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In patients with unresectable hepatocellular carcinoma, the combination of atezolizumab and bevacizumab was associated with better progression-free and overall survival outcomes, response rate, and preservation of quality of life than sorafenib. Serious toxic effects were noted in 38% of patients, similar to that seen in previous studies of these agents.

The incidence of neuroendocrine tumors (NETs) in the US is rising, with 8.3 cases per 100,000 individuals diagnosed in 2018 compared with 6.98 cases per 100,000 individuals diagnosed in 2012.1,2 Most patients with NETs are diagnosed with metastatic disease, at which point curative surgery is no longer a treatment option.3 Prior to 2017, available treatments for advanced NETs included somatostatin analogues (lanreotide [Somatuline] and octreotide [Sandostatin]), targeted therapy (everolimus [Afinitor] and sunitinib [Sutent]), and chemotherapy.4-7 In 2017, the World Health Organization added a classification for well-differentiated grade 3 NETs (Ki67 > 20% and ≤ 55%).8 Previously these tumors were placed under the umbrella of poorly differentiated neuroendocrine carcinomas. Given that well-differentiated grade 3 NETs are relatively new, standard-of-care treatment options are undefined.

Understanding patients' experience of cancer treatment is important. We aimed to evaluate patient-reported outcomes (PROs) with atezolizumab plus bevacizumab versus sorafenib in patients with advanced hepatocellular carcinoma in the IMbrave150 trial, which has already shown significant overall survival and progression-free survival benefits with this combination therapy. We did an open-label, randomised, phase 3 trial in 111 hospitals and cancer centres across 17 countries or regions. We included patients aged 18 years or older with systemic, treatment-naive, histologically, cytologically, or clinically confirmed unresectable hepatocellular carcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with disease that was not amenable to curative surgical or locoregional therapies, or progressive disease after surgical or locoregional therapies. Participants were randomly assigned (2:1; using permuted block randomisation [blocks of six], stratified by geographical region; macrovascular invasion, extrahepatic spread, or both; baseline alpha-fetoprotein concentration; and ECOG performance status) to receive 1200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously once every 3 weeks or 400 mg sorafenib orally twice a day, until loss of clinical benefit or unacceptable toxicity. The independent review facility for tumour assessment was masked to the treatment allocation. Previously reported coprimary endpoints were overall survival and independently assessed progression-free survival per Response Evaluation Criteria in Solid Tumors 1.1. Prespecified secondary and exploratory analyses descriptively evaluated treatment effects on patient-reported quality of life, functioning, and disease symptoms per the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire for cancer (QLQ-C30) and quality-of-life questionnaire for hepatocellular carcinoma (QLQ-HCC18). Time to confirmed deterioration of PROs was analysed in the intention-to-treat population; all other analyses were done in the PRO-evaluable population (patients who had a baseline PRO assessment and at least one assessment after baseline). The trial is ongoing; enrolment is closed. This trial is registered with ClinicalTrials.gov, NCT03434379. Between March 15, 2018, and Jan 30, 2019, 725 patients were screened and 501 patients were enrolled and randomly assigned to atezolizumab plus bevacizumab (n=336) or sorafenib (n=165). 309 patients in the atezolizumab plus bevacizumab group and 145 patients in the sorafenib group were included in the PRO-evaluable population. At data cutoff (Aug 29, 2019) the median follow-up was 8·6 months (IQR 6·2–10·8). EORTC QLQ-C30 completion rates were 90% or greater for 23 of 24 treatment cycles in both groups (range 88–100% in the atezolizumab plus bevacizumab group and 80–100% in the sorafenib group). EORTC QLQ-HCC18 completion rates were 90% or greater for 20 of 24 cycles in the atezolizumab plus bevacizumab group (range 88–100%) and 21 of 24 cycles in the sorafenib group (range 89–100%). Compared with sorafenib, atezolizumab plus bevacizumab reduced the risk of deterioration on all EORTC QLQ-C30 generic cancer symptom scales that were prespecified for analysis (appetite loss [hazard ratio (HR) 0·57, 95% CI 0·40–0·81], diarrhoea [0·23, 0·16–0·34], fatigue [0·61, 0·46–0·81], pain [0·46, 0·34–0·62]), and two of three EORTC QLQ-HCC18 disease-specific symptom scales that were prespecified for analysis (fatigue [0·60, 0·45–0·80] and pain [0·65, 0·46–0·92], but not jaundice [0·76, 0·55–1·07]). At day 1 of treatment cycle five (after which attrition in the sorafenib group was more than 50%), the mean EORTC QLQ-C30 score changes from baseline in the atezolizumab plus bevacizumab versus sorafenib groups were: –3·29 (SD 17·56) versus –5·83 (20·63) for quality of life, –4·02 (19·42) versus –9·76 (21·33) for role functioning, and –3·77 (12·82) versus –7·60 (15·54) for physical functioning. Prespecified analyses of PRO data showed clinically meaningful benefits in terms of patient-reported quality of life, functioning, and disease symptoms with atezolizumab plus bevacizumab compared with sorafenib, strengthening the combination therapy's positive benefit–risk profile versus that of sorafenib in patients with unresectable hepatocellular carcinoma. F Hoffmann–La Roche and Genentech.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer mortality worldwide. Heterogeneity of clinical conditions contributes to the complex management of care for patients with advanced HCC. Recently, the treatment landscape for advanced HCC has expanded rapidly, with the additional FDA approvals of several oral tyrosine kinase inhibitors (lenvatinib, regorafenib, and cabozantinib), as well as immunotherapies such as immune check point inhibitors (nivolumab and pembrolizumab) and the monoclonal IgG1 antibody, ramucirumab. This expansion has generated a need for novel treatment sequencing strategies in this patient population. In light of these developments, an evaluation of the impact of FDA-approved therapeutics on patient-centered outcomes such as health-related quality of life (HRQoL) is warranted. An increased understanding of HRQoL in patients included in advanced HCC clinical trials could potentially help physician decision-making for treatment sequencing in patients with advanced HCC.

