A phase II study of weekly carboplatin and concurrent radiotherapy in older adults with locally advanced non-small cell lung cancer (LOGIK1902).

BACKGROUND: Concurrent chemoradiotherapy is the standard therapy for locally advanced non-small cell lung cancer (NSCLC). However, there is little evidence supporting its use in older adults. Low-dose daily carboplatin combined with thoracic radiotherapy is considered a standard regimen for this population. To establish a simple and feasible carboplatin administration method, we conducted a study of weekly carboplatin and concurrent radiotherapy for older adults with locally advanced NSCLC. METHODS: This prospective, single-arm, multicenter, phase II clinical trial included patients aged ≥75 years with unresectable stage III NSCLC and Eastern Cooperative Oncology Group performance status 0-1. Patients received chemoradiotherapy (60 Gy/30 fractions plus concurrent weekly carboplatin at an area under curve of 2 mg mL-1 min-1). The primary endpoint was the overall response rate (ORR). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: From July 2020 to June 2022, 37 patients were enrolled from 15 institutions, and 36 patients were evaluable for efficacy and safety. The ORR was 63.9% (95% confidence interval [CI] = 47.6-77.5). Median PFS was 14.6 months (95% CI = 9.1-18.1). Median OS was 25.5 months (95% CI = 17.4-not reached). Grade 4 leucopenia, neutropenia, and thrombocytopenia were observed in one patient (2.8%) each. CONCLUSION: Weekly carboplatin and concurrent radiation therapy was safe in older adults with locally advanced NSCLC, and promising activity was observed.

Cardiovascular safety of pimitespib in patients with advanced solid tumors: An open-label, nonrandomized, phase 1 study.

BACKGROUND: Pimitespib (TAS-116), a first-in-class, oral, selective heat-shock protein 90 inhibitor, is approved as fourth-line treatment for gastrointestinal stromal tumors in Japan. This phase 1 study evaluated the cardiac safety of pimitespib. METHODS: In this open-label, nonrandomized, multicenter study, Japanese patients (aged ≥20 years) with refractory, advanced solid tumors received placebo on day -1, then pimitespib 160 mg daily on days 1-5 of the cardiac safety evaluation period. Electrocardiograms were conducted at baseline, and on days -2, -1, 1, and 5; and blood samples were collected on days 1 and 5. Patients then received once-daily pimitespib for 5 days every 3 weeks. The primary end point was the time-matched difference in QT interval corrected for heart rate using the Fridericia correction (QTcF) between pimitespib and placebo. Pharmacokinetics, safety, and preliminary efficacy were also assessed. RESULTS: Of the 22 patients in the cardiac safety-evaluable population, no clinically relevant QTc prolongation was observed; the upper bound of the one-sided 95% confidence interval for the time-matched difference in change from baseline in QTcF was <20 msec at all time points on days 1 and 5. Pimitespib pharmacokinetic parameters were consistent with previous data, and the time-matched difference in change from baseline in QTcF showed no marked increase as plasma concentrations increased. The safety profile was acceptable; 40% of patients experienced grade 3 or greater adverse drug reactions, mostly diarrhea (20%). The median progression-free survival was 3.1 months. CONCLUSIONS: In Japanese patients with refractory, advanced solid tumors, pimitespib was not associated with clinically relevant QTc prolongation, and there were no cardiovascular safety concerns. PLAIN LANGUAGE SUMMARY: Pimitespib is a new anticancer drug that is being used to treat cancer in the stomach or intestines (gastrointestinal stromal tumors). This study demonstrated that pimitespib had no marked effect on heart rhythm or negative effects on the heart or blood vessels and had promising anticancer effects in Japanese patients with advanced solid tumors who were unable to tolerate or benefit from standard treatment.

Multicenter Pharmacokinetic and Pharmacodynamic Study of Pembrolizumab for Non-small-Cell Lung Cancer in Patients Aged 75 Years and Older.

