Real-World Pharmacokinetics, Effectiveness, and Safety of Atezolizumab in Patients With Unresectable Advanced or Recurrent NSCLC: An Exploratory Study of J-TAIL.

Introduction: This study validated real-world pharmacokinetic (PK) data using an established population PK (PopPK) model for atezolizumab in Japanese patients with NSCLC and explored the relationship between PK parameters, effectiveness, and adverse events (AEs) for the 1200 mg once every three weeks regimen. Methods: A subgroup of 262 of 1039 patients from J-TAIL consented to this exploratory research for PK evaluation of atezolizumab monotherapy for unresectable advanced/recurrent NSCLC (August 2018 to October 2019; 197 institutions). We evaluated plasma concentrations before the start of the third cycle of atezolizumab infusion classified into quartiles 1 to 4, their association with effectiveness, and the association between atezolizumab maximum plasma concentrations (Cmax) calculated using the existing PopPK model and AEs of special interest (AESIs). Results: Overall, 175 of 262 patients were included; baseline characteristics were similar to those of patients enrolled in J-TAIL (Eastern Cooperative Oncology Group performance status ≥ 2, 12.0%; age ≥ 75 y, 28.9%; atezolizumab as more than or equal to third-line treatment, 57.5%). Atezolizumab plasma concentrations were similar to previously reported data among Japanese/non-Japanese patients. The overall survival was significantly shorter in patients with lower atezolizumab plasma concentrations in Q1 versus Q2 to Q4, although progression-free survival remained the same. The PK data adequately fit the PopPK model, with the frequency of AESIs increasing as the calculated Cmax at cycle 1 increased. Conclusions: In real-world Japanese patients with unresectable advanced/recurrent NSCLC, PKs were similar to previous reports. Certain patient populations had shorter overall survival, and atezolizumab plasma concentrations in cycle 3 were lower in this population. Elevated Cmax at cycle 1 may be associated with an increased frequency of AESIs.

Genomic Biomarkers to Predict Response to Atezolizumab Plus Bevacizumab Immunotherapy in Hepatocellular Carcinoma: Insights from the IMbrave150 Trial.

Introduction: Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge. Methods: Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full model. We further validated ISS10 in an independent HCC cohort treated with nivolumab plus ipilimumab. Results: The study identified a significant association between the ISS and treatment response. Among patients classified as high responders, those treated with the atezolizumab plus bevacizumab combination exhibited improved overall and progression-free survival as well as better objective response rate compared to those treated with sorafenib. We also observed a significant correlation between ISS10 and response to nivolumab plus ipilimumab treatment. Analysis of immune cell subpopulations revealed distinct characteristics associated with ISS subtypes. In particular, the ISS10 high subtype displayed a more favorable immune environment with higher proportions of anti-tumor macrophages and activated T-cells, potentially explaining its better response. Conclusions: Our study suggests that ISS and ISS10 are promising predictive biomarkers for enhanced therapeutic outcomes in HCC patients undergoing combination immunotherapy. These markers are crucial for refining patient stratification and personalized treatment approaches to advance the effectiveness of standard-of-care regimens.

STELLAR-303: randomized phase III study of zanzalintinib + atezolizumab in previously treated metastatic colorectal cancer.

Most patients with metastatic colorectal cancer (mCRC) have limited treatment options following standard-of-care therapy. VEGFR-tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity in mCRC in combination with immune checkpoint inhibitors (ICIs), particularly in patients without liver metastases. The TKI zanzalintinib (XL092) targets VEGFR, MET and TAM kinases, proteins that are involved in tumor growth, angiogenesis, metastasis and immunosuppression. Zanzalintinib has immunomodulatory properties that may enhance response to ICIs. Presented is the design of STELLAR-303, a global, phase III, open-label, randomized study evaluating zanzalintinib plus atezolizumab versus regorafenib in patients with non-MSI-H mCRC who progressed during/after or are refractory/intolerant to standard-of-care therapy. The primary end point is overall survival in patients without liver metastases.Clinical Trial Registration: NCT05425940 (ClinicalTrials.gov).

