Tadaaki Yamada

• M.D. & Ph.D.
• Professor (Associate) at Kyoto Prefectural University of Medicine

This study was performed to determine the incidence rates of resistance factors, i.e., high-level hepatocyte growth factor (HGF) expression, epidermal growth factor receptor (EGFR) T790M secondary mutation, and MET amplification, in tumors with intrinsic and acquired EGFR tyrosine kinase inhibitor (TKI) resistance in EGFR mutant lung cancer. Ninety...

Cancer cell microenvironments, including host cells, can critically affect cancer cell behaviors, including drug sensitivity. Although crizotinib, a dual tyrosine kinase inhibitor (TKI) of ALK and Met, shows dramatic effect against EML4-ALK lung cancer cells, these cells can acquire resistance to crizotinib by several mechanisms, including ALK ampl...

LKB1 is a commonly mutated tumor suppressor in non-small cell lung cancer (NSCLC) that exerts complex effects on signal transduction and transcriptional regulation. To better understand the downstream impact of loss of functional LKB1, we developed a transcriptional fingerprint assay representing this phenotype. This assay was predictive of LKB1 fu...

EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of β-catenin in EGFR TKI resistance has been previously reported, however, the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition r...

A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and H...

The efficacy of immune checkpoint inhibitor (ICI) monotherapy on non-small-cell lung cancer (NSCLC) varies by epidermal growth factor receptor (EGFR) mutation subtypes. However, the impact of these subtypes on the clinical outcomes of chemoimmunotherapy (Chemo+ICI) or platinum-based chemotherapy (Chemo) in real-world practice remains unclear. This...

Introduction Human epidermal growth factor receptor 2 (HER2) is an oncogene target in various cancers, including lung, stomach, and breast cancers. Several HER2-tyrosine kinase inhibitors (TKIs) have been developed for clinical use in patients with tumors exhibiting HER2 aberrations. However, achieving complete tumor remission remains challenging....

Background Based on our prior preclinical research, a clinical trial is currently underway to assess the safety and efficacy of combining the third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib with the AXL inhibitor ONO-7475 in treatment-naive patients with advanced EGFR-mutated non-small cell lung ca...

Background KRAS is the most frequent oncogene in non-small cell lung cancer (NSCLC), and some KRAS G12C inhibitors have been clinically developed for treatment of KRAS G12C-mutated NSCLC patients. However, these KRAS G12C inhibitors have shown limited efficacy, and developing novel treatment strategy is warranted to improve clinical prognosis in th...

Background. During pregnancy, lung cancer is often diagnosed at an advanced stage, leading to a poor prognosis in the mother. Case. A 38-year-old woman, 26 weeks pregnant, presented with a cough for 6 months that had not improved with antitussive medications. She was brought to a local doctor, and chest X-ray revealed masses in the right middle and...

This retrospective, multicenter cohort study aimed to determine whether cancer cachexia serves as a biomarker for determining the most effective treatment for patients having non-small-cell lung cancer (NSCLC) with high programmed death ligand 1 (PD-L1) expression treated with immune checkpoint inhibitors (ICIs) alone or combined with chemotherapy...

Introduction Pembrolizumab with pemetrexed and cisplatin/carboplatin is an approved first-line treatment for metastatic nonsquamous NSCLC. Nevertheless, its efficacy and safety in patients aged 75 years and above remain unclear. We assessed the efficacy and safety of pembrolizumab with pemetrexed in patients with programmed cell death-ligand 1 expr...

Introduction This study aimed to describe the course of patients with lung cancer from treatment initiation to end-of-life. Methods This retrospective cohort study used Claims Data from the National Health Insurance and Advanced Elderly Medical Service System. We analyzed data from patients newly diagnosed with lung cancer between April 2013 and M...

Background The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is widely used as a first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC). However, there is no established treatment for osimertinib resistance, so second-generation afatinib is an alternative treatment option. The...

Purpose: Rearranged during transfection (RET) aberrations represent a targetable oncogene in several tumor types, with RET inhibitors displaying marked efficacy. However, some patients with RET-aberrant cancer are insensitive to RET tyrosine kinase inhibitors (TKIs). Recently, drug-tolerant mechanisms have attracted attention as targets for initia...