Pembrolizumab is a major treatment for recurrent or advanced non-small-cell lung cancer (NSCLC). However, data on its use and pharmacokinetics (PK) in older patients are limited. This open-label, multicenter, observational study evaluated real-world data on the safety, efficacy, and PK of pembrolizumab in older patients with NSCLC. In 99 patients aged ≥75 years, PK was determined by liquid chromatography-mass spectrometry on pretreatment samples. Performance status (PS), geriatric assessment (GA), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. The median age was 78 (75-87) years. PS was 2-3 in 14 patients. The median ORR, PFS, and OS were 47.5%, 8.0, and 20.5 months, respectively. Although PK and ORR were not significantly associated, patients with the lowest Cycle 1-trough quartile (Q1) experienced poorer PFS (Q1 vs. Q2-4; 3.4 vs. 11.8 months, P = 0.006) and OS (Q1 vs. Q2-4; 9.9 vs. 21.7 months, P = 0.005) than in other quartiles overall, and even in the PD-L1 ≥50% subset (PFS, Q1 vs. Q2-4; 4.1 vs. 14.7 months, P = 0.005; OS, Q1 vs. Q2-4; 9.4 vs. 22.1 months, P = 0.010). The Q1 subgroup was characterized by poor PS and lower albumin, and more frequent "weight loss ≥ 10%" on the GA. Pembrolizumab therapy had similar PK and efficaciousness in older as well as younger patients. In patients with PS ≥2, low albumin, and vulnerable GA, early increases in PK levels are less likely, potentially diminishing efficacy even when PD-L1 ≥50%.

Reconsidering the Cutoff Value for Sensitive and Refractory Relapses in Extensive-Stage SCLC in the Era of Immunotherapy.

INTRODUCTION: Traditionally, relapsed SCLC has been classified as "sensitive" or "refractory" on the basis of cutoff values (60 or 90 d) for the duration between the last chemotherapy and disease progression. Nevertheless, these cutoff values are not derived from rigorous analytical methods, and their applicability to contemporary treatments remains uncertain. METHODS: We conducted a retrospective multicenter study on patients with extensive-stage SCLC who underwent second-line therapy after platinum-doublet chemotherapy with or without immune checkpoint inhibitor (ICI) resistance before (pre-ICI cohort) and after (post-ICI cohort) approval of combination immunotherapy. We selected the optimal platinum-free interval cutoff value with the lowest two-sided p value in the multivariable Cox regression model for second-line overall survival. The internal validity of the chosen cutoff value was assessed using twofold cross-validation. RESULTS: There were 235 and 98 patients in the pre-ICI and post-ICI cohorts, respectively. In the pre-ICI cohort, the optimal cutoff was 59 days (p = 0.0001); the hazard ratio calculated using twofold cross-validation was 1.31 (95% confidence interval: 0.95-1.82]). In the post-ICI cohort, although the 60- and 90-day cutoff values could predict prognosis (60 d; p = 0.002, 90 d; p = 0.005), the optimal cutoff value was 75 days (p = 0.0002), which resulted in a median second-line overall survival of 15.9 and 5.0 months for patients with sensitive and refractory relapse, respectively (hazard ratio = 2.77, 95% confidence interval: 1.56-4.93). CONCLUSIONS: We clarified the previously ambiguous cutoff values for classifying relapsed SCLC and revealed that the 75-day cutoff most accurately predicts subsequent prognosis than the traditional cutoffs in the post-ICI era.

A Phase â ¡ Study of Ubenimex Combined With Pembrolizumab, Nab-Paclitaxel, and Carboplatin for Previously Untreated Advanced Squamous Non-Small-Cell Lung Cancer: TORG2241 (UBE-Q).