Metastatic colorectal cancer (mCRC) is cancer of the colon or rectum that has spread to other parts of the body, most often to the liver, lungs and abdomen. People with mCRC that has worsened after initial treatment have limited options. Zanzalintinib is a novel oral investigational drug that can slow or stop cancer growth. It works by blocking certain proteins that play important roles in the development, growth and spread of cancer. Zanzalintinib may also help improve the effectiveness of another class of cancer drugs called immune checkpoint inhibitors (ICIs), which work by activating the patient's immune system to fight cancer. Here, we describe the design of STELLAR-303, an ongoing study that is comparing the effects of combining zanzalintinib and an ICI drug called atezolizumab with an approved treatment for mCRC called regorafenib. About 900 participants with mCRC will be enrolled in the study worldwide. To be included in the study, participants must have mCRC that worsened after previous therapies and must not have a high level of microsatellite instability, which is a specific feature of some mCRCs. Participants will be randomly given one of the two treatments. The main goal of the study is to evaluate zanzalintinib plus atezolizumab compared with regorafenib by measuring the length of time participants are alive after starting treatment, specifically in patients with mCRC that has not spread to the liver. Additionally, the study will look at the side effects with each treatment. The study is currently seeking participants.

Atezolizumab and bevacizumab plus transarterial chemoembolization and hepatic arterial infusion chemotherapy for patients with high tumor burden unresectable hepatocellular carcinoma: A multi-center cohort study.

BACKGROUND: Though atezolizumab plus bevacizumab (A+B) offer promise for unresectable hepatocellular carcinoma (uHCC) treatment, the response rate remains suboptimal. Our previous studies highlighted the potential of transarterial chemoembolization (TACE) when combined with FOLFOX-based hepatic arterial infusion chemotherapy (HAIC) in HCC treatment. This study aims to evaluate the safety and efficacy of A+B plus TACE-HAIC for high tumor burden uHCC (HTB-uHCC). METHODS: This three-center retrospective study involved 82 HTB-uHCC patients administered with TACE-HAIC followed by A+B. We characterized HTB-uHCC patients as those surpassing the up-to-11 criteria, exhibiting VP 3-4, or presenting extrahepatic metastases. The primary outcomes were the objective response rate (ORR) and progression-free survival (PFS). Secondary outcomes encompassed the incidence of treatment-related adverse events (TRAEs) and overall survival (OS). RESULTS: Employing the mRECIST criteria, the ORR was 62.2 %, wherein 18 (22.0 %) patients achieved complete response, 33 (40.2 %) demonstrated partial response, 21 (25.6 %) maintained stable disease, and 10 (12.2 %) exhibited disease progression. Impressively, 11 (13.4 %) patients were converted to resectable HCC and underwent curative hepatectomy. The median PFS was 10.1 months (95 % CI, 8.4 to NA), and the median OS was still pending. At the one-year mark, the OS and PFS rates were 92.8 % (95 % CI, 86.1 to 100.0) and 42.9 % (95 % CI, 31.3 to 58.7), respectively. 79 (96.3 %) experienced TRAEs, and 39 (47.6 %) had grade 3-4 TRAEs, though no treatment-related death was recorded. CONCLUSIONS: The findings underscore the potential of the A+B and TACE-HAIC combined treatment for HTB-uHCC patients, marking it as a viable therapeutic option, given its potent efficacy and tolerable safety profile.

Clinical significance of circulating biomarkers of immune-checkpoint molecules with atezolizumab plus bevacizumab therapy in unresectable hepatocellular carcinoma.

