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.

Elements of End-of-Life Discussions Associated With Patients' Reported Outcomes and Actual End-of-Life Care in Patients With Pretreated Lung Cancer.

BACKGROUND: End-of-life discussions for patients with advanced cancer are internationally recommended to ensure consistency of end-of-life care with patients' values. This study examined the elements of end-of-life discussions associated with end-of-life care. MATERIALS AND METHODS: We performed a prospective observational study among consecutive patients with pretreated non-small cell lung cancer after the failure of first-line chemotherapy. We asked oncologists whether they had ever discussed "prognosis," "do not attempt resuscitation," "hospice," and "preferred place of death" with a patient at baseline. The quality of life (QOL) and depressive symptoms of patients were assessed using validated questionnaires at baseline and 3 months later. The end-of-life care that patients received was investigated using medical records. Oncologists' compassion and caregivers' preferences for hospice care were also assessed using questionnaires. Multiple regression analyses were conducted to examine the association between elements of end-of-life discussions and patient-reported outcomes as well as actual end-of-life care. RESULTS: We obtained 200 valid responses at baseline, 147 valid responses 3 months later, and 145 data points for medical care at the end-of-life stage. No element of the end-of-life discussion between the patient and their oncologist was significantly associated with patients' reported outcomes or actual end-of-life care. In addition, oncologists' compassion was significantly associated with improvement in both comprehensive QOL and depressive symptoms, and caregivers' preferences for hospice care and high educational level were significantly associated with hospice death. CONCLUSION: Oncologist-patient alliances and caregivers' involvement in end-of-life discussions may be influential in achieving optimal end-of-life care.

Pneumonitis During Durvalumab Consolidation Therapy Affects Survival in Stage III NSCLC.

Introduction: Durvalumab consolidation therapy is the standard of care after concurrent chemoradiotherapy (CRT) for stage III NSCLC. Immune-related pneumonitis during durvalumab treatment is potentially fatal; however, information is lacking regarding the impact of pneumonitis on patient survival. This study investigates the effect of pulmonary and nonpulmonary immune-related adverse events (irAEs) on the efficacy of durvalumab treatment in patients with stage III NSCLC. Methods: We retrospectively assessed 158 patients who received durvalumab after CRT at nine Japanese institutions between July 2018 and March 2020. Survival outcomes were compared between patients who developed pneumonitis with those who developed irAEs other than pneumonitis. Patients who survived for less than 3 months were excluded to reduce immortal time bias. Results: Among 158 evaluated patients, 76 (48%) experienced grade less than or equal to one irAEs, whereas 82 (52%) experienced grade greater than or equal to two irAEs. Among the patients with grade greater than or equal to two irAEs, those with grade greater than or equal to two pneumonitis (n = 55) were compared with those with grade greater than or equal to two irAEs other than pneumonitis (n = 27). Patients with grade greater than or equal to two pneumonitis exhibited a significantly worse overall survival than those with grade greater than or equal to two irAEs that excluded pneumonitis. Multivariate analysis revealed that grade greater than or equal to two pneumonitis (hazard ratio = 3.71; 95% confidence interval, 1.85-7.45; p < 0.001) and squamous histology (hazard ratio = 2.64; 95% confidence interval, 1.29-5.42; p = 0.008) were independently associated with worse overall survival. Conclusions: After minimizing immortal time bias, pneumonitis grade two or greater and squamous histology were poor prognostic factors in patients who received consolidation durvalumab after CRT.

Enhancing tumour content and tumour cell count using microdissection contributes to higher detection rate of genetic mutations by next-generation sequencers.

