CD163+ Tumor-Associated Macrophage Recruitment Predicts Papillary Thyroid Cancer Recurrence.

INTRODUCTION: Skewed immune response plays a pivotal role in tumor progression. Systemic inflammatory responses represented by combined peripheral leukocyte fractions are prognostic predictors of multiple cancers, including thyroid cancer. We previously reported the prognostic significance of lymphocyte-to-monocyte ratio (LMR) in curatively resected papillary thyroid cancer (PTC). Therefore, this study aimed to analyze immune cell profiles in the tumor microenvironment and their association with LMR in curatively resected PTC. MATERIALS AND METHODS: The immune cell profiles of primary tumors in 162 patients with curatively resected PTC were analyzed clinicopathologically. Immunohistochemistry of tumor-associated macrophages (TAMs), myeloid-derived suppressor cells, and lymphocytes was performed using CD163, CD33, and CD3 antibodies, respectively. Prognostic analysis and correlation assays were performed using the immunocyte profiles. The gene expression of tumor-derived chemokines was assessed using a The Cancer Genome Atlas database. RESULTS: Patients with a higher density of CD163+ TAMs exhibited a significantly worse prognosis than their counterparts (10-y recurrence-free survival: 80.9% versus 91.2%, P = 0.011). Multivariate prognostic analyses revealed that high CD163+ cell density (P = 0.011), low preoperative LMR (P = 0.003), pN1b (P = 0.005), and high thyroglobulin level (P = 0.038) were independent predictors of recurrence. High CD163+ cell density had a prognostic impact on stage II and III PTC. Interestingly, high CD163+ cell density correlated with low LMR and high monocyte fraction in peripheral blood. Indeed, the expression of TAM-inducible, tumor-derived chemokines is increased in the The Cancer Genome Atlas database. CONCLUSIONS: A high density of infiltrated CD163+ TAMs predicts recurrence in correlation with low LMR and circulating monocyte accumulation. Thus, TAMs should be considered when assessing advanced PTC.

Thoracic Angiosarcoma Arising from Chronic Tuberculous Pyothorax: A Case Report.

Angiosarcoma is a rare malignancy that can arise from chronic pyothorax. We herein report a 75-year-old Japanese man with a history of tuberculosis who presented with left-sided chest pain that had persisted for 4 months. Chest computed tomography revealed an encapsulated left-sided pleural effusion with chest wall invasion, and histopathology confirmed angiosarcoma arising from a chronic tuberculous pyothorax. Chemotherapy with paclitaxel (80 mg/m2 weekly) was ineffective and was discontinued after 3 months. Our findings emphasize that physicians should inform patients with chronic tuberculous pyothorax about malignant complications for which chest pain is the initial symptom, in addition to highlighting the need for careful follow-up.

Phase II study of carboplatin plus weekly paclitaxel with bevacizumab for non-squamous, non-small cell lung cancer with idiopathic interstitial pneumonia (Hanshin Cancer Group IP002).

BACKGROUND: There is an increased risk of acute exacerbation of idiopathic interstitial pneumonia when treating patients with advanced non-small cell lung cancer with idiopathic interstitial pneumonia. There is no standard optimal treatment regimen for patients with lung cancer complicated with idiopathic interstitial pneumonia. We aimed to evaluate the efficacy and safety of carboplatin (CBDCA), bevacizumab (Bmab) and weekly paclitaxel (PXT) in patients with idiopathic interstitial pneumonia. METHODS: This phase 2 study involved chemotherapy-naïve patients with advanced non-small cell lung cancer with idiopathic interstitial pneumonia. Patients received CBDCA (area under the curve: 5 on day 1), PXT (70 mg/m2 on days 1, 8 and 15) and Bmab (15 mg/kg on day 1) every 4 weeks. The primary endpoint was the overall response rate. RESULTS: Twenty-one patients were enrolled between January 2013 and October 2018 and received at least one course of the protocol treatment. The study was terminated before enrolling the planned number of patients because of poor accrual. The median patient age was 69 (range: 62-79) years, and 19 (90.5%) patients were men. The overall response rate was 61.9% (95% confidence interval [CI], 38.4-81.9), meeting the primary endpoint. The median progression-free survival, time to treatment failure, and overall survival were 9.69 (95% CI, 5.78-11.63), 8.21 (95% CI, 3.75-11.63) and 20.93 (95% CI, 13.17-29.83) months, respectively. There was no acute exacerbation or treatment-related death during protocol treatment. CONCLUSION: The results indicate that patients with advanced non-squamous, non-small cell lung cancer with idiopathic interstitial pneumonia could be effectively and safely treated using a combination of CBDCA, PXT and Bmab.