BACKGROUND: The aims of this study were to identify clinically significant biomarkers of a response to atezolizumab plus bevacizumab (ATZ + BV) therapy and to develop target strategies against unresectable hepatocellular carcinoma (u-HCC). METHOD: We first investigated the potential of circulating tumor DNA (ctDNA) to serve as a biomarker for predicting the therapeutic outcome in 24 u-HCC patients treated with ATZ + BV therapy. Next, we analyzed levels of immune-related cytokines in blood samples from 134 u-HCC patients who received ATZ + BV. For this, serum immune-related molecules or cancer-immune cycle-related molecules that have been reported in HCC patient sera, namely CD274, LAG-3, CCL2, 4, 5, CXCL1, 9, 10, 12, 13, CX3CL1, CCR5, IFNγ and IL-6, 8 were measured using enzyme-linked immunosorbent assay. RESULTS: More than 1% of variant read frequency (VRF) mutations were found in TP53, APC, PIK3CA and VHL, although with no correlation with treatment response. Among the 15 cytokines evaluated, CXCL9 and LAG-3 levels were significantly different between patients with objective response (OR), stable disease (SD), and progressive disease (PD) following ATZ + BV treatment. Receiver-operating characteristic curve analyses of CXCL9 (cut-off value: 419.1 pg/ml) and LAG-3 (cut-off value: 3736.3 pg/ml) indicated areas of 0.779 and 0.697, respectively, for differentiating PD from non-PD and OR from non-OR. In multivariate analysis of progression-free survival (PFS) and overall survival (OS), high serum CXCL9 (hazard ratio (HR) and 95% confidence interval (CI): 0.412 (0.251-0.677) (p = 0.0005) for PFS and 0.252 (0.125-0.508) (p = 0.0001) for OS), and low serum LAG-3 (HR and 95% CI 0.419 (0.249-0.705) (p = 0.0011) for PFS and 0.294 (0.140-0.617) (p = 0.0012) for OS) were independent positive predictive factors. CONCLUSION: Although, as far as we examined, no ctDNA mutations in blood were found to be related to ATZ + BV treatment efficacy, serum CXCL9 and LAG-3 levels, which are related to the cancer-immune cycle, were associated with treatment efficacy and could be predictive markers of the efficacy of ATZ + BV treatment in HCC patients.

Biological Agents for Treating Atezolizumab-Induced Psoriasis in Small-Cell Lung Cancer: A Case Report.

One of the immune-related adverse events from immune checkpoint inhibitors (ICIs) is skin toxicity. Oral corticosteroids are the first-line treatment for severe cutaneous immune-related adverse events. However, corticosteroids may conflict with the efficacy of ICIs. A 55-year-old Japanese man with a history of psoriasis vulgaris was diagnosed with small-cell lung cancer (Stage ⅣA) and administered combined chemoimmunotherapy, including atezolizumab, which resulted in exacerbation of psoriasis. In response, he was treated with biological agents, such as anti-IL-23 and IL-17 antibodies, risankizumab, and secukinumab, respectively, and achieved long-term survival with continued treatment with atezolizumab. This case report suggests that biological agents might be the best course of treatment against autoimmune-related adverse events caused by ICI therapy.

Outcomes of hepatocellular carcinoma patients treated in the lenvatinib and immunotherapy era (2018-2021) compared to the sorafenib era (2008-2018).

BACKGROUND: Lenvatinib (LEN) and atezolizumab + bevacizumab (A + B) have drastically changed the treatment paradigm for advanced hepatocellular carcinoma (HCC). Before these landmark trials, sorafenib (SOR) served as the standard first-line treatment for a decade. Our study aimed to assess the outcomes of HCC patients treated during the SOR era (2008-2018) in contrast to those in the post-SOR era (2018-2021), of which the predominant first-line treatments were LEN or A + B. METHODS: Inclusion criteria of the study were all HCC patients in the Canadian province of Alberta who started first-line systemic therapy at cancer centers between 1 January 2008 and 31 December 2021. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), along with clinician-assessed response rate (RR), were subject to retrospective analysis. RESULTS: Of 372 total patients, 230 received treatment in the SOR era and 142 in the post-SOR era. The demographic and clinical characteristics for the SOR era and post-SOR era groups are as follows, respectively: the median age was 63 and 64 years, 80% and 81% were male, and 24% and 11% were of East Asian ethnicity. Before receiving systemic treatment, 40% and 33% received TACE, 7% and 9% received TARE, and 3% and 14% received SBRT in the two eras, respectively. In the post-SOR era, patients received A + B (23%), LEN (51%), and SOR (23%) as first-line treatment. There was a statistically significant improvement in RR (15% vs. 26%; p = 0.02), median PFS (3.8 months vs. 7.9 months; p < 0.0001), and median OS (9.8 months vs. 17.0 months; p < 0.0001). CONCLUSIONS: In this retrospective multicenter real-world study, HCC patients treated in the post-SOR era, where LEN and A + B were commonly used first-line treatments, exhibited superior OS, PFS, and RR compared to patients treated in the SOR era. The findings of this study affirm the tangible progress achieved in the real world in enhancing outcomes for HCC patients through advancements in treatments over the past 15 years.