Background: Next-generation sequencing (NGS) analysis is becoming indispensable for the treatment of advanced lung cancer. NGS analysis requires a large number of cancer cell-containing tissues; however, it is often difficult for small biopsies to obtain the required quantities. In microdissection, only the tumour parts of a tissue specimen are obtained, which thereby increases the tumour content and tumour cell count of the tissue specimen. In this study, we investigated the extent to which the detection rate of genetic mutations changes by increasing the tumour content using microdissection. Patients and methods: This is a retrospective study. In the genetic panel test using the Oncomine Dx Target Test (ODxTT), participants were divided into two groups: before (group A; April 2021-March 2022) and after (group B; April 2022-December 2022) the introduction of microdissection. The submission criteria for ODxTT were tumour content and tumour cell count >30 % and >2000 in group A, and >40 % and >5000 in group B, respectively. We compared the rate of genetic mutations detected using ODxTT between the two groups. Results: This study included 214 consecutive ODxTT cases between April 2021 and December 2022. In group A (n = 112), 65 cases were adenocarcinoma, 84 involved lung tissue, and 64 underwent bronchoscopic sampling, whereas in group B (n = 102), 55 cases were adenocarcinoma, 91 cases involved lung tissue, and 79 cases underwent bronchoscopic sampling. Furthermore, genetic mutations were detected in 39 of 112 cases (35 %) in group A and 59 of 102 cases (58 %) in group B, which was statistically higher in group B (P = 0.0006). Genetic mutations were detected in 45 of 55 adenocarcinoma cases in group B. The genetic mutations detected in epidermal growth factor rescepor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and mesenchymal epithelial transition (MET) were higher in group B. Conclusion: Increasing the number of tumour cells and tumour content can enhance the detection rate of genetic mutations using ODxTT.

Osteoblastic bone reaction in non-small cell lung cancer harboring epidermal growth factor receptor mutation treated with osimertinib.

BACKGROUND: Osteoblastic bone reaction (OBR) refers to an increase in bone density at the site of bone metastasis or the appearance of new sclerotic bone lesions after anticancer treatment. OBR can be misunderstood as disease progression. In this study, we aimed to investigate the prevalence and details of OBR and its association with clinical outcomes in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) treated with osimertinib. METHODS: This was a single-center, retrospective cohort study. We reviewed patients who were diagnosed with EGFR-mutant NSCLC with bone metastasis and received osimertinib as a first-line treatment between February 2018 and October 2022. The OBR was evaluated by comparing baseline computed tomography (CT) scans with the first CT scan after treatment initiation. RESULTS: A total of 45 patients were included in this study. Thirty-seven patients (82%) developed OBR. OBR developed in 94% (n = 16) of patients with sclerotic bone lesions (n = 17) at baseline. Similarly, OBR developed in lytic and mixed bone lesions in 76% and 82% of patients with lytic and mixed lesions, respectively. Progression-free survival (PFS) did not differ significantly between patients with (OBR group) and without OBR (non-OBR group) (median PFS, 24 months vs. 17 months; hazard ratio (HR), 0.62; 95% CI, 0.24-1.6; p = 0.31). In univariate analysis, the OBR group showed a trend toward longer skeletal-related events-free survival (SRE-FS) than the non-OBR group (median SRE-FS, 26 months vs. 12 months; HR, 0.53; 95% CI, 0.21-1.33; p = 0.16). Multivariate analysis showed OBR was a significant independent predictor of SRE-FS (HR, 0.35; 95% CI, 0.13-0.92; p = 0.034). CONCLUSIONS: OBR developed in most patients with NSCLC and bone metastasis who received osimertinib treatment. The increased incidence of OBR in patients with EGFR-mutant NSCLC with bone metastasis treated with osimertinib should not be confused with disease progression, and treatment decisions should be made carefully.

Impact of Lymphopenia Recovery After Chemoradiotherapy on Durvalumab Consolidation Therapy in Stage III NSCLC.