PD-L1 and VEGF blockade with atezolizumab plus bevacizumab has been shown to improve survival in unresectable hepatocellular carcinoma. TIGIT is an immune checkpoint regulator implicated in many cancers, including unresectable hepatocellular carcinoma. Here, we evaluate the clinical activity and safety of the addition of tiragolumab, an anti-TIGIT monoclonal antibody, to atezolizumab plus bevacizumab. This randomised, open-label, phase 1b–2 umbrella study was conducted at 26 centres across China, France, Israel, New Zealand, South Korea, Taiwan, and the USA. Eligible patients were adults aged 18 years old or older with previously untreated locally advanced unresectable hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0–1, Child-Pugh class A disease, and a life expectancy of at least 3 months. Eligible patients were randomly assigned (2:1) using permuted block randomisation to receive either tiragolumab 600 mg plus atezolizumab 1200 mg plus bevacizumab 15 mg/kg or atezolizumab 1200 mg plus bevacizumab 15 mg/kg, administered via intravenous infusion every 3 weeks on day 1 of each 21-day cycle. Patients received treatment until unacceptable toxic effects or loss of clinical benefit, whichever occurred first. The primary endpoint was objective response rate. Analysis of clinical activity was done in the efficacy-evaluable population (all patients who received at least one dose of each drug for their assigned treatment regimen) and safety was assessed in all patients who received any study treatment. The trial is registered with ClinicalTrials.gov, NCT04524871, and is ongoing. Between Aug 20, 2020, and Feb 10, 2022, we assessed 154 patients for eligibility and 59 eligible patients were randomly assigned to receive tiragolumab plus atezolizumab plus bevacizumab (n=41) or atezolizumab plus bevacizumab (n=18); one patient in the tiragolumab plus atezolizumab plus bevacizumab group experienced an adverse event before receiving any treatment and withdrew from the study. Median age was 65·0 years (IQR 61·0–73·0). 46 (79%) of 58 patients were male and 12 (21%) were female. Most patients were Asian (23 [40%]) or White (21 [36%]). At the time of clinical cutoff (Aug 21, 2023), median follow-up was 20·6 months (IQR 10·6–28·0) in the tiragolumab plus atezolizumab plus bevacizumab group and 14·0 months (4·2–18·5) in the atezolizumab plus bevacizumab group. The confirmed objective response rate was 43% (95% CI 27–59, n=17) in the tiragolumab plus atezolizumab plus bevacizumab group and 11% (1–35, n=2) in the atezolizumab plus bevacizumab group. All patients in both groups experienced an adverse event. The incidence of pruritis (20 [50%] of 40 patients vs three [17%] of 18 patients), arthralgia (13 [33%] vs two [11%]), and diarrhoea (12 [30%] vs one [6%]) was notably higher in the tiragolumab plus atezolizumab plus bevacizumab group than in the atezolizumab plus bevacizumab group, although these were mainly grade 1–2. The most common grade 3–4 adverse events were hypertension (six [15%] of 40 patients in the tiragolumab plus atezolizumab plus bevacizumab group vs two [11%] of 18 patients in the atezolizumab plus bevacizumab group), aspartate aminotransferase increased (three [8%] of 40 patients vs one [6%] of 18 patients), and proteinuria (two [5%] of 40 patients vs two [11%] of 18 patients). Serious adverse events occurred in 21 (53%) of 40 patients in the tiragolumab plus atezolizumab plus bevacizumab group and in ten (56%) of 18 patients in the atezolizumab plus bevacizumab group. Treatment-related deaths occurred in one patient in the tiragolumab plus atezolizumab plus bevacizumab group (due to cholestasis) and two patients in the atezolizumab plus bevacizumab group (due to oesophageal varices haemorrhage and upper gastrointestinal haemorrhage). The addition of tiragolumab to atezolizumab plus bevacizumab did not appear to result in a substantial worsening of treatment-related or immune-mediated adverse events, and no new safety signals were identified. This signal-seeking study suggests that the addition of tiragolumab to atezolizumab and bevacizumab might be more clinically active than atezolizumab plus bevacizumab alone in unresectable hepatocellular carcinoma. Based on these data, further study of combination tiragolumab plus atezolizumab plus bevacizumab is warranted. F Hoffmann-La Roche and Genentech.

