A Phase II Trial on Osimertinib as a First-Line Treatment for EGFR Mutation-Positive Advanced NSCLC in Elderly Patients: The SPIRAL-0 Study.

BACKGROUND: Osimertinib is one of the standard first-line treatments for advanced non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) mutations, because it achieves significantly longer progression-free survival (PFS) than conventional first-line treatments (hazard ratio: 0.46). However, the efficacy and safety of osimertinib as a first-line treatment for patients aged ≥75 years remain unclear. METHODS: This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. The primary endpoint was 1-year PFS rate; secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. RESULTS: Thirty-eight patients were included in the analysis. The 1-year PFS rate was 59.4% (95% confidence interval [CI], 46.1%-72.7%), which did not meet the primary endpoint (the threshold 1-year PFS rate of 50% predicted using data from the NEJ003 study). The most common grade 3/4 adverse events were rash/dermatitis acneiform/ALT increased/hypokalemia (2 patients, 5%). Seven patients developed pneumonitis (17.5%). There were no other cases of treatment discontinuation due to adverse events other than pneumonitis. CONCLUSION: Although this study did not meet the primary endpoint, osimertinib was tolerable for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. (Japan Registry of Clinical Trials [JRCT] ID number: jRCTs071180007).

Serial interferon-gamma release assay in lung cancer patients receiving immune checkpoint inhibitors: a prospective cohort study.

Recent advancements in cancer immunotherapy using immune checkpoint inhibitors (ICIs) have received considerable attention. Although advantageous, ICI therapies cause unique immune-related adverse events (irAEs) in some patients. Moreover, infectious diseases, such as tuberculosis, have been recognized as emerging concerns during immunotherapy. We aimed to evaluate the interferon-gamma release assay (IGRA) conversion rate and active tuberculosis incidence during immunotherapy to elucidate the incidence of tuberculosis reactivation after ICI therapy induction.We prospectively assessed IGRA results in lung cancer patients who received ICI monotherapy before ICI treatment and at 6 and 12 months after ICI treatment. We also assessed computed tomography findings to determine the presence of active tuberculosis when positive IGRA results were obtained. The ICIs used were nivolumab, pembrolizumab, atezolizumab, and durvalumab.In all, 178 patients were prospectively recruited between March 2017 and March 2020. Of these, 123 completed serial IGRAs, of whom 18, 101, and 4, respectively, had positive, negative, and indeterminate IGRAs at baseline. Three and four patients, respectively, showed IGRA reversion and conversion during immunotherapy. One patient with a sustained, stable positive IGRA and one with IGRA conversion developed active pulmonary tuberculosis during immunotherapy.We found that 3.3% and 1.6% of the patients developed IGRA conversion and active tuberculosis, respectively. Of the four patients who developed IGRA conversion, one developed active pulmonary tuberculosis during immunotherapy. Another patient with sustained, stable positive IGRA developed active tuberculosis. Physicians should be alert to tuberculosis development during ICI therapy, and IGRA testing is a useful tool to assess the risk of developing active tuberculosis.

Primary Pulmonary Malignant Melanoma Successfully Treated with Immunotherapy in a 90-Year-Old Patient.

Malignant melanoma is a rare and high-grade cancer. It most commonly affects the skin, but it has the potential to involve all areas of the body. Primary pulmonary malignant melanoma is rare, accounting for only 0.01% of all pulmonary tumors. We present a case of primary pulmonary malignant melanoma in a 90-year-old patient. The pretreatment computed tomography (CT) showed a pulmonary mass in the right upper lobe, multiple pleural nodules, enlarged mediastinal lymph nodes, and bone metastases. Positron emission tomography-CT showed a region of fluorodeoxyglucose hyperaccumulation that was consistent with the abnormal shadows. Advanced stage lung cancer was initially suspected, but bronchoscopy revealed a malignant melanoma. The patient was diagnosed with a primary pulmonary malignant melanoma. Although the patient was older, he wanted to receive immediate treatment. Thus, he was treated with immune checkpoint inhibitors. He responded well to the medication, and neither major adverse events nor tumor size reduction was observed. We report a rare case of primary pulmonary malignant melanoma in an older adult. Immune checkpoint inhibitor therapy, as in this case, was a viable treatment option for older adults.