Purpose: Thyroid transcription factor 1 (TTF-1) expression is a useful predictor of treatment efficacy in advanced non-squamous non-small-cell lung cancer (NSCLC). This study aimed to evaluate whether TTF-1 could predict the effectiveness of chemotherapy versus chemoimmunotherapy in patients with non-squamous NSCLC with programmed death ligand-1 (...

Simple Summary Sarcopenia refers to a progressive and systemic reduction in skeletal muscle mass and strength and is a primary component of cancer cachexia. This retrospective study examined the impact of the rate of muscle loss between two time points during the pretreatment period with concurrent chemoradiotherapy on the clinical outcomes during...

The association between depth of response (DpR) and treatment outcomes has been documented across various types of cancer. Immune checkpoint inhibitor (ICI)-based treatment is globally used as first-line treatment for non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) expression ≥ 50%. However, in this population, the signifi...

Background Advances in anticancer drugs for lung cancer (LC) have improved the prognosis of LC. Chronic pulmonary aspergillosis (CPA) is a progressive and often exacerbating respiratory disease with a poor prognosis. To date, the prognosis of LC complicated by CPA has not been elucidated. This study investigated the clinical implications of concomi...

Background: Tumor markers such as serum carcinoembryonic antigen (CEA) and cytokeratin fragment 19 (CYFRA 21-1) are utilized for assessing the effectiveness of chemotherapy in non-small cell lung cancer (NSCLC) patients. Yet, it remains uncertain whether these markers can reliably forecast responses to combined chemoimmunotherapy. Our study aimed...

Lazertinib, a novel third‐generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI), demonstrates marked efficacy in EGFR‐mutant lung cancer. However, resistance commonly develops, prompting consideration of therapeutic strategies to overcome initial drug resistance mechanisms. This study aimed to elucidate the adaptive resis...

Introduction Several studies explored the association between thyroid transcription factor-1 (TTF-1) and the therapeutic efficacy of immunotherapy. However, the effect of TTF-1 on the therapeutic efficacy of programmed death-1 (PD-1) inhibitor/chemoimmunotherapy in patients with non-squamous non-small cell lung cancer (non-Sq NSCLC) with a programm...

Objective. The Japan Lung Cancer Society established the Early Career Support Committee in 2023. This survey was conducted to understand the needs and current situations of society members. Methods. The survey targeted 7,734 members of the Japan Lung Cancer Society utilizing SurveyMonkey®. The questionnaire comprised six questions related to person...

8101 Background: Although the combination of an anti-PD-L1 antibody and platinum-based chemotherapy has become the standard care for ES-SCLC patients (pts), its safety and efficacy for those with a poor PS are unclear. Since SCLC is highly sensitive to chemotherapy, we hypothesized that ES-SCLC pts with a poor PS may benefit from anti-PD-L1 antibod...

8540 Background: Immune checkpoint inhibitor plus platinum-containing chemotherapy is the standard of care for patients with advanced non-small cell lung cancer (NSCLC). Pembrolizumab combined with pemetrexed and cisplatin/carboplatin is approved as first line treatment for patients with metastatic non-squamous NSCLC based on the results of KEYNOTE...

Background: Recent therapeutic strategies for KRAS-mutated cancers that inhibit the MAPK pathway have attracted considerable attention. The RAF/MEK clamp avutometinib (VS-6766/CH5126766/RO5126766/CKI27) is promising for patients with KRAS-mutated cancers. Although avutometinib monotherapy has shown clinical activity in patients with KRAS-mutated c...

Background and Aim: Immune checkpoint inhibitors (ICIs) have been widely used for the initial treatment of non-small cell lung cancer (NSCLC). Although both ICI monotherapy and the combination of ICI plus chemotherapy (chemo-ICI) are promising therapeutic options for patients with a programmed cell death ligand-1 tumor proportion score of 50% or hi...

Lazertinib, a novel third-generation EGFR-tyrosine kinase inhibitor, has shown marked efficacy in patients with EGFR-mutant lung cancer. However, after various periods of therapeutic intervention, most patients eventually acquire resistance to lazertinib. A potential therapeutic approach to address this clinical issue is to overcome the initial dru...

Background and Aim: The proportion of elderly patients diagnosed with advanced stage lung cancer has been increasing owing to the aging of the population. Thus, formulating a treatment strategy for elderly non-small cell lung cancer (NSCLC) patients is essential. For NSCLC with programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) ≧ 5...