Background IMbrave150 is a phase III trial that assessed atezolizumab + bevacizumab (ATEZO/BEV) versus sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (HCC) and demonstrated a significant improvement in clinical outcomes. Exploratory analyses characterized objective response rate (ORR), depth (DpR), and duration of response (DoR), and patients with a complete response (CR). Methods Patients were randomized 2:1 to intravenous ATEZO (1200 mg) + BEV (15 mg/kg) every 3 weeks or oral SOR (400 mg) twice daily. Tumors were evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and HCC‐modified RECIST (mRECIST). ORR by prior treatment and largest baseline liver lesion size, DoR, time to response (TTR), and complete response (TTCR) were analyzed. Results For both criteria, responses favored ATEZO/BEV versus SOR regardless of prior treatment and in patients with lesions ≥3 cm. Median TTR was 2.8 months per RECIST 1.1 (range: 1.2–12.3 months) and 2.8 months per mRECIST (range: 1.1–12.3 months) with ATEZO/BEV. Patients receiving ATEZO/BEV had a greater DpR, per both criteria, across baseline liver lesion sizes. Characteristics of complete responders were similar to those of the intent‐to‐treat population. In complete responders receiving ATEZO/BEV per mRECIST versus RECIST 1.1, respectively, median TTCR was shorter (5.5 vs. 7.0 months), mean baseline sum of lesion diameter was longer (5.0 [SD, 5.1] vs. 2.6 [SD, 1.4] cm), and mean largest liver lesion size was larger (4.8 [SD, 4.2] vs. 2.3 [SD, 1.0] cm). Conclusions These data highlight the improved ORR, DpR, and CR rates with ATEZO/BEV in unresectable HCC. IMbrave150 is a randomized phase III trial that showed statistically significant and clinically meaningful improvements in overall survival and progression‐free survival with atezolizumab plus bevacizumab versus sorafenib. The post hoc analyses presented here further highlight the ability of ATEZO/BEV to improve overall response rates, depth of response, and complete response rates in unresectable hepatocellular carcinoma versus sorafenib.