No need to hesitate: immune-related neutropenia and thrombocytopenia that improved by corticosteroids.

Unlike cytotoxicity, haematological toxicity is a rare immune-related adverse event that is occasionally irreversible and refractory. A 67-year-old man was diagnosed with advanced lung squamous cell carcinoma. After 41 cycles of nivolumab as third-line chemotherapy, the patient developed severe neutropenia and thrombocytopenia. The bone marrow biopsy and serum immunological tests indicated no evidence of bone marrow failure and suggested autoimmune mature blood cell destruction. After initiating treatment with prednisolone 50 mg orally and filgrastim 75 µg subcutaneously once daily, neutropenia and thrombocytopenia recovered within four and nine days, respectively. The filgrastim was discontinued four days later, and the corticosteroid was discontinued three months later; there has been no haemocytopenia recurrence since then. The patient has remained untreated for more than two years without progression of lung cancer. In conclusion, corticosteroids should be considered for the treatment of autoimmune haemocytopenia if refractory bone marrow dysplasia can be ruled out.

Afebrile tension pyopneumothorax due to anaerobic bacteria: Fistula or gas production?

Pyopneumothorax is characterized by a pleural collection of pus and air requiring emergent thoracic drainage. A 65-year-old diabetic woman presented with a two-week history of fatigue and dyspnea but without fever. Chest computed tomography showed extensive pleural effusion and air in the left pleural cavity, which caused a mediastinal shift with peripheral circulatory failure. There was no evidence of a pulmonary fistula. Anaerobic bacteria were found in the pus smear after microscopy. After 17 days of chest drainage and 18 days of antibiotic treatment, the patient recovered without any complications. The etiology of pyopneumothorax in this case was slowly progressive pyothorax due to gas-producing anaerobic bacteria. In conclusion, we should pay careful attention to serious infectious diseases, including pyothorax, in diabetic patients due to the high prevalence and subclinical symptoms.

Successful management of a lung cancer patient harbouring both EGFR mutation and EML4-ALK fusion gene with disseminated intravascular coagulation.

Lung cancer patients harbouring driver oncogene alterations are markedly responsive to molecular target agents, such as epidermal growth factor receptor (EGFR), tyrosine kinase inhibitor (TKI), and echinoderm microtubule-associated protein like 4 - anaplastic lymphoma kinase (EML4-ALK)-TKI. We encountered an exceptionally rare case, harbouring both EGFR mutation and EML4-ALK fusion gene, and suffering from severe disseminated intravascular coagulation. In this case report, we present two notable points. First, our patient was successfully treated with a third-generation EGFR-TKI, osimertinib. Second, osimertinib could manage severe conditions, such as disseminated intravascular coagulation. Third-generation EGFR-TKIs may be a viable option for patients harbouring both EGFR mutations and EML4-ALK fusion genes, even in severe conditions.

Small cell transformation of non-small cell lung cancer under immunotherapy: Case series and literature review.

In advanced lung cancer treatment, immunotherapy provides durable responses in some patients. However, other patients experience progressive disease and the resistance mechanisms to immunotherapy have yet been fully elucidated. Small cell transformation of non-small cell lung cancer (NSCLC) is commonly recognized as one of the resistance mechanisms to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in EGFR-mutant NSCLC treatment. As a resistant mechanism for immunotherapy, we report the first case of small cell transformation in 2017. Since then, eight similar cases have been reported and the concept of small cell transformation is now becoming more prevalent as a mechanism of immunotherapy resistance. In our facility, we have experienced four cases of small cell transformation after immunotherapy (including the reported case in 2017). The histology of each primary tumor was squamous cell carcinoma, large cell type neuroendocrine carcinoma, or poorly differentiated NSCLC. None had driver gene mutations. Nivolumab was administered in all four cases and atezolizumab was administered as a next line to nivolumab treatment in one case. The best response to immunotherapy was partial response or stable disease. There was a wide range of periods from the start of immunotherapy to confirmation of small cell transformation (from 2 weeks to almost 3 years). In conclusion, small cell transformation is an important resistance mechanism in cancer immunotherapy. When NSCLC progresses after immunotherapy, the possibility of small cell transformation and rebiopsy should always be encouraged, as it leads to clarification of the resistance mechanisms and frequency.