Characterization of pre- and on-treatment soluble immune mediators and the tumor microenvironment in NSCLC patients receiving PD-1/L1 inhibitor monotherapy.

BACKGROUND: Despite the favorable therapeutic efficacy observed with ICI monotherapy, the majority of non-small cell lung cancer (NSCLC) patients do not respond. Therefore, identifying patients who could optimally benefit from ICI treatment remains a challenge. METHODS: Among 183 patients with advanced or recurrent NSCLC who received ICI monotherapy, we analyzed 110 patients whose pre- and post-treatment plasma samples were available. Seventy-three soluble immune mediators were measured at ICI initiation and 6 weeks later. To identify useful biomarkers, we analyzed the association of pre-treatment levels and on-treatment changes of soluble immune mediators with survival of patients. The associations of pre-treatment or on-treatment biomarkers with irAE development, PD-L1 expression, CD8+ TIL density, and neutrophil to lymphocyte ratio (NLR) were also analyzed. RESULTS: Univariate analysis showed that pre-treatment biomarkers included 6 immune mediators, whereas on-treatment biomarkers included 8 immune mediators. Multivariate analysis showed that pre-treatment biomarkers included 4 immune mediators (CCL19, CCL21, CXCL5, CXCL10), whereas on-treatment biomarkers included 5 immune mediators (CCL7, CCL19, CCL23, CCL25, IL-32). IrAE development was associated with on-treatment change in CCL23. PD-L1 expression was associated with the pre-treatment levels of TNFSF13B and the on-treatment change in CCL25. CD8+ TIL density was associated with the pre-treatment CXCL10 level, whereas NLR was correlated with pre-treatment levels of CCL13 and CCL17. CONCLUSION: We identified several soluble immune mediators as pre-treatment and on-treatment biomarkers of survival in patients with NSCLC treated with ICI monotherapy. Some of these biomarkers were associated with other possible predictors, including irAE development, PD-L1 expression, CD8+ TIL density and NLR. Further large-scale studies are needed to establish biomarkers for patients with NSCLC who received ICI monotherapy.

Real-World Efficacy and Safety of Durvalumab Administration Following Chemoradiotherapy in Elderly Patients With Unresectable Locally Advanced Nonsmall Cell Lung Cancer: A Multicenter, Retrospective Study.

BACKGROUND: The PACIFIC trial established durvalumab administration after chemoradiotherapy as the standard of care for unresectable locally advanced nonsmall cell lung cancer (LA-NSCLC). However, the efficacy and safety of durvalumab in elderly patients aged 75 years or above remains unclear. This study aimed to investigate the real-world efficacy and safety of durvalumab for LA-NSCLC, with a specific focus on elderly patients. PATIENTS AND METHODS: We reviewed 214 patients who received durvalumab out of 278 patients with unresectable LA-NSCLC who underwent chemoradiotherapy at 7 institutions between July 2018 and March 2022. Propensity score matching (PSM) analysis was performed to evaluate the efficacy of durvalumab in elderly patients. RESULTS: The 2-year progression-free survival (PFS) and 2-year overall survival (OS) rates were 42.2% (95% confidence interval [CI], 34.7%-49.5%) and 77.1% (95% CI, 70.1-82.7%), respectively. Grade ≥ 3 immune-related adverse events (irAEs) occurred in 8.2% of patients. PSM analysis revealed that OS was significantly shorter in elderly patients (≥ 75 years) than in younger patients (< 75 years) (hazard ratio [HR]; 95% CI, 1.39-8.99; P = .008), whereas PFS did not differ significantly between the 2 groups (HR: 1.50, 95% CI, 0.84-2.68, P = .169). The frequency of irAEs did not differ between these groups. CONCLUSIONS: The real-world efficacy and safety of durvalumab administration following chemoradiotherapy for LA-NSCLC coincided with the PACIFIC trial's findings. Disease control achieved with this protocol did not differ significantly between elderly and younger patients but had acceptable tolerability, demonstrating its benefit even in elderly LA-NSCLC patients aged 75 years or above.

Pembrolizumab with external radiation therapy effectively controlled TMB-high unresectable recurrent parathyroid cancer: a case report with review of literature.

