Durvalumab after chemoradiotherapy in non-small cell lung cancer with EGFR mutation: A real-world study (HOT2101).

Durvalumab has been administered to patients with unresectable stage III non-small cell lung cancer (NSCLC). However, it remains unclear whether durvalumab benefits these patients with epidermal growth factor receptor (EGFR) mutation. We conducted a retrospective, multicenter study of patients with EGFR mutation who received chemoradiotherapy (CRT) between June 2018 and March 2021. We assessed patient characteristics, efficacy of durvalumab, and durvalumab safety before and after targeted therapy. We collected data on a total of 673 patients, of whom 401 (59.6%) underwent EGFR mutation testing. Fifty-one patients were EGFR positive and 311 were EGFR negative. In the EGFR-positive group, there were higher proportions of females, never-smokers, and patients with adenocarcinoma histology. Of the 51 patients in the positive group and 311 in the negative group who received CRT, 45 (88.2%) and 247 (79.4%) received durvalumab, with median progression-free survival of 23.0 and 24.2 months in the positive and negative groups, respectively (hazard ratio 1.03; 95% confidence interval: 0.64-1.67). The main adverse event was pneumonitis (positive group: 62.2%; 4.4% grade 3; negative group: 62.3%; 6.9% grade 3). No treatment-related deaths were observed. Of the 45 patients in the positive group who received durvalumab, 14 (31.1%) received targeted therapy after durvalumab at the data cutoff. One patient discontinued targeted therapy after developing pneumonitis. In patients with unresectable stage III NSCLC with EGFR mutation, durvalumab after CRT is potentially safe and effective. This may be a suitable treatment sequence for these patients.

Design of an optical linear-discriminant filter: optimization for enhancement of filter transmittance and discrimination accuracy.

To discriminate fine concave and convex defects on a dielectric substrate, an optical machine learning system is proposed. This system comprises an optical linear-discriminant filter (OLDF) that performs linear discriminant analysis (LDA) of the scattered-wave distribution from target samples. However, the filter output from the OLDF is considerably weak and cannot be measured experimentally. Therefore, an algorithm is also proposed to improve the discrimination accuracy and filter transmittance. The designed filter is validated using a rigorous optical simulator based on vector diffraction theory. We also analyze and discuss a mechanism that provides high transmittance with high discrimination accuracy.

Inverse scattering algorithm for profile reconstruction of a buried defect beneath a dielectric rough surface based on the domain-boundary integral hybrid method.

A reconstruction algorithm for the defect profile beneath a dielectric rough surface using scattered far fields is proposed. This is a fundamental technique for optical measurements, such as diffraction tomography, for defect inspection of microfabricated devices. In general, the profile reconstruction process is considerably time consuming. We propose a domain-boundary integral hybrid method to reduce the number of operations while maintaining the rigor of scattering; the polarization properties, scattering, and multiscattering in the sample are considered. We present reconstruction simulations to validate the proposed algorithm. The reconstruction limit as well as its dependency on sample illumination and rough surface shape are also discussed.

Design of an optical linear discriminant filter for classification of subwavelength concave and convex defects on dielectric substrates.

Identification of the defect type on substrate materials is essential for enhancing their yield ratio. We propose a novel optical filter to discriminate between subwavelength-order concave and convex defects on flat surfaces. This filter performs Fisher's linear discriminant analysis using light wave diffraction. The defect type is discriminated by simply comparing the irradiance at an observation point with the threshold value. Neither the defect image nor phase data, nor a large amount of data processing by a computer, is necessary. Numerical discrimination simulations indicate a discrimination error of 0.85%, and the noise tolerance of the proposed system is also discussed.

