Brigatinib in Japanese patients with ALK-positive non-small-cell lung cancer: Final results of the phase 2 J-ALTA trial.

The phase 2, single-arm, multicenter, open-label J-ALTA study evaluated the efficacy and safety of brigatinib in Japanese patients with advanced ALK+ non-small-cell lung cancer (NSCLC). One expansion cohort of J-ALTA enrolled patients previously treated with ALK tyrosine kinase inhibitors (TKIs); the main cohort included patients with prior alectinib ± crizotinib. The second expansion cohort enrolled patients with TKI-naive ALK+ NSCLC. All patients received brigatinib 180 mg once daily (7-day lead-in at 90 mg daily). Among 47 patients in the main cohort, 5 (11%) remained on brigatinib at the study end (median follow-up: 23 months). In this cohort, the independent review committee (IRC)-assessed objective response rate (ORR) was 34% (95% CI, 21%-49%); median duration of response was 14.8 months (95% CI, 5.5-19.4); median IRC-assessed progression-free survival (PFS) was 7.3 months (95% CI, 3.7-12.9). Among 32 patients in the TKI-naive cohort, 25 (78%) remained on brigatinib (median follow-up: 22 months); 2-year IRC-assessed PFS was 73% (90% CI, 55%-85%); IRC-assessed ORR was 97% (95% CI, 84%-100%); the median duration of response was not reached (95% CI, 19.4-not reached); 2-year duration of response was 70%. Grade ≥3 adverse events occurred in 68% and 91% of TKI-pretreated and TKI-naive patients, respectively. Exploratory analyses of baseline circulating tumor DNA in ALK TKI-pretreated NSCLC showed associations between poor PFS and EML4-ALK fusion variant 3 and TP53. Brigatinib is an important treatment option for Japanese patients with ALK+ NSCLC, including patients previously treated with alectinib.

Tumor-derived semaphorin 4A improves PD-1-blocking antibody efficacy by enhancing CD8+ T cell cytotoxicity and proliferation.

Immune checkpoint inhibitors (ICIs) have caused revolutionary changes in cancer treatment, but low response rates remain a challenge. Semaphorin 4A (Sema4A) modulates the immune system through multiple mechanisms in mice, although the role of human Sema4A in the tumor microenvironment remains unclear. This study demonstrates that histologically Sema4A-positive non-small cell lung cancer (NSCLC) responded significantly better to anti-programmed cell death 1 (PD-1) antibody than Sema4A-negative NSCLC. Intriguingly, SEMA4A expression in human NSCLC was mainly derived from tumor cells and was associated with T cell activation. Sema4A promoted cytotoxicity and proliferation of tumor-specific CD8+ T cells without terminal exhaustion by enhancing mammalian target of rapamycin complex 1 and polyamine synthesis, which led to improved efficacy of PD-1 inhibitors in murine models. Improved T cell activation by recombinant Sema4A was also confirmed using isolated tumor-infiltrating T cells from patients with cancer. Thus, Sema4A might be a promising therapeutic target and biomarker for predicting and promoting ICI efficacy.

First-Line Lorlatinib Versus Crizotinib in ALK-Positive NSCLC: Japanese Subgroup Analysis of CROWN.

Introduction: Lorlatinib, a third-generation ALK inhibitor, was found to have improved efficacy versus crizotinib in patients with previously untreated, advanced ALK-positive NSCLC in the ongoing, global, randomized, phase 3 CROWN study. Methods: The study's primary end point was progression-free survival assessed by blinded independent central review. Secondary end points included objective and intracranial response. Here, we report efficacy and safety data of the Japanese subgroup of the CROWN study (lorlatinib 100 mg once daily, n = 25; crizotinib 250 mg twice daily, n = 23). Results: Progression-free survival was not reached (95% confidence interval [CI]: 11.3 mo-not reached) for lorlatinib and 11.1 months (95% CI: 5.4-14.8) for crizotinib (hazard ratio = 0.44, 95% CI: 0.19-1.01). Objective response (lorlatinib versus crizotinib) was 68.0% (95% CI: 46.5-85.1) versus 52.2% (95% CI: 30.6-73.2) in all patients, and intracranial response was 100.0% (three of three, 95% CI: 29.2-100.0) versus 28.6% (two of seven; 95% CI: 3.7-71.0) in patients with brain metastases at baseline. The most common adverse events with lorlatinib were hypertriglyceridemia, hypercholesterolemia, and weight increase; 28.0% and 8.0% of patients had cognitive and mood effects (all grades 1 or 2), respectively. Lorlatinib was associated with more grade 3 or 4 events than crizotinib (80.0% versus 72.7%). Treatment was discontinued owing to adverse events in 16.0% and 27.3% of patients in the lorlatinib and crizotinib groups, respectively. Conclusions: The efficacy and safety of lorlatinib in the Japanese subgroup were similar to those in the CROWN global population, revealing improved outcomes versus crizotinib in Japanese patients with previously untreated, advanced ALK-positive NSCLC.

