The efficacy and safety of anamorelin among patients with diabetes.

BACKGROUND: Anamorelin is a selective ghrelin receptor agonist approved for cancer cachexia in Japan. Little is known about predictors of anamorelin efficacy. This study aimed to assess the effect of diabetes on the efficacy and safety of anamorelin in patients with cancer cachexia. METHODS: Medical records of patients with advanced non-small-cell lung, gastric, pancreatic, or colorectal cancer who received anamorelin between January 2021 and March 2023 were retrospectively reviewed. The diabetic (DM) group included patients with a confirmed diagnosis of type 2 diabetes mellitus, random plasma glucose of ≥ 200 mg/dL, or hemoglobin A1c of ≥ 6.5%. The maximum body weight gain and adverse events during anamorelin administration were compared between the DM and non-DM groups. Patients with a maximum body weight gain ≥ 0 kg were classified as the responders. RESULTS: Of 103 eligible patients, 31 (30.1%) were assigned to the DM group. The DM group gained less weight (median of -0.53% vs. + 3.00%, p < 0.01) and had fewer responders (45.2% vs. 81.9%, p < 0.01) than the non-DM group. The odds ratio for non-response in the DM group was 6.55 (95% confidential interval 2.37-18.06, p < 0.01), adjusted by age and performance status. The DM group had a higher cumulative incidence of hyperglycaemic adverse events (72.2% vs. 6.3%, p < 0.01) and more discontinuations due to hyperglycaemic adverse events (25.8% vs. 4.2%, p < 0.01) than the non-DM group. CONCLUSIONS: Patients with diabetes and cancer cachexia are less likely to gain weight with anamorelin despite a high risk of hyperglycaemic adverse events.

Relationship between patterns of immunohistochemical conventional neuroendocrine markers and efficacy of immune check point inhibitors in patients with extensive disease small cell lung cancer.

BACKGROUND: Which patients benefit from the addition of immune checkpoint inhibitors (ICIs) to chemotherapy for small cell lung cancer (SCLC) remains unclear. There have been few reports on the efficacy of ICIs based on conventional immunohistochemical neuroendocrine (NE) markers (synaptophysin, chromogranin A, and neural cell adhesion molecule [NCAM]). In the present study, we aimed to analyze the relationship between the expression of immunohistochemical NE markers and the efficacy of ICIs in patients with extensive disease (ED)-SCLC, to assess whether conventional NE markers are predictive of ICIs. METHODS: Patients with untreated ED-SCLC who received first-line therapy at the Shizuoka Cancer Center between November 2002 and July 2021 were retrospectively reviewed. We evaluated the efficacy of first-line chemotherapy according to the expression status of each immunohistochemical NE marker in patients treated with ICI plus chemotherapy (ICI-chemo group) and with chemotherapy alone (chemo group). RESULTS: A total of 227 patients were included in the ICI-chemo and chemo groups, respectively. The progression-free survival (PFS) tended to be better in patients in the ICI-chemo group than those treated with chemotherapy alone in patients with NE marker-positive SCLC. In particular, it was statistically significant in patients with chromogranin A-positive SCLC (p = 0.036). In patients with NE marker-negative SCLC, no significant differences were observed in PFS between the two groups. There were no significant differences in overall survival (OS), regardless of the expression of any conventional NE marker. CONCLUSION: Our study suggests that the efficacy of ICIs in addition to chemotherapy may be poor in patients with NE marker-negative SCLC.

Delayed iliopsoas abscess following COVID-19 pneumonia.

Bacterial co-infection has been reported to contribute to a poor prognosis in patients with COVID-19. However, iliopsoas abscess (IPA) has not been previously reported as a comorbidity during the course of COVID-19. We report two cases of IPA in patients with COVID-19 pneumonia. Both patients required prolonged immunosuppressive therapy for COVID-19 pneumonia and developed bacteremia due to Serratia marcescens in one and Staphylococcus aureus in the other. Although immunosuppressive therapy is commonly used for COVID-19 pneumonia with hypoxemia, the comorbidity of IPA may have been underestimated in these cases.