Atezolizumab plus bevacizumab as first-line systemic therapy for hepatocellular carcinoma: a multi-institutional cohort study.

BACKGROUND: Atezolizumab plus bevacizumab is the standard of care for advanced hepatocellular carcinoma (HCC) in the first-line setting, although was only evaluated in patients with Child-Pugh (CP) A liver function in the IMbrave150 trial. We sought to determine the outcomes of these patients based on CP score and ALBI grade in the US population. METHODS: This multicenter cohort study included patients with HCC who received atezolizumab with bevacizumab as first-line systemic therapy between March 2018 and November 2023. Overall survival (OS) was determined using the Kaplan-Meier method and multivariate analyses were performed using Cox proportional hazard regression method. RESULTS: Among 322 patients, 226, 86, and 10 patients had CP-A, CP-B, and CP-C liver function, respectively. Median age was 66.5 years, 78.6% were male, and 82.6% were White. Median OS (mOS) was 21.6 months for those with CP-A, 9.1 months for those with CP-B7, and 4.7 months for those with CP-B8-C12 (P < .0001). Among patients with CP-A, those with ALBI grade 1 had an mOS of 34.9 months versus 14.2 months in those with grade 2. In multivariate analyses, CP score, ALBI grade, hepatitis B, performance status, and macrovascular invasion were significantly associated with survival. CONCLUSIONS: CP score is an important prognostic tool for patients with HCC receiving atezolizumab plus bevacizumab, and this regimen remains a viable option for patients with CP-B7 with no additional safety concern, although the benefit is significantly less than those with CP-A. ALBI score has independent predictive value in patients with CP-A liver function.

A Case of Immune Aplastic Anemia during Combined Treatment with Atezolizumab and Chemotherapy for Non-Small Cell Lung Cancer.

Immune check point inhibitors (ICIs) have durable antitumor effects. However, autoimmune toxicities, termed immune-related adverse events, occur in some patients. We report a case of severe immune aplastic anemia (AA) in a patient with non-small cell lung cancer who was receiving atezolizumab with bevacizumab/carboplatin/paclitaxel. Although the cancer has not recurred, his bone marrow is depleted and he did not respond to immunosuppressive therapy. He has survived for 1.5 years with blood transfusions and infection control. Immune AA associated with ICIs is rare, and a treatment has not yet been established. This case report provides information on the management and treatment response of patients with AA caused by ICIs. Further studies should investigate the mechanism and pathogenesis of immune AA caused by ICIs.

A DPC Database Study on the Safety of Atezolizumab/Bevacizumab/Carboplatin/Paclitaxel in Non-small Cell Lung Cancer in Japanese Patients.

INTRODUCTION: Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) combination therapy is a standard of care for advanced non-squamous non-small cell lung cancer (NSQ-NSCLC); however, the lack of safety data limits its clinical application in Japan. METHODS: This study compared the safety of ABCP with that of bevacizumab, carboplatin, and paclitaxel (BCP) combination for the treatment of advanced NSQ-NSCLC in Japanese patients by evaluating the clinical background and incidence of adverse events (AEs) based on data extracted from the Diagnosis Procedure Combination (DPC) database. Incidence rates and restricted mean survival times (RMSTs) for up to 1 year were analyzed for 19 clinically important AEs. Covariates were adjusted using the inverse probability weighting method. RESULTS: A search conducted using the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes identified 350,987 patients, of whom 202 were included in the ABCP cohort and 232 in the BCP cohort. Among the 19 AEs, the incidence of skin disorder and febrile neutropenia (FN) was significantly higher in the ABCP cohort versus the BCP cohort. The adjusted incidence rate ratios were 2.65 [95% confidence interval (CI) 1.43-4.91] for skin disorder and 1.70 (95% CI 1.01-2.85) for FN. The adjusted RMST differences were - 64.2 days (95% CI - 93.0 to - 35.4 days) and - 46.0 days (95% CI - 73.5 to - 18.5 days) for skin disorder and FN, respectively. These results were comparable to those of other pivotal clinical trials. CONCLUSIONS: The findings of this DPC database study highlight the safety of ABCP in Japanese clinical practice, and this methodology may facilitate more efficient research in real-world settings. TRIAL REGISTRATION: UMIN Clinical Trials Registry ID UMIN000041507.