Parathyroid cancer (PC) is extremely resistant to chemotherapy and radiotherapy (RT), but hormonally functional by producing excessive parathyroid hormone (PTH), causing remarkable hypercalcemia even in biochemical disease recurrence. Accordingly, management of hypercalcemia by calcimimetics and bisphosphonates has been main treatment for unresectable PC. Here, we report a case of unresectable tumor mutational burden (TMB)-high recurrent PC that has been effectively controlled by pembrolizumab (PEM) with RT. A 48-year-old male patient, with previous history of left single parathyroidectomy for primary hyperparathyroidism, underwent surgeries for recurrent hyperparathyroidism at 47 and 48 years of age, and was pathologically diagnosed with PC. He was referred to our hospital due to persistent hypercalcemia and elevated PTH. The recurrent tumors were identified in the superior mediastinum and radically resected, then the hyperparathyroidism was improved. A FoundationOne® CDx of the specimen called TMB-high. He demonstrated recurrent hyperparathyroidism at 49 years of age, and underwent a gross curative resection. However, hyperparathyroidism achieved only insufficient improvement, indicating biochemical residual cancer cells. PEM treatment was initiated in combination with RT to the left central-lateral neck and superior mediastinum. He successfully achieved evocalcet and zoledronate withdrawal, and the PTH level improvement was continuously observed for 8 months at present, with only grade 2 subclinical hypothyroidism. Interestingly, leukocyte fraction ratios were reversed corresponding to disease improvement. A combination of PEM and RT is a promising treatment of unresectable TMB-high PC. Recent evidence on the immunomodulatory effect of RT provides the rationale for the combination of RT and PEM.

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab as first-line treatment for metastatic non-small cell lung cancer with high levels of programmed death-ligand 1: a randomized, double-blind phase 2 study.

BACKGROUND: Pembrolizumab is a first-line therapy for certain patients with advanced/metastatic non-small cell lung cancer (NSCLC). Combining pembrolizumab with other immunotherapies may enhance tumor cell killing and clinical outcomes. Epacadostat is a selective inhibitor of indoleamine 2,3-dioxygenase 1, an immuno-regulatory enzyme involved in tryptophan to kynurenine metabolism that inhibits T cell-mediated immune responses. METHODS: In this randomized phase II study, patients with metastatic NSCLC expressing high (≥ 50%) programmed death-ligand 1 (PD-L1) levels received pembrolizumab 200 mg every 21 days plus oral epacadostat 100 mg twice daily (combination) or matching placebo (control). The primary objective was objective response rate (ORR); secondary objectives were progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety/tolerability. RESULTS: 154 patients were randomized (77 per group). Median (range) follow-up was 6.8 months (0.1-11.4) and 7.0 months (0.2-11.9) in the combination and control groups, respectively Confirmed ORR was similar between groups (combination: 32.5%, 95% CI 22.2-44.1; control: 39.0%, 95% CI 28.0-50.8; difference: - 6.5, 95% CI - 21.5 to 8.7; 1-sided P = 0.8000). Median (range) DOR was 6.2 months (1.9 + to 6.5 +) and not reached (1.9 + to 8.6 +) in the combination and control groups, respectively. Although not formally tested, median PFS was 6.7 and 6.2 months for the combination and control groups, respectively, and median OS was not reached in either group. Circulating kynurenine levels increased from C1D1 to C2D1 (P < 0.01) in the control group and decreased from C1D1 to C2D1 (P < 0.01) in the combination group but were not normalized in most patients. The most frequent serious adverse events (AEs) (≥ 2%) were pneumonia (4.0%), anemia (2.7%), atelectasis (2.7%) and pneumonitis (2.7%) in the combination group and pneumonia (3.9%), pneumonitis (2.6%) and hypotension (2.6%) in the control group. Two deaths due to drug-related AEs were reported, both in the control group. CONCLUSIONS: Addition of epacadostat to pembrolizumab therapy for PD-L1-high metastatic NSCLC was generally well tolerated but did not demonstrate an improved therapeutic effect. Evaluating higher doses of epacadostat that normalize kynurenine levels when given in combination with checkpoint inhibitors may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03322540. Registered 10/26/2017.

Treatment patterns and clinical outcomes of resectable clinical stage III non-small cell lung cancer in a Japanese real-world setting: Surgery cohort analysis of the SOLUTION study.

