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Transarterial chemoembolisation (TACE) is standard of care for patients with unresectable hepatocellular carcinoma that is amenable to embolisation; however, median progression-free survival is still approximately 7 months. We aimed to assess whether adding durvalumab, with or without bevacizumab, might improve progression-free survival. In this multiregional, randomised, double-blind, placebo-controlled, phase 3 study (EMERALD-1), adults aged 18 years or older with unresectable hepatocellular carcinoma amenable to embolisation, an Eastern Cooperative Oncology Group performance status of 0 or 1 at enrolment, and at least one measurable intrahepatic lesion per modified Response Evaluation Criteria in Solid Tumours (RECIST) were enrolled at 157 medical sites including research centres and general and specialist hospitals in 18 countries. Eligible patients were randomly assigned (1:1:1), stratified by TACE method, region, and portal vein invasion, using an interactive voice response or web response system, to TACE plus either durvalumab plus bevacizumab (1500 mg intravenous durvalumab once every 4 weeks, then 1120 mg durvalumab plus 15 mg/kg intravenous bevacizumab once every 3 weeks), durvalumab plus placebo (same regimen using placebo instead of bevacizumab), or placebo alone (same regimen using placebo instead of durvalumab and instead of bevacizumab). Participants, investigators, and those assessing outcomes were masked to treatment assignment until data analysis. The primary endpoint was progression-free survival, by blinded independent central review (BICR), and per RECIST version 1.1, with durvalumab plus bevacizumab versus placebo alone in the intention-to-treat population (ITT; ie, all participants assigned to treatment). Key secondary endpoints were progression-free survival by BICR per RECIST version 1.1 with durvalumab plus placebo versus placebo alone, overall survival, and time to deterioration in select patient-reported outcomes. Participants continue to be followed up for overall survival, and overall survival and patient-reported outcomes will be reported in a later publication. Safety was assessed in the safety analysis set, which included all participants assigned to treatment who received any study treatment (ie, any durvalumab, bevacizumab, or placebo) by treatment received. This study is registered with ClinicalTrials.gov, NCT03778957, and is closed to accrual. Between Nov 30, 2018, and July 19, 2021, 887 patients were screened, of whom 616 were randomly assigned to durvalumab plus bevacizumab (n=204), durvalumab plus placebo (n=207), or placebo alone (n=205; ITT population). Median age was 65·0 years (IQR 59·0–72·0), 135 (22%) of 616 participants were female, 481 (78%) were male, 375 (61%) were Asian, 176 (29%) were White, 22 (4%) were American Indian or Alaska Native, nine (1%) were Black or African American, one (<1%) was native Hawaiian or other Pacific Islander, and 33 (5%) were other races. As of data cutoff (Sept 11, 2023) median follow-up for progression-free survival was 27·9 months (95% CI 27·4–30·4), median progression-free survival was 15·0 months (95% CI 11·1–18·9) with durvalumab plus bevacizumab, 10·0 months (9·0–12·7) with durvalumab, and 8·2 months (6·9–11·1) with placebo. Progression-free survival hazard ratio was 0·77 (95% CI 0·61–0·98; two-sided p=0·032) for durvalumab plus bevacizumab versus placebo, and 0·94 (0·75–1·19; two-sided p=0·64) for durvalumab plus placebo versus placebo. The most common maximum grade 3–4 adverse events were hypertension in participants who received durvalumab and bevacizumab (nine [6%] of 154 participants), anaemia in participants who received durvalumab and placebo (ten [4%] of 232 participants), and post-embolisation syndrome in participants who received placebo alone (eight [4%] of 200 participants). Study treatment-related adverse events that led to death occurred in none of 154 participants who received durvalumab and bevacizumab, three (1%) of 232 who received durvalumab and placebo (n=1 for arterial haemorrhage, liver injury, and multiple organ dysfunction syndrome), and three (2%) of 200 who received placebo alone (n=1 for oesophageal varices haemorrhage, upper gastrointestinal haemorrhage, and dermatomyositis). Durvalumab plus bevacizumab plus TACE has the potential to set a new standard of care. With additional follow-up of the EMERALD-1 study, future analyses, including the final overall survival data and patient-reported outcomes, will help to further characterise the potential clinical benefits of durvalumab plus bevacizumab plus TACE in hepatocellular carcinoma amenable to embolisation. AstraZeneca.