BACKGROUND: According to the results of the KEYNOTE-407 trial, pembrolizumab plus platinum-based chemotherapy is the standard of care for patients with previously untreated advanced squamous non-small-cell lung cancer (NSCLC). Ubenimex, a potent aminopeptidase inhibitor, is an oral drug with immunostimulatory and antitumor activities. We aim to assess the safety and efficacy of ubenimex in combination with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. PATIENTS AND METHODS: This prospective, single-arm, multicenter, phase II clinical trial is conducted to confirm the tolerability and efficacy of the tested drugs. Patients with previously untreated advanced squamous NSCLC will receive a predetermined daily dose of ubenimex orally plus 4 cycles of pembrolizumab, nab-paclitaxel, and carboplatin, followed by continuous administration of ubenimex and pembrolizumab for a maximum of 2 years. To confirm tolerability, the daily dose of ubenimex will begin at level 1 (30 mg), which will be increased to levels 2 (60 mg) and 3 (120 mg) according to the escalation criteria, with a standard 3 + 3 design for achieving the target dose-limiting toxicity rate of 33%. The efficacy, safety, and tolerability of ubenimex at the determined dose level will be analyzed. The primary endpoint of the efficacy evaluation will be the objective response rate assessed by an independent review committee. CONCLUSIONS: This is the first study to evaluate the efficacy and safety of ubenimex combined with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. The results will help devise future treatment strategies.

Tumor microenvironment-mediated immune profiles and efficacy of anti-PD-L1 antibody plus chemotherapy stratified by DLL3 expression in small-cell lung cancer.

BACKGROUND: Delta-like ligand 3 (DLL3) is a therapeutic target in small-cell lung cancer (SCLC). However, how DLL3 expression status affects the tumor microenvironment (TME) and clinical outcomes in SCLC remains unclear. METHODS: This retrospective study included patients with postoperative limited-stage (LS)-SCLC and extensive-stage (ES)-SCLC treated with platinum and etoposide (PE) plus anti-programmed cell death ligand 1 (PD-L1) antibody. We investigated the relationship of DLL3 expression with TME, mutation status, tumor neoantigens, and immunochemotherapy. RESULTS: In the LS-SCLC cohort (n = 59), whole-exome sequencing revealed that DLL3High cases had significantly more neoantigens (P = 0.004) and a significantly higher rate of the signature SBS4 associated with smoking (P = 0.02) than DLL3Low cases. Transcriptome analysis in the LS-SCLC cohort revealed that DLL3High cases had significantly suppressed immune-related pathways and dendritic cell (DC) function. SCLC with DLL3High had significantly lower proportions of T cells, macrophages, and DCs than those with DLL3Low. In the ES-SCLC cohort (n = 30), the progression-free survival associated with PE plus anti-PD-L1 antibody was significantly worse in DLL3High cases than in DLL3Low cases (4.7 vs. 7.4 months, P = 0.01). CONCLUSIONS: Although SCLC with DLL3High had a higher neoantigen load, these tumors were resistant to immunochemotherapy due to suppressed tumor immunity by inhibiting antigen-presenting functions.

The Glasgow Prognostic Score Predicts Survival Outcomes in Patients with Extensive-Stage Small Cell Lung Cancer.

INTRODUCTION: The Glasgow prognostic score (GPS) is an inflammation-related score based on C-reactive protein and albumin concentrations. Few studies have assessed the correlation between the GPS and the efficacy of chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). Therefore, this study aimed to evaluate the utility of the GPS in predicting the survival outcomes of patients with ES-SCLC. METHODS: This retrospective study evaluated patients with ES-SCLC who had undergone chemotherapy between February 2008 and November 2021. GPS values were evaluated before the initiation of first-line chemotherapy. The Kaplan-Meier method and Cox proportional hazards models were used to assess progression-free survival (PFS) and overall survival (OS). RESULTS: The GPS values of the 113 patients were zero (54 patients, 48%), 1 (37 patients, 33%), and 2 (22 patients, 19%). The median follow-up duration was 10.7 months. Median PFS was 6.2, 5.6, and 3.8 months in the GPS 0, 1, and 2 groups, respectively, suggesting that the GPS zero group had a significantly more favorable PFS than the GPS 2 group (p < 0.001). Median OS was 17.1, 9.4, and 5.6 months in the GPS 0, 1, and 2 groups, respectively, suggesting that the GPS zero group had a significantly more favorable OS than the GPS 2 group (p = 0.001). Multivariate analysis confirmed that a GPS of 2 independently predicted unfavorable PFS (hazard ratio [HR], 2.89; 95% confidence interval [CI]: 1.68-4.88; p < 0.001) and OS (HR, 3.49 [95% CI: 1.83-6.63], p < 0.001). CONCLUSION: The study's findings suggest that the GPS can predict the survival outcomes of patients with ES-SCLC who have undergone chemotherapy. The GPS is an easy-to-calculate biomarker and would be ideal for routine use in clinical settings.