BACKGROUND: To elucidate the treatment and surgery outcomes with or without perioperative therapies in Japanese patients with clinical stage III non-small cell lung cancer (NSCLC) in real-world settings. METHODS: We performed subset analyses of the SOLUTION study, a multicenter, noninterventional, observational study of Japanese patients diagnosed with clinical stage III NSCLC, for those who started first-line treatment (surgery±perioperative therapy) between January 2013 and December 2014 (study registration: UMIN000031385). Follow-up data were obtained using medical records from diagnosis to March 1, 2018. RESULTS: Of 149 eligible patients, 67 underwent surgery alone (median age 71 years) and 82 underwent surgery+perioperative therapy (median age 63 years). Lung resection was performed in 137 patients and the others underwent exploratory thoracotomy or other procedures. Perioperative therapies included adjuvant therapy only (n = 41), neoadjuvant therapy only (n = 24), and neoadjuvant+adjuvant therapy (n = 17). The median overall survival (OS) and 3-year OS rate were 29.3 months and 44.0%, respectively, in patients who underwent surgery alone, and not reached and 61.1%, respectively, in patients who underwent surgery+perioperative therapy. The 3-year progression-free survival (PFS) and disease-free survival (DFS) rates were 42.4% and 47.1%, respectively, in patients who underwent surgery+perioperative therapy and 28.5% and 28.9%, respectively, in patients who underwent surgery alone. In multivariable Cox regression, perioperative therapy was associated with improved OS (hazard ratio [95% confidence interval] 0.49 [0.29-0.81]), PFS (0.62 [0.39-0.96]), and DFS (0.62 [0.39-0.97]) versus surgery alone. CONCLUSIONS: Our study suggested that perioperative therapy may be associated with better survival among patients undergoing surgical treatment of clinical stage III NSCLC.

Real-World Data on Subsequent Therapy for First-Line Osimertinib-Induced Pneumonitis: Safety of EGFR-TKI Rechallenge (Osi-risk Study TORG-TG2101).

BACKGROUND: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear. OBJECTIVE: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis. PATIENTS AND METHODS: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020. RESULTS: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03). CONCLUSIONS: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge.

Clinical Outcome of Nivolumab Plus Ipilimumab in Patients with Locally Advanced Non-Small-Cell Lung Cancer with Relapse after Concurrent Chemoradiotherapy followed by Durvalumab.

Nivolumab plus ipilimumab showed promising efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). The efficacy of the nivolumab plus ipilimumab combination regimen in NSCLC patients who relapse after durvalumab consolidation following concurrent chemoradiotherapy (CCRT) has not been determined. Between January 2021 and June 2022, clinical data were retrospectively extracted from the medical records of patients with NSCLC who received nivolumab plus ipilimumab after CCRT and durvalumab consolidation. A total of 30 patients were included in this analysis. The median number of durvalumab treatment cycles was 11. Median PFS and OS with nivolumab plus ipilimumab were 4.2 months (95% confidence interval [CI]: 0.7-7.7) and 18.5 months (95% CI: 3.5-33.5), respectively. The 6-month and 12-month PFS rates were 46.7% (95% CI: 28.8-64.5) and 36.4% (95% CI: 19.0-53.7). In multivariate analysis, a significant correlation was observed between a durvalumab treatment duration of 6 months or more and PFS (p = 0.04) as well as OS (p = 0.001). Grade 3 adverse events, including pneumonitis, dermatitis, and colitis, occurred in 10% of the patients. This study suggests that nivolumab plus ipilimumab is effective, especially in patients who have received durvalumab for 6 months or more, and tolerable for patients who relapsed after durvalumab following CCRT.

Association of immune-related adverse events with durvalumab efficacy after chemoradiotherapy in patients with unresectable Stage III non-small cell lung cancer.

BACKGROUND: Immune-related adverse events (irAEs) have been found to predict PD-L1 inhibitor efficacy in metastatic NSCLC. However, the relation of irAEs to clinical outcome for nonmetastatic NSCLC has remained unknown. METHODS: In this multicenter prospective study of Stage III NSCLC treated with PACIFIC regimen, the relation of irAEs to PFS was evaluated by 8-week landmark analysis to minimise lead-time bias as well as by multivariable analysis adjusted for baseline factors. irAEs were categorised as mild or nonmild according to whether they were treated with systemic steroid. RESULTS: Median PFS was 16.0 months, not reached, and 9.7 months for patients without (85 cases) or with mild (21 cases) or nonmild (21 cases) irAEs, respectively. Multivariable analysis indicated that nonmild irAEs were associated with poor PFS, with HRs of 3.86 (95% CI, 1.31-11.38) compared with no irAEs and 11.58 (95% CI, 2.11-63.63) compared with mild irAEs. This pattern was consistent after irAE grade, the number of durvalumab doses and immune profiles (PD-L1 score, CD8+ tumour-infiltrating lymphocyte density, and tumour mutation burden) were taken into consideration. CONCLUSIONS: The development of mild irAEs might predict a better survival outcome, whereas immunosuppressive steroid-treated irAEs were associated with a worse outcome, regardless of baseline clinical and immune profiles.