Efficacy and safety of mycophenolate mofetil in treating immune-related hepatitis induced by immune checkpoint inhibitor use: A retrospective study.

Background and Aim: To investigate the outcomes in eight Japanese patients with cancer treated with mycophenolate mofetil (MMF) and corticosteroids for immune checkpoint inhibitor treatment-induced severe immune-related hepatitis (ir-hepatitis) and the efficacy and safety of MMF. Methods: We retrospectively examined patient background, treatment course, as well as examination and imaging data using electronic medical records. Results: The ratio of male to female patients was 7:1, and the median age was 60 years (27-72 years). There were five and two cases of kidney cancer and malignant melanoma, respectively, and one case of lung cancer. The median number of days until MMF administration in addition to systemic corticosteroid therapy after the onset of ir-hepatitis was 14.5 (2-42). The patients were categorized as four "good responders" who showed an improvement in the liver function tests following MMF treatment and four "poor responders" who did not. Furthermore, the time from the onset of ir-hepatitis to initial MMF administration was significantly shorter in good responders (median 3 days, range 2-15 days) than in poor responders (median 25.5 days, range 14-42 days) (P = 0.042). No significant intergroup difference was observed in other clinical factors. No serious adverse events caused by MMF were observed in any case. Conclusions: According to these findings, early recognition of corticosteroid refractoriness and the use of MMF may be beneficial in patients with ir-hepatitis.

Prevalence and characteristics of immune checkpoint inhibitor-related myocardial damage: A prospective observational study.

An increasing number of patients with cancer are being treated with immune checkpoint inhibitors. Consequently, the incidence of immune checkpoint inhibitor-related myocarditis has been increasing. Nonetheless, the diagnostic criteria for the immune checkpoint inhibitor-related myocarditis have not been sufficiently established. Therefore, the real-world incidence or prevalence of immune checkpoint inhibitor-related myocardial damage remains unknown. This was a single-center cohort study that included 100 patients admitted for immune checkpoint inhibitor therapy for any type of cancer. The patients underwent monthly measurement of cardiac troponin I and N-terminal pro-brain natriuretic peptide levels with electrocardiography. Additionally, echocardiography was performed every 3 months. Our protocol was continued until 6 months after the initiation of immune checkpoint inhibitors. We defined immune checkpoint inhibitor-related myocardial damage as an increase in cardiac troponin I levels by >0.026 ng/mL and/or a decrease in the left ventricular ejection fraction by >10% to <53% on echocardiography. The mean patient age was 64 years; 71% were men. The most commonly used immune checkpoint inhibitor was nivolumab (47%), followed by pembrolizumab (29%). Overall, 5% of patients received combination therapy. Among 100 patients, 10 (10%) were diagnosed with immune checkpoint inhibitor-related myocardial damage. Among them, five patients underwent endomyocardial biopsy. Of these patients, four were histopathologically observed to have lymphocyte infiltration in their myocardium. In conclusion, serial cardiac troponin I measurement during immune checkpoint inhibitor treatment could help detect early-phase myocardial damage. The prevalence of myocardial damage was much higher than previously expected.

Fragment size and dynamics of EGFR-mutated tumor-derived DNA provide prognostic information regarding EGFR-TKI efficacy in patients with EGFR-mutated NSCLC.