Association Between Skin Reaction and Clinical Benefit in Patients Treated with Anti-Programmed Cell Death 1 Monotherapy for Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Anti-programmed cell death 1 antibody is a standard therapy for advanced non-small cell lung cancer (NSCLC). However, immune-related adverse events (irAEs), such as skin reactions, are frequently observed. Although skin reactions are associated with clinical efficacy in melanoma, this association in advanced NSCLC and predictors of irAEs remain unclear. Accordingly, this study identified potential correlations of skin reactions with clinical efficacy and clinical predictors of development of skin reactions. SUBJECTS, MATERIALS, AND METHODS: We retrospectively surveyed patients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital (n = 155) during January 2016 to April 2018. Treatment efficacy was evaluated in patients with and without skin reactions, and associated predictive markers were determined. A 6-week landmark analysis was conducted to assess the clinical benefit of early skin reactions. RESULTS: Skin reactions were observed in 51 patients with a median time to onset of 6.4 weeks. The overall response rate (ORR) was significantly higher in patients with skin reactions (57% vs. 19%, p < .001). Median progression-free survival (PFS) durations of 12.9 and 3.5 months and overall survival durations of not reached and 11.4 months were observed in patients with and without skin reactions, respectively. In the 6-week landmark analysis, the ORR was significantly higher in patients with skin reactions, and skin reactions were significantly associated with increased PFS. A multivariate analysis identified pre-existing rheumatoid factor (RF) as an independent predictor of skin reactions. CONCLUSION: Skin reactions appeared beneficial in patients treated with nivolumab/pembrolizumab for advanced NSCLC and could be predicted by pre-existing RF. Further large-scale validations studies are warranted. IMPLICATIONS FOR PRACTICE: This single-institutional medical record review that included 155 patients with advanced non-small cell lung cancer who were treated with nivolumab or pembrolizumab monotherapy revealed that overall response rate and progression-free survival were significantly better in patients with skin reactions. Pre-existing rheumatoid factor was an independent predictor of skin reactions.

Outcomes associated with immune-related adverse events in metastatic non-small cell lung cancer treated with nivolumab: a pooled exploratory analysis from a global cohort.

BACKGROUND: Immune-related adverse events (irAEs) comprise a distinct spectrum of auto-inflammatory manifestations triggered due to immune checkpoint inhibitors (ICI). Current data on the association of irAEs with outcomes in NSCLC treated with nivolumab are limited. METHODS AND OBJECTIVES: We pooled data from 531 metastatic NSCLC patients from five centers treated with nivolumab after failing platinum-based chemotherapy. The primary objective was to investigate the relationship between irAEs with clinical benefit to nivolumab as well as to elucidate patterns of irAE-related ICI discontinuations and their impact on survival. RESULTS: 33.0% (173/531) of patients treated with nivolumab were noted to have an irAE. Patients with irAEs had a significantly longer median PFS [6.1 vs. 3.1 months, HR 0.68 95% CI (0.55-0.85); p = 0.001] and OS [14.9 vs. 7.4 months, HR 0.66 95% CI (0.52-0.82); p < 0.001)] compared to those without irAEs. In multivariate analysis, the presence of irAEs showed a significantly better PFS [HR 0.69, 95% CI (0.55-0.87); p = 0.002] and a trend for better OS [HR 0.62, 95% CI (0.55-1.03); p = 0.057]. Patients with permanent ICI discontinuation secondary to index irAE had a significantly shorter median PFS [2.3 vs. 6.6 months, HR 1.74 95% CI (1.06-2.80); p = 0.02] and median OS [3.6 vs. 17.6 months; HR 2.61 95% CI (1.61-4.21); p < 0.001] compared to those that did not have permanent ICI discontinuation. CONCLUSIONS: Our pooled exploratory analysis demonstrates improved clinical benefit to nivolumab in NSCLC patients experiencing irAEs. We also observed negative impact of irAE-related treatment discontinuation on survival in this group of patients.

Correction to: Outcomes associated with immune-related adverse events in metastatic non-small cell lung cancer treated with nivolumab: a pooled exploratory analysis from a global cohort.

The original version of this article unfortunately contained a mistake. The second sentence of the section "irAEs and ICI efficacy" should read as.

Profile reconstruction of a local defect in a groove structure and the theoretical limit under the vector diffraction theory.

The profile of a fine local defect in a periodic surface relief structure is reconstructed from a scattered wave. This defect cannot be imaged with an optical imaging system owing to the diffraction limit, and complicated multiscattering among the high-aspect-ratio grooves and the defect makes it difficult to reconstruct the profile using the scalar diffraction theory. We propose and numerically demonstrate a reconstruction algorithm by applying an efficient vector analysis method-the difference-field boundary element method. We also classify the profile according to the difficulty of reconstruction, which depends on the observation system and the noise level. Finally, this analysis provides the accuracy and limit of reconstruction under the vector diffraction theory.

Association of Immune-Related Adverse Events with Clinical Benefit in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Nivolumab.

