Adverse effects of immunotherapeutic treatments like atezolizumab remain largely unknown due to limited experience. We present a 65-year-old man with sudden dyspnea and other symptoms, implicating immunotherapy. Prompt intervention and suspension were crucial. This study identifies a novel unreported adverse effect-bilateral vocal cord and velopalatine paralysis-associated with atezolizumab use.

OBJECTIVE: This exploratory integrated analysis of the randomized Phase III IMpower130 and IMpower132 trials evaluated the efficacy and safety of atezolizumab plus platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC) who were aged ≥75 years or had renal dysfunction.
METHODS: Chemotherapy-naïve patients with stage IV non-squamous NSCLC received atezolizumab-containing therapy or platinum-doublet chemotherapy in IMpower130 and IMpower132. This integrated analysis assessed efficacy (including overall survival [OS], progression-free survival [PFS], and objective response rates) and safety in the integrated population and in patients ≥75 years old. Subgroup analyses by baseline creatinine clearance (<45, 45 to <60, and ≥60 mL/min) were conducted for each study population.
RESULTS: This integrated analysis included 1224 patients: 737 in the atezolizumab-containing group and 487 in the chemotherapy group. At data cutoff, the hazard ratio (HR) for PFS was 0.62 (95% CI: 0.54-0.71) in the integrated population and 0.59 (95% CI: 0.40-0.88) in the ≥75-years subgroup. The HR for OS was 0.81 (95% CI: 0.68-0.95) in the integrated population and 0.65 (95% CI: 0.39-1.07) in the ≥75-years subgroup. PFS and OS benefits with the atezolizumab combination vs chemotherapy were maintained across subgroups with varying renal function in IMpower130, and PFS benefits were maintained across subgroups in IMpower132.
CONCLUSIONS: The results of this post hoc integrated analysis of IMpower130 and IMpower132 show that the efficacy and safety of atezolizumab plus platinum-doublet chemotherapy is maintained in patients ≥75 years old and in patients with renal dysfunction.

UNASSIGNED: The phase III IMbrave150 study established atezolizumab + bevacizumab as the global standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis examined the impact of bevacizumab interruption due to bevacizumab adverse events of special interest (AESIs).
UNASSIGNED: Patients in IMbrave150 who were randomized to atezolizumab + bevacizumab and received treatment for ≥6 months (to reduce immortal time bias) were included in group A-1 if bevacizumab had ever been skipped due to bevacizumab AESIs or to group A-2 otherwise. Efficacy analyses included overall survival (OS) and progression-free survival (PFS) by whether bevacizumab was skipped (group A-1 vs. A-2). PFS was evaluated per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and HCC-modified RECIST (IRF-HCC mRECIST). Safety was also evaluated.
UNASSIGNED: Of the 210 patients who received ≥6 months of atezolizumab + bevacizumab, 69 were assigned to group A-1 and 141 to A-2. At data cutoff (August 20, 2020), hazard ratio (HR) for OS was 1.04 (95% CI: 0.64, 1.69) for group A-1 versus A-2. HR for PFS was 1.07 (95% CI: 0.74, 1.55) per IRF-assessed RECIST 1.1 and 1.10 (95% CI: 0.76, 1.59; 15.5 vs. 9.7 months) per IRF-HCC mRECIST for group A-1 versus A-2. Safety profiles for atezolizumab and bevacizumab were largely similar between groups. More group A-1 patients had grade 3/4 adverse events. A separate analysis investigating the impact of immortal time bias in patients who received ≥3 months of atezolizumab + bevacizumab supported the appropriateness of the ≥6-month landmark analysis.
UNASSIGNED: Efficacy was similar between patients who skipped bevacizumab due to bevacizumab AESIs and those who did not. Although this comparison was nonrandomized and exploratory, results suggest that skipping bevacizumab due to bevacizumab AESIs did not considerably impact the efficacy and safety of atezolizumab + bevacizumab.

