Vasculitis associated with atezolizumab and bevacizumab combination therapy.

Simple SummaryA phase 3 IMbrave150 trial showed that atezolizumab plus bevacizumab combination therapy had an improved survival benefit over sorafenib. An excellent direct anti-cancer effect, including progression-free survival and objective response rate, was also observed with this combination therapy. It also showed very favorable effects in patients who had poor prognoses, with main portal vein invasion, tumor occupancy ≥50%, or biliary tract invasion. The liver function was determined through the albumin–bilirubin score, which was well-maintained throughout the treatment period. Patients reported excellent outcomes in terms of quality of life. With these favorable features, the treatment paradigm for hepatocellular carcinoma was drastically changed by atezolizumab plus bevacizumab combination therapy. This was especially observed in intermediate-stage hepatocellular carcinoma, where cancer-free and drug-free status was achieved through the switch to a curative therapy such as resection, ablation, or curative transarterial chemoembolization. This review covers these important issues in this paradigm shift, in addition to recently raised and debated issues, such as its response to tumors with WNT/β-catenin mutations and non-alcoholic steatohepatitis-related hepatocellular carcinoma.Atezolizumab plus bevacizumab combination therapy was approved worldwide for use in 2020. A 30% objective response rate with 8% complete response (CR) was achieved in a phase 3 IMbrave150 trial. Here, the change in the treatment strategy for hepatocellular carcinoma (HCC) using atezolizumab plus bevacizumab combination therapy is reviewed. The phase 3 IMbrave150 clinical trial was successful because of the direct antitumor effect of bevacizumab, which shifted the suppressive immune microenvironment to a responsive immune microenvironment, in addition to its synergistic effects when combined with atezolizumab. The analysis of CR cases was effective in patients with poor conditions, particularly tumor invasion in the main portal trunk (Vp4), making the combination therapy a breakthrough for HCC treatment. The response rate of the combination therapy was 44% against intermediate-stage HCC. Such a strong tumor-reduction effect paves the way for curative conversion (ABC conversion) therapy and, therefore, treatment strategies for intermediate-stage HCC may undergo a significant shift in the future. As these treatment strategies are effective in maintaining liver function, even in elderly patients, the transition frequency to second-line treatments could also be improved. These strategies may be effective against nonalcoholic steatohepatitis-related hepatocellular carcinoma and WNT/β-catenin mutations to a certain degree.

Liver cancer, particularly hepatocellular carcinoma, is a global concern. This study focuses on the evaluation of Atezolizumab and Bevacizumab combination therapy as a promising alternative in the treatment of advanced hepatocellular carcinoma. The objectives of this systematic review include evaluating the efficacy of Atezolizumab and Bevacizumab combination therapy compared to conventional therapies with Sorafenib and other conventional therapies, analyzing the associated adverse effects, and exploring prognostic factors in the setting of advanced hepatocellular carcinoma. A systematic literature review was carried out using the PubMed and Web of Science databases. Fifteen related articles were included and evaluated according to their level of evidence and recommendation. Results: The combination therapy of Atezolizumab and Bevacizumab, along with Sorafenib, showed positive results in the treatment of patients with advanced hepatocellular carcinoma. Significant adverse effects were identified, such as gastrointestinal bleeding, arterial hypertension, and proteinuria, which require careful attention. In addition, prognostic factors, such as transforming growth factor beta (TGF-β), alpha-fetoprotein (AFP), and vascular invasion, were highlighted as key indicators of hepatocellular carcinoma progression. Conclusions: The combination of Atezolizumab and Bevacizumab is shown to be effective in the treatment of advanced hepatocellular carcinoma, although it is essential to take into consideration the associated adverse effects. The prognostic factors identified may provide valuable information for the clinical management of this disease. This study provides a comprehensive overview of a promising emerging therapy for liver cancer.

Background: Despite the significant progress in prevention and therapy, hepatocellular carcinoma (HCC) is still one of the most prevalent and lethal human cancers worldwide. Purpose: Recently, the combination of atezolizumab (an immune checkpoint inhibitor, anti-programmed death ligand 1 antibody) and bevacizumab (an antiangiogenic agent, anti-vascular endothelial growth factor antibody) has emerged as a new and effective first-line systemic therapy in the treatment of patients with unresectable HCC. However, the development of prognostic biomarkers for the early identification and timely intervention of HCC patients with poor prognosis after atezolizumab plus bevacizumab combination therapy remains a key goal to achieve better patient survival.Research Design: This review provides a comprehensive summary of the evidence in the literature validating a single or a combination of biomarker(s) in various sampling sources at diverse time points with prognostic value in predicting the outcomes of HCC patients receiving atezolizumab plus bevacizumab combination therapy. A plethora of promising prognostic biomarkers is identified here, and further studies to implement these biomarkers in clinical practices are urgently needed.