Introduction: Durvalumab maintenance therapy after definitive concurrent chemoradiotherapy (CRT) is the standard treatment modality for stage III NSCLC. Although severe treatment-related lymphopenia (TRL) during CRT may impair the efficacy of subsequent durvalumab therapy, data on the effect of TRL recovery on consolidation durvalumab therapy are lacking. Methods: This retrospective study evaluated patients with unresectable stage III NSCLC treated with durvalumab after concurrent CRT. The patients were enrolled across nine institutes throughout Japan between August 2018 and March 2020. The effect of TRL recovery on survival was evaluated. The patients were divided into two groups on the basis of their lymphocyte recovery status: the recovery group involved patients who did not experience severe TRL or experienced TRL but exhibited lymphocyte count recovery at durvalumab initiation, and the nonrecovery group involved patients who experienced severe TRL and did not exhibit lymphocyte count recovery on durvalumab initiation. Results: Among the 151 patients evaluated, 41 (27%) and 110 (73%) patients were classified into the recovery and the nonrecovery groups, respectively. The nonrecovery group had significantly worse progression-free survival than the recovery group (21.9 mo versus not reached, p = 0.018). Recovery from TRL (p = 0.027) and high pre-CRT lymphocyte count (p = 0.028) independently influenced progression-free survival. Conclusions: Baseline lymphocyte count and recovery from TRL at the start of durvalumab therapy were predictive factors for survival outcomes in patients with NSCLC treated with durvalumab consolidation after concurrent CRT.

Possible False Results With cobas® EGFR Mutation Test v2 and Oncomine Dx Target Test for EGFR Mutation.

BACKGROUND/AIM: Disparities in the results of next-generation sequencing-based multiplex gene panel tests and those of single-gene tests when detecting epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) have been reported. However, the possible underlying causes have not been investigated. The aim of this study was to explore the possibilities and causes of false results obtained using cobas® EGFR Mutation Test v2 (cobas® EGFR) and Oncomine Dx Target Test (ODxTT). PATIENTS AND METHODS: The data of patients with NSCLC who underwent gene assessment using both cobas® EGFR and ODxTT between April 2021 and May 2022 were retrospectively reviewed. Disparate results of EGFR mutation analyses were then reviewed. RESULTS: One hundred and sixteen patients were included in the analysis. The results of six samples were inconsistent. In four samples, exon 20 insertion mutations were detected using cobas® EGFR, but not identified using ODxTT. A fragment analysis was performed on three of the four samples, and all showed negative results for exon 20 insertion. Furthermore, one false negative result was obtained in the ODxTT for both exon 19 deletion and L858R mutations. For exon 19 deletion mutation, a single nucleotide variant from adenine to thymine was identified close to the mutation site. CONCLUSION: False positives for exon 20 insertion may occur when using cobas® EGFR, and false negatives for exon 19 deletion and L858R mutations may occur when using ODxTT.

Right-sided vocal cord paralysis following stereotactic body radiation therapy for non-small-cell lung cancer: A case report.

Vocal code paralysis (VCP) is a rare complication of stereotactic body radiation therapy (SBRT). In most previously reported cases of VCP after SBRT, VCP was left-sided because of anatomic vulnerability. Here, we report a case of right-sided VCP following SBRT for non-small-cell lung cancer. The patient was an 81-year-old man who underwent SBRT for synchronous lung cancer of the right upper and inferior lobes. He subsequently developed radiation pneumonitis and received corticosteroids. Lung contraction persisted, and the mediastinum shifted to the right because of lung volume reduction. After corticosteroids discontinuation, the patient developed hoarseness and voice weakness. An endoscopic test showed right-sided VCP. Imaging examinations did not reveal new lesions, including lung cancer recurrence. Therefore, we diagnosed the patient with SBRT-associated VCP and speculated that the injury to the right vagal nerve and recurrent laryngeal nerve resulted from mechanical traction due to intense lung contraction, which might have induced VCP. We should be alert to VCP following SBRT, even if the target lesions are right-sided.

Cerebral infarction after treatment with dabrafenib plus trametinib for BRAF-V600E-positive non-small cell lung cancer: A case report.

