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Background: The aim of the COSMIC-312 trial was to evaluate cabozantinib plus atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma. In the initial analysis, cabozantinib plus atezolizumab significantly prolonged progression-free survival versus sorafenib. Here, we report the pre-planned final overall survival analysis and updated safety and efficacy results following longer follow-up., Methods: COSMIC-312 was an open-label, randomised, phase 3 study done across 178 centres in 32 countries. Patients aged 18 years or older with previously untreated advanced hepatocellular carcinoma were eligible. Patients must have had measurable disease per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1), and adequate marrow and organ function, including Child-Pugh class A liver function; those with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were ineligible. Patients were randomly assigned (2:1:1) using a web-based interactive response system to a combination of oral cabozantinib 40 mg once daily plus intravenous atezolizumab 1200 mg every 3 weeks, oral sorafenib 400 mg twice daily, or oral single-agent cabozantinib 60 mg once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were for cabozantinib plus atezolizumab versus sorafenib: progression-free survival per RECIST 1.1, as assessed by a blinded independent radiology committee, in the first 372 randomly assigned patients (previously reported) and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib. The secondary endpoint was progression-free survival in all patients randomly assigned to cabozantinib versus sorafenib. Outcomes in all randomly assigned patients, including final overall survival, are presented. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03755791., Findings: Between Dec 7, 2018, and Aug 27, 2020, 432 patients were randomly assigned to combination treatment, 217 to sorafenib, and 188 to single-agent cabozantinib, and included in all efficacy analyses. 704 (84%) patients were male and 133 (16%) were female. 824 of these patients received at least one dose of study treatment and were included in the safety population. Median follow-up was 22·1 months (IQR 19·3-24·8). Median overall survival was 16·5 months (96% CI 14·5-18·7) for the combination treatment group and 15·5 months (12·2-20·0) for the sorafenib group (hazard ratio [HR] 0·98 [0·78-1·24]; stratified log-rank p=0·87). Median progression-free survival was 6·9 months (99% CI 5·7-8·2) for the combination treatment group, 4·3 months (2·9-6·1) for the sorafenib group, and 5·8 months (99% CI 5·4-8·2) for the single-agent cabozantinib group (HR 0·74 [0·56-0·97] for combination treatment vs sorafenib; HR 0·78 [99% CI 0·56-1·09], p=0·05, for single-agent cabozantinib vs sorafenib). Grade 3 or 4 adverse events occurred in 281 (66%) of 429 patients in the combination treatment group, 100 (48%) of 207 patients in the sorafenib group, and 108 (57%) of 188 patients in the single-agent cabozantinib group; the most common were hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), palmar-plantar erythrodysaesthesia (36 [8%] vs 18 [9%] vs 16 [9%]), aspartate aminotransferase increased (42 [10%] vs eight [4%] vs 17 [9%]), and alanine aminotransferase increased (40 [9%] vs six [3%] vs 13 [7%]). Serious adverse events occurred in 223 (52%) patients in the combination treatment group, 84 (41%) patients in the sorafenib group, and 87 (46%) patients in the single agent cabozantinib group. Treatment-related deaths occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) in the sorafenib group (general physical health deterioration), and four (2%) in the single-agent cabozantinib group (asthenia, gastrointestinal haemorrhage, sepsis, and gastric perforation)., Interpretation: First-line cabozantinib plus atezolizumab did not improve overall survival versus sorafenib in patients with advanced hepatocellular carcinoma. The progression-free survival benefit of the combination versus sorafenib was maintained, with no new safety signals., Funding: Exelixis and Ipsen., Competing Interests: Declaration of interests TY reports a consulting or advisory role with Bristol Myers Squibb, MSD, AstraZeneca, Eisai, and Ipsen; research funding from Bristol Myers Squibb, MSD, Exelixis, Eli Lilly, AstraZeneca, Roche, and Taiho; travel, accommodations, or expenses from Roche and Bayer; stock and other ownership interests in Moderna; and other financial or non-financial interests with Taiho and Ipsen. AK reports honoraria from Exelixis, Bristol Myers Squibb, Merck, Roche, and Eisai; a consulting or advisory role with Exelixis, Bristol Myers Squibb, Merck, Roche, and Eisai; research funding from Exelixis, Roche, Merck, Bristol Myers Squibb, AdaptImmune, and Tvardi; and travel, accommodations, or expenses from Exelixis, Bristol Myers Squibb, Merck, Roche, and Eisai. A-LC reports honoraria from Merck Sharp Dohme, Bristol Myers Squibb, Bayer Healthcare, AstraZeneca, Genentech/Roche, Ipsen Innovation, BeiGene, and Exelixis; a consulting or advisory role with Merck Sharp Dohme, Bristol Myers Squibb, Bayer Healthcare, AstraZeneca, Genentech/Roche, Ipsen Innovation, BeiGene, and Exelixis; and participation on a data safety monitoring board or advisory board for Abbisko Therapeutics Co. AXZ reports employment and leadership with I-Mab Biopharma; a consulting or advisory role with Lilly, Sanofi, Merck, Exelixis, Roche, Eisai, and Bayer; and stock and other ownership interests in I-Mab Biopharma. SLC reports honoraria from MSD, AstraZeneca, Eisai, Roche, and Bristol Myers Squibb; a consulting or advisory role with MSD, AstraZeneca, Eisai, Roche, and Bayer; and travel, accommodations, or expenses from Ipsen and Novartis. VB reports honoraria from AstraZeneca, Roche, Novartis, Eisai, Bristol Myers Squibb, and Pfizer; and participation on a data safety monitoring board or advisory board with AstraZeneca, Roche, Novartis, Eisai, Bristol Myers Squibb, and Pfizer. GV reports travel, accommodations, and expenses from Roche, Bayer, Terumo, and Ipsen; and participation on a data safety monitoring board or advisory board with Roche, Eisai, and AstraZeneca. EG reports participation on a data safety monitoring board or advisory board with Gilead, Janssen, and Aligos. IB reports honoraria from Roche, Servier, Ipsen, Eisai, and AstraZeneca; travel, accommodations, and expenses with Ipsen and Roche; and participation on a data safety monitoring board or advisory board with AstraZeneca. PM reports a consulting or advisory role with Roche, AstraZeneca, MSD, Bayer