Circulating tumor DNA (ctDNA)-based next-generation sequencing (NGS) is a complementary and alternative test to tissue-based NGS. We performed NGS analysis of ctDNA samples collected from patients with EGFR-mutated non-small cell lung cancer (NSCLC) who received osimertinib; the samples were collected after second-line treatment, before osimertinib treatment, one week and one month after osimertinib treatment, and at the time of resistance formation. We examinedthe correlation with osimertinib efficacy. From January to December 2018, 34 patients with EGFR-mutated NSCLC harboring EGFR T790M mutations were enrolled, and a total of 132 peripheral blood samples were collected. The fragment sizes of EGFR-mutated ctDNAs were significantly shorter than that of their corresponding normal fragments. Osimertinib treatment of patients with shorter EGFR-mutated ctDNA fragments resulted in shorter progression-free survival (PFS). The disappearance time of EGFR-mutated fragment fractions and clonal evolution patterns (new driver mutation group, additional mutation group vs. attenuation group) were each associated with the PFS achieved with osimertinib treatment; however,multivariate analysis revealed that only shorter EGFR-mutated ctDNA fragments were associated with the PFS resulting from osimertinib treatment. EGFR-mutated ctDNA fragment size, time of disappearance of these fragments, and clonal evolution pattern were related to the effects of osimertinib. In particular, short EGFR-mutated ctDNA fragmentation may be closely related to osimertinib efficacy prediction.

Brigatinib in Japanese patients with tyrosine kinase inhibitor-naive ALK-positive non-small cell lung cancer: first results from the phase 2 J-ALTA study.

BACKGROUND: We evaluated the safety and efficacy of the anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) brigatinib in Japanese patients with TKI-naive ALK-positive non-small cell lung cancer (NSCLC) from the phase 2, open-label, single-arm, multicenter J-ALTA study. METHODS: In the TKI-naive cohort of J-ALTA, the primary end point was independent review committee (IRC)-assessed 12-month progression-free survival (PFS). Secondary end points included objective response rate (ORR), intracranial response, overall survival (OS), and safety. RESULTS: The data were cut approximately 12 months after last patient enrollment. Thirty-two patients with ALK TKI-naive ALK-positive NSCLC were enrolled (median age [range], 60.5 [29-85] years; median duration of follow-up, 14.2 [3.2-19.3] months; median treatment duration, 13.8 [0.4-19.3] months). IRC-assessed 12-month PFS was 93.0% (90% confidence interval (CI) 79.2-97.8%); ORR, 96.9% (95% CI 83.8-99.9%), 12-month OS, 96.9% (95% CI 79.8-99.6%), and median OS was not reached. Of five patients with measurable baseline CNS metastases, two had partial intracranial response. The most common treatment-emergent adverse events were increased blood creatine phosphokinase (81%), hypertension (59%), and diarrhea (47%). Grade ≥ 3 adverse events occurred in 91% of patients; pneumonitis was reported in 3 (9%) patients. CONCLUSIONS: In the J-ALTA TKI-naive cohort, brigatinib demonstrated clinically meaningful efficacy consistent with the international phase 3 study. The safety profile in Japanese patients was consistent with previous studies. Brigatinib is an important first-line option for Japanese patients with ALK-positive NSCLC. CLINICAL REGISTRATION: NCT03410108.

A Case of Lung Cancer with Very-Late-Onset Immune Checkpoint Inhibitor-Related Myocarditis.

Immune checkpoint inhibitor (ICI)-related myocarditis has been reported to appear in the early phase after ICI initiation. Herein, we report the case of a 78-year-old man with non-small cell lung cancer. Pembrolizumab was introduced as first-line therapy. After 9 months, second-line therapy, including bevacizumab, was initiated. After another 7 months, echocardiography showed diffuse left ventricular dysfunction. Based on the histopathologic examination of the myocardium, the patient was diagnosed with ICI-related myocarditis. Initiation of prednisolone therapy improved cardiac function. This case of late-onset ICI-related myocarditis illustrates that endomyocardial biopsy can be useful in the differential diagnosis of cancer-related left ventricular dysfunction.