Long-term experience with tepotinib in Japanese patients with MET exon 14 skipping NSCLC from the Phase II VISION study.

Tepotinib is a highly selective MET tyrosine kinase inhibitor (TKI) that has demonstrated robust and durable clinical activity in patients with MET exon 14 (METex14) skipping non-small-cell lung cancer (NSCLC). In the Phase II VISION study, patients received oral tepotinib 500 mg once daily. The primary endpoint was an objective response by an independent review committee (IRC) according to RECIST v1.1 criteria. The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Here we report the analysis of the efficacy and safety of tepotinib in all Japanese patients with advanced METex14 skipping NSCLC from VISION (n = 38) with >18 months' follow-up. The median age of the Japanese patients was 73 years (range 63-88), 39.5% of patients were ≥75 years old, 68.4% were male, 55.3% had a history of smoking, 76.3% had adenocarcinoma, and 10.5% of patients had known brain metastases at baseline. Overall, the objective response rate (ORR) was 60.5% (95% confidence interval (CI): 43.4, 76.0) with a median DOR of 18.5 months (95% CI: 8.3, not estimable). ORR in treatment-naïve patients (n = 18) was 77.8% (95% CI: 52.4, 93.6), and in patients aged ≥75 years (n = 15), ORR was 73.3% (95% CI: 44.9, 92.2). The most common treatment-related adverse event (AE) with any grade was blood creatinine increase (65.8%), which resolved following tepotinib discontinuation. Other common treatment-related AEs were peripheral edema (60.5%), hypoalbuminemia (34.2%), diarrhea (28.9%), and nausea (15.8%). In summary, tepotinib demonstrated robust and durable clinical activity irrespective of age or therapy line, with a manageable safety profile in Japanese patients with METex14 skipping NSCLC enrolled in VISION.

Nintedanib plus Chemotherapy for Small Cell Lung Cancer with Comorbid Idiopathic Pulmonary Fibrosis.

Rationale: A fatal acute exacerbation (AE) occasionally develops during chemotherapy for small cell lung cancer (SCLC) with comorbid idiopathic pulmonary fibrosis (IPF).Objectives: This study aimed to assess the safety and efficacy of carboplatin, etoposide, and nintedanib combination therapy for unresectable SCLC with comorbid IPF.Methods: The NEXT-SHIP study is a multicenter, single-arm, phase 2 trial for unresectable SCLC with IPF (Japan Registry of Clinical Trials registry number jRCTs031190119). The patients received carboplatin, etoposide, and nintedanib (150 mg twice daily). The primary endpoint was the incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy, and the sample size was set at 33 (5.0% expected, 20.0% threshold).Results: A total of 33 patients were registered; 87.9% were male, the median age was 73 years, the median percentage forced vital capacity was 85.2%, and 51.5% had honeycomb lungs. The median observation period was 10.5 months. The incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy was 3.0% (90% confidence interval [CI], 0.2-13.6). The objective response rate was 68.8% (95% CI, 50.0-83.9). The median progression-free survival and overall survival times were 4.2 months (95% CI, 4.2-5.5) and 13.4 months (95% CI, 8.1-21.6), respectively. The most common adverse event of grade 3 or higher was neutropenia (81.8%), followed by leukopenia (39.4%) and thrombocytopenia (30.3%).Conclusions: This study met its primary endpoint regarding the incidence of IPF-AEs with promising results for efficacy. Carboplatin, etoposide, and nintedanib combination therapy may be one of the standard treatment options for SCLC with comorbid IPF.Clinical trial registered with the Japan Registry of Clinical Trials (jRCTs031190119).

Phase 1 study of pembrolizumab plus chemotherapy in Japanese patients with extensive-stage small-cell lung cancer.