Effect of cyclooxygenase inhibitor use on immunotherapy efficacy in non-small cell lung cancer.

BACKGROUND: A synergistic effect of cyclooxygenase inhibitors (COX-I) and immune checkpoint inhibitors (ICIs) has been suggested. However, the impact of COX-I on the efficacy of ICIs is unclear. Here, we aimed to evaluate the relationship between COX-I use and the efficacy of ICI in patients with non-small cell lung cancer (NSCLC). METHODS: We retrospectively reviewed NSCLC patients who received ICI monotherapy. We defined COX-I use as regular use of COX-I other than low-dose aspirin during the initiation of ICIs to the first evaluation of efficacy. The efficacy of ICIs was evaluated with response rate (RR), disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Differences in baseline characteristics by COX-I use were controlled by using an inverse probability of treatment weighting (IPW) adjusted analysis. RESULTS: A total of 198 patients with NSCLC received ICIs; 128, 50, and 20 patients received nivolumab, pembrolizumab, and atezolizumab, respectively; there were 65 (32.8%) COX-I users. While there was no significant difference in RR (15.4% vs. 13.5%; p = 0.828), DCR (41.5% vs. 49.6%; p = 0.294), PFS (median, 2.69 vs. 3.68 months; 95% confidence intervals [CI], 1.77-5.19 vs. 2.20-4.60 months; p = 0.630), COX-I users had significantly shorter OS than non-COX-I users (median, 6.08 vs. 16.10 months; 95% CI: 3.78-11.66 vs. 9.49-19.68 months; p = 0.003). On IPW adjusted analysis, there was no significant difference in OS (median, 7.85 vs. 15.11 months; 95% CI: 5.03-14.92 vs. 9.49-19.32 months; p = 0.081). CONCLUSIONS: There was no additional or negative impact of COX-I use on the efficacy of ICIs in NSCLC.

Efficacy and safety of immune checkpoint inhibitors in patients with non-small cell lung cancer aged 80 years or older.

BACKGROUND: In Japan, over 25% of the population is elderly. As the risk of lung cancer increases with age, the number of elderly patients with lung cancer also increases. Given the challenges of an aging society, it is critical that elderly patients receive safe therapies. AIM: We assessed the safety and efficacy of immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC) aged ≥80 years. METHODS: We retrospectively reviewed NSCLC patients aged ≥80 years old who received ICIs in the National Hospital Organization Kyoto Medical Center. We collected data on patient characteristics, prior treatments, number of cycles, response, and immune-related adverse events (irAEs) during ICI monotherapy. RESULTS: A total of 45 patients were reviewed. The patients' median age was 85 years. Twenty-one, 17, and 7 patients received nivolumab, pembrolizumab, and atezolizumab, respectively. The disease control rate (partial response [PR] + stable disease [SD]) was 60.0%, and the progression-free survival was 3.4 months. In patients with nivolumab, seven patients (33.3%) achieved SD, and three patients (14.2%) achieved PR. In patients treated with pembrolizumab, seven patients (41.2%) achieved SD, and six patients (35.3%) achieved PR. In patients with atezolizumab, three patients (42.9%) achieved SD, and one patient (14.2%) achieved PR. Sixteen (36%) patients presented with a poor performance status. Three patients treated with pembrolizumab experienced grade 3 pneumonia, while one patient treated with nivolumab experienced grade 5 pneumonia. CONCLUSION: This study suggested that ICIs are an acceptable treatment option for NSCLC patients aged ≥80 years. Oncologists should pay attention to severe irAEs.