Acute asthma exacerbation due to the SARS-CoV-2 vaccine (Pfizer-BioNTech BNT162b2 messenger RNA COVID-19 vaccine [ComirnatyⓇ]).

The messenger RNA vaccine against SARS-CoV-2 is effective at preventing COVID-19-associated hospitalization, and the Centers for Disease Control and Prevention has recommended vaccination for all eligible individuals. We demonstrate a case involving a patient who developed a life-threatening acute asthma exacerbation after receiving their third dose of the BNT16b2 vaccine. Because eosinophilia was observed after the second inoculation, it was considered likely that the patient had been sensitized to the BNT16b2 vaccine. Theoretically, the SARS-CoV-2 vaccine could trigger the exacerbation of asthma. It should be recognized that repeated SARS-CoV-2 vaccination may be a risk factor for the acute exacerbation of asthma.

Impact of losing adipose tissue on outcomes from PD-1/PD-L1 inhibitor monotherapy in non-small cell lung cancer.

BACKGROUND: Adipose tissue induces inflammation, which desensitizes the efficacy of immunotherapy. However, several reports show that the therapeutic effect of programed cell death 1 (PD-1)/programed death-ligand 1 (PD-L1) inhibitor(s) monotherapy is significantly better in obese patients. Therefore, the effect of adipose tissue on immunotherapy is unclear. METHODS: In this study, we retrospectively reviewed patients with advanced non-small cell lung cancer (NSCLC) who received PD-1/PD-L1 inhibitor monotherapy between May 2016 and December 2018. We classified patients into total adipose tissue maintenance or loss groups according to adipose tissue change during the 6 months before treatment and compared the therapeutic effect of PD-1/PD-L1 inhibitors between these groups along with the presence or absence of cachexia, a poor prognostic factor. RESULTS: Of the 74 patients, 40 (54.1%) were cachexic. Among cachexic patients, we found no clear difference in the overall response rate (ORR) and progression-free survival (PFS) between the total adipose tissue maintenance and loss group. However, among noncachexic patients, the total adipose tissue loss group had a higher ORR (64.7% vs. 23.5%, p < 0.05) and longer PFS (18.5 months vs. 2.86 months, p = 0.037) than the maintenance group. CONCLUSIONS: This study showed that decreasing adipose tissue without cachexia might favor the therapeutic effects of immunotherapy.

Prognostic impact of pneumonitis after durvalumab therapy in patients with locally advanced non-small cell lung cancer.

BACKGROUND: Prognostic data on Japanese patients receiving durvalumab after chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (LA-NSCLC) are insufficient. Whether pneumonitis has prognostic implications in patients with LA-NSCLC who have received durvalumab also remains unclear. METHODS: We retrospectively assessed the data of 82 consecutive patients who had received durvalumab after CRT at our institution between May 2018 and August 2020. A multi-state model was used to establish the associations between co-variables and progression-free survival (PFS). RESULTS: The median observation period for all the censored cases was 14.5 months (5.7-28.9 months), the median PFS was 22.7 months, and the 12-month PFS rate was 62.3% (95% CI: 50.2%-72.3%). The median percentage of the lung volume receiving a radiation dose in excess of 20 Gray (V20) was 22% (4%-35%). Thirteen patients (16%) had Grade 1 pneumonitis before receiving durvalumab, and 62 patients developed pneumonitis after durvalumab (Grades 1, 2, and 3 in 25 [30%], 32 [39%], and 4 [5%], respectively). Twenty-four patients (29%) completed the 1-year durvalumab treatment period, 16 patients (20%) were continuing to receive treatment, and 42 (51%) had discontinued treatment. In a multi-state analysis, patients with pneumonitis before durvalumab therapy had a poorer PFS than those without pneumonitis (HR: 4.29, p = 0.002). The development of Grade 2 or higher pneumonitis after durvalumab was not a significant prognostic factor for PFS (HR: 0.71, p = 0.852). CONCLUSION: Grade 2 or higher pneumonitis after durvalumab was not a prognostic factor of PFS in LA-NSCLC patients received durvalumab.

