that when treating patients with EGFR-mutant NSCLC with ICIs, chest physicians should consider discontinuing ICI with close monitoring.

NSCLC Patients Achieving Long-term Progression-free Survival With Docetaxel Plus Ramucirumab: A Retrospective Study.

BACKGROUND/AIM: The antineoplastic drug docetaxel (DOC) and the antivascular endothelial growth factor inhibitor ramucirumab (RAM) are widely used in combination for second or later-line regimens for advanced non-small cell lung cancer (NSCLC). While the median progression-free survival (PFS) of DOC+RAM has been reported to be less than six months in both clinical trials and clinical practice, there appear to be some patients with long-term PFS. This study aimed to clarify the existence and characteristics of these patients. PATIENTS AND METHODS: We conducted a retrospective review of patients with advanced NSCLC treated with DOC+RAM between April 2009 and June 2022 at our three hospitals. There was no established definition of long-term PFS, thus in this study, a PFS of 12 months or longer was defined as long-term PFS. RESULTS: During the study period, 91 patients received DOC+RAM treatment. Of these, 14 (15.4%) achieved long-term PFS. There were no significant differences in patient characteristics between patients with PFS ≥12 months and those with PFS <12 months, except for 'clinical stage IIIA-C' at DOC+RAM initiation and 'post-surgical recurrence'. In uni- and multivariate analyses, favorable factors for PFS were 'Stage III at the start of DOC+RAM' in driver gene-negative patients, and 'under 70 years old' in driver gene-positive patients. CONCLUSION: Many patients in this study achieved long-term PFS with DOC+RAM treatment. In the future, it is expected that long-term PFS will be defined, and the background of patients who achieve such PFS will become clearer.

Relationship Between TTF-1 Expression and PFS of Pemetrexed-containing Chemotherapy in Non-squamous-NSCLC Patients With and Without Driver Genes.

BACKGROUND/AIM: We performed a retrospective study too clarify whether the presence or absence of driver genes affects the relationship between thyroid transcription factor-1 (TTF-1) expression and response to pemetrexed (PEM) in non-squamous non-small cell lung cancer (non-sq-NSCLC) patients. PATIENTS AND METHODS: We reviewed the medical charts of patients treated with PEM-containing chemotherapy during the period from February 2016 to February 2022 at Mito Medical Center-University of Tsukuba, Ryugasaki Saiseikai General Hospital, and University of Tsukuba Hospital. RESULTS: During the period of the study, 185 driver gene-negative patients negative, and 65 driver gene-positive patients were evaluated. Among the 165 driver gene-negative patients, progression free survival (PFS) of TTF-1-expressing patients treated with PEM-containing chemotherapy was significantly longer compared to that of TTF-1-negative patients. In the analysis of 65 driver gene-positive patients, the PFS of TTF-1-positive patients treated with PEM-containing chemotherapy did not differ significantly from that of TTF-1-negative patients. There was no significant difference in PFS between driver gene-negative and driver gene-positive patients treated with PEM-containing chemotherapy. Comparison between four groups defined according to the presence of driver gene and TTF-1 expression indicated shorter PFS only in 'driver gene-negative and TTF-1-negative' patients. CONCLUSION: In driver gene-positive non-sq NSCLC patients, expression of TTF does not affect the survival outcome of PEM-containing-chemotherapy. In other words, in these patients, second-line or later-line PEM-containing chemotherapy after development of resistance for specific-tyrosine kinase inhibitor could be expected to have the same level of efficacy as first-line PEM containing chemotherapy in driver gene-negative, TTF-1-positive non-sq NSCLC patients.

Effects of lymphopenia on survival in proton therapy with chemotherapy for non-small cell lung cancer.

Lymphocytes play an important role in the cancer immune system. In the present study, we aimed to evaluate the associations of lymphopenia during proton beam therapy (PBT) and concurrent chemotherapy with clinical outcomes and to determine whether lung or bone is more influential on lymphopenia during PBT. Data from 41 patients with stage III non-small cell lung cancer (NSCLC) who received PBT of 74 GyE with concurrent chemotherapy between 2007 and 2017 were reviewed retrospectively. The correlation between dosimetry parameters obtained from dose-volume histograms of the bone and lung and lymphopenia during PBT were analyzed. Minimum absolute lymphocyte count (ALCmin) and maximum neutrophil/lymphocyte ratio (NLRmax) were used as indicators of lymphopenia. Bone V5-20 and lung V5-50 were significantly correlated with the ALCmin and NLRmax during PBT. Multivariable analysis showed that the NLRmax, but not the ALCmin, was associated with overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS). The 3-year rates of OS, PFS and DMFS of patients with a low (≤ 6.3) versus high (> 6.3) NLRmax were 73.9% vs 44.4% (P = 0.042), 26.1% vs 5.6% (P = 0.022) and 39.1% vs 5.6% (P < 0.001), respectively. Lung V20 was significantly associated with DMFS on multivariable analyses (hazard ratio: 1.094, P = 0.008), whereas bone V5 had no impact on survival outcomes. We concluded that the NLRmax was a better prognostic indicator than the ALCmin, and the lung dose had more influence than the bone dose on the main survival outcomes in stage III NSCLC patients treated with PBT combined with concurrent chemotherapy.