Impact of COVID-19 pandemic on lung cancer treatment scheduling.

The current coronavirus disease 2019 (COVID-19) pandemic is associated with a heavy burden on the mental and physical health of patients, regional healthcare resources, and global economic activity. Many patients with lung cancer are thought to be affected by this situation. Therefore, in this study, we aimed to evaluate the impact of COVID-19 pandemic on lung cancer treatment scheduling. We retrospectively reviewed the medical records of lung cancer patients who were undergoing anticancer treatment at the National Hospital Organization Kyoto Medical Center (600 beds) in Kyoto, Japan, between 1 March 2020 and 31 May 2020. After the medical records were reviewed, the patients were assigned to one of two groups, depending on whether their lung cancer treatment schedule was delayed. We assessed the characteristics, types of histopathology and treatment, and the reason for the delay. A total 15 (9.1%) patients experienced a delay in lung cancer treatment during the COVID-19 pandemic. Patients with a treatment delay received significantly more immune checkpoint inhibitor (ICI) monotherapy than patients without a treatment delay (P = 0.0057). On the contrary, no patients receiving molecular targeted agents experienced a treatment delay during the COVID-19 pandemic period (P = 0.0027). The treatments of most of the patients were delayed at their request. We determined that 9.1% lung cancer patients suffered anxiety and requested a treatment delay during the COVID-19 pandemic. Oncologists should bear in mind that patients with cancer have more anxiety than expected under unprecedented circumstances such as the COVID-19 pandemic.

Development of Mycobacterium avium Complex Lung Disease in Patients With Lung Cancer on Immune Checkpoint Inhibitors.

Immunotherapy with immune checkpoint inhibitors (ICIs), while ameliorating lung cancer, can cause infectious diseases, including tuberculosis, in addition to immune-related noninfectious complications. In the clinical setting, the efficacy of ICIs to treat mycobacterial infection remains controversial. We report 3 cases of acute Mycobacterium avium complex lung disease during immunotherapy with ICIs.

Pleural involvement of diffuse large B-cell lymphoma mimicking malignant pleural mesothelioma.

Diffuse large B-cell lymphoma (DLBCL) is a common cancer in haematology. We report a case of DLBCL mimicking malignant pleural mesothelioma (MPM). A 75-year-old man with a 1-week exacerbation of dyspnoea on exertion and right pleural effusion on chest radiography was admitted to our hospital. Positron emission tomography/computed tomography revealed diffuse pleural thick lesions and massive pleural effusion, and these lesions had accumulation of fluorodeoxyglucose. Because we suspected MPM or lung cancer, we performed a biopsy with thoracoscopy to confirm the diagnosis. A biopsy of the pleural effusion with thoracoscopy revealed DLBCL. Chemotherapy was immediately selected, and the diffuse thickened pleural wall and massive pleural effusion of the right chest were significantly improved after two cycles of chemotherapy.

Incidence of Active Tuberculosis in Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.

Although it ameliorates lung cancer, immunotherapy with immune checkpoint inhibitors (ICIs) presents complications of infectious diseases, including tuberculosis. Incidence of tuberculosis during immunotherapy remains unclear. We found that 1.7% of patients developed active tuberculosis during immunotherapy at our institution. In patients with a positive interferon-gamma release assay status before ICI therapy, physicians should pay close attention to developing tuberculosis.

Retreatment with anti-PD-1 antibody in non-small cell lung cancer patients previously treated with anti-PD-L1 antibody.