Background Cognitive decline is among the most feared treatment-related outcomes of older adults with cancer. The majority of older patients with breast cancer self-report cognitive problems during and after chemotherapy. Prior neuroimaging research has been performed mostly in younger patients with cancer. The purpose of this study was to evaluate longitudinal changes in brain volumes and cognition in older women with breast cancer receiving adjuvant chemotherapy. Methods Women aged ≥ 60 years with stage I–III breast cancer receiving adjuvant chemotherapy and age-matched and sex-matched healthy controls were enrolled. All participants underwent neuropsychological testing with the US National Institutes of Health (NIH) Toolbox for Cognition and brain magnetic resonance imaging (MRI) prior to chemotherapy, and again around one month after the last infusion of chemotherapy. Brain volumes were measured using Neuroreader™ software. Longitudinal changes in brain volumes and neuropsychological scores were analyzed utilizing linear mixed models. Results A total of 16 patients with breast cancer (mean age 67.0, SD 5.39 years) and 14 age-matched and sex-matched healthy controls (mean age 67.8, SD 5.24 years) were included: 7 patients received docetaxel and cyclophosphamide (TC) and 9 received chemotherapy regimens other than TC (non-TC). There were no significant differences in segmented brain volumes between the healthy control group and the chemotherapy group pre-chemotherapy ( p  > 0.05). Exploratory hypothesis generating analyses focusing on the effect of the chemotherapy regimen demonstrated that the TC group had greater volume reduction in the temporal lobe (change = − 0.26) compared to the non-TC group (change = 0.04, p for interaction = 0.02) and healthy controls (change = 0.08, p for interaction = 0.004). Similarly, the TC group had a decrease in oral reading recognition scores (change = − 6.94) compared to the non-TC group (change = − 1.21, p for interaction = 0.07) and healthy controls (change = 0.09, p for interaction = 0.02). Conclusions There were no significant differences in segmented brain volumes between the healthy control group and the chemotherapy group; however, exploratory analyses demonstrated a reduction in both temporal lobe volume and oral reading recognition scores among patients on the TC regimen. These results suggest that different chemotherapy regimens may have differential effects on brain volume and cognition. Future, larger studies focusing on older adults with cancer on different treatment regimens are needed to confirm these findings. Trial registration ClinicalTrials.gov, NCT01992432 . Registered on 25 November 2013. Retrospectively registered.

Gastric cancer (GC) remains a major cause of cancer‐related mortality worldwide, driven by late‐stage diagnoses and poor survival outcomes. Leukemia inhibitory factor (LIF) and leukemia inhibitory factor receptor (LIFR) are increasingly recognized as critical players in GC pathophysiology, though their exact roles are not fully understood. LIF, a multifunctional cytokine in the interleukin‐6 family, signals through the LIFR/gp130 complex and activates oncogenic pathways such as JAK/STAT3, MAPK/ERK, and Hippo‐YAP. Emerging evidence indicates that LIF drives tumor progression by promoting epithelial–mesenchymal transition, immune evasion, and chemoresistance. Clinically, high LIF expression is associated with poor prognosis, peritoneal metastasis, and resistance to chemotherapy and immunotherapy. This review explores the molecular mechanisms of LIF/LIFR signaling in GC, highlighting its potential as a prognostic biomarker and therapeutic target. Mini Conclusion The LIF/LIFR pathway contributing to gastric cancer is complex with context‐dependent pro‐ versus anti‐tumorigenic roles in GC progression, marking it as a significant biomarker and target for future therapies.

Immune checkpoint inhibitors have demonstrated broad single-agent antitumor activity and a favorable safety profile that render them attractive agents to combine with other systemic anticancer therapies. Pancreatic cancer has been fairly resistant to monotherapy blockade of programmed cell death protein 1 receptor, programmed death ligand 1, and cytotoxic T-lymphocyte associated protein 4. However, there is a growing body of preclinical evidence to support the rational combination of checkpoint inhibitors and various systemic therapies in pancreatic cancer. Furthermore, early clinical evidence has begun to support the feasibility and efficacy of checkpoint inhibitor-based combination therapy in advanced pancreatic cancer. Despite accumulating preclinical and clinical data, there remains several questions as to the optimal dosing and timing of administration of respective agents, toxicity of combination strategies, and mechanisms by which immune resistance to single-agent checkpoint blockade are overcome. Further development of biomarkers is also important in the advancement of combination systemic therapies incorporating checkpoint blockade in pancreatic cancer. Results from an impressive number of ongoing prospective clinical trials are eagerly anticipated and will seek to validate the viability of combination immuno-oncology strategies in pancreatic cancer.

As the worldwide population ages, oncologists are often required to make difficult and complex decisions regarding the treatment of older people (aged 65 years and older) with cancer. Chronological age alone is often a poor indicator of the physiological and functional status of older adults, and thus should not be the main factor guiding treatment decisions in oncology. By contrast, a geriatric assessment can provide a much more comprehensive understanding of the functional and physiological age of an older person with cancer. The geriatric assessment is a multidimensional tool that evaluates several domains, including physical function, cognition, nutrition, comorbidities, psychological status, and social support. In this Series paper, we discuss the use of a geriatric assessment-based approach to cancer care, and provide clinicians with tools to better assess the risks and benefits of treatment to engage in shared decision making and provide better personalised care for older people with cancer.