BACKGROUND: Part E of the KEYNOTE-011 (NCT01840579) study assessed the safety and antitumor activity of pembrolizumab plus platinum-etoposide chemotherapy in Japanese patients with previously untreated extensive-stage small-cell lung cancer (ES-SCLC). METHODS: Patients received 4 cycles of pembrolizumab (200 mg) every 3 weeks in combination with cisplatin (75 mg/m2) and etoposide (100 mg/m2; days 1, 2, 3) in cohort 1; with carboplatin (AUC 5 mg/mL/min) and etoposide (100 mg/m2; days 1, 2, 3) in cohort 2; or with cisplatin/etoposide and pegfilgrastim (3.6 mg; cycle 1, day 4) in cohort 3. Combination therapy was followed by pembrolizumab monotherapy (31 cycles). The primary endpoint was safety and tolerability (including dose-limiting toxicities; DLTs). RESULTS: Fifteen patients were included in the study (cohort 1, n = 6; cohort 2, n = 6; cohort 3, n = 3). Median time from treatment allocation to data cutoff was 22.1 months (range, 4.1‒32.4 months). DLTs occurred in 3 patients in cohort 1 (one patient with grade 4 laryngeal stenosis and grade 3 febrile neutropenia; two patients with grade 3 febrile neutropenia); no patients in cohorts 2 or 3 experienced DLTs. Grade ≥ 3 treatment-related adverse events included leukopenia (67%) and neutropenia (87%). Among all patients, ORR was 67% (95% CI, 38%‒88%) and median DOR was 4.5 months (range, 2.8‒28.8 months). Median PFS was 4.2 months (95% CI, 3.0‒7.8 months) and median OS was 22.1 months (95% CI, 7.4‒25.9 months). CONCLUSION: Pembrolizumab in combination with platinum-etoposide therapy had manageable toxicity with no new safety signals and was associated with antitumor activity in Japanese patients with ES-SCLC. TRIAL REGISTRATION: ClinicalTrials.gov , NCT01840579.

Five Cases of Cytokine Release Syndrome in Patients Receiving Cytotoxic Chemotherapy Together With Nivolumab Plus Ipilimumab: A Case Report.

We conducted a phase 3 clinical trial to compare the efficacy of platinum-based combination chemotherapy together with nivolumab plus ipilimumab relative to that of platinum-based combination chemotherapy together with pembrolizumab in previously untreated patients with advanced NSCLC. The trial was terminated prematurely after treatment of 295 patients because of a high proportion of treatment-related deaths, three of which were due to cytokine release syndrome (CRS), in the nivolumab plus ipilimumab treatment arm. In addition, we encountered two cases of CRS that were effectively managed, for a total of five cases (3.4%) among the 148 patients in the nivolumab plus ipilimumab arm. We here provide details of these five cases. Although patient background and timing of CRS onset differed, fever was observed before the emergence of CRS in all five cases. Oncologists should thus be aware that the development of fever during treatment of patients with nivolumab plus ipilimumab may herald the onset of CRS.

Biomarker Testing in Patients With Unresectable Advanced or Recurrent Non-Small Cell Lung Cancer.

Importance: Biomarker testing for driver mutations is essential for selecting appropriate non-small cell lung cancer (NSCLC) treatment but is insufficient. Objective: To investigate the status of biomarker testing and drug therapy for NSCLC in Japan for identifying problems in treatment. Design, Setting, and Participants: The REVEAL cohort study included retrospective data collection and prospective follow-up from 29 institutions across Japan. Of 1500 patients diagnosed with advanced or recurrent NSCLC between January 1 and March 18, 2021, 1479 were eligible. Cases recognized at the wrong clinical stage (n = 12), diagnosed outside the study period (n = 6), not treated according to eligibility criteria before recurrence (n = 2), and with deficient consent acquisition procedure (n = 1) were excluded. Main Outcomes and Measures: The primary end point was the biomarker testing status. Treatment-related factors were examined. Results: Among the 1479 patients included in the analysis, the median age was 72 (range, 30-95) years; 1013 (68.5%) were men; 1161 (78.5%) had an Eastern Cooperative Oncology Group performance status 0 or 1; 1097 (74.2%) were current or past smokers; and 947 (64.0%) had adenocarcinoma. Biomarker status was confirmed in 1273 patients (86.1%). Multigene testing was performed in 705 cases (47.7%); single-gene testing, in 847 (57.3%); and both, in 279 (18.9%). Biomarker testing was performed for EGFR in 1245 cases (84.2%); ALK, in 1165 (78.8%); ROS1, in 1077 (72.8%); BRAF, in 803 (54.3%); and MET, in 805 (54.4%). Positivity rates among 898 adenocarcinoma cases included 305 (34.0%) for EGFR, 29 (3.2%) for ALK, 19 (2.1%) for ROS1, 11 (1.2%) for BRAF, and 14 (1.6%) for MET. Positivity rates among 375 nonadenocarcinoma cases were 14 (3.7%) for EGFR, 6 (1.6%) for ALK, 1 (0.3%) for ROS1, 3 (0.8%) for BRAF, and 8 (2.1%) for MET. Poor physical status, squamous cell carcinoma, and other comorbidities were associated with hampered multigene testing. Targeted therapy was received as first-line treatment by 263 of 278 cases (94.6%) positive for EGFR, 25 of 32 (78.1%) positive for ALK, 15 of 24 (62.5%) positive for ROS1, 9 of 12 (75.0%) positive for BRAF, and 12 of 19 (63.2%) positive for MET. Median overall survival of patients with positive findings for driver gene alteration and who received targeted therapy was 24.3 (95% CI, not reported) months; with positive findings for driver gene alteration and who did not receive targeted therapy, 15.2 (95% CI, 7.7 to not reported) months; and with negative findings for driver gene alteration, 11.0 (95% CI, 10.0-12.5) months. Multigene testing for nonadenocarcinomas and adenocarcinomas accounted for 705 (47.7%) of all NSCLC cases. Conclusions and Relevance: These findings suggest that multigene testing has not been sufficiently implemented in Japan and should be considered prospectively, even in nonadenocarcinomas, to avoid missing rare driver gene alterations.