Sorafenib was approved for the treatment of hepatocellular carcinoma more than 10 years ago; however, the efficacy is limited. The IMbrave150 trial demonstrated better overall survival and progression-free survival with atezolizumab plus bevacizumab combination therapy compared to sorafenib, and so it has become the choice of first-line treatment. However, the optimal choice of subsequent therapy after atezolizumab plus bevacizumab is unknown. We present a case with advanced hepatocellular carcinoma who achieved a complete response for more than 2 years under sorafenib treatment after progression with atezolizumab and bevacizumab combination therapy.

Immunotherapy has revolutionized the treatment of hepatocellular carcinoma (HCC). However, whether adding immunotherapy to antiangiogenic therapy benefits patients with unresectable HCC (uHCC) more in the first-line setting remains controversial. In this analysis, we compared the clinical outcomes of lenvatinib monotherapy with atezolizumab plus bevacizumab combination therapy in advanced uHCC in real-world clinical practice. The MEDLINE, Embase, and Cochrane CENTRAL databases were systematically searched on 23 April 2023. The "metaSurvival" and "meta" packages of the R software (version 4.2.2) were used to summarize the survival curves and meta-analyze the survival data. Overall survival (OS) and progression-free survival (PFS) were defined as dual primary endpoints. Secondary endpoints included the objective response rate (ORR) and disease control rate (DCR). Overall, the pooled median OS was 18.4 months in the lenvatinib group versus 18.5 months in the atezolizumab plus bevacizumab group; the pooled median PFS was 6.9 months in the lenvatinib group versus 7.3 months in the atezolizumab plus bevacizumab group. Lenvatinib therapy showed similar OS [hazard ratio (HR): 0.91, 95% confidence interval (CI): 0.55-1.52, p = 0.72] and PFS (HR: 0.79, 95% CI: 0.56-1.12, p = 0.19) compared with atezolizumab plus bevacizumab therapy. In addition, a comparable ORR [odds ratio (OR): 0.89, 95% CI: 0.65-1.20, p = 0.44) was observed between lenvatinib and atezolizumab plus bevacizumab. Comprehensive analysis suggested that lenvatinib monotherapy exhibited survival outcomes comparable to those of atezolizumab plus bevacizumab combination therapy, which may provide useful insights for clinicians in future clinical practice.

Background/Objectives: Atezolizumab and bevacizumab combination therapy has been established as a standard of care for first-line treatment; however, its efficacy and safety have not been fully evaluated for patients previously treated with systemic therapy. Methods: In this phase II trial, patients with advanced hepatocellular carcinoma previously treated with lenvatinib were enrolled to receive a dose of 1,200 mg of atezolizumab and 15 mg/kg of bevacizumab every 3 weeks. The primary endpoint was progression-free survival. The secondary endpoints included overall survival, objective response rate, disease control rate, subsequent therapy, and frequency of adverse events. The threshold and expected progression-free survival were 3 and 6.8 months, respectively. Considering a one-sided significance level of 0.05 and a statistical power of 80%, the minimum required sample size was 26 patients. Results: The median progression-free survival from the start of treatment was 9.70 [90% confidence interval, 5.10-14.24] months, and the lower limit of the 90% CI was above the predefined threshold. The objective response and disease control rates were 34.6% and 73.1%, respectively. Sixteen patients (61.5%) received subsequent therapies, and the median overall survival was 17.23 [90% confidence interval, 13.18-27.85] months. Severe adverse events, adverse events leading to treatment delays, and adverse events leading to treatment discontinuation occurred in eight (30.8%), fourteen (53.8%), and five (19.2%) patients, respectively, and no treatment-related deaths occurred. Conclusions: Atezolizumab and bevacizumab combination therapy is effective and can safely be administered to patients with advanced HCC previously treated with lenvatinib.