UNASSIGNED: Despite the emergence of atezolizumab and bevacizumab (A + B) as standard first-line systemic therapy for unresectable hepatocellular carcinoma (HCC), a comprehensive understanding of the clinical significance of immune-related adverse events (irAEs) remains limited. We aimed to assess the impact of irAEs on patients with HCC undergoing A + B treatment.
UNASSIGNED: This multicentre retrospective study included consecutive patients with HCC who were treated with the A + B regimen from September 2020 to December 2022. Patients were categorized into three groups based on the severity of irAEs, ranging from those without any experience of irAEs to those with severe irAEs.
UNASSIGNED: This study included 150 patients with HCC, with a mean age of 63.3 years. Among them, 93.3% of patients were classified as Barcelona Clinic Liver Cancer stage C, 52.0% had portal vein tumour thrombosis (PVTT), and 60.7% extrahepatic spread. Patients were classified as follows: group 1 (n = 84) had no irAEs, group 2 (n = 37) had mild irAEs (grade 1-2), and group 3 (n = 29) had severe irAEs (grade ≥3). The median overall survival (OS), progression-free survival (PFS), and time-to-treatment discontinuation (TTD) were 13.6, 5.7, and 3.6 months, respectively. Group 2 demonstrated significantly superior OS compared to group 1 (9.5 months) and group 3 (5.6 months), with a median OS of 23.0 months (p < 0.001). Furthermore, group 2 demonstrated significantly better outcomes in terms of PFS and TTD compared to both group 1 and group 3 (p < 0.001 for both). Multivariate analysis identified mild irAEs (hazard ratio [HR], 0.353; p = 0.010), ALBI grade 1 (HR, 0.389; p = 0.006), Child-Pugh class A (HR, 0.338; p = 0.002), and the absence of PVTT (HR, 0.556; p = 0.043) as independent predictors of better OS.
UNASSIGNED: Our study highlights the significant impact of irAE severity on the outcomes of patients with HCC receiving A + B. Notably, the occurrence of mild irAEs was independently associated with favourable survival, suggesting their potential role as surrogate indicators of HCC prognosis.

BACKGROUND: Atezolizumab/bevacizumab is emerging as the new standard for advanced hepatocellular carcinoma (HCC), with ongoing real-world implementation to study its effectiveness. As the use of atezolizumab/bevacizumab increases, various side effects have been reported in clinical practice, most notably increased bleeding caused by bevacizumab.
METHODS: In this case report, we present a rare and fatal case of intratumoral hemorrhage in a patient with advanced HCC following successful treatment with atezolizumab/bevacizumab. A 63-year-old male diagnosed with HCC initially underwent four cycles of intra-arterial chemotherapy. However, follow-up abdominal computed tomography (CT) revealed disease progression. Subsequently, the treatment plan was modified to atezolizumab/bevacizumab. After the fifth cycle of atezolizumab/bevacizumab, CT showed partial regression of HCC. One week later, he visited the emergency room due to severe abrupt abdominal pain. Abdominal CT revealed focal rupture of HCC in the medial segment inferior portion with active bleeding and a large amount of hemoperitoneum. Angiography was performed on the same day, and embolization of A4 and A8 branches using lipiodol and gelfoam was implemented. Despite successful hemostasis, the patient subsequently developed liver failure and died.
CONCLUSIONS: Atezolizumab/bevacizumab for advanced HCC suggests that intratumoral hemorrhage may be crucial despite good tumor response after immunotherapy, emphasizing the continuous monitoring of this side effect.

Circulating tumor cells (CTCs) are noninvasive biomarkers that can indicate the therapeutic response and prognosis. The study aimed to investigate the cellular characteristics of CTCs focusing on monitoring during atezolizumab and bevacizumab (Atezo-Bev) therapy in patients with hepatocellular carcinoma (HCC). Peripheral blood samples were collected from 10 healthy controls and 40 patients with HCC. CTCs enriched using RosetteSep™ Human CD45 depletion cocktail were analyzed by multiparametric flow cytometry. CTC isolation was based on PanCK(+)CD45(-) cells, and CTCs exhibiting markers CD90, CD133, EpCAM, or vimentin. The total number of CTCs and the number of CTCs expressing CD90, CD133, EpCAM, and vimentin were correlated with the BCLC stage of HCC. The change in total CTC count accurately reflected the initial response to Atezo-Bev therapy. The numbers and mean fluorescence intensity of the CTC subsets expressing CD90 and EpCAM molecules decreased in patients with partial response/stable disease, and increased in patients with progressive disease and were markedly correlated with overall survival. CD90(+) and EpCAM(+) CTCs may be candidate biomarkers for the early prediction of the treatment response and the overall survival of patients with HCC receiving Atezo-Bev therapy.