Dabrafenib plus trametinib is the standard treatment for BRAF V600E-mutated non-small cell lung cancer. No treatment-related cerebral infarction (CI) has been reported in previous clinical trials. Here, we described a 61-year-old Japanese man with BRAF V600E-mutated lung adenocarcinoma treated with dabrafenib plus trametinib as a third-line treatment. On the 10th day of dabrafenib plus trametinib treatment, the patient developed fever and was urgently hospitalized on the 18th day owing to impaired consciousness. The patient had disseminated intravascular coagulation because of infection, was treated with thrombomodulin and ceftriaxone, and subsequently improved. On the 44th day, dabrafenib plus trametinib was resumed with a one-step dose reduction. Three hours after the first oral administration, the patient developed chills, fever, and hypotension. He received intravenous fluids. On the 64th day, 20 mg prednisolone was administered from the previous day, and dabrafenib plus trametinib was resumed with a further one-step reduction in dose. Five hours after the first oral administration, the patient developed fever, hypotension, paralysis of the right upper and lower limbs, and dysarthria appeared. Head magnetic resonance imaging revealed multiple cerebral infarcts. Hemoconcentration because of intravascular dehydration may have caused CI. In conclusion, CI should be taken into consideration during treatment with dabrafenib plus trametinib.

Sequencing strategies with ramucirumab and docetaxel following prior treatments for advanced non-small cell lung cancer: a multicenter retrospective cohort study.

OBJECTIVES: Ramucirumab (RAM) and docetaxel (DOC) are commonly used after first-line therapy for advanced non-small cell lung cancer (NSCLC). Therefore, we aimed to elucidate sequencing strategies of RAM and DOC following prior treatments, including immune checkpoint inhibitor (ICI), cytotoxic agent (CTx) alone, bevacizumab (BEV), and tyrosine kinase inhibitor (TKI). METHODS: We recruited patients with NSCLC who received RAM and DOC and compared the groups with and without prior ICI, CTx alone, BEV, and TKI, respectively. By tumor response to such treatments, the patients were further classified into "complete response (CR) + partial response (PR)," "stable disease," and "progressive disease" groups, respectively. We compared RAM and DOC efficacy among these groups. RESULTS: In total, 237 patients were registered. In the group with prior ICI, the objective response rate and disease control rate were significantly higher than those without prior ICI (p = 0.012 and 0.028, respectively), and the median progression-free survival (PFS) was also significantly longer (p = 0.027). There were no significant differences in PFS between the groups with and without CTx alone, BEV, and TKI. Multivariate analysis revealed that prior ICI was an independent factor associated with better PFS. Furthermore, the prior ICI group with CR + PR significantly prolonged PFS compared to the group without prior ICI (p = 0.013). CONCLUSION: RAM and DOC may be preferably administered after ICI, rather than after CTx alone, BEV, or TKI, and, furthermore, enhanced if the prior ICI has a favorable tumor response.

Bevacizumab Plus Carboplatin Plus Nab-paclitaxel for Non-squamous Non-small Cell Lung Cancer in a Real-world Setting.

BACKGROUND/AIM: Regimens with bevacizumab (Bev) have high response rates. We previously showed the efficacy of Bev plus carboplatin (CBDCA)/nab-paclitaxel (nab-PTX) in the treatment of non-squamous (non-SQ) non-small lung cell cancer (NSCLC) with malignant pleural effusion in a phase II trial. However, few studies have reported the efficacy and safety of this regimen. Therefore, we conducted a retrospective analysis of the efficacy and safety of Bev plus CBDCA/nab-PTX for patients with NSCLC. PATIENTS AND METHODS: We included patients with non-SQ NSCLC that underwent any number of treatment lines. Patients received a maximum of six cycles of Bev plus CBDCA/nab-PTX every three to four weeks followed by Bev plus nab-PTX every three to four weeks without disease progression or severe toxicities. The administration dose was left to the discretion of the attending physician. RESULTS: We enrolled 48 patients treated with Bev plus CBDCA/nab-PTX between June 2015 and August 2021. The best response rate was 56.3% and the disease control rate was 79.2%. Twenty-three patients received maintenance therapy. Median progression-free and overall survival times were 6.8 and 10.4 months, respectively. Common adverse events included hematological toxicities, including ≥grade 3 neutropenia and neurosensory toxicity. One patient experienced severe bleeding events (grade 3 gastrointestinal bleeding) and another experienced grade 5 toxicity (infection). CONCLUSION: The combination of Bev plus CBDCA/nab-PTX showed good efficacy with acceptable toxicities in non-SQ NSCLC patients, despite the inclusion of patients with late treatment lines and poor performance status.