Background: KRAS is the most frequent targetable oncogene in non-small cell lung cancer (NSCLC). Recently, novel KRAS inhibitor have been clinically developed for treatment of KRAS G12C-mutated NSCLC patients. However, it is difficult to achieve complete remission of tumor. Therefore, the optimal combined therapeutic intervention with KRAS G12C inh...

Combination therapy with docetaxel (DTX) and ramucirumab (RAM) has been used as a second-line treatment for advanced or recurrent lung cancer. However, there is insufficient evidence regarding the safety of angiogenesis inhibitors in older patients. This multicenter retrospective study aimed to investigate the efficacy and safety of second-line tre...

Driver oncogenes are investigated upfront at diagnosis using multi‐CDx systems with next‐generation sequencing techniques or multiplex reverse‐transcriptase polymerase chain reaction assays. Additionally, from 2019, comprehensive genomic profiling (CGP) assays have been available in Japan for patients with advanced solid tumors who had completed or...

Introduction Multiple programmed death-ligand 1 (PD-L1) immunohistochemistry assays performed using different antibodies including DAKO 22C3, DAKO 28-8, and Ventana SP142 PD-L1—predictive markers for response to various immune checkpoint inhibitors in NSCLC—have been approved in several countries. The differences in multiple PD-L1 immunohistochemis...

Background/aim: The prognosis of patients with malignant pleural mesothelioma (MPM) remains poor due to lack of effective therapeutic targets. DNA damage caused by long-time exposure to asbestos fibers has been associated with the development of MPM, with mutations at genes encoding DNA damage repair (DDR)-related molecules frequently expressed in...

Introduction The proportion of older patients diagnosed with advanced-stage non-small cell lung cancer (NSCLC) has been increasing. Immune checkpoint inhibitor (ICI) monotherapy (MONO) and combination therapy of ICI and chemotherapy (COMBO) are standard treatments for patients with NSCLC and programmed cell death ligand-1 (PD-L1) tumor proportion s...

Introduction The efficacy of second-line immune checkpoint inhibitor (ICI) therapy is limited in non-small cell lung cancer (NSCLC) patients with ≤ 49% PD-L1 expression. Although chemoimmunotherapy is a promising strategy, platinum-based chemotherapy followed by ICI monotherapy is often used to avoid synergistic adverse events. However, predictors...

Background A history of pre-administration of immune checkpoint inhibitors has been reported to be associated with good outcomes of ramucirumab (RAM) plus docetaxel (DOC) combination therapy for advanced non-small-cell lung cancer (NSCLC). However, existing knowledge on the clinical significance of RAM and DOC following combined chemoimmunotherapy...

Recent therapeutic strategies that inhibit the MAPK pathway, a key effector pathway in KRAS-mutated cancers, have attracted considerable attention. Among several molecular-targeted drugs, the RAF/MEK clamp avutometinib (VS-6766 /CH5126766/RO5126766/CKI27) is promising for patients with KRAS-mutated cancers. Although avutometinib monotherapy has sho...

Background and Objective The clinical development of immune checkpoint inhibitors (ICIs) has led to substantial advances in the treatment of lung cancer. In particular, the contribution of ICIs to the long-term survival of certain patients with non-small cell lung cancer (NSCLC) has been reported. With the accumulated experience in the use of ICIs,...

Immune checkpoint inhibitor (ICI) monotherapy and ICI plus chemotherapy are approved first-line treatments for patients with non-small cell lung cancer (NSCLC) expressing high levels of programmed cell death-ligand 1 (PD-L1). However, appropriate treatment for patients showing high PD-L1 expression and poor performance status (PS) is not well defin...

Background: The long overall survival (OS) observed among patients with non-small cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression in chemoimmunotherapy (CIT) groups in previous phase III trials suggests the limited efficacy of CIT among the subgroup with ≤49% PD-L1 expression on tumor cells. Hence, sequential treatm...

Few treatment options exist for pleural mesothelioma (PM), which is a progressive malignant tumor. However, the efficacy of molecular-targeted monotherapy is limited, and further therapeutic strategies are warranted to treat PM. Recently, the cancer cell cycle checkpoint inhibitors have attracted attention because they disrupt cell cycle regulation...

Background The physical tolerance in the advanced non-small cell lung cancer (NSCLC) patient often deteriorates, with a limited effective rate of the third-line treatment. This study retrospectively analyzed the efficacy and safety of etoposide soft capsules combined with anlotinib in the third-line treatment of advanced NSCLC. Methods A retrospec...