BACKGROUND: This study evaluated the efficacy and safety of retreatment with anti-programmed death 1 (anti-PD-1) antibodies in patients with advanced non-small cell lung cancer (NSCLC) after prior treatment with anti-programmed death-ligand 1 (anti-PD-L1) antibodies. METHODS: Data (N = 15) on patients' characteristics, number of cycles, regimens, their best response and immune-related adverse events (irAEs) were recorded retrospectively. RESULTS: NSCLC was initially treated with anti-PD-L1 antibody atezolizumab (N = 14) or durvalumab (N = 1). No patients had a high (≥50%) tumor expression of PD-L1. The median cycles for atezolizumab were five (range 1-15), and median progression-free survival was 2.8 and 6.0 months for atezolizumab and durvalumab, respectively. Five (33.3%) and nine (60.0%) patients showed stable and progressive disease as their best response, respectively. No differences in irAEs between anti-PD-L1 and anti-PD-1 antibodies occurred. CONCLUSION: Patients treated with anti-PD-L1 antibodies for NSCLC received limited benefits from retreatment with anti-PD-1 antibodies.

Single-center analysis of antiresorptive agent-related osteonecrosis of the jaw in lung cancer patients.

BACKGROUND: Over the past two decades, antiresorptive agent-related osteonecrosis of the jaw (ARONJ) has become a growing concern. We examined the incidence of ARONJ and identified its risk factors in lung cancer patients in the real-world clinical setting. To our knowledge, we are the first to do so. PATIENTS AND METHODS: We retrospectively analyzed lung cancer patients with bone metastases who had received anti-resorptive agents (zoledronate or denosumab) at the National Hospital Organization Kyoto Medical Center from October 2012 to September 2018. All ARONJ cases were diagnosed by the dentists according to the established diagnostic criteria. RESULTS: A total of 171 patients were reviewed, 13 (7.6%) of whom experienced ARONJ. Among the 13 patients, six (46.2%), four (30.8%) and three (23.1%) had adenocarcinoma, squamous carcinoma and not otherwise specified, respectively. ARONJ was stage 2 in three (23.1%) patients and stage 3 in 10 (76.9%). More cycles of antiresorptive agents (odds ratio [OR] = 11.54; 95% confidence interval [CI], 2.47-53.99; P < 0.01), use of immune checkpoint inhibitors (ICIs; OR = 5.05; 95% CI, 1.56-16.37; P < 0.01) and longer survival duration (≥2 years; OR = 12.16; 95% CI, 3.17-46.65; P < 0.01) were independently associated with ARONJ in a multivariate analysis. CONCLUSIONS: The incidence of ARONJ was relatively high in lung cancer patients with bone metastases. When using antiresorptive agents, oncologists should closely monitor patients for ARONJ during the course of treatment and regularly consult with dentists, especially in patients receiving ICIs.

Therapy-related acute myeloid leukemia after chemotherapy in extensive disease-small cell lung cancer.

We experienced therapy-related acute myeloid leukemia (t-AML) in a patient with extensive disease-small cell lung cancer (ED-SCLC). This case is rare and has educational message because ED-SCLC has a poor prognosis and often cannot survive until developing therapy related hematological malignancy. Furthermore this case had unique chromosomal abnormalities. With recent advances in chemotherapy and radiotherapy, the prognosis of lung cancer has improved, while t-AML has been increasing in frequency.

The clinical benefits of immune checkpoint inhibitor for thymic carcinomas ∼experience of single public hospital in Japan∼.

Thymic carcinomas is rare and highly aggressive carcinoma. Most patients with them are diagnosed as being at surgically unresectable stages due to it. There are several reports which showed the effect of chemotherapy, however, it is controversial. Recently, immune checkpoint inhibitors have changed conventional chemotherapy due to their effect against various types of cancers. We administered nivolumab, anti-Programmed Cell Death (PD)-1 antibody, to four patients with unresectable thymic carcinomas who had previously undergone conventional chemotherapy. A histopathology on tumors from these patients revealed the presence of squamous cell carcinoma and PD-L1 high expression. After treatment with nivolumab, it seemed to be beneficial to all patients; The best clinical responses of 3 patients were partial response and that of the other one was stable disease. None of them experienced severe immune-related adverse events. Our results suggest the potential benefits of using these inhibitors to treat thymic carcinomas in real world clinical setting as is the cases in recent clinical trials for the evaluation of immune checkpoint inhibitors for the treatment of thymic carcinoma.