Impact of weight loss on treatment with PD-1/PD-L1 inhibitors plus chemotherapy in advanced non-small-cell lung cancer.

PURPOSE: Programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors plus chemotherapy have become the standard first line of treatment in patients with advanced non-small-cell lung cancer (NSCLC). However, few studies have explicitly focused on the impact of weight loss on the efficacy of PD-1/PD-L1 inhibitors plus chemotherapy. Thus, we evaluated the clinical implications of weight loss on the survival outcomes in patients who received this treatment. METHODS: We conducted a retrospective review of medical records of patients with advanced NSCLC who were treated with PD-1/PD-L1 inhibitors plus chemotherapy from December 2018 to December 2020. Significant weight loss was defined as an unintentional weight loss of 5% or more over 6 months. We evaluated the progression-free survival (PFS) and overall survival (OS) of patients with or without weight loss. RESULTS: Among the 80 included patients, 37 (46%) had weight loss, and were associated with a lower objective response rate (30 vs 51%, P < 0.05), poorer PFS (2.3 vs 12.0 months, P < 0.05), and poorer OS (10.8 vs 23.9 months, P < 0.05) than those without weight loss. The Cox proportional-hazard ratios (95% confidence interval) of weight loss were 1.77 (1.01-3.10) for PFS and 2.90 (1.40-6.00) for OS, with adjustments for Eastern Cooperative Oncology Group performance status, PD-L1 tumour proportion score, histology, and central nervous system metastases. CONCLUSION: Pre-treatment weight loss may reduce treatment efficacy and shorten survival time in patients receiving PD-1/PD-L1 inhibitors plus chemotherapy. Early evaluation and intervention for weight loss might improve oncological outcomes in patients with advanced NSCLC.

Long-term outcomes in extensive disease small cell lung cancer patients treated without immune checkpoint inhibitors.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have been approved as first-line treatment for patients with untreated extensive disease-small cell lung cancer (ED-SCLC). However, there are few reports about the long-term outcomes in patients with ED-SCLC treated without ICIs. Thus, we analyzed the long-term outcomes in patients with ED-SCLC. METHODS: We retrospectively examined the medical records of patients with SCLC who were treated at our hospital between September 2002 and September 2019. The main inclusion criteria were as follows: (i) histological or cytological confirmation of SCLC, (ii) diagnosed with ED-SCLC and (iii) received chemotherapy, not including ICIs, as the first-line treatment. To assess the trends of treatment outcomes, we compared the survival outcomes between 2002-2010 (early) and 2011-2019 (late) groups. RESULTS: A total of 314 patients were included in this study. Patient characteristics at the time of first-line treatment were as follows: median age was 69 years; 82% of the patients were male and 70% had a performance status of 0 or 1. The median follow-up time of overall survival (OS) was 7.4 years, and 89% of the patients died. The median progression-free survival and survival time were 4.9 and 12.1 months, respectively. Five-year survival rate was 2%. There was no significant difference in survival between the early and late groups. CONCLUSIONS: We found that the long-term outcomes in ED-SCLC patients treated without ICIs were poor. Prior to the approval of ICI treatment for ED-SCLC, there was no improvement in the OS for ~20 years.