Outcomes of Chemoimmunotherapy Among Patients With Extensive-Stage Small Cell Lung Cancer According to Potential Clinical Trial Eligibility.

Importance: Chemoimmunotherapy is the standard first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). However, whether findings from pivotal trials can be extrapolated to the clinical practice setting remains unclear. Objective: To compare treatment outcome gaps following first-line chemoimmunotherapy for patients with ES-SCLC between those who met and did not meet the eligibility criteria used in previous clinical trials. Design, Setting, and Participants: A prospective cohort study was conducted from September 1, 2019, to September 30, 2020, at 32 hospitals in Japan, with at least 12 months of follow-up. Participants included consecutive patients with ES-SCLC who received carboplatin and etoposide with atezolizumab as first-line therapy. Exposures: Patients who met eligibility criteria for pivotal phase 3 clinical trials were considered trial-eligible. Main Outcomes and Measures: The primary outcome was 6-month progression-free survival. The secondary outcomes were differences in progression-free survival, overall survival, and safety according to whether key clinical trial eligibility criteria were met. Results: A total of 207 patients were analyzed (median age, 72 years; range, 46-87 years; 170 [82%] were male). Sixty-four patients (31%) were older adults (age ≥75 years), and most (184 [89%]) had an Eastern Cooperative Oncology Group performance status of 0 or 1. There were 132 (64%) trial-eligible patients. The 6-month progression-free survival rate for all patients was 38.8% (95% CI, 32.4%-45.7%). The median progression-free survival was 5.1 months in trial-eligible patients and 4.7 months in trial-ineligible patients (hazard ratio, 0.72; 95% CI, 0.53-0.97; P = .03). The proportion of patients who achieved disease control was 93% (118 of 127) in trial-eligible patients and 77% (55 of 71) in trial-ineligible patients (P = .002). The median overall survival was 15.8 months in trial-eligible patients and 13.1 months in trial-ineligible patients (hazard ratio, 0.73; 95% CI, 0.51-1.07; P = .10). The rate of severe adverse events was numerically higher among trial-ineligible patients than among trial-eligible patients (39% vs 27%; P = .07). Conclusions and Relevance: In this cohort study, the overall treatment outcome was comparable to that reported in pivotal clinical trials. However, treatment outcomes after chemoimmunotherapy might differ between trial-eligible and trial-ineligible patients. These findings suggest that trial-eligibility criteria may be useful in clinical practice, and further studies using data from clinical practice settings are required to inform regulatory approval and clinical decision-making.

Opioids impair nivolumab outcomes: a retrospective propensity score analysis in non-small-cell lung cancer.

OBJECTIVES: Opioids are often administered for cancer-related pain relief. However, few reports have evaluated the association between opioids and immune checkpoint inhibitor treatment for patients with non-small-cell lung cancer (NSCLC). The aim of this retrospective study was to reveal the effect of opioids on the prognosis of patients harbouring NSCLC treated with nivolumab. METHODS: The medical records of consecutive patients with NSCLC receiving nivolumab at our institution were retrospectively reviewed. We collected clinical data at the time of nivolumab treatment initiation. Propensity score matching (PSM) was performed to minimise potential selection bias. We compared clinical outcomes with and without baseline opioid use. RESULTS: Of the 296 patients identified in the study, after PSM, 38 cases with opioid use and matched 38 cases without opioid use were selected. The overall response rate was significantly lower in patients with opioid use than in those without (2.63%, 95% CI 0.47% to 13.49%, vs 21.05%, 95% CI 11.07% to 36.35%; p=0.0284). The median progression-free survival in patients with opioid use was significantly shorter than that in patients without (1.17, 95% CI 0.93 to 1.73 months, vs 2.07 95% CI 1.23 to 4.73 months; p=0.002). The median overall survival in patients with opioid use was significantly shorter than that in patients without (4.20, 95% CI 2.53 to 6.20 months, vs 9.57, 95% CI 2.23 to not reached months; p=0.018). CONCLUSIONS: Patients with NSCLC receiving regular opioid administration at nivolumab treatment initiation had a worse nivolumab treatment outcome than patients without opioid use.