Docetaxel Plus Ramucirumab With Primary Prophylactic Pegylated Granulocyte-Colony Stimulating Factor Support for Elderly Patients With Advanced NSCLC: A Multicenter Prospective Single Arm Phase 2 Trial: DRAGON Study (WJOG9416L).

Introduction: Docetaxel plus ramucirumab could be a promising treatment for chemo-naive elderly patients with NSCLC, but high incidence of febrile neutropenia (FN) is a critical concern. We thus adopted a routine primary prophylactic pegylated-granulocyte-colony stimulating factor (PEG-G-CSF) to reduce FN and maximize the efficacy of docetaxel plus ramucirumab in elderly patients. Methods: This is a single arm phase 2 trial for chemo-naive elderly patients (aged ≥75 y) with advanced NSCLC. Docetaxel (60 mg/m2, d 1) plus ramucirumab (10 mg/kg, d 1) with PEG-G-CSF (3.6 mg, d 2) was administered every 3 weeks until progression. The primary end point was overall response rate (ORR) (expected ORR: 35%). Results: Between February 2018 and January 2021, 54 patients were enrolled. Median age was 78 (range: 75-86). A total of 21 (38.9%) partial response, 22 (40.7%) stable disease, nine (16.7%) progressive disease, and two (3.7%) not assessable were confirmed, resulting in ORR of 38.9% (90% confidence interval [CI]: 27.7%-51.0%) and disease control rate of 79.6%. Median progression-free survival and overall survival were 5.2 (95% CI: 4.2-6.9) and 12.7 (95% CI: 10.2-18.9) months, respectively. There were one (1.9%) FN, two (3.7%) bleeding grade greater than or equal to 3, and one (1.9%) treatment-related death (pneumonitis). Pneumonitis occurred in five patients (9.3%). Main adverse events grade greater than or equal to 3 were observed: four (7%) thrombocytopenia; three (5.6%) neutropenia; six (11.1%) hyposodium; five (9.3%) infection; five (9.3%) hypertension; four (7.4%) anorexia; and three (5.6%) oral mucositis. Conclusions: Docetaxel plus ramucirumab with PEG-G-CSF revealed efficacy and safety for chemo-naive elderly patients with NSCLC. Primary prophylactic PEG-G-CSF highly prevented FN.

Survival and biomarkers for cachexia in non-small cell lung cancer receiving immune checkpoint inhibitors.

BACKGROUND: The presence of cachexia negatively impacts the prognosis of patients with cancer. However, the mechanisms behind the development of cachexia and its prognostic impact on immunotherapy efficacy are not fully understood. MATERIALS AND METHODS: We retrospectively screened patients with advanced or recurrent non-small cell lung cancer (NSCLC) who received PD-1/PD-L1 inhibitor monotherapy. Among 183 patients, pre-treatment plasma samples were available from 100 patients. We defined cancer cachexia as weight loss of at least 5% during the past 6 months or weight loss of at least 2% and BMI <20. We analyzed 75 soluble immune mediators in pre-treatment plasma samples to explore the possible mechanisms behind the development of cancer cachexia. We also investigated whether cancer cachexia affects prognosis. RESULTS: Among 100 patients, 35 had cancer cachexia. Logistic regression analysis identified ghrelin, c-reactive protein (CRP), pentraxin-3 (PTX-3), and osteopontin (OPN) as factors associated with cachexia. Patients with cachexia had worse progression-free survival (PFS) and overall survival (OS), although we did not detect statistically significant differences. Analyzing the soluble immune mediators associated with cachexia, the combination of cachexia and PTX-3 or OPN expression levels was predictive for PFS and the combination of cachexia and CRP or OPN expression levels was predictive for OS. CONCLUSIONS: Pre-treatment ghrelin, CRP, PTX-3, and OPN may be associated with cachexia. Among patients with NSCLC who received PD-1/L1 inhibitor monotherapy, those with cachexia had worse survival than those without cachexia. Larger studies will be required to confirm our data and better understand the mechanisms behind the development of cachexia.