Octogenarians With Anaplastic Lymphoma Kinase-rearranged Non-small-cell Lung Cancer: A Case Series.

BACKGROUND/AIM: Anaplastic lymphoma kinase (ALK) rearrangements define a distinct group of patients with non-small-cell lung cancer (NSCLC), mainly represented by never-smoking young individuals. However, we also encounter elderly patients with ALK-rearranged NSCLC over the age of 80 years. We report herein three cases of these patients that we have experienced. CASE REPORT: Three patients with ALK-rearranged NSCLC aged 80 years or older received therapy with the ALK-tyrosine kinase, alectinib. Of them, one was male and two had a history of smoking. Comorbidities, especially heart diseases, were prominent. Long-term survival was achieved with alectinib treatment in two patients. CONCLUSION: ALK-rearranged mutations should be evaluated even in octogenarians with NSCLC, regardless of sex and smoking history. Even if they have comorbid diseases, long-term control might be achieved with alectinib therapy in cooperation with physicians other than chest physicians and medical oncologists.

Distant organ metastasis patterns in lung cancer patients with pancreatic metastasis - a cluster analysis.

Introduction: Pancreatic metastasis of lung cancer is rare, but the narrowing or obstruction of the biliary tract from pancreatic metastases limits the choice of antitumour agents. Lung cancer patients with pancreatic metastasis often have metastasis of other organs. For these patients, however, no studies have been conducted to evaluate distant metastasis sites as metastasis patterns. This study aims to assess whether these patients have specific metastasis patterns at the time of diagnosis of lung cancer. Material and methods: Data were collected from consecutive lung cancer patients with pancreatic metastasis between April 2012 and March 2022. Metastatic patterns were analysed using cluster analysis in patients with lung cancer. Results: During the study period, 33 (2.0%) of 1659 patients were diagnosed as having pancreatic metastasis. Of the 33 patients, 28 (84.8%) were male. Eighteen, 14, and one patient had small cell lung cancer (SCLC), lung adenocarcinoma, and large cell neuroendocrine carcinoma, respectively. They were divided into 3 groups by cluster analysis. A statistically significant difference in metastasis frequency was confirmed among these 3 groups (χ2 test, p = 0.001). Conclusions: In lung cancer patients with pancreatic metastasis, knowledge of the metastatic patterns might be useful for clinical practice in the foreseeable future because it enables more efficient detection of metastatic disease through imaging, and more effective treatment at predicted metastatic sites.

Discontinuation of Immune Checkpoint Inhibitor and Survival in Patients With Non-small-cell Lung Cancer Without a Driver Gene Mutation.

BACKGROUND/AIM: Patients with non-small-cell lung cancer treated with immune checkpoint inhibitors (ICI) might be forced to discontinue treatment for various reasons. We conducted a retrospective study to evaluate the impact of discontinuation of ICI treatment on patient prognosis. PATIENTS AND METHODS: We performed a retrospective study that reviewed the medical charts of 86 patients treated with ICI monotherapy and 34 patients treated with a combination of ICI and chemotherapy during the period from February 2016 to February 2022 at our two hospitals. 'Discontinuation' was defined as a cessation of ICI treatment for more than two cycles for any reason. RESULTS: The two most common reasons for discontinuation were immune-related adverse events and at the request of the patient. Nineteen patients who had discontinued ICI, resumed ICI or another therapy. Discontinuation of ICI treatment was a favorable factor in overall survival in 84 patients with ICI monotherapy as well as in 34 patients treated with chemotherapy combined with ICI. CONCLUSION: This analysis found discontinuation of ICI treatment did not adversely affect prognosis. This suggests that when treating patients with non-small-cell lung cancer with ICI, chest physicians should respond flexibly, and, with careful monitoring, consider discontinuation of ICI.

Prognostic Implication of PD-L1 Expression on Osimertinib Treatment for EGFR-mutated Non-small Cell Lung Cancer.

BACKGROUND/AIM: Real-world data on the clinical outcomes of first-line osimertinib treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations is lacking. This study aimed to reveal the treatment outcomes and prognostic factors of osimertinib as first-line therapy in clinical practice settings. PATIENTS AND METHODS: We retrospectively evaluated clinical outcomes of patients with EGFR-mutated NSCLC treated with osimertinib as first-line therapy across 12 institutions in Japan between August 2018 and March 2020. RESULTS: Among 158 enrolled patients, the objective response rate (ORR) was 68%, and the estimated median progression-free survival (PFS) was 17.1 months [95% confidence interval (CI)=14.5-19.7]. Subgroup analysis showed that PFS in the group with high programmed death-ligand 1 (PD-L1) expression was significantly shorter than that in groups with low or no PD-L1 expression (10.1 vs. 16.1 vs. 19.0 months; p=0.03). Univariate and multivariate analyses demonstrated that high PD-L1 expression was the only independent adverse prognostic factor of osimertinib outcome related to PFS (hazard ratio=2.71; 95%CI=1.26-5.84; p=0.01). In terms of anti-tumor response, there was no statistically significant correlation between PD-L1 expression and the ORR (67% vs. 76% vs. 65%; p=0.51). No significant correlation was also found between PD-L1 and the incidence of de novo resistance to osimertinib (p=0.39). CONCLUSION: Although PD-L1 expression was not associated with either the ORR or frequency of de novo resistance, high PD-L1 expression could be an independent adverse prognostic factor related to PFS in osimertinib treatment.