Background: Durvalumab consolidation after chemoradiotherapy (CRT) is a standard treatment for locally advanced non-small cell lung cancer (NSCLC). However, studies on immunological and nutritional markers to predict progression-free survival (PFS) and overall survival (OS) are inadequate. Systemic inflammation causes cancer cachexia and negativel...

With the increased use of granulocyte colony-stimulating factor (G-CSF) preparations, there is concern about the increase in G-CSF-associated large-vessel vasculitis; however, there have been no previous reports of vasculitis caused by multiple types of G-CSF preparations. We experienced a case of drug-induced large-vessel vasculitis caused by two...

Background: Osimertinib monotherapy is a common treatment for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC); however, standard treatment strategies for acquired resistance to this drug have not been established. In addition, the clinical significance of first-generation (1G) or second-generation (2G) EGFR-tyrosi...

Endobronchial metastasis (EBM) of hepatocellular carcinoma (HCC) is rare though HCC often metastasizes to the lungs. In this case report, a 74‐year‐old man with a history of HCC with chronic hepatitis C experienced hemoptysis and a dry cough. During immunotherapy for postoperative recurrent HCC, chest computed tomography (CT) revealed soft tissue s...

Importance: Immune checkpoint inhibitor (ICI) monotherapy with pembrolizumab and ICI plus chemotherapy have been approved as first-line treatments for non-small cell lung cancer (NSCLC) for patients with a programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) of 50% or more, but the choice between these 2 therapeutic options is uncle...

Background Osimertinib is a standard treatment option for epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, osimertinib monotherapy yields poor clinical outcomes in some patients, necessitating the development of novel treatment strategies. In addition, several studies have suggested that high pr...

Background: Dacomitinib significantly improves progression-free survival and overall survival (OS) compared with gefitinib in patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. However, dacomitinib often causes skin toxicities, resulting in treatment discontinuation. We aimed to...

It is recommended to get the multiple coronavirus disease 2019 (COVID-19) vaccinations for almost all people including asthma patients. A 70-year-old Japanese woman with asthma experienced worsening of respiratory symptoms after the second dose of the mRNA-based COVID-19 vaccine BNT162b2. The patient had hypercapnic respiratory failure and cardiac-...

Background: Programmed death-ligand 1 (PD-L1) inhibitor plus platinum-etoposide chemotherapy is used as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC), regardless of age. Objective: We examined the role of the Geriatric 8 (G8) screening tool for evaluating treatment outcomes in patients with ES-SCLC treated with PD-L...

Introduction: EGFR tyrosine kinase inhibitors are standard therapeutic agents for patients with advanced NSCLC harboring EGFR mutations. Nevertheless, some patients exhibit primary resistance to EGFR tyrosine kinase inhibitors in the first-line treatment setting. AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is in...

Purpose Growth differentiation factor-15 (GDF-15) is one of the key cachexia-inducing factors. Clinical trials on therapies targeting GDF-15 for cancer and cancer cachexia are underway. While the role of circulating GDF-15 in cachexia has been clarified, the effects of GDF-15 expression within cancer cells remain to be fully elucidated. Hence, the...

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), including lorlatinib have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare, as a small population of tumor cells survives due to adaptive resistance. In this preclinical study, we investigated the adaptive resis...

Chronic inflammation is a risk factor for various types of cancer. The pressure in the interstitial tissues has been reported to be elevated in chronic inflammation and cancer. However, little is known about the biological effect of pressure from the basal side on epithelia, and a significance of the elevated interstitial fluid pressure in cancer b...

Background: Current evidence indicates that immune checkpoint inhibitors (ICIs) have a limited efficacy in patients with lung cancer harboring epidermal growth factor receptor (EGFR) mutations. However, there is a lack of data on the efficacy of ICIs after osimertinib treatment, and the predictors of ICI efficacy are unclear. Methods: We retrospect...

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard treatments for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, some patients show primary resistance to EGFR-TKIs at the first-line treatment setting. AXL, a member of the TAM family of receptor tyrosine kinase, wa...

Background: Patients with epidermal growth factor receptor (EGFR)-mutated, advanced non-small cell lung cancer have received immunochemotherapy as one of the treatment options after tyrosine kinase inhibitor (TKI) failure. Methods: We retrospectively examined EGFR-mutant patients treated with atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP...