Survival and soluble immune mediators of immune checkpoint inhibitor-induced interstitial lung disease in patients with non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitor-related interstitial lung disease (ICI-ILD) is a serious adverse event frequently observed in patients with non-small cell lung cancer (NSCLC). We investigated the clinical effects and mechanism of action of ICI-ILD in NSCLC patients treated with ICI. METHODS: We retrospectively screened patients with advanced or recurrent NSCLC who received PD-1/PD-L1 inhibitor monotherapy and examined the prognostic impact of ICI-ILD. In addition, we analyzed the levels of 72 different soluble immune mediators in pre-treatment plasma to explore possible mechanisms associated with the development of ICI-ILD. Furthermore, the relationships between soluble immune mediators associated with ICI-ILD development and survival were analyzed. RESULTS: Of 141 patients with NSCLC, 25 (17.7%) developed ICI-ILD. Logistic regression analysis revealed that pre-treatment CXCL9, MMP-1, IL-6, and IL-19 levels were associated with ICI-ILD development. There were no significant differences in progression-free survival (PFS) and overall survival (OS) between patients with or without ICI-ILD. In patients with ICI-ILD, patients with lower grade ICI-ILD had better OS than those with higher-grade ICI-ILD. In ICI-ILD patients, there was a trend for patients with lower-grade ICI-ILD to have better PFS and OS than those with higher-grade ICI-ILD. Among four soluble immune mediators associated with ICI-ILD, a high level of IL-19 was significantly correlated with worse OS and PFS. CONCLUSION: The identified soluble immune mediators, including CXCL9, MMP-1, IL-6, and IL-19, may be useful as biomarkers to associate with ICI-ILD development. Although we did not detect significant differences in PFS and OS between patients with and without ICI-ILD, PFS and OS were longer in those with lower-grade ICI-ILD than in patients with higher-grade ICI-ILD. Among biomarkers, IL-19 may be a causal and prognostic factor for ICI-ILD.

Machine learning for prediction of immunotherapeutic outcome in non-small-cell lung cancer based on circulating cytokine signatures.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has substantially improved the overall survival (OS) in patients with non-small-cell lung cancer (NSCLC); however, its response rate is still modest. In this study, we developed a machine learning-based platform, namely the Cytokine-based ICI Response Index (CIRI), to predict the ICI response of patients with NSCLC based on the peripheral blood cytokine profiles. METHODS: We enrolled 123 and 99 patients with NSCLC who received anti-PD-1/PD-L1 monotherapy or combined chemotherapy in the training and validation cohorts, respectively. The plasma concentrations of 93 cytokines were examined in the peripheral blood obtained from patients at baseline (pre) and 6 weeks after treatment (early during treatment: edt). Ensemble learning random survival forest classifiers were developed to select feature cytokines and predict the OS of patients undergoing ICI therapy. RESULTS: Fourteen and 19 cytokines at baseline and on treatment, respectively, were selected to generate CIRI models (namely preCIRI14 and edtCIRI19), both of which successfully identified patients with worse OS in two completely independent cohorts. At the population level, the prediction accuracies of preCIRI14 and edtCIRI19, as indicated by the concordance indices (C-indices), were 0.700 and 0.751 in the validation cohort, respectively. At the individual level, patients with higher CIRI scores demonstrated worse OS [hazard ratio (HR): 0.274 and 0.163, and p<0.0001 and p=0.0044 in preCIRI14 and edtCIRI19, respectively]. By including other circulating and clinical features, improved prediction efficacy was observed in advanced models (preCIRI21 and edtCIRI27). The C-indices in the validation cohort were 0.764 and 0.757, respectively, whereas the HRs of preCIRI21 and edtCIRI27 were 0.141 (p<0.0001) and 0.158 (p=0.038), respectively. CONCLUSIONS: The CIRI model is highly accurate and reproducible in determining the patients with NSCLC who would benefit from anti-PD-1/PD-L1 therapy with prolonged OS and may aid in clinical decision-making before and/or at the early stage of treatment.