Pseudoprogression during successful rechallenge of immune checkpoint inhibitor in a NSCLC patient.

Rechallenge of immune checkpoint inhibitors (ICPIs) is one of the attractive but unestablished treatment for recurrent non-small cell lung cancer (NSCLC) patients who have been treated with several-lines of systemic chemotherapy. In some NSCLC patients, effects of ICPI rechallenge therapy have become apparent. In ICPI treatment, although very rare, a phenomenon called pseudoprogression is known. We report the first case of a patient who had pseudoprogression during successful rechallenge of ICPI in a NSCLC patient. Although not fully clarified, factors related to the onset of pseudoprogression and good response to ICPI rechallenge are being investigated. Our case showed that pseudoprogression could be developed even in patients with ICPI rechallenge therapy.

Association between time to treatment failure and peripheral eosinophils in patients with non-small cell lung cancer treated with immune checkpoint inhibitors.

Introduction: There is an unmet clinical need to identify biomarkers predicting which patients with non­small cell lung cancer (NSCLC) would benefit from treatment with immune checkpoint inhibitors (ICPIs). Objectives: The purpose of this study was to draw a detailed time to treatment failure (TTF) curve with information on the changes in peripheral eosinophil expression during ICPI treatment for NSCLC, and to clarify whether eosinophil expression can predict prolonged TTF. Patients and methods: In 259 patients with NSCLC treated with ICPI therapy, peripheral eosinophil counts and percentages at the time of each ICPI administration were evaluated from the beginning of ICPI treatment up to TTF. Univariable and multivariable analyses were performed to identify clinical factors associated with TTF. Results: Patients receiving ICPI monotherapy (n = 180) were divided into 3 groups (TTF ≤6 weeks, TTF >6 weeks and ≤24 weeks, and TTF >24 weeks) and the number of patients with an eosinophil percentage of 5% or more within 6 weeks of ICPI therapy initiation was significantly different among these groups. In univariable and multivariable analyses, performance status of 0 to 1, immune-related adverse event not requiring ICPI discontinuation as well as an eosinophil percentage of 5% or more and an eosinophil count of 330/µ or more within 6 weeks of ICPI therapy initiation were significant favorable factors for prolonged TTF. In patients treated with combination therapy of ICPI and chemotherapy (n = 79), the number of patients with an eosinophil percentage of 5% or more within 12 weeks of therapy initiation was significantly different between patients with a TTF of up to 12 weeks and those with a more prolonged TTF. However, the only significant favorable factor for TTF was female sex. Conclusions: In NSCLC patients treated with ICPI therapy, particularly ICPI monotherapy, eosinophil measurements during treatment might be useful for predicting prolonged TTF.

Long-term outcomes of high-dose (74 GyE) proton beam therapy with concurrent chemotherapy for stage III nonsmall-cell lung cancer.

BACKGROUND: To evaluate the long-term outcomes of high-dose (74 GyE) proton beam therapy (PBT) with concurrent chemotherapy for stage III non-small cell lung cancer (NSCLC). METHODS: Between July 2007 and March 2018, 45 patients with stage III NSCLC were treated with passive-scattering PBT of 74 GyE and concurrent chemotherapy. Among the 45 patients, the median age was 62 years (range 39-79 years) and 32 patients were men. The clinical stages were stage IIIA in 14 patients and stage IIIB in 31 patients. Thirty-six patients received chemotherapy consisting of cisplatin and vinorelbine. RESULTS: The median follow-up time was 42.1 months (range 6.4-127.0 months) for all patients and 63.5 months (range 9.4-127.0 months) for the 12 survivors. The 3- and 5-year overall survival rates were 63.7% and 38.8%, respectively, and the median overall survival was 49.1 months. Over the follow-up period, disease recurrence was observed in 32 (71%) patients. The 3- and 5-year progression-free survival rates were 22.2% and 17.7%, respectively, with a median progression-free survival of 13.1 months. In-field control improved survival and the in-field control rate was better in patients with T0-3 tumors (p = 0.023) and stage IIIA/IIIB-N3 disease (p = 0.030). Dosimetric parameters of the heart and lung were not associated with survival. No grade 4 or 5 acute or late non-hematologic toxicities were observed. CONCLUSIONS: Passive-scattering PBT of 74 GyE with chemotherapy showed favorable survival and a low incidence of severe adverse events in patients with stage III NSCLC.