Severe febrile neutropenia and pancytopenia in a patient with advanced hepatocellular carcinoma treated with atezolizumab and bevacizumab: a case report.

Background: Immune checkpoint inhibitors (ICIs), agents that stimulate T-cell function, have become the standard first-line treatment for unresectable hepatocellular carcinoma (HCC). However, they may also cause immune-related adverse events (irAEs), which are rare and have not been extensively reported. Here, we describe a case of severe febrile neutropenia and pancytopenia after atezolizumab plus bevacizumab (atezo/bev) therapy and its treatment course. Case Description: The combination of atezo/bev was initiated as the first-line treatment for a man in his early 50s, who was diagnosed with unresectable HCC. The first treatment cycle was administered in the outpatient setting, and the patient developed a fever of 39.0 ℃ 10 days after therapy initiation. He presented 5 days later with persistent fever as well as a headache, vomiting, chills, generalized pain, fatigue, mild abdominal discomfort, and a burning rash present on his neck and face. Complete blood counts showed severe neutropenia [absolute neutrophil count (ANC) of 90 cells/µL], leukopenia [white blood cell (WBC) count 500 cells/µL], thrombocytopenia [platelet count (PC) 18,000 cells/µL], and mild anemia (hemoglobin level 12.6 gm/dL). Imaging findings showed colitis on computed tomography (CT). Atezo/bev therapy was discontinued. Treatment plan constituted of cefepime and filgrastim, a recombinant form of the naturally occurring granulocyte colony-stimulating factor (G-CSF) for febrile neutropenia, metronidazole for colitis, and intravenous methylprednisolone for immune-related toxicities. The patient fully recovered after 4 days of admission. Conclusions: In conclusion, we observed temporary severe febrile neutropenia and pancytopenia during systemic immunotherapy in a patient with unresectable HCC. Healthcare providers should consider hematological irAEs (hem-irAEs) in patients after the administration of ICIs.

Immunogenicity of Atezolizumab: Influence of Testing Method and Sampling Frequency on Reported Anti-drug Antibody Incidence Rates.

Measurement of anti-drug antibodies (ADA) to assess the incidence of ADA in a clinical trial is a critical step in immunogenicity assessment during the development of a protein therapeutic. We developed novel graphical approaches to illustrate clinical trial ADA data for the PD-L1 inhibitor atezolizumab (Tecentriq) that included a systematic analysis of the impact of the timing of ADA sampling and ADA assay drug tolerance on reported ADA incidence. We found that approaches used across the industry for ADA incidence analysis provide a limited view of immunogenicity in oncology studies, where ADA detection may be confounded by both drug dosage and patient attrition. Moreover, these approaches can miss important temporal information about the immune response. Our results demonstrated that the methodology of ADA assessment for the atezolizumab program was specifically designed to capture most ADA responses to ensure accurate reporting of ADA incidence. We further showed that the use of sparse sampling and/or ADA test methods with insufficient drug tolerance may result in a significant underreporting of ADA incidence. We conclude that the comparison of ADA incidence between different drugs can be highly misleading and that a test method with appropriate sensitivity in the presence of the drug and a clinical sampling scheme that is aligned with ADA responses to a drug is required to accurately report ADA incidence.

A case of biopsy-proven acute interstitial nephritis following atezolizumab-bevacizumab treatment of advanced unresectable hepatocellular carcinoma.

BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) represented a significant breakthrough in cancer therapy. Recently, the combined use of atezolizumab and bevacizumab was approved as first-line treatment for unresectable hepatocellular carcinoma (HCC). Exposure to a novel and diverse spectrum of immune-related adverse events (irAEs) has increased with the growing utilization of ICIs, however, a comprehensive understanding surrounding newer agents is still lacking. The incidence of kidney toxicities is rare but rising, often underreported due to the lack of confirmatory biopsies. Here, we present a rare case of biopsy-proven acute interstitial nephritis (AIN) following atezolizumab-bevacizumab treatment of advanced unresectable HCC. CASE: An 84-year-old male with T4N0M0 hepatocellular carcinoma was admitted after cycle 5 of atezolizumab due to decreased urine output and dysuria with a serum creatine of 4.7 mg/dL compared to a baseline of 1.3 mg/dL. To confirm the diagnosis of possible intrinsic renal injury, an ultrasound-guided non-focal biopsy of the left kidney was performed, revealing AIN. Potential exacerbatory medications, such as proton-pump inhibitors, were discontinued. The patient was discharged on oral steroids with improvement in serum creatinine. Before completing the steroid taper, the patient developed pneumocystis pneumonia and eventually transitioned to hospice care. CONCLUSION: This case highlights the valuable role renal biopsy can play in accurately capturing irAEs and guiding appropriate management in the setting of ICI-induced AKI. It also exemplifies important considerations for steroid treatment of irAEs in the setting of comorbidities, such as diabetes.

Immune-Related Adverse Events Associated with Atezolizumab: Insights from Real-World Pharmacovigilance Data.

The advancement of immuno-oncology has brought about a significant shift in cancer treatment methods, with antibody-based immune checkpoint inhibitors like atezolizumab leading the way in this regard. However, the use of this checkpoint blockade can result in immune-related adverse events due to increased T-cell activity. The full spectrum of these events is not yet completely understood. In this study, the United States FDA Adverse Event Reporting System (FAERS) was utilized to investigate immune-related adverse events linked with the use of atezolizumab. The study identified forty-nine immune-related adverse events that affected multiple organ systems, including cardiovascular, respiratory, hematologic, hepatic, renal, gastrointestinal, neurologic, musculoskeletal, dermatologic, endocrine, and systemic disorders. The strongest signals for relative risk occurred for immune-mediated encephalitis (RR = 93.443), autoimmune myocarditis (RR = 56.641), immune-mediated hepatitis (RR = 49.062), immune-mediated nephritis (RR = 40.947), and autoimmune arthritis (RR = 39.382). Despite the morbidity associated with these adverse events, emerging evidence suggests potential associations with improved survival outcomes. Overall, this report sheds light on the widespread immune-related adverse events that cause significant morbidity and mortality in patients with cancer being treated with atezolizumab and brings attention to them for the clinicians treating these patients.

Durable Response to Atezolizumab in Extensive-Stage Small-Cell Lung Cancer Leading to 60 Months Overall Survival: A Case Report.

Small-cell lung cancer (SCLC) remains a disease with poor prognosis, particularly in extensive-stage SCLC (ES-SCLC). Current standard-of-care treatment includes chemotherapy with platinum agents and etoposide plus immunotherapy with atezolizumab or durvalumab, which has achieved a mean overall survival of 12-13 months in clinical trials. However, long-term survival in ES-SCLC, even with the addition of immunotherapy, continues to be rare. We present the case of a middle-aged male patient diagnosed with ES-SCLC who was treated with four cycles of induction chemotherapy (carboplatin and etoposide) and atezolizumab, starting maintenance atezolizumab every 21 days thereafter, and thoracic radiotherapy. After 9 months, he experienced mild disease progression and was rechallenged with six cycles of carboplatin and etoposide with continued atezolizumab. Subsequent imaging showed near-complete disease resolution which has been sustained since. He has continued on maintenance atezolizumab since diagnosis and has achieved 60 months overall survival and 44 months progression-free survival. Throughout treatment, he has maintained a high functional capacity and only experienced one immune-related adverse event. Our patient is representative of a small subset who are capable of achieving durable responses to immunotherapy and his case highlights the need for further research to elucidate the clinical and biological factors driving this response.

A DPC Database Study on the Safety of Atezolizumab/Carboplatin/Etoposide in Extensive-Disease Small Cell Lung Cancer in Japanese Patients.