Efficacy and safety of single-dose ivermectin in mild-to-moderate COVID-19: the double-blind, randomized, placebo-controlled CORVETTE-01 trial.

Background: To investigate whether ivermectin inhibits SARS-CoV-2 proliferation in patients with mild-to-moderate COVID-19 using time to a negative COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) test. Methods: CORVETTE-01 was a double-blind, randomized, placebo-controlled study (August 2020-October 2021) conducted in Japan. Overall, 248 patients diagnosed with COVID-19 using RT-PCR were assessed for eligibility. A single oral dose of ivermectin (200 µg/kg) or placebo was administered under fasting. The primary outcome was time to a negative COVID-19 RT-PCR test result for SARS-CoV-2 nucleic acid, assessed using stratified log-rank test and Cox regression models. Results: Overall, 112 and 109 patients were randomized to ivermectin and placebo, respectively; 106 patients from each group were included in the full analysis set (male [%], mean age: 68.9%, 47.9 years [ivermectin]; 62.3%, 47.5 years [placebo]). No significant difference was observed in the occurrence of negative RT-PCR tests between the groups (hazard ratio, 0.96; 95% confidence interval [CI] 0.70-1.32; p = 0.785). Median (95% CI) time to a negative RT-PCR test was 14.0 (13.0-16.0) and 14.0 (12.0-16.0) days for ivermectin and placebo, respectively; 82.1% and 84% of patients achieved negative RT-PCR tests, respectively. Conclusion: In patients with COVID-19, single-dose ivermectin was ineffective in decreasing the time to a negative RT-PCR test. Clinical Trial Registration: ClinicalTrials.gov, NCT04703205.

Multicenter, single-arm phase II study of modified carboplatin/nab-paclitaxel in untreated performance status 2 patients with advanced non-small cell lung cancer: TORG1426.

Background: Currently, only a few treatment options exist for performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC), whereas the carboplatin/nab-paclitaxel (CBDCA/nab-PTX) regimen is attracting attention as a standard of care for PS 0-1 patients because of its wide suitability and modest risk of peripheral neuropathy. However, the treatment dose and schedule should be optimized for PS 2 patients. Therefore, we planned a single-arm phase II study to characterize the efficacy and tolerability of our modified CBDCA/nab-PTX regimen for untreated PS 2 patients with advanced NSCLC. Methods: Enrolled patients were treated with CBDCA (area under the curve 5 on day 1) plus nab-PTX (70 mg/m2 on days 1, 8, and 15) every 4 weeks for up to six cycles. The primary endpoint was the progression-free survival (PFS) rate at 6 months. As exploratory analyses, the reasons for PS 2 (disease burden versus comorbidities/indeterminant) and the Charlson Comorbidity Index (CCI) were evaluated as efficacy indicators. Results: This study was terminated early because of slow accrual. Seventeen patients [median age, 68 years (range, 50-73 years)] received a median of three cycles. The 6-month PFS rate, median PFS, and median overall survival were 20.8% [95% confidence interval (CI): 0-41.6], 3.0 months (95% CI: 1.7-4.3), and 9.5 months (95% CI: 5.0-14.0), respectively. Exploratory analyses suggested better overall survival in patients whose PS was not attributable to the disease burden (median, 9.5 vs. 7.2 months) or whose CCI was ≤3 (median, 15.5 vs. 7.2 months). Grade 3-4 adverse events occurred in 12 (71%) patients, and grade 5 pleural infection occurred in one (6%) patient. Meanwhile, only one (6%) patient each experienced grade 1 peripheral neuropathy and grade 2 interstitial pneumonitis. Conclusions: No conclusion could be drawn from this study because of its early termination. However, our modified CBDCA/nab-PTX regimen might be useful for PS 2 patients who hesitate to use regimens other than nab-PTX, and particularly patients concerned about peripheral neuropathy or interstitial pneumonitis. The potential role of PS 2 and CCI as efficacy predictors for this regimen should be further examined.