Introduction: Lung adenocarcinoma with negative TTF-1 expression is believed to be a poor prognostic factor for certain systemic treatments. Nevertheless, the impact of TTF-1 expression on combined chemoimmunotherapy remains unclear. We aimed to investigate the relationship between tumor TTF-1 expression and the efficacy of combined chemoimmunothe...

Simple Summary Chemoimmunotherapy improved overall survival (OS) and progression-free survival (PFS) in patients with extensive-stage small cell lung cancer (ES-SCLC) in two phase III trials, which set the age-stratified subgroup analyses at 65 years. Considering the super-aged society of Japan, treatment efficacy and safety in elderly patients ≥ 7...

Introduction: In recent years, programmed cell death-ligand 1 (PD-L1) inhibitor plus platinum-etoposide chemotherapy was found to have favorable clinical outcomes in patients with extensive-stage SCLC (ES-SCLC). The usefulness of early tumor shrinkage (ETS) has been reported in various types of cancers. Nevertheless, there have been few reports ev...

Background: Lung cancer patients face a high risk of thromboembolism (TE), which is considered to be a poor prognostic factor. However, the impact of symptomatic cerebral infarction (CI) and pulmonary embolism (PE) on the prognosis of advanced non-small cell lung cancer (NSCLC) patients is not fully understood. Methods: We retrospectively identi...

Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors rarely elicit complete responses in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC), as a small population of tumor cells survives due to adaptive resistance. Therefore, we focused on the mechanisms underlying adaptive resistance to lorlatinib and therapeutic strat...

Recent studies have reported that coronavirus disease-2019 (COVID-19) vaccination can exacerbate asthma. Status asthmaticus sometimes induces takotsubo cardiomyopathy. We present a case of takotsubo cardiomyopathy triggered by asthma exacerbation after the mRNA-based vaccination. Therapies for status asthmaticus resulted in prompt improvement of re...

Background and objective: Cancer cachexia presents with weight loss, anorexia, and fatigue and worsens the prognosis and quality of life of cancer patients. We aimed to summarize the current relevant discourse in the literature about cancer cachexia in the setting of non-small cell lung carcinoma and the possible current and future treatments. Me...

Background Current evidence indicates that immune checkpoint inhibitors (ICIs) have a limited efficacy in patients with lung cancer harboring epidermal growth factor receptor (EGFR) mutations. However, there is a lack of data on the efficacy of ICIs after osimertinib treatment, and the predictors of ICI efficacy are unclear. Methods We retrospectiv...

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare. Here, we investigated the molecular mechanisms underlying the emergence and maintenance of drug-tolerant cells in ALK-rearranged lung cancer. Cell based-assa...

For non-small cell lung cancer (NSCLC) patients with EGFR mutations, the initial therapeutic interventions will have crucial impacts on their clinical outcomes. Drug tolerant factors reportedly have an impact on EGFR-TKI sensitivity. This prospective study investigated the impacts of drug tolerant-related protein expression in tumors based on the e...

Purpose Growth differentiation factor 15 (GDF-15) is one of the key cachexia-inducible factors. Clinical trials on therapies targeting GDF-15 for cancer and cancer cachexia are underway. While the role of circulating GDF-15 in cachexia has been clarified, the effects of GDF-15 expression within cancer cells remain to be fully elucidated. Hence, the...

Background/aim: Systemic chemotherapy is effective for patients with untreated advanced small cell lung cancer (SCLC); however, most patients eventually experience recurrence. Therefore, development of novel beneficial and tolerable treatments for patients with relapsed SCLC is important. Patients and methods: In this retrospective observational...

Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) with a broad coverage against ALK mutations, has demonstrated dramatic effects in patients with ALK-rearranged lung cancer. The mechanisms of acquired resistance to lorlatinib by secondary ALK compound mutations have recently been reported; however, resi...

Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors rarely elicit complete responses in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC), as a small population of tumor cells survives due to adaptive resistance. Therefore, we focused on the mechanisms underlying adaptive resistance to lorlatinib and therapeutic strat...

Objectives We investigated the efficacy and safety of pembrolizumab monotherapy as first-line treatment for poor Eastern Cooperative Oncology Group performance status (PS) and elderly patients with programmed cell death-ligand 1 (PD-L1)-positive advanced non-small cell lung cancer (NSCLC). We also investigated clinical prognostic factors for the ef...