Retreatment With Anti-PD-L1 Antibody in Advanced Non-small Cell Lung Cancer Previously Treated With Anti-PD-1 Antibodies.

AIM: To evaluate the efficacy and safety of re-treatment with anti-programmed death (PD)-L1 antibody (atezolizumab) after anti-PD-1 antibody (nivolumab/pembrolizumab) treatment in advanced non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: We retrospectively reviewed 18 NSCLC patients who received atezolizumab after anti-PD-1 antibody treatment. Data on patient characteristics, number of cycles of anti-PD-1 antibody and atezolizumab, regimens between anti-PD-1 antibody and atezolizumab, best response, and immune-related adverse events (irAEs) were collected and analyzed. RESULTS: Nine patients a had high (≥50%) PD-L1 expression. The median number of cycles of atezolizumab was 3 (range=2-7). The median progression-free survival was 2.9±1.8 months. Seven (38.9%) and 11 (61.1%) patients had stable and progressive disease, respectively. No patient achieved partial or complete response. There were no significant differences in the occurrence of irAEs between anti-PD-1 antibodies and atezolizumab. CONCLUSION: Preliminary results showed that patients previously treated with anti PD-1 antibodies received only limited benefit from subsequent atezolizumab.

Acute progression of aspergillosis in a patient with lung cancer receiving nivolumab.

A 65-year-old man with chronic progressive pulmonary aspergillosis (CPPA) was admitted for the treatment of lung adenocarcinoma while receiving an immune checkpoint inhibitor, nivolumab. The tumour responded well to the therapy, but the cavity of CPPA became large in contrast to the tumour after 20 courses of therapy. He was diagnosed as having exacerbation of CPPA and successfully and concurrently treated with an antifungal agent and nivolumab. Since there was absence of obvious immunosuppression and the presence of a drastic effect on tumour remission during nivolumab therapy, this phenomenon suggested that the trigger of CPPA progression was dependent not on immunosuppression but on a hyperreaction to microorganisms, which was similar to the immune reconstitution inflammatory syndrome caused by nivolumab. This was a thought-provoking case in which the immune checkpoint inhibitor had a paradoxical effect for the tumour and infection.

Retreatment with pembrolizumab in advanced non-small cell lung cancer patients previously treated with nivolumab: emerging reports of 12 cases.

PURPOSE: After approval of anti-programmed cell death (PD)-1 antibodies, treatment for non-small cell lung cancer (NSCLC) has drastically changed. However, even in patients with favorable effects, therapeutic efficacy does not last long. Recently, retreatment with anti-PD-1 antibody has received attention. The aim of this study was to evaluate the efficacy and safety of retreatment with pembrolizumab in NSCLC patients previously treated with nivolumab. PATIENTS AND METHODS: We retrospectively reviewed NSCLC patients retreated with pembrolizumab who were previously treated with nivolumab. We collected the following data: patient characteristics, number of cycles of nivolumab and pembrolizumab, treatment interval between nivolumab and pembrolizumab, best response, and immune-related adverse events. RESULTS: Twelve patients were reviewed. The median number of cycles of nivolumab was 12.5 (range 2-32 cycles). Seven patients (58.3%) achieved a partial response (PR) and two patients (16.7%) achieved stable disease (SD). Eight patients (66.7%) received cytotoxic chemotherapy between nivolumab and pembrolizumab. The median number of cycles of chemotherapy treatment was 4 (range 1-9 cycles). The median number of cycles of pembrolizumab was 3.5 (range 1-17 cycles). One patient (8.3%) achieved PR and four patients (33.3%) achieved SD as their best response to pembrolizumab. All patients showing response to pembrolizumab had very high (≥ 80%) tumor PD-Ligand 1 expression. CONCLUSIONS: This study suggested that retreatment with anti-PD-1 antibody is a reasonable option for selected NSCLC patients.