INTRODUCTION: Atezolizumab, carboplatin, and etoposide (ACE) therapy is a standard of care for extensive-disease small cell lung cancer (SCLC); however, its safety data are scarce, limiting generalization to the Japanese population. METHODS: This study aimed to compare the safety of ACE versus carboplatin and etoposide (CE) therapies in Japanese patients using the Diagnosis Procedure Combination (DPC) database by comparing the incidence of adverse events (AEs). Retrospective data on clinical background and AEs were extracted from the DPC database. Incidence rates and restricted mean survival times (RMSTs) up to 6 months were analyzed for 19 clinically important AEs. Covariates were adjusted using the inverse probability weighting method. RESULTS: A total of 330,774 patients were identified using the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes, of whom 277 were included in the ACE cohort and 478 in the CE cohort. Among the 19 AEs, the incidence of skin disorder and thyroid dysfunction was significantly higher in the ACE cohort compared with the CE cohort. The adjusted incidence rate ratios were 2.38 (95% confidence interval [CI] 1.04-5.43) for skin disorder and 6.92 (95% CI 2.00-23.89) for thyroid dysfunction. The adjusted RMST differences were - 8.2 days (95% CI - 16.0 to - 0.4 days) for skin disorder and - 8.8 days (95% CI - 15.7 to - 1.9 days) for thyroid dysfunction. CONCLUSIONS: This study provides evidence regarding the safety of ACE combination therapy in Japanese clinical practice using the DPC database, with results comparable to those reported in pivotal clinical trials. TRIAL REGISTRATION: UMIN Clinical Trials Registry ID UMIN000041508.

Real-world comparison of chemo-immunotherapy and chemotherapy alone in the treatment of extensive-stage small-cell lung cancer.

INTRODUCTION: Small cell lung cancer (SCLC) is a high-grade neuroendocrine carcinoma responsible for 200,000 deaths per year worldwide. Platinum-etoposide-based chemotherapy has been the standard of treatment for the past 40 years, with an overall survival of 10 months. Since 2019, the addition of immunotherapy (atezolizumab or durvalumab) to chemotherapy has become the standard of care for first-line treatment of extensive-stage SCLC following the demonstration of an improvement in overall survival in phase 3 studies. We aimed to evaluate the efficacy and safety of chemo-immunotherapy compared with chemotherapy alone in a "real-world" setting. METHODS: Retrospective observational study including patients undergoing first-line treatment for extensive-stage SCLC between 2014 and 2022. We separated the study population into two arms (chemo-immunotherapy/chemotherapy). For each arm, progression-free survival (PFS), overall survival (OS) and serious side effects were collected. Associations between treatments and survival outcomes were adjusted for potential confounders. Consolidative palliative thoracic radiotherapy was introduced in the models as a time-dependent variable. RESULTS: A total of 118 patients with a median age of 63 years were included. 65.2 % of patients were performance status 0 or 1. In univariate analysis, PFS and OS were not significantly different between the chemo-immunotherapy and chemotherapy alone groups (p = 0.70 and 0.24 respectively). In multivariate analysis, the addition of immunotherapy to chemotherapy was not significantly associated with better PFS (HR 0.76, IC (0.49 - 1.19), p = 0.23), but it was significantly associated with better OS (HR 0.61, IC (0.38 - 0.98), p = 0.04). Consolidative palliative thoracic radiotherapy (time-dependent variable), when applied (almost only in the chemotherapy alone group), was significantly associated with better PFS and OS. DISCUSSION: In this real-world study, chemo-immunotherapy was associated with slightly better OS compared to chemotherapy alone as a first-line treatment in ES-SCLC patients in multivariate analysis, which is not explained by a benefit in PFS. However, consolidative palliative thoracic radiotherapy seems to be significantly associated with better OS and PFS, suggesting that we should also consider using it in patients receiving chemo-immunotherapy.

A case of sialadenitis observed as an irAE of atezolizumab: A case report.

Various symptoms emerge as immune-related adverse events of immune checkpoint inhibitor (ICI). A 73-year-old woman, a non-smoker, receiving chemotherapy including atezolizumab for lung adenocarcinoma, presented with fever, bilateral parotid swelling and sicca syndrome after four courses of chemotherapy. Because the lesions were not localized, the diagnosis was ICI-related sialadenitis rather than infectious. Prednisolone improved salivary gland swelling quickly. Six months after the last administration of ICI, there was no obvious progression of lung cancer. To our knowledge, this is the first case of sialadenitis caused by atezolizumab. ICI-related sialadenitis may be a good prognostic marker for lung cancer.