BACKGROUND: In 2021, the LEOPARD trial reported that the combination of lenvatinib+one-shot cisplatin infusion might contribute to improving the results of conventional advanced hepatocellular carcinoma (HCC) treatment. Thus, combination therapy with lenvatinib and catheterization has emerged as a focal point in treating advanced HCC. Conversely, the New FP regimen consists of low-dose cisplatin (CDDP) combined with 5-fluorouracil (5-FU) and lipiodol via hepatic arterial infusion chemotherapy (HAIC), with a high response rate of approximately 70%. Therefore, lenvatinib+New FP (LEN-New FP) may be a more promising treatment for HCC. Here, we report six patients who were administered LEN+New FP and achieved high therapeutic efficacy. Among them, one case had an interesting clinical course, which has been described in detail.
METHODS: This study included six patients who were administered 12 mg or 8 mg of lenvatinib once daily based on a body weight of ≥60 kg or <60 kg, respectively, along with 50 mg of cisplatin in 5-10 mL lipiodol, and a continuous infusion of 5-FU (1500 mg/5 days) infused every 2-4 weeks. Tumor evaluations were performed 4-8 weeks after the initiation of New FP administration and every 8-12 weeks thereafter.
RESULTS: The median patient age was 65 years. All patients had a history of prior treatment with atezolizumab and bevacizumab and one of the factors associated with poor overall survival for New FP monotherapy, such as a maximum tumor diameter ≥7 cm and bilobular multifocal distribution. Four (67%) patients had severe vascular invasion. The best objective response and disease control rates were 83% and 100%, respectively. The best response of the target lesion was complete remission in four out of six patients.
CONCLUSIONS: The LEN-New FP combination for advanced HCC showed a high response rate and was more effective in high-risk patients with factors associated with poor overall survival than that reported with conventional New FP monotherapy. Additionally, LEN-New FP exhibited extremely high objective response and disease control rates and was well tolerated, including in cases where it was considered second- or third-line systemic chemotherapy for advanced HCC. Thus, LEN-New FP can serve as a breakthrough therapy for advanced HCC based on appropriate case selection.

Immune checkpoint inhibitor (ICI)-related type 1 diabetes is an immune-related adverse event (irAE), occurring in slightly less than 1% of patients undergoing ICI therapy. Most cases develop during ICI treatment, with occurrences long after discontinuation being extremely rare. A 76-year-old woman, with no history of glucose tolerance issues, was diagnosed with lung adenocarcinoma with pleural invasion and underwent chemotherapy, including atezolizumab, an anti-programmed death-ligand 1 antibody. This treatment was discontinued due to disease progression, although she continued with other chemotherapy regimens. Approximately 5.5 months (166 days) after her last atezolizumab dose, she developed diabetic ketoacidosis, fulfilling the diagnostic criteria for fulminant type 1 diabetes. Anti-glutamic acid decarboxylase antibodies were positive. The patient carried susceptibility human leukocyte antigen (HLA) haplotypes, which are associated with type 1 diabetes. To date, including our patient, only nine cases of ICI-related type 1 diabetes developed after ICI discontinuation have been precisely reported. Eight cases originated from East Asia, with six exhibiting fulminant type 1 diabetes, and seven tested negative for islet-related autoantibodies. The reported cases were independent of ICI types, cycle number, or HLA haplotypes. Median time from the last ICI administration to diabetes onset was 4 months (range: 2-7 months). Although reports of cases occurring after ICI discontinuation are currently limited, their frequency may increase with the wider use of ICIs and improved survival rates of patients post-treatment. Therefore, it is crucial to remain vigilant for the development of ICI-related type 1 diabetes, not only during ICI administration, but also long after discontinuation.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s13340-024-00719-4.

OBJECTIVE: The BETAcc clinical trial demonstrated that chemotherapy combined with bevacizumab plus atezolizumab (CBA) significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with metastatic, persistent, or recurrent cervical cancer. However, to our knowledge, the economic value of using this new therapy for this indication is currently unknown. Therefore, our study aims to evaluate the cost-effectiveness of CBA for the first-line treatment of metastatic, persistent, or recurrent cervical cancer from the United States healthcare payers perspective.
METHODS: A state-transition Markov model over a 10-year lifetime horizon was developed to compare the cost and effectiveness of CBA versus chemotherapy plus bevacizumab (CB). The primary outcomes of our study included costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the results.
RESULTS: CBA was associated with an additional 0.58 QALY at an extra cost of $172,495.90 compared to CB. The ICER was $295,972.43/QALY, significantly higher than the willingness-to-pay (WTP) threshold value of $150,000/QALY. One-way sensitivity analyses revealed that results were most sensitive to the PFD utility, the unit cost of atezolizumab, and PD utility. Probabilistic sensitivity analysis indicated that CBA achieved a 4.3% probability of cost-effectiveness at a $150,000/QALY threshold. To achieve cost-effectiveness, the unit price of atezolizumab must be reduced by approximately 56.6%.
CONCLUSIONS: CBA treatment is unlikely to be a cost-effective option compared with CB for patients with persistent, recurrent, or metastatic cervical cancer in the United States.

UNASSIGNED: 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.
UNASSIGNED: 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).
UNASSIGNED: 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.
UNASSIGNED: 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.