BACKGROUND: Immune-related adverse events (irAEs) are frequently observed with nivolumab monotherapy. This study aimed to evaluate whether the development of irAEs correlates with treatment response in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We conducted a retrospective study of patients who received nivolumab monotherapy at Sendai Kousei Hospital (n = 70). The patients were categorized into two groups based on the incidence of irAEs: those with irAEs (irAE group) or those without (non-irAE group). Treatment efficacy was evaluated in each group. The patients were further categorized into responders and nonresponders, and predictive factors of treatment response were determined. RESULTS: The objective response rate was 57% in the irAE group versus 12% in the non-irAE group. Median progression-free survival was 12.0 months in the irAE versus 3.6 months in the non-irAE group. The incidence of both irAEs and pre-existing antithyroid antibody was significantly higher in responders than in nonresponders. Multivariate analysis identified incidence of irAEs and pre-existing antithyroid antibody as an independent predictor of treatment response. CONCLUSION: Objective response rate and progression-free survival were significantly better in the irAE than in the non-irAE group in patients with advanced NSCLC treated with nivolumab monotherapy. The development of irAEs was associated with clinical efficacy, and the presence of pre-existing antithyroid antibody might be correlated with treatment response to nivolumab monotherapy. IMPLICATIONS FOR PRACTICE: Immune-related adverse events (irAEs) are frequently observed with nivolumab monotherapy. This study evaluted whether the development of irAEs correlates with treatment response in advanced non-small-cell lung cancer. Results showed that the objective response rate and progression-free survival were significantly better in the patients who developed irAEs than in the patients who did not develop irAEs, and the incidence of irAEs and positivity for antithyroid antibody at pretreatment were independent predictors of treatment response of nivolumab monotherapy. Therefore, the development of irAEs predicts clinical benefit and suggests that cautious management of irAEs can lead to achieving maximum clinical benefit from nivolumab monotherapy.

Field-stitching boundary element method for accurate and rapid vectorial diffraction analysis of large-sized one-dimensional diffractive optical elements.

We propose a field-stitching boundary element method (FSBEM) for diffraction analyses for large diffractive optical elements (DOEs). A field stitching (FS) method separately computes the divided sections of a large DOE and provides the field distribution without field mismatching. However, a divided section must be largely overlapped, which is not efficient in terms of computational resources. In the FSBEM, in addition to spatial division, the electromagnetic field is computed for each component-the reflected, difference, and stitching fields-for rapid convergence of the solution. We validate the FSBEM by computing a one-dimensional DOE and evaluating the convergence property. The sample structure is also computed by the conventional FS method, and the advantages of the FSBEM are discussed.

Fast actual-size vectorial simulation of concave diffraction gratings with structural randomness.

In this study, an actual-size concave grating with structural randomness is numerically analyzed. Numerical electromagnetic analyses that solve Maxwell's equations can provide rigorous diffracted fields including the polarization characteristics. However, because of high computational costs, actual-size gratings with no periodicity have seldom been analyzed. We apply the difference-field boundary element method (DFBEM) for the analyses of actual-size concave gratings with 10,000 random blazed grooves. The DFBEM provides vectorial diffracted or scattered waves with very low computational resources. First, we estimate the accuracy of the computation results, and then we show some relations between the degree of randomness and the diffraction efficiency, including the polarization dependency.

Expansion of the difference-field boundary element method for numerical analyses of various local defects in periodic surface-relief structures.

We expand the difference-field boundary element method (DFBEM) to calculate wave scattering from a variety of local periodic structure defects. The DFBEM is a numerical method for simulating the diffraction caused by a periodic surface-relief structure with a defect. Although it is more efficient than conventional techniques such as the finite-difference time-domain (FDTD) method, the original DFBEM is limited to projection defects. Here, we derive the integral equations and expressions for crack and buried-pillar defects, and also demonstrate some numerical analyses, validating the results by comparison with results from the FDTD method and the dielectric interface boundary conditions.

Successful application of lorlatinib in a 23-year-old patient with anaplastic lymphoma kinase (ALK)-positive lung cancer and multiple brain metastases.

BACKGROUND: Anaplastic lymphoma kinase (ALK)-positive lung cancer has a better long-term prognosis with ALK-inhibitor than other lung cancers. However, resistance to ALK-inhibitors and the control of metastases in the central nervous system (CNS) remain to be a challenge in the management of ALK-positive lung cancer. CASE: We present the case of a 23-year-old man who developed multiple brain metastases while receiving alectinib treatment for ALK-positive lung cancer. After 3 months of lorlatinib initiation, brain metastases disappeared, and complete response (CR) was maintained. CONCLUSION: While lorlatinib can be used as first line therapy, this drug may be considered as second line or later option for patients with multiple brain metastases if the patient has already been treated with other ALK-inhibitors since lorlatinib is thought to have good CNS penetration. This treatment option should be verified by further research.