The Glasgow Prognostic Score Predicts Survival in Patients with Advanced Non-Small Cell Lung Cancer Harboring Sensitive Epidermal Growth Factor Receptor Mutations Who Are Treated with Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors.

INTRODUCTION: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with sensitive EGFR mutations. The Glasgow prognostic score (GPS) is an inflammation-assessing score based on C-reactive protein and albumin concentrations. Information regarding the association between the GPS and EGFR-TKI treatment effectiveness is limited; hence, we investigated whether the GPS can predict the response of NSCLC to EGFR-TKIs. METHODS: We evaluated 340 patients with NSCLC harboring sensitive EGFR mutations who received EGFR-TKI monotherapy between March 2009 and July 2021. The Kaplan-Meier method and Cox proportional hazards models were used to assess progression-free survival (PFS) and overall survival (OS). RESULTS: After a median follow-up of 26.6 months, patients with a GPS of 0, 1, and 2 had PFS of 15.7, 10.0, and 6.3 months, respectively, and OS of 40.1, 25.8, and 14.4 months, respectively; patients with a GPS of 0 had significantly better PFS and OS than those with a GPS of 1 (p = 0.03, p = 0.001, respectively) or 2 (p < 0.001, p < 0.001, respectively). Multivariate analysis identified poor performance status, stage 4 at diagnosis, type of EGFR-TKI (gefitinib/erlotinib vs. afatinib), and GPS = 2 as predictors of a short PFS. Meanwhile, poor performance status, gefitinib/erlotinib administration, and GPS = 2 were predictors of a short OS. CONCLUSION: The GPS predicted the survival of NSCLC patients harboring sensitive EGFR mutations who were undergoing EGFR-TKI treatment. The GPS might be ideal for routine use in clinical practice, given that it is an easily calculated parameter.

Effects of Ephedra Herb extract on the expression of EGFR-activating mutations and c-Met in non-small-cell lung cancer cell line, H1975, and its combined effects with osimertinib.

We previously reported that the combined application of Ephedra Herb extract (EHE) and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), erlotinib, is effective in suppressing the growth of erlotinib-resistant non-small-cell lung cancer (NSCLC) cell line, H1993, xenograft tumor, and cell proliferation, and that EHE downregulates c-Met and wild-type EGFR in H1993 cells. However, it was unclear whether EHE could affect EGFR with active mutations. Clinically, advanced NSCLC patients who are eligible for EGFR-TKI treatment are those with detected EGFR with activating mutations. Therefore, it is important to clarify the effect of EHE on EGFR with activating mutations. H1975 cells express EGFR with activating mutations, L858R and T790M, and c-Met; this NSCLC cell line was used in the present study. EHE downregulated the expression of EGFR with activating mutations and c-Met, and inhibited autophosphorylation of c-Met. Proliferation of H1975 cells was suppressed by EHE in a concentration-dependent manner. These results suggest that EHE may be effective against NSCLC harboring EGFR with activating mutations. Considering the fact that advanced NSCLC patients, with an EGFR T790M mutation, are currently widely treated with the third-generation EGFR-TKI, osimertinib, we examined the combined effects of osimertinib and EHE on H1975 cells. The osimertinib and EHE combination downregulated the expression of these receptors and suppressed the proliferation of H1975 cells more effectively than did osimertinib alone, suggesting that this combination may be effective in treating patients with advanced NSCLC with the L858R + T790M EGFR mutation and c-Met. Graphical Abstract was created with BioRender.com.