Impact of angiogenesis inhibitor eligibility on the prognosis of patients with non-small cell lung cancer harboring EGFR mutation.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are currently the primary treatment option for patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, the effect of EGFR-TKIs are eventually weakened due to resistance, and there is also a differential efficacy based on EGFR mutation subtypes. The combination of angiogenesis inhibitor (AI) with EGFR-TKI has shown better efficacy than EGFR-TKI monotherapy, regardless of the mutation subtypes. Nevertheless, the effect of AI eligibility on overall survival (OS) and progression-free survival (PFS) remains to be elucidated. Thus, we assessed this impact on patients with NSCLC harboring EGFR mutation. METHODS: In this study, the data for 450 patients with EGFR-mutant NSCLC, who were treated with EGFR-TKI monotherapy, were retrospectively analyzed for AI eligibility. The patients were categorized into AI-eligible (AI fit) and ineligible groups (AI unfit). RESULTS: The median PFS of the AI fit group was 12.9 months, compared to 9.6 months in the unfit group (p = 0.007), and OS was also significantly longer in the AI fit group (median OS = 33.0 months) compared to that in the unfit group (18.5 months, p < 0.001). Multivariate analysis indicated that AI ineligibility was associated with shorter PFS and poor prognosis. Also, in the AI fit group, there was no significant difference in the PFS between EGFR L858R mutation and EGFR exon 19 deletion (median PFS = 11.5 months vs. 13.8 months; p = 0.17). CONCLUSIONS: From our study, AI eligibility resulted in longer OS and PFS, and also had different effects on patients with EGFR L858R and exon 19 deletion. Since this selection bias may have affected previous clinical trial data on the efficacy of AI combination therapy, their results should be carefully considered henceforth.

Rechallenge with previously administered epidermal growth factor receptor-tyrosine kinase inhibitors in EGFR-mutated non-small cell lung cancer with leptomeningeal metastasis.

Objectives In EGFR-mutated non-small cell lung cancer (NSCLC) patients, approximately 80-90% of leptomeningeal metastasis (LM) develops after failed initial treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI). However, the efficacy of rechallenging with previously administered EGFR-TKIs in patients with EGFR-mutated NSCLC and the LM that develops following EGFR-TKI treatment failure remains unknown. Materials and methods We retrospectively reviewed medical records of patients with EGFR-mutated NSCLC and LM, from November 2011 to August 2019. The patients were classified according to the LM treatment type: switched to previously unadministered EGFR-TKIs (Switch-TKI) or rechallenge with previously administered EGFR-TKIs (Rechallenge-TKI). Results In total, 50 patients treated with EGFR-TKI after LM diagnosis were included; 35 were treated with Switch-TKI and 15 with Rechallenge-TKI. The median overall survival (OS) from the time of LM diagnosis was 6.2 months in all study patients. According to the treatment type, the median OS from the time of LM diagnosis was 6.9 months in Switch-TKI patients and 4.9 months in Rechallenge-TKI patients. There was no significant difference in the OS between the Switch-TKI and Rechallenge-TKI groups (P = 0.864). Thirty-five patients were treated with erlotinib and 15 with osimertinib; Regardless of the type for EGFR-TKI, there was no significant difference in OS between patients treated with Switch-TKI and those treated with Rechallenge-TKI. Conclusion Rechallenge of previously administered EGFR-TKIs may be a therapeutic option for LM development after EGFR-TKI treatment failure in patients with EGFR-mutated NSCLC, not only switching to previously unadministered EGFR-TKIs.

Detection of programmed cell death-ligand 1 using 22C3 antibody in patients with unresectable stage III non-small cell lung cancer receiving chemoradiotherapy.

BACKGROUND: The expression of programmed cell death-ligand 1 (PD-L1) is a biomarker for administering immune check point inhibitors in patients with advanced stage non-small cell lung cancer. Although the consolidation therapy of durvalumab after definitive chemoradiotherapy has become the new standard of care for patients with unresectable stage III non-small cell lung cancer, the prevalence and prognostic role of PD-L1 expression in this population remain unclear. METHODS: We retrospectively reviewed data from patients with unresectable stage III non-small cell lung cancer who received definitive chemoradiotherapy at our institution between 2012 and 2017. Levels of PD-L1 were assessed using 22C3 antibody, and associations of progression-free and overall survival rates with PD-L1 statuses at a tumor proportion score cutoff of 1% were analyzed. RESULTS: Among the 104 patients enrolled, PD-L1 statuses were as follows: tumor proportion score < 1%, 73 (70.2%); 1-49%, 21 (20.2%); and ≥ 50%, 10 (9.6%). The number of patients with stage III non-small cell lung cancer with pretreatment PD-L1 tumor proportion score ≥ 1% was less than the number with advanced stage disease. There was no association between patient characteristics and PD-L1 status, and no significant differences were observed in progression-free and overall survival rates relative to PD-L1 status. CONCLUSION: Expression of PD-L1 in patients with stage III non-small cell cancer before chemoradiotherapy should be assessed because of the low prevalence of tumors with tumor proportion scores ≥ 1%. Further studies are needed to clarify whether durvalumab improves survival after definitive chemoradiotherapy, irrespective of tumor PD-L1 expression.