Three patients aged 79, 75, and 81years with unresectable hepatocellular carcinoma (HCC) and undergoing maintenance hemodialysis were treated with a combination of atezolizumab and bevacizumab. The patients, respectively, received their 22nd, 2nd, and 4th treatment cycles, and one achieved long-term stable disease. No serious adverse events, including immune-related adverse events, were observed in any patient. Remarkable progress has been made in chemotherapy for cancer; however, the efficacy and safety of chemotherapy in patients undergoing hemodialysis have not been adequately elucidated. This report provides novel insights into the feasibility and outcomes of atezolizumab and bevacizumab combination therapy in patients with HCC undergoing hemodialysis, highlighting its potential as a viable treatment option with manageable side effects.

Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial.

Atezolizumab and bevacizumab combination therapy was initiated in a 71-year-old female patient with unresectable hepatocellular carcinoma. Severe anemia, which was managed with blood transfusion and demonstrated improvement, was observed after the treatment. However, anemia subsequently reoccurred, accompanied by signs of hemolysis. The condition was diagnosed as autoimmune hemolytic anemia due to atezolizumab. Steroid therapy exhibited improvement, and second-line treatment with lenvatinib was successfully initiated. The possibility of autoimmune hemolytic anemia should be considered when anemia is observed during immunotherapy for hepatocellular carcinoma.

Atezolizumab plus Bevacizumab combination therapy has recently emerged as the new standard of care for unresectable HCC. Significant tumor burden reduction can be observed under that treatment, raising the question of liver transplantation (LT). The safety of another immune checkpoint inhibitor (ICI), nivolumab, is unclear in the pre-transplant setting. We report the case of a 57-y old man, with initial unresectable multinodular HCC contraindicated to LT and locoregional therapies, who achieves complete tumor response after Atezolizumab/Bevacizumab, and subsequently underwent LT for liver failure. Explant analysis revealed complete pathological response with no tumor remnant. The patient suffered from several post-operative complications but no HCC recurrence or biopsy-proven acute rejection occurred 10 months after LT. Atezolizumab/Bevacizumab therapy may enable complete pathological response of advanced HCC. Safety of prolonged treatment need to be assessed.

We report a case of recurrent small cell carcinoma of the uterine cervix that showed a complete response to paclitaxel, carboplatin, and bevacizumab (TC + Bev) combination therapy. Small cell carcinoma of the uterine cervix is extremely rare, with an incidence of only 1.3% in Japan, and a poor outcome. The patient was a 62-year-old woman with a chief complaint of irregular vaginal bleeding. Magnetic resonance imaging showed a 10-cm irregular mass from the uterine corpus’s posterior wall to the cervix. Abdominal total hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node sampling were performed for suspected uterine sarcoma. Histopathological findings revealed small cell carcinoma with lymph node metastasis. Although 6 cycles of etoposide + cisplatin were performed, para-aortic lymph node recurrence was found 3 months after chemotherapy. Subsequently, the patient received 8 cycles of TC + Bev, which eliminated the metastases. The patient is currently alive at 24 months.

BackgroundGlobally, cervical cancer is the fourth most common cancer in women. Here, we report a case of cutaneous lymphangitis carcinomatosa arising from cervical cancer, an extremely rare and treatment-resistant condition.Case presentationA 64-year-old Japanese woman presented with genital bleeding. She was diagnosed as having stage IB1 squamous cell cervical cancer and subsequently treated with radiotherapy. Approximately 2 years after the curative radiotherapy, she developed itching, skin rash, and small nodules on her left femoral and pubic area. Slight 18F-fluorodeoxyglucose uptake was detected at her left femoral skin on positron emission tomography with computed tomography. A histopathological examination was performed on a biopsy sample from an erythematous macule on her left femoral skin and vulva. Consequently, she was diagnosed as having cutaneous lymphangitis carcinomatosa arising from cervical cancer. Paclitaxel (135 mg/m2), cisplatin (50 mg/m2), and bevacizumab (15 mg/kg) combination therapy was administered every 21 days. Both itching and rash improved after three treatment cycles. After the completion of six cycles, skin erythema in the femoral and vulval area disappeared completely. Our patient experienced a 25-month symptom-free interval after the last chemotherapy session.ConclusionOur findings suggest that combination chemotherapy plus bevacizumab is an effective therapeutic option in patients with cutaneous lymphangitis carcinomatosa arising from cervical cancer.