Combination carboplatin and nab-paclitaxel as a first-line treatment for advanced thymic carcinoma.

Thymic carcinoma is a very rare neoplasm for which no optimal chemotherapeutic regimen has been established to date. Hence, we performed this study to investigate the efficacy and safety of carboplatin plus nanoparticle albumin-bound (nab)-paclitaxel as a first-line regimen for patients with advanced thymic carcinoma. We conducted this multi-institutional retrospective cohort study of patients with advanced thymic carcinoma who had received carboplatin plus nab-paclitaxel as a first-line chemotherapy between August 2013 and December 2021. Twelve patients were included in this study and were subjected to efficacy and safety analysis. Their median age was 62 years (range, 47-74 years), and all had an Eastern Cooperative Oncology Group performance status score of 0 or 1. After a median follow-up time of 19.7 months, the overall response rate was 50%; the median progression-free and overall survival times were 8.8 months and 23.3 months, respectively. Chemotherapy-related peripheral neuropathy was observed in 2 patients (16%; each with grade 1). Other toxicities were manageable, and there were no treatment-related deaths. Carboplatin plus nab-paclitaxel as a first-line chemotherapy regimen showed good efficacy and safety in patients with advanced thymic carcinoma.

The Glasgow Prognostic Score Predicts Outcomes of Pembrolizumab or Atezolizumab Monotherapy in Patients with Pretreated Non-Small Cell Lung Cancer.

INTRODUCTION: Predictors of the effectiveness of immune checkpoint inhibitor (ICI) monotherapy in previously treated patients with non-small cell lung cancer (NSCLC) remain ill-defined. We investigated whether the Glasgow prognostic score (GPS) could serve as such predictors. METHODS: Eighty patients treated with pembrolizumab or atezolizumab monotherapy as second- or subsequent-line therapy for NSCLC were retrospectively reviewed, and the associations between GPS, body mass index (BMI), and each of progression-free survival (PFS) and overall survival (OS) were assessed. RESULTS: The median follow-up period was 11.1 months. Patients with a BMI ≥20.4 kg/m2 had significantly longer PFS and OS (3.7 and 22.2 month, respectively) than did those with a BMI <20.4 kg/m2 (2.2 and 11.5 months, respectively). Patients with a GPS of 0 had a significantly longer PFS (6.6 months) than did those with a GPS of 1 (2.2 months, p = 0.002) and 2 (1.8 months, p = 0.029). Patients with a GPS of 0 also had a significantly longer OS (22.2 month) than did those with a GPS of 1 (9.2 months, p = 0.002) and 2 (4.7 months, p = 0.002). Notably, the GPS, BMI, and clinical stage were independent predictors of PFS, while the GPS and performance status were independent predictors of OS. The response rate of patients with a GPS of 0 was significantly higher than that of patients with a GPS of 1-2 (26.2% vs. 7.9%, p = 0.03). CONCLUSION: The GPS is an independent predictor of PFS and OS in patients with NSCLC who received second- or subsequent-line pembrolizumab or atezolizumab monotherapy.

Rationale and protocol design of a phase II study of first-line osimertinib treatment for patients with poor performance status and EGFR mutation-positive non-small cell lung cancer (OPEN/TORG2040).