Immunotherapy or Chemoimmunotherapy in Older Adults With Advanced Non-Small Cell Lung Cancer.

Importance: Immune checkpoint inhibitor (ICI) plus chemotherapy combination treatment (ICI-chemotherapy) is now a standard treatment for non-small cell lung cancer (NSCLC) without targetable oncogene alterations, but there are few data on ICI-chemotherapy for patients 75 years and older. Objective: To inform the choice of first-line drugs in clinical practice and assess the safety and efficacy of ICI-chemotherapy combination treatment in older adult patients with previously untreated advanced NSCLC. Design, Setting, and Participants: This retrospective cohort study included 58 centers in Japan. The cohort consisted of patients 75 years and older with clinical stage IIIB, IIIC, IV, postoperative or radiotherapy recurrent NSCLC. Patients started first-line systemic therapy between December 2018 and March 2021. Those receiving first-line molecular targeted drugs were excluded. The data were analyzed from February 2022 to October 2022. Exposures: Systemic therapy. Main Outcomes and Measures: The main outcomes were overall survival (OS), progression-free survival (PFS), and safety. Results: A total of 1245 patients (median [range] age, 78 [75-95] years; 967 [78%] male) with NSCLC were included in the cohort. Programmed death ligand-1 (PD-L1) expression of less than 1% occurred in 268 tumors (22%); 1% to 49% in 387 tumors (31%); 50% and higher in 410 tumors (33%), and unknown expression in 180 tumors (14%). Median OS was 20.0 (95% CI, 17.1-23.6) months for the 354 patients receiving ICI-chemotherapy (28%); 19.8 (95% CI, 16.5-23.8) months for the 425 patients receiving ICI alone (34%); 12.8 (95% CI, 10.7-15.6) months for the 311 patients receiving platinum-doublet chemotherapy (25%); and 9.5 (95% CI, 7.4-13.4) months for the 155 patients receiving single-agent chemotherapy (12%). After propensity score matching, no differences in OS and PFS were found between the patients receiving ICI-chemotherapy vs ICI alone. Each group consisted of 118 patients. For PD-L1 expression of 1% and higher the OS hazard ratio (HR) was 0.98 (95% CI, 0.67-1.42; P = .90), and the PFS HR was 0.92 (95% CI, 0.67-1.25; P = .59). Significance was also not reached when separately analyzed for lower or higher PD-L1 expression (1%-49% or ≥50%). However, grade 3 or higher immune-related adverse events occurred in 86 patients (24.3%) treated with ICI-chemotherapy and 76 (17.9%) with ICI alone (P = .03). Conclusions and Relevance: In this study, ICI-chemotherapy combination treatment did not improve survival and increased the incidence of grade 3 and higher immune-related adverse events compared with ICI alone in patients 75 years and older. Based on these results, ICI alone may be recommended for older adult patients with PD-L1-positive NSCLC.

Machine learning analysis of pathological images to predict 1-year progression-free survival of immunotherapy in patients with small-cell lung cancer.

BACKGROUND: In small-cell lung cancer (SCLC), the tumor immune microenvironment (TIME) could be a promising biomarker for immunotherapy, but objectively evaluating TIME remains challenging. Hence, we aimed to develop a predictive biomarker of immunotherapy efficacy through a machine learning analysis of the TIME. METHODS: We conducted a biomarker analysis in a prospective study of patients with extensive-stage SCLC who received chemoimmunotherapy as the first-line treatment. We trained a model to predict 1-year progression-free survival (PFS) using pathological images (H&E, programmed cell death-ligand 1 (PD-L1), and double immunohistochemical assay (cluster of differentiation 8 (CD8) and forkhead box P3 (FoxP3)) and patient information. The primary outcome was the mean area under the curve (AUC) of machine learning models in predicting the 1-year PFS. RESULTS: We analyzed 100,544 patches of pathological images from 78 patients. The mean AUC values of patient information, pathological image, and combined models were 0.789 (range 0.571-0.982), 0.782 (range 0.750-0.911), and 0.868 (range 0.786-0.929), respectively. The PFS was longer in the high efficacy group than in the low efficacy group in all three models (patient information model, HR 0.468, 95% CI 0.287 to 0.762; pathological image model, HR 0.334, 95% CI 0.117 to 0.628; combined model, HR 0.353, 95% CI 0.195 to 0.637). The machine learning analysis of the TIME had better accuracy than the human count evaluations (AUC of human count, CD8-positive lymphocyte: 0.681, FoxP3-positive lymphocytes: 0.626, PD-L1 score: 0.567). CONCLUSIONS: The spatial analysis of the TIME using machine learning predicted the immunotherapy efficacy in patients with SCLC, thus supporting its role as an immunotherapy biomarker.