Prospective multicenter cohort study of durvalumab for patients with unresectable stage III non-small cell lung cancer and grade 1 radiation pneumonitis.

OBJECTIVE: Durvalumab was safe and effective in patients with unresectable stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT) in a phase 3 trial (PACIFIC trial). Although a history of radiation pneumonitis (RP) has been reported to increase the risk of exacerbation of pneumonitis associated with programmed death-1 axis inhibitors, the detailed clinical results of durvalumab treatment in patients with baseline grade 1 RP were not reported in the PACIFIC trial. Therefore, we aimed to evaluate the safety and effectiveness of durvalumab therapy in these patients. MATERIALS AND METHODS: This was a multicenter prospective cohort study involving 35 patients. Patients were eligible if they met the following criteria: inoperable stage III NSCLC, administration of durvalumab within 42 days after CCRT using platinum-based chemotherapy, no disease progression after CCRT, Eastern Cooperative Oncology Group performance status of 0-1, and presence of grade 1 RP at baseline. We assessed the effectiveness and safety of durvalumab with a minimum 1-year follow-up period for all patients. RESULTS: Thirty-five patients were enrolled in our study from February 2019 to December 2019. The median progression-free survival was 11.4 months (95 % confidence interval, 7.1 months-not reached), and the median overall survival was not reached. Eleven (31 %) patients had grade ≥2 pneumonitis/RP, 10 (28 %) developed grade 2 pneumonitis/RP, and 1 (3 %) developed grade 5 pneumonitis/RP. Five (14 %) patients experienced treatment-related grade ≥3 adverse events. CONCLUSION: Durvalumab might be safe and effective in patients with stage III NSCLC with baseline grade 1 RP following chemoradiotherapy.

Efficacy of Immune Checkpoint Inhibitor With or Without Chemotherapy for Nonsquamous NSCLC With Malignant Pleural Effusion: A Retrospective Multicenter Cohort Study.

Introduction: Malignant pleural effusion (MPE) is associated with poor treatment outcome in patients with NSCLC receiving immune checkpoint inhibitors (ICIs). ICIs and chemotherapy (ICI/Chemo) combination therapy is currently the standard therapy for NSCLC, and some ICI/Chemo regimens for nonsquamous (non-Sq) NSCLC contain bevacizumab (BEV), which is effective for controlling MPE and may enhance immune response. This study aimed to determine the optimal first-line treatment for this clinical population. Methods: We retrospectively enrolled consecutive patients with non-Sq NSCLC with MPE who received ICI/Chemo or pembrolizumab monotherapy. Treatment outcomes were analyzed in patients with programmed death-ligand 1 (PD-L1) tumor proportion score more than or equal to 50% who were administered ICI/Chemo or pembrolizumab monotherapy (PD-L1 high cohort) and in patients with any PD-L1 status, treated with ICI/Chemo with or without BEV (ICI/Chemo cohort). We used propensity score matching (PSM) to reduce bias. Results: PD-L1 high and ICI/Chemo cohorts included 143 and 139 patients, respectively. In PD-L1 high cohort, 37 patients received ICI/Chemo. With PSM, the median progression-free survival was significantly longer in the ICI/Chemo group than in the pembrolizumab group (11.1 versus 3.9 mo, respectively, p = 0.0409). In the ICI/Chemo cohort, 23 patients received BEV. With PSM, no significant difference occurred in median progression-free survival between BEV and non-BEV groups (6.1 versus 7.4 mo, p = 0.9610). Conclusion: ICI/Chemo seemed more effective than pembrolizumab monotherapy for patients with non-Sq NSCLC with MPE. Nevertheless, the synergistic effect of BEV with ICI/Chemo may be limited. Further studies are needed to clarify the key factor in the tumor-induced immunosuppression environment in these patients.