BACKGROUND: Cancer chemotherapy indications for patients with poor performance status and advanced lung cancer are limited. Molecular targeted drugs, including epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors, can be used in patients with poor performance status owing to their high efficacy and safety. The third-generation EGFR-tyrosine kinase inhibitor osimertinib has demonstrated effectiveness in the initial treatment of advanced EGFR mutation-positive non-small cell lung cancer in patients with good performance status; however, no evidence exists of the drug's effectiveness in patients with poor performance status in a prospective study. We designed a study that aims to investigate the efficacy and safety of first-line osimertinib treatment in patients with advanced non-small cell lung cancer harboring sensitive EGFR mutations and with poor performance status. METHODS: The OPEN/TORG2040 study is a multicenter, single-arm, phase II trial for patients with unresectable, advanced EGFR mutation-positive non-small cell lung cancer with a poor performance status (≥ 2). Eligible patients will receive osimertinib until disease progression or unacceptable toxicity. The primary endpoint is the objective response rate of the first-line osimertinib treatment. Considering a threshold value of 45%, expected value of 70% for objective response rate, one-sided significance level of 5%, statistical power of 80%, and ineligible patients, the sample size was set to 30. The secondary endpoints are disease control rate, performance status improvement rate, and safety and patient-reported outcomes using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Quality of Life Questionnaire and Lung Cancer 13. Time to treatment failure, progression-free survival, and overall survival will also be assessed. DISCUSSION: Our study can determine the clinical benefits of osimertinib treatment in patients with poor performance status, since the clinical outcomes of patients with EGFR mutation-positive non-small cell lung cancer with poor performance status treated with this drug as a first-line treatment have not been sufficiently evaluated. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs041200100 (registration date: February 12, 2021).

Most Important Things and Associated Factors With Prioritizing Daily Life in Patients With Advanced Lung Cancer.

PURPOSE: Patients' values and priorities in their lives should be appreciated from an early phase of incurable diseases such as advanced cancer. However, studies examining these characteristics have been lacking. This study attempted to determine what patients with advanced lung cancer valued most, once they had been diagnosed, and any associated factors. METHODS: Patients with newly diagnosed advanced lung cancer (N = 248) were enrolled in a questionnaire survey conducted at 16 hospitals in Japan. Their priorities were assessed using a free-text response to the question what is the most important thing to you now? at the time of diagnosis and 3 months after diagnosis. The free-text responses were classified into 10 categories for quantification. The clinical characteristics associated with the category describing daily life were further examined. RESULTS: Free-text comments were obtained from 103 (44.0%) and 66 (42.6%) patients at the time of diagnosis and at 3 months, respectively. The most frequent categories were family (at diagnosis: 50.5%; at 3 months: 50.0%) and daily life (at diagnosis: 33.0%; at 3 months: 36.4%), followed by health (at diagnosis: 32.0%; at 3 months: 27.3%) at both time points. The patients mentioning daily life, the issues related to how to spend daily life, showed significantly higher total scores and functional well-being subscale scores on the Functional Assessment of Cancer Therapy-Lung scale at both time points and lower depression scores at diagnosis and lower anxiety scores at 3 months on the Hospital Anxiety and Depression Scale. CONCLUSION: Family and daily life were highly valued by patients with advanced lung cancer at diagnosis. A better quality of life and better mood were associated with mentioning daily life, which should be taken into account in care planning to maintain patients' involvement in daily life even with incurable diseases.

Promising Response to Dabrafenib Plus Trametinib in a Patient with Peritoneal Carcinomatosis from Non Small Lung Cancer Harboring BRAF V600E Mutation.

Background: The prognosis of peritoneal carcinomatosis in patients with lung cancer is poor. However, some cases of peritoneal carcinomatosis from lung cancer harboring specific gene alterations have responded to molecular targeted drugs. B-Raf proto-oncogene (BRAF) mutations occur in about 2-4% of NSCLCs, with about half of these cases having the BRAF V600E mutation. Concomitant inhibition of BRAF with dabrafenib and inhibition of the downstream mitogen-activated protein kinase with trametinib showed efficacy in NSCLC patients with the BRAF V600E mutation. Herein, we report a patient with peritoneal carcinomatosis from lung cancer with the BRAF V600E mutation who responded to dabrafenib plus trametinib. Case Presentation: A 67-year-old Japanese male never-smoker was diagnosed with stage IA3 lung adenocarcinoma. He underwent thoracoscopic left lower lobectomy but developed recurrence of the cancer with peritoneal carcinomatosis 33 months after the operation. An Oncomine Dx target test of the resected specimen was positive for the BRAF V600E mutation. He was started on dabrafenib 150 mg twice per day and trametinib 2 mg once per day. He had a good clinical response to dabrafenib/trametinib therapy with resolution of abdominal distention. He continued dabrafenib/trametinib treatment without disease progression for 7 months, with no severe adverse effects. Conclusion: This case highlights the importance of assessing genetic alterations in lung cancer patients with peritoneal carcinomatosis and treating them with appropriate molecular targeted drugs.