We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69–1.45) and 1.19 (95% CI, 0.82–1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38–1.08) and 1.03 (95% CI, 0.63–1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade. An exploratory randomized controlled clinical trial of renal cell carcinoma identifies molecular patterns distinguishing responders to immune checkpoint blockade alone or combined with angiogenesis inhibitor versus angiogenesis inhibitor alone.

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.

In the TRIBE study, FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab significantly improved progression-free survival of patients with metastatic colorectal cancer compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. In this updated analysis, we aimed to provide mature results for overall survival—a secondary endpoint—and report treatment efficacy in RAS and BRAF molecular subgroups. TRIBE was an open-label, multicentre, phase 3 randomised study of patients (aged 18–70 years with Eastern Cooperative Oncology Group [ECOG] performance status of 2 or less and aged 71–75 years with an ECOG performance status of 0) with unresectable metastatic colorectal cancer who were recruited from 34 Italian oncology units. Patients were randomly assigned (1:1) via a web-based procedure to receive FOLFIRI plus bevacizumab or FOLFOXIRI plus bevacizumab. Bevacizumab was given as a 5 mg/kg intravenous dose. FOLFIRI consisted of a 180 mg/m2 intravenous infusion of irinotecan for 60 min followed by a 200 mg/m2 intravenous infusion of leucovorin for 120 min, a 400 mg/m2 intravenous bolus of fluorouracil, and a 2400 mg/m2 continuous infusion of fluorouracil for 46 h. FOLFOXIRI consisted of a 165 mg/m2 intravenous infusion of irinotecan for 60 min, followed by an 85 mg/m2 intravenous infusion of oxaliplatin given concurrently with 200 mg/m2 leucovorin for 120 min, followed by a 3200 mg/m2 continuous infusion of fluorouracil for 48 h. Tissue samples for RAS and BRAF mutational status analyses were centrally collected. In this updated analysis, we assessed the secondary endpoint of overall survival in the main cohort and treatment efficacy in RAS and BRAF molecular subgroups. All analyses were by intention to treat. TRIBE was concluded on Nov 30, 2014. The trial is registered with ClinicalTrials.gov, number NCT00719797. Between July 17, 2008, and May 31, 2011, 508 patients were randomly assigned. At a median follow-up of 48·1 months (IQR 41·7–55·6), median overall survival was 29·8 months (95% CI 26·0–34·3) in the FOLFOXIRI plus bevacizumab group compared with 25·8 months (22·5–29·1) in the FOLFIRI plus bevacizumab group (hazard ratio [HR] 0·80, 95% CI 0·65–0·98; p=0·03). Median overall survival was 37·1 months (95% CI 29·7–42·7) in the RAS and BRAF wild-type subgroup compared with 25·6 months (22·4–28·6) in the RAS-mutation-positive subgroup (HR 1·49, 95% CI 1·11–1·99) and 13·4 months (8·2–24·1) in the BRAF-mutation-positive subgroup (HR 2·79, 95% CI 1·75–4·46; likelihood-ratio test p<0·0001). Treatment effect was not significantly different across molecular subgroups (pinteraction=0·52). FOLFOXIRI plus bevacizumab is a feasible treatment option for those patients who meet the inclusion criteria of the present study, irrespective of baseline clinical characteristics and RAS or BRAF mutational status. GONO (Gruppo Oncologico del Nord Ovest) Cooperative Group and ARCO Foundation.