Retrospective analysis of long-term survival factors in patients with advanced non-small cell lung cancer treated with nivolumab.

BACKGROUND: Nivolumab, an immune checkpoint inhibitor (ICI), has changed the treatment paradigm for advanced non-small cell lung cancer (NSCLC). However, factors associated with long-term survival in NSCLC patients treated with ICIs remain unknown. This study aimed to evaluate patient characteristics and clinical laboratory changes related to long-term survival in NSCLC patients treated with nivolumab, using real-world data. METHODS: We retrospectively reviewed the medical records of consecutive patients with advanced NSCLC with Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1 treated with nivolumab. We defined patients with overall survival (OS) ≥3 years as long-term survivors. We evaluated the differences in patient characteristics and tumor response between nonlong-term survivors and long-term survivors and performed univariate and multivariate analyses of factors associated with long-term survival. RESULTS: Out of 213 patients with advanced NSCLC treated with nivolumab, 162 patients with ECOG-PS ≤1 were included in the study. Young age, ECOG-PS 0, absolute neutrophil count decrease, lymphocyte percentage increase, and neutrophil-to-lymphocyte ratio (NLR) change (ΔNLR) <1 were significantly associated with long-term survival. Long-term survivors had significantly higher response and disease control rates than nonlong-term survivors. Multivariate analysis showed that ΔNLR <1 was significantly associated with long-term survival. Further, OS was significantly different between the PS 0 and PS 1 groups (median OS: 32.0 months vs. 10.6 months) and the nonincreasing NLR and increasing NLR groups (median OS: 20.8 months vs. 5.7 months). CONCLUSIONS: ΔNLR <1 was a significant long-term survival factor compared to ΔNLR ≥1 in advanced NSCLC patients treated with nivolumab.

Efficacy and safety of ramucirumab plus docetaxel in older patients with advanced non-small cell lung cancer: A multicenter retrospective cohort study.

OBJECTIVE: Ramucirumab (RAM) plus Docetaxel (DOC) is one of the standard treatments after first-line treatment failure in patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the efficacy and safety of RAM plus DOC in older patients. We aimed to clarify these and elucidate the prognostic factors. MATERIALS AND METHODS: In this multicenter retrospective study, conducted at four medical facilities in Japan, we evaluated the efficacy and safety data for two groups (<65 and ≥ 65 years). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and log-rank test. Multivariate analysis was performed to reveal the prognostic factors for better PFS and OS. Patient characteristics and adverse events (AEs) in both groups were compared using the Mann-Whitney's U and Fisher's exact tests for categorical variables. RESULTS: A total of 237 patients were included, of whom 43% (n = 103), and 57% (n = 134) were aged <65, and ≥ 65 years. Median OS was 12.2 (95% CI: 9.4-15.0), and 14.8 months (95% CI: 10.8-18.8), respectively, and there were no significant differences between the groups (p = 0.534). Multivariate analysis identified DOC dose reduction (none vs performed, HR: 2.66, 95% CI: 1.62-4.35, p < 0.001) as an independent prognostic factor for OS in older patients, and a similar result was shown for the PFS. Grade ≥ 3 all AEs were identified in 42.7% and 56.7% of younger and older patients, respectively, and there was a significant difference between the groups (p = 0.033); however, the difference between the groups disappeared with primary DOC dose reduction (p = 0.526). CONCLUSION: The efficacy of RAM plus DOC administration in older, pretreated patients with advanced NSCLC was comparable to those of younger patients, whereas RAM plus DOC should be cautiously administered to older patients because of severe toxicity. Moreover, appropriate DOC dose reduction may be recommended for increased survival benefit and safety in such patients.

Effectiveness and safety of opioids for dyspnea in patients with lung cancer: secondary analysis of multicenter prospective observational study.