Efficacy of paclitaxel-carboplatin with bevacizumab as a late-line therapy for patients with advanced nonsquamous non-small cell lung cancer: A platinum rechallenge.

BACKGROUND: There is no well-established late-line treatment for advanced nonsquamous non-small cell lung cancer (NSCLC). Therefore, we retrospectively determined the efficacy and safety of platinum rechallenge with paclitaxel-carboplatin and bevacizumab in patients with nonsquamous NSCLC as a late-line therapy in a clinical setting. METHODS: Thirty patients with nonsquamous NSCLC who received paclitaxel-carboplatin with bevacizumab therapy as a late-line treatment at Sendai Kousei Hospital (Miyagi, Japan) between December 2011 and December 2021 were enrolled into the study. The efficacy and safety of this treatment were evaluated. The patients were further categorized into responders and nonresponders, and predictive factors of treatment response were estimated. RESULTS: The median progression-free survival (PFS) was 6.3 (range, 4.9-6.8) months, and the median overall survival (OS) was 11.8 (range, 7.2-17.2) months. There were no significant differences in PFS and OS between patients with and those without epidermal growth factor receptor mutations. In the univariate analyses of this study, responders were younger than nonresponders (p = 0.012). No fatal adverse events were reported. CONCLUSIONS: With the increase in the number of treatment options in recent years, the sequence of treatments and overall therapeutic strategy are becoming increasingly important. Thus, platinum rechallenge with paclitaxel-carboplatin and bevacizumab, a late-line treatment for patients with nonsquamous NSCLC, may be an effective therapeutic option.

Fast and highly accurate boundary element method for scattering calculation of defective gratings.

A numerical scattering calculation method for defective gratings is proposed. This method is based on an integral equation method that computes a difference-field distribution, which is the difference between the scattering fields with and without the defect, and it is possible to simulate the arbitrary (finite) size and shape of a defect in the grating without any limitation. A calculation example is also presented to demonstrate the fast convergence and high accuracy of this method.

Color digital holography using a single monochromatic imaging sensor.

Color digital holography utilizing the Doppler effect is proposed. The time variation of holograms produced by superposing images at three wavelengths is recorded using a high-speed monochromatic imaging sensor. The complex amplitude at each wavelength can be extracted from frequency information contained in the Fourier transforms of the recorded holograms. An image of the object is reconstructed by the angular spectrum method. Reconstructed monochromatic images at the three wavelengths are combined to produce a color image for display.

Simultaneous two-wavelength Doppler phase-shifting digital holography.

This paper presents a method based on the use of an image sensor for obtaining the complex amplitudes of beams diffracted from an object at two different wavelengths. The complex amplitude for each wavelength is extracted by the Doppler phase-shifting method. The principle underlying the proposed method is experimentally verified by using the method with two lasers having different wavelengths to measure the surface shape of a concave mirror.

Pharmacokinetics of edoxaban in EGFR-mutated non-small cell lung cancer patients with venous thromboembolism.

BACKGROUND: The risk of venous thromboembolism (VTE) is increased 7-fold in patients with cancer than in those without. Low-molecular-weight heparin is the standard treatment for cancer-associated VTE. Direct oral anticoagulants (DOACs) are not inferior to low-molecular-weight heparin with respect to the general outcome of recurrent VTE. Warfarin is associated with a risk of bleeding when used in combination with gefitinib or erlotinib which are epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). It is unclear, however, whether combination treatments with EGFR-TKIs and DOACs pose the same risk. We aimed to identify anticancer drugs and anticoagulants that can be used safely in combination, as accompanying research to an observational study on VTE incidence rates in lung cancer patients (Rising-VTE/NEJ037 study). METHODS: Twelve patients receiving EFGR-TKI monotherapy and VTE treatment were enrolled. Blood samples were collected in time series after the first dose of edoxaban, and further samples were collected within 8-15 days after administering EGFR-TKIs. The pharmacokinetics (PK) of edoxaban were analyzed using a non-compartmental model. RESULTS: Edoxaban concentrations (30 mg once daily) were measured in eight patients. PK analyses showed no significant differences before and after co-administration of EGFR-TKIs (gefitinib, erlotinib, and afatinib). CONCLUSIONS: Our findings indicate that the PK of edoxaban was not considerably affected by co-administration of EGFR-TKIs (gefitinib, erlotinib, and afatinib).