A Randomized Comparison of Nivolumab versus Nivolumab + Docetaxel for Previously Treated Advanced or Recurrent ICI-Naïve Non-Small Cell Lung Cancer: TORG1630.

PURPOSE: The addition of cytotoxic chemotherapy to immune-checkpoint inhibitor (ICI) may enhance antitumor effects. We conducted an open-label randomized phase II/III study to evaluate nivolumab + docetaxel combination therapy in comparison with nivolumab monotherapy for previously treated ICI-naïve non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The primary endpoint of the phase III study was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and toxicity. As ICI and platinum-doublet combination chemotherapy was approved in the first-line setting during this study, patient accrual was discontinued. RESULTS: One hundred twenty-eight patients (each arm, n = 64) were included in the full analysis set. The median OS in nivolumab (arm A) and nivolumab + docetaxel (arm B) was 14.7 months (95% CI, 11.4-18.7) and 23.1 months (95% CI, 16.7-NR), respectively. The HR for OS was 0.63 (90% CI, 0.42-0.95; P = 0.0310). The median PFS in arms A and arm B was 3.1 months (95% CI, 2.0-3.9) and 6.7 months (95% CI, 3.8-9.4), respectively. The HR for progression was 0.58 (95% CI, 0.39-0.88; P = 0.0095). The ORR was 14.0% (95% CI, 6.3-25.8) in arm A and 41.8% (95% CI, 28.7-55.9) in arm B. Hematotoxicity and gastrointestinal adverse events were more common in arm B than in arm A. Two treatment-related deaths were observed, including one patient in arm A who died of pneumonitis and one in arm B who died of myocarditis. CONCLUSIONS: Despite a slightly elevated toxicity, the addition of docetaxel to nivolumab has significantly prolonged the OS and PFS of patients with previously treated ICI-naïve NSCLC.

First-line osimertinib for poor performance status patients with EGFR mutation-positive non-small cell lung cancer: A prospective observational study.

OBJECTIVE: The clinical outcomes of poor performance status (PS) patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who are treated with osimertinib as a first-line treatment have not been sufficiently evaluated. This study aimed to assess the efficacy and safety of osimertinib in chemotherapy-naive and poor PS (2 or more) patients with NSCLC harboring sensitive EGFR mutations. MATERIALS AND METHODS: We assessed the clinical effects of osimertinib as a first-line treatment for patients with poor PS NSCLC with an exon 19 deletion or exon 21 L858R mutation in EGFR. All patients were administered osimertinib (80 mg/day) as the initial treatment. RESULTS: Sixteen patients (nine women and seven men) who were treated between August 2018 and July 2021 were included in this study; their median age was 78 years. The overall objective response rate was 56.3%. The median progression-free survival (PFS) of the entire patient population was 10.5 months and the PS score improved in 8 of 16 patients (50%). The most common adverse event was acneiform rash (42%), followed by diarrhea (36%) and paronychia (36%); none of these were of grade ≥ 3. Interstitial lung disease occurred in 2 patients (12.5%); however, no treatment-related deaths occurred. CONCLUSION: Considering the findings of this study, osimertinib appears to be an effective and safe treatment option for patients with poor PS and advanced NSCLC harboring sensitive EGFR mutations. To obtain conclusive results, further studies with larger cohorts are warranted.