BackgroundAtezolizumab (ATZ) plus bevacizumab (BEV) combination therapy has recently been approved for the treatment of unresectable hepatocellular carcinoma. However, immune-related adverse events (irAEs), including peripheral neuropathy, have also been reported. This case report describes a multidisciplinary intervention for a patient who developed peripheral neuropathy as an irAE following ATZ+BEV combination therapy.Case presentationThe patient was a 60-year-old man with a history of hypertension. ATZ + BEV combination therapy was initiated for unresectable hepatocellular carcinoma on day 0. On day 6, he experienced a grade 2 hypertensive episode with a systolic blood pressure of 160 mmHg, despite being on amlodipine (5 mg) and azilsartan (20 mg). Based on the pharmacist’s recommendations, the amlodipine dose was increased to 10 mg. However, as hypertension persisted, an additional 20 mg of azilsartan was prescribed, ultimately stabilizing the patient’s blood pressure to approximately 110/60 mmHg. On day 23, the patient reported numbness in his extremities, which was later diagnosed as grade 3 peripheral neuropathy. Notably, data from the IMbrave150 trial indicated that the of peripheral neuropathy as an irAE was 1.5%. This prompted a consultation with a neurologist. Prednisolone (40 mg/day) was initiated on day 26, followed by steroid pulse therapy with methylprednisolone (1000 mg/day for three days) starting on day 37. Despite these interventions, the symptoms did not improve. Rehabilitation therapy was commenced on day 42 after steroid tapering. On day 48, the patient underwent a five-day course of high-dose intravenous immunoglobulin therapy, which also failed to yield improvement. Rehabilitation efforts subsequently shifted to enhancing activities of daily living. Initially, the patient required assistance to stand and faced significant difficulty walking. With consistent strength and mobility training, the patient progressed to walking with crutches and demonstrated increased walking distance.ConclusionsThe pathophysiology of irAE-induced peripheral neuropathy associated with immune checkpoint inhibitors remains poorly understood. This case underscores the challenges of managing irAE-related neuropathy, which may exhibit limited responsiveness to conventional treatments. Early detection, timely intervention, and multidisciplinary approaches are crucial for optimizing patient outcomes and mitigating the impact of severe side effects.

An 86-year-old man presented with recurrence of hepatocellular carcinoma (HCC) after surgery. Atezolizumab plus bevacizumab was initiated. After the third course of atezolizumab plus bevacizumab therapy, petechial purpura appeared on the extremities and trunk. Laboratory tests revealed isolated severe thrombocytopenia without evidence of combined coagulopathy. He was diagnosed with immune thrombocytopenic purpura (ITP), and high-dose immunoglobulin and Helicobacter pylori eradication therapies were administered. Improvement in thrombocytopenia was observed; however, 20days after the onset of ITP, laboratory data revealed hemolytic anemia. Both direct and indirect Coombs tests were positive, and he was diagnosed with Evan's syndrome complicated by ITP and autoimmune hemolytic anemia (AIHA) induced by immune-related adverse events (irAEs). After treatment with prednisolone, the hemoglobin level increased, and hemolytic findings improved on blood tests. We encountered a rare case of Evans' syndrome due to atezolizumab plus bevacizumab therapy for HCC. In atezolizumab plus bevacizumab therapy, hematologic toxicities are not rare adverse events and attention is required.

Atezolizumab plus bevacizumab (AB) combination therapy is the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). The management of immune-related adverse events (irAEs) is an important issue associated with achieving a good therapeutic response in patients receiving AB therapy. However, few studies have reported irAE development in patients receiving AB therapy. This study focused on the association between irAE development and autoantibodies at baseline in patients receiving AB therapy. Sixty-one patients receiving AB therapy were enrolled. For autoantibodies, the following antibodies were tested before the start of AB therapy: antinuclear antibodies, rheumatoid factor (RF), anti-thyroglobulin antibodies, thyroid peroxidase antibodies, anti-thyroid stimulating hormone receptor antibodies, and acetylcholine receptor antibodies. A patient was considered to have pre-existing antibodies if any of the listed antibodies were present at baseline. Ten patients (16%) developed irAEs during the observation period. The irAEs included liver injury, hypothyroidism, adrenal insufficiency, adrenocorticotropic hormone deficiency, and rhabdomyolysis. Patients with irAE (n=10) were more likely to be positive for any autoantibody (hazard ratio [HR] 3.7, p=0.047) and RF at baseline (HR 5.4, p=0.035) and to achieve complete response (HR 5.8, p=0.027) than those without. The presence of autoantibodies at baseline was an independent factor associated with irAE development. In the real world, 16% of patients receiving AB therapy for u-HCC developed irAEs. Patients with autoantibodies at baseline are at high risk of developing irAEs and require cautious follow-up.