Background: Patients with lung cancer are more likely to have comorbidities [e.g., interstitial lung disease (ILD)], chronic obstructive pulmonary disease) and metastases that may affect dyspnea and the effectiveness and safety of opioids for dyspnea than other cancer types. Therefore, this study examined the effectiveness and safety of opioids for dyspnea, among the patients with lung cancer. Methods: The present study is a secondary analysis of a multicenter prospective observational study examining the effectiveness and safety of opioids for dyspnea in patients with cancer in Japan. For this secondary analysis, patients with lung cancer with a documented dyspnea Numerical Rating Scale (NRS) at baseline were included. The primary outcome was dyspnea NRS, and Integrated Palliative care Outcome Scale/Support Team Assessment Schedule (IPOS/STAS) scores change between baseline and 24 hours after baseline. As secondary outcomes, we investigated the predictors of opioid effectiveness for dyspnea improvement and adverse events (nausea, somnolence, and delirium). Results: This study analyzed 124 patients with lung cancer with known dyspnea NRS at baseline. The median age was 74, and the Eastern Cooperative Oncology Group performance status of 107 patients were 3-4. Both NRS and IPOS/STAS score of dyspnea significantly improved 24 hours after opioid initiation [-1.64, 95% confidence interval (CI): -2.12 to -1.17, P<0.001; -1.03; 95% CI: -1.21 to -0.85, P<0.001; respectively]. Moreover, the improvement of NRS score was greater than the minimal clinically important difference of 1 point. In the multivariate logistic regression analysis, ILD was significantly associated with a better improvement [(hazard ratio (HR): 3.39, 95% CI: 1.34-11.09, P=0.043]. Somnolence was the most common grade 3-4 adverse event (n=16), followed by delirium (n=9). Conclusions: Opioids were effective and safe for treating dyspnea in patients with lung cancer. Furthermore, lung cancer patients with ILD may benefit more from opioids.

Real-world survey of pneumonitis and its impact on durvalumab consolidation therapy in patients with non-small cell lung cancer who received chemoradiotherapy after durvalumab approval (HOPE-005/CRIMSON).

OBJECTIVES: The incidence of real-world pneumonitis and durvalumab rechallenge during chemoradiotherapy and durvalumab consolidation for non-small cell lung cancer is unknown. MATERIALS AND METHODS: We retrospectively evaluated the medical records of 302 consecutive patients diagnosed with non-small cell lung cancer who started chemoradiotherapy between May 2018 and May 2019. RESULTS: Median age was 70 (range: 40-87) years. Volume of lung parenchyma that received 20 Gy (V20) exceeded 35% in 2% and mean lung dose exceeded 20 Gy in 1% of patients. Durvalumab consolidation was delivered to 225 patients (75%). Overall, 83% (n = 251), 34% (n = 103), 7% (n = 21), and 1% (n = 4) of the patients developed any grade of pneumonitis, symptomatic pneumonitis, ≥grade 3 pneumonitis, and fatal (grade 5) pneumonitis, respectively. Corticosteroids were administered to 25% of the patients to treat pneumonitis. Multivariate analysis identified the predictive factors for the development of symptomatic pneumonitis: V20 Gy or more ≥ 25% (odds ratio [OR]: 2.37, P = 0.008) and mean lung dose (MLD) ≥ 10 Gy (OR: 1.93, P < 0.0047). Of the 52 patients who received corticosteroids for pneumonitis after durvalumab initiation, 21 were rechallenged with durvalumab. Overall, 81% of patients met the PACIFIC study's rechallenge criteria and did not experience a severe pneumonitis relapse. CONCLUSION: High V20 and MLD were independent risk factors of symptomatic pneumonitis. More than 80% of the patients who were rechallenged with durvalumab after pneumonitis met the PACIFIC study's rechallenge criteria. Consequently, severe relapse did not occur. Cooperation between radiation and medical oncologists is important for safe chemoradiotherapy and the safe completion of durvalumab consolidation therapy.