Efficacy of pembrolizumab in patients with brain metastasis caused by previously untreated non-small cell lung cancer with high tumor PD-L1 expression.

OBJECTIVES: Pembrolizumab is recommended for patients with previously untreated non-small cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of ≥1%. The KEYNOTE-024 study described the efficacy of pembrolizumab in patients with previously untreated NSCLC who had a PD-L1 TPS of at least 50 %. However, patients with untreated brain metastasis (BM) were excluded from many clinical trials. Therefore, we assessed the efficacy of pembrolizumab against BM of NSCLC with high tumor PD-L1 expression. MATERIALS AND METHODS: We retrospectively reviewed patients who received pembrolizumab as first-line treatment against NSCLC with PD-L1 TPS ≥ 50 % between March 2017 and September 2019. Treatment efficacy was compared between patients with (BM group) and without BM (non-BM group). In addition, the BM group was divided into patients who previously received treatment for BM before pembrolizumab (BM-T group) and those with no prior treatment for BM (BM-not T group). RESULTS: Eighty-seven patients (23 BM group and 64 non-BM group) were assessable for efficacy. No significant differences in patient characteristics were found between the BM and non-BM groups, but proportion of patients with stage IV at diagnosis was significantly higher in the BM group. Median progression-free survival (PFS) (6.5 months vs. 7.0 months) and overall survival (OS) (21.6 months vs. 24.6 months) did not significantly differ between the two groups. The response rate of BM was 70 %. The BM group was subdivided into 13 patients in the BM-T group and 10 patients in the BM-not T group. No significant differences in patient characteristics were found between the two groups, but maximum diameter of BM and proportion of patients with symptomatic BM were significantly greater in the BM-T group. PFS and OS did not significantly differ between the two groups. The median PFS of BM was 13.6 months in the BM-T group and 18.6 months in the BM-not T group. CONCLUSION: Pembrolizumab may be effective for BM caused by previously untreated NSCLC with high PD-L1 tumor expression.

Retrospective analysis of osimertinib re-challenge after osimertinib-induced interstitial lung disease in patients with EGFR-mutant non-small cell lung carcinoma.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has exhibited efficacy in patients with EGFR-mutant non-small cell lung cancer (NSCLC). Interstitial lung disease (ILD) is a fatal adverse event of osimertinib treatment, and it requires treatment discontinuation. There are few reports regarding the safety and efficacy of osimertinib re-challenge in patients who experienced osimertinib-induced ILD. This retrospective study assessed this treatment option. We retrospectively collected data for patients treated with osimertinib who developed ILD at Shizuoka Cancer Center from April 2016 to March 2020. ILD was diagnosed by two doctors based on imaging tests and blood tests to exclude other causes. Among 215 patients treated with osimertinib, 28 developed ILD. The median age of patients with ILD was 69.5 years (range, 39.0-80.0). In addition, 29% of patients were men, and 46% had a history of smoking. Eleven patients were re-administered EGFR TKIs, including eight patients treated with osimertinib and three patients treated with alternative EGFR TKIs. Among patients re-challenged with osimertinib, none who previously experienced grade 1 ILD exhibited ILD relapse, even with the same osimertinib dose and without the concurrent administration of systemic steroids. Meanwhile, one of the four patients who previously exhibited grade 2 ILD experienced despite a dose reduction for osimertinib and systemic steroid administration. For patients with EGFR-mutant NSCLC who experience grade 1 ILD during osimertinib therapy, osimertinib re-challenge may be suitable when no other treatments are available.