Abstract Background In PAOLA-1/ENGOT-ov25, the addition of olaparib to bevacizumab maintenance improved overall survival in patients with newly diagnosed advanced ovarian cancer. We describe the safety profile and quality of life (QoL) of this combination in older patients in PAOLA-1. Methods Safety (CTCAE v4.03) and QoL (EORTC QoL Questionnaires Core 30 and Ovarian 28) data were collected. We compared safety by age (≥70 vs <70 years) in the olaparib-containing arm. QoL by treatment arm was assessed in older patients. Geriatric features, including Geriatric Vulnerability Score (GVS), were also gathered. Results Of 806 patients randomized, 142 were ≥70 years old (olaparib-containing arm: n = 104; placebo arm: n = 38). Older patients treated with olaparib exhibited a similar safety profile to younger patients, except for higher rates of all grades of lymphopenia and grade ≥3 hypertension (31.7% vs 21.6%, P =.032 and 26.9% vs 16.7%, P =.019, respectively). No hematological malignancy was reported. Two years after randomization, mean Global Health Status and cognitive functioning seemed better with olaparib than bevacizumab alone (adjusted mean difference: +4.47 points [95% CI, −0.49 to 9.42] and +4.82 [−0.57 to 10.21], respectively), and other QoL items were similar between arms. In the olaparib-containing arm, older patients with baseline GVS ≥ 1 (n = 48) exhibited increased toxicity and poorer QoL than those with GVS of 0 (n = 34). Conclusion Among older patients in PAOLA-1, olaparib plus bevacizumab had a manageable safety profile and no adverse impact on QoL. Additional data are required to confirm these results in more vulnerable patients. (ClinicalTrials.gov Identifier: NCT02477644).

Some insurance companies mandate a form of step therapy, which involves initial use of an inexpensive drug, bevacizumab, to treat diabetic macular edema. This trial compared two treatments: step therapy and use of a more expensive drug.

In a previous phase 3 trial, treatment with trifluridine-tipiracil (FTD-TPI) prolonged overall survival among patients with metastatic colorectal cancer. Preliminary data from single-group and randomized phase 2 trials suggest that treatment with FTD-TPI in addition to bevacizumab has the potential to extend survival. We randomly assigned, in a 1:1 ratio, adult patients who had received no more than two previous chemotherapy regimens for the treatment of advanced colorectal cancer to receive FTD-TPI plus bevacizumab (combination group) or FTD-TPI alone (FTD-TPI group). The primary end point was overall survival. Secondary end points were progression-free survival and safety, including the time to worsening of the Eastern Cooperative Oncology Group (ECOG) performance-status score from 0 or 1 to 2 or more (on a scale from 0 to 5, with higher scores indicating greater disability). A total of 246 patients were assigned to each group. The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD-TPI group (hazard ratio for death, 0.61; 95% confidence interval [CI], 0.49 to 0.77; P<0.001). The median progression-free survival was 5.6 months in the combination group and 2.4 months in the FTD-TPI group (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.54; P<0.001). The most common adverse events in both groups were neutropenia, nausea, and anemia. No treatment-related deaths were reported. The median time to worsening of the ECOG performance-status score from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the FTD-TPI group (hazard ratio, 0.54; 95% CI, 0.43 to 0.67). Among patients with refractory metastatic colorectal cancer, treatment with FTD-TPI plus bevacizumab resulted in longer overall survival than FTD-TPI alone. (Funded by Servier and Taiho Oncology; SUNLIGHT ClinicalTrials.gov number, NCT04737187; EudraCT number, 2020-001976-14.).

It remains unclear whether metronomic chemotherapy is superior to conventional chemotherapy when combined with immune checkpoint blockade. Here we performed a phase 2 clinical trial of metronomic chemotherapy combined with PD-1 blockade to compare the efficacy of combined conventional chemotherapy and PD-1 blockade using Bayesian adaptive randomization and efficacy monitoring. Eligible patients had metastatic HER2-negative breast cancer and had not received more than one prior line of standard chemotherapy. Patients (total n  = 97) were randomized to receive (1) metronomic vinorelbine (NVB) monotherapy ( n  = 11), (2) NVB plus anti-PD-1 toripalimab ( n  = 7), (3) anti-angiogenic bevacizumab, NVB and toripalimab ( n  = 27), (4) conventional cisplatin, NVB and toripalimab ( n  = 26), or (5) metronomic cyclophosphamide, capecitabine, NVB and toripalimab (the VEX cohort) ( n  = 26). The primary endpoint was disease control rate (DCR). Secondary objectives included progression-free survival (PFS) and safety. The study met the primary endpoint. The VEX (69.7%) and cisplatin (73.7%) cohorts had the highest DCR. The median PFS of patients in the VEX cohort was the longest, reaching 6.6 months, followed by the bevacizumab (4.0 months) and cisplatin (3.5 months) cohorts. In general, the five regimens were well tolerated, with nausea and neutropenia being the most common adverse events. An exploratory mass cytometry analysis indicated that metronomic VEX chemotherapy reprograms the systemic immune response. Together, the clinical and translational data of this study indicate that metronomic VEX chemotherapy combined with PD-1 blockade can be a treatment option in patients with breast cancer. ClinicalTrials.gov Identifier: NCT04389073 . In a Bayesian adaptive randomized trial comparing various metronomic chemotherapy regimens versus conventional chemotherapy plus anti-PD-1 in women with HER2-negative breast cancer, a metronomic chemotherapy-based regimen appears to be clinically effective, with evidence that on-treatment immune changes may be trackable for assessing response.