Il a été rapporté qu'une myocardite pouvait survenir peu après l'instauration d'un traitement par des inhibiteurs des points de contrôle immunitaire (ICI). Nous présentons le cas d'un homme de 78 ans atteint d'un cancer du poumon non à petites cellules. Le pembrolizumab a été administré comme traitement de première intention. Neuf mois plus tard, un traitement de deuxième intention par le bévacizumab a été instauré. Après sept autres mois, l'échocardiographie a montré une dysfonction ventriculaire gauche diffuse. À la suite des résultats de l'examen histopathologique du myocarde, une myocardite liée aux ICI a été diagnostiquée. L'instauration d'un traitement par la prednisolone a amélioré la fonction cardiaque du patient. Ce cas de myocardite tardive liée aux ICI montre l'utilité éventuelle de la biopsie de l'endomyocarde dans le diagnostic différentiel d'une dysfonction ventriculaire gauche liée au cancer.

Successful weaning of a patient with severe COVID-19 pneumonia under prolonged midazolam sedation using morphine.

The coronavirus disease 2019 (COVID-19) pandemic continues to spread around the world. In April 2021, Japan experienced a fourth wave of COVID-19 infections, which led to the breakdown of the medical system. Osaka, Japan, was particularly affected, with many severe cases and the highest number of COVID-19-associated deaths in Japan. Herein, we present a patient with severe COVID-19 infection who received prolonged midazolam (MDZ) treatment since propofol was not available due to shortage of medical resources. Moreover, the duration of mechanical ventilation was extended due to the development of a pneumothorax. When MDZ tapering was initiated, tachypnea was observed, which resulted failure in ventilator weaning. However, the use of continuous morphine infusion led a successful weaning off the ventilator. We suggest that the administration of morphine may allow for a smoother weaning process for some patients with severe COVID-19 infection.

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

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

TP53 Loss of Heterozygosity Induces De Novo SCLC Formation in EGFR-Mutated Lung Adenocarcinoma: A Case Report.

SCLC transformation in EGFR-mutated lung adenocarcinoma is one of the major phenotypic changes that is observed during the resistance to EGFR tyrosine kinase inhibitors. However, the mechanism of this transformation remains unclear. In this study, we found a small de novo SCLC component in surgically resected specimens of EGFR-mutated lung adenocarcinoma before EGFR tyrosine kinase inhibitor treatment. By using laser microdissection and whole-exome sequencing, TP53 loss of heterozygosity was found to be possibly involved in SCLC transformation.

Manual route modification using an oblique method following automatic virtual bronchoscopic navigation.

ABSTRACT: Virtual automatic bronchoscopic navigation (VBN) systems to determine the route to peripheral pulmonary lesions (PPLs) in lung cancer can improve diagnostic biopsy yields. However, compared with VBN, drawing manual routes using computed tomography images, especially with oblique methods, can identify more routes. The Ziostation2 VBN system combines the benefits of these 2 methods; we evaluated this performance by comparing 3 different route-determining methods.We retrospectively collected data from 50 patients with PPLs measuring <30 mm who underwent transbronchial biopsy with an ultrathin bronchoscope at the Osaka International Cancer Institute during January to December 2018. We compared automatic VBN (Ziostation2), manual route modification using an oblique method after automatic VBN, and manual navigation using a general application computed tomography viewer. Concordance between predicted and actual branching were determined. We also compared the predicted relationship between the terminal bronchi and the lesion by 2 of the methods with ultrasonographic images (radial-probe endobronchial ultrasonography [radial-EBUS]).Manual modification after automatic VBN significantly increased the rate of determining routes to the target (66%) versus with the automatic VBN alone (32%) (P < .001). Expected route bifurcations were exact matches with actual branching in 45/48 of the patients using manual modification after automatic VBN. The predicted relationship between the terminal bronchi and the lesion using manual modification after VBN matched the radial-EBUS images in 35/50 of the patients.Manual modification of routes to PPLs using an oblique method after automatic VBN predicted actual radial-EBUS route imaging and could help determine appropriate patients for bronchoscopy.

Bronchoalveolar lavage fluid reveals factors contributing to the efficacy of PD-1 blockade in lung cancer.

Bronchoalveolar lavage is commonly performed to assess inflammation and identify responsible pathogens in lung diseases. Findings from bronchoalveolar lavage might be used to evaluate the immune profile of the lung tumor microenvironment (TME). To investigate whether bronchoalveolar lavage fluid (BALF) analysis can help identify patients with non-small cell lung cancer (NSCLC) who respond to immune checkpoint inhibitors (ICIs), BALF and blood were prospectively collected before initiating nivolumab. The secreted molecules, microbiome, and cellular profiles based on BALF and blood analysis of 12 patients were compared with regard to therapeutic effect. Compared with ICI nonresponders, responders showed significantly higher CXCL9 levels and a greater diversity of the lung microbiome profile in BALF, along with a greater frequency of the CD56+ subset in blood T cells, whereas no significant difference in PD-L1 expression was found in tumor cells. Antibiotic treatment in a preclinical lung cancer model significantly decreased CXCL9 in the lung TME, resulting in reduced sensitivity to anti-PD-1 antibody, which was reversed by CXCL9 induction in tumor cells. Thus, CXCL9 might be associated with the lung TME microbiome, and the balance of CXCL9 and lung TME microbiome could contribute to nivolumab sensitivity in patients with NSCLC. BALF analysis can help predict the efficacy of ICIs when performed along with currently approved examinations.

Comparison of sampling methods for next generation sequencing for patients with lung cancer.

INTRODUCTION: Success of next generation sequencing (NGS) analysis is becoming indispensable in the treatment of advanced lung cancer. However, the advantages and disadvantages of each sampling method in the NGS analysis have not yet been clarified. METHODS: We compared the success rates of NGS analysis, and DNA and RNA yields for transbronchial biopsy (TBB), endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), computed tomography (CT)-guided biopsy, fluid sample, and surgical biopsy for NGS analysis in patients through the lung cancer genomic screening project for individualized medicine (LC-SCRUM)-Asia, a nationwide NGS screening project. In case, sufficient samples could not be collected by TBB and EBUS-TBNA, re-biopsy (genome re-biopsy) was performed. RESULTS: A total of 223 patients were enrolled and success rates of NGS analysis were not different between samples obtained through TBB, EBUS-TBNA, and CT-guided biopsy; however, success rates for fluid samples and surgical biopsy samples were significantly higher than those of other methods. The risk of genome re-biopsy was higher with TBB for centrally located lesions. CT-guided biopsy yielded more samples but had a lower success rate for analysis of RNA-based NGS than TBB. CONCLUSIONS: TBB is the mainstay of sampling methods, but for centrally located lesions, EBUS-TBNA may be a better strategy. For CT-guided biopsy, the success rate of RNA-based NGS analysis is low. Fluid samples are expected to yield successful results as surgical biopsy samples, but the latter are better for sample preservation. Determining the optimal method for genome biopsy for each case is important.

Sinus Node Dysfunction Co-occurring with Immune Checkpoint Inhibitor-associated Myocarditis.

Immune checkpoint inhibitor (ICI)-induced myocarditis is a potentially life-threatening adverse event. We herein report a rare case of sick sinus syndrome (SSS) co-occurring with ICI-associated myocarditis. A 71-year-old woman with lung cancer undergoing pembrolizumab monotherapy was admitted owing to a fever, worsening kidney function, and sinus bradycardia. She was diagnosed with multi-organ immune-related adverse events, including myocarditis. Pulse steroid therapy was initiated immediately under the support of a temporary pacemaker, which resulted in the resolution of SSS in a few days. Biopsy specimens of the endomyocardium showed active myocarditis. Thus, we should be aware that SSS can co-occur with ICI-induced myocarditis.

Classification and regression tree for estimating predictive markers to detect T790M mutations after acquired resistance to first line EGFR-TKI: HOPE-002.

BACKGROUND AND OBJECTIVE: Osimertinib as first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor (EGFR) mutations remains controversial. Sequential EGFR-tyrosine kinase inhibitor (TKI) might be superior to the first line osimertinib in patients at risk of developing acquired T790M mutations. METHODS: We enrolled consecutive patients with EGFR-mutated (deletion 19 or L858R) advanced NSCLC treated with first-line drugs and evaluated predictive markers using classification and regression tree (CART) for the detection of T790M mutations based on patient backgrounds prior to initial treatment. RESULTS: Patients without acquired T790M mutations had worse outcomes than those with T790M mutations (median OS: 798 days vs. not reached; HR: 2.70; P < 0.001). CART identified three distinct groups based on variables associated with acquired T790M mutations (age, CYF, WBC, liver metastasis, and LDH; AUROC: 0.77). Based on certain variables, CART identified three distinct groups in deletion 19 (albumin, LDH, bone metastasis, pleural effusion, and WBC; AUROC: 0.81) and two distinct groups in L858R (age, CEA, and ALP; AUROC: 0.80). The T790M detection frequencies after TKI resistance of afatinib and first-generation EGFR-TKIs were similar (35.3% vs. 37.4%, P = 0.933). Afatinib demonstrated longer PFS (398 vs. 279 days; HR: 0.67; P = 0.004) and OS (1053 vs. 956 days; HR: 0.68; P = 0.051) than first-generation EGFR-TKIs. CONCLUSION: Identification of patients at risk of acquiring T790M mutations after EGFR-TKI failure may aid in choice of first-line EGFR-TKI. Furthermore, afatinib may be the more effective 1st-line EGFR-TKI treatment for patients at risk of developing T790M as initial EGFR-TKI resistance.

Efficacy and safety of ramucirumab and docetaxel in previously treated patients with squamous cell lung cancer: a multicenter retrospective cohort study.

OBJECTIVE: Ramucirumab plus docetaxel (RAM/DOC) therapy is currently the standard for previously treated advanced non-small cell lung cancer (NSCLC), irrespective of histology. However, in the clinical trial, only the first-line platinum-based chemotherapy refractory patients were enrolled and the eligible criteria was strict to avoid hemoptysis, especially in squamous cell NSCLC (Sq). Thus, the efficacy and safety data on ramucirumab for Sq in real-world settings after immune checkpoint inhibitors monotherapy or combination therapy approved as novel first-line therapy is lacking. METHODS: We retrospectively analyzed previously treated patients with advanced NSCLC who underwent RAM/DOC therapy at four institutions. Clinical data on the initiation of RAM/DOC were collected from medical records. Treatment outcomes were assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1. Incidence of pulmonary hemorrhage was assessed according to the Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Overall, 237 patients with NSCLC were included and 38 (16%) had squamous cell carcinoma. There were no significant differences in median progression-free survival and overall survival between Sq and non-Sq patients (5.8 months vs. 4.3 months, P = 0.0937; 15.2 months vs. 13.4 months, P = 0.714, respectively). Of all patients, 13 (5%) developed pulmonary hemorrhage. According to histological analysis, there was no significant difference in pulmonary hemorrhage proportion between Sq and non-Sq cohorts (2/38 vs. 11/199, respectively, P = 0.947). CONCLUSIONS: For previously treated patients with Sq, the efficacy and safety of RAM/DOC therapy were confirmed in a real-world setting and were similar to non-Sq.

Cytokine Release Syndrome and Immune-Related Pneumonitis Associated With Tumor Progression in a Pulmonary Pleomorphic Carcinoma Treated With Nivolumab Plus Ipilimumab Treatment: A Case Report.

Effective control of severe immune-related adverse events, including cytokine release syndrome (CRS), is essential for the success of immunotherapy. We present a case of a granulocyte colony-stimulating factor-producing pleomorphic lung carcinoma treated with nivolumab plus ipilimumab which developed CRS and severe immune-related pneumonitis. The effect of immunotherapy was heterogeneous; gastric metastasis was eliminated, but the pulmonary lesion had primary resistance. Steroid and tocilizumab were successful in controlling CRS, but additional infliximab was necessary to control pneumonitis. To control immune-related adverse events, it is important to choose immunosuppressive agents to the specific target organ and inflammatory cells.