When used as maintenance therapy, the PARP inhibitor olaparib provided a significant progression-free survival benefit in women with ovarian cancer who had a response to primary chemotherapy, particularly in those whose tumors were deficient in homologous recombination (e.g., BRCA -mutated tumors). Hematologic toxic effects were observed.

Resistance to first-generation or second-generation EGFR tyrosine kinase inhibitor (TKI) monotherapy develops in almost half of patients with EGFR-positive non-small-cell lung cancer (NSCLC) after 1 year of treatment. The JO25567 phase 2 trial comparing erlotinib plus bevacizumab combination therapy with erlotinib monotherapy established the activity and manageable toxicity of erlotinib plus bevacizumab in patients with NSCLC. We did a phase 3 trial to validate the results of the JO25567 study and report here the results from the preplanned interim analysis. In this prespecified interim analysis of the randomised, open-label, phase 3 NEJ026 trial, we recruited patients with stage IIIB–IV disease or recurrent, cytologically or histologically confirmed non-squamous NSCLC with activating EGFR genomic aberrations from 69 centres across Japan. Eligible patients were at least 20 years old, and had an Eastern Cooperative Oncology Group performance status of 2 or lower, no previous chemotherapy for advanced disease, and one or more measurable lesions based on Response Evaluation Criteria in Solid Tumours (1.1). Patients were randomly assigned (1:1) to receive oral erlotinib 150 mg per day plus intravenous bevacizumab 15 mg/kg once every 21 days, or erlotinib 150 mg per day monotherapy. Randomisation was done by minimisation, stratified by sex, smoking status, clinical stage, and EGFR mutation subtype. The primary endpoint was progression-free survival. This study is ongoing; the data cutoff for this prespecified interim analysis was Sept 21, 2017. Efficacy was analysed in the modified intention-to-treat population, which included all randomly assigned patients who received at least one dose of treatment and had at least one response evaluation. Safety was analysed in all patients who received at least one dose of study drug. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000017069. Between June 3, 2015, and Aug 31, 2016, 228 patients were randomly assigned to receive erlotinib plus bevacizumab (n=114) or erlotinib alone (n=114). 112 patients in each group were evaluable for efficacy, and safety was evaluated in 112 patients in the combination therapy group and 114 in the monotherapy group. Median follow-up was 12·4 months (IQR 7·0–15·7). At the time of interim analysis, median progression-free survival for patients in the erlotinib plus bevacizumab group was 16·9 months (95% CI 14·2–21·0) compared with 13·3 months (11·1–15·3) for patients in the erlotinib group (hazard ratio 0·605, 95% CI 0·417–0·877; p=0·016). 98 (88%) of 112 patients in the erlotinib plus bevacizumab group and 53 (46%) of 114 patients in the erlotinib alone group had grade 3 or worse adverse events. The most common grade 3–4 adverse event was rash (23 [21%] of 112 patients in the erlotinib plus bevacizumab group vs 24 [21%] of 114 patients in the erlotinib alone group). Nine (8%) of 112 patients in the erlotinib plus bevacizumab group and five (4%) of 114 patients in the erlotinib alone group had serious adverse events. The most common serious adverse events were grade 4 neutropenia (two [2%] of 112 patients in the erlotinib plus bevacizumab group) and grade 4 hepatic dysfunction (one [1%] of 112 patients in the erlotinib plus bevacizumab group and one [1%] of 114 patients in the erlotinib alone group). No treatment-related deaths occurred. The results of this interim analysis showed that bevacizumab plus erlotinib combination therapy improves progression-free survival compared with erlotinib alone in patients with EGFR-positive NSCLC. Future studies with longer follow-up, and overall survival and quality-of-life data will be required to further assess the efficacy of this combination in this setting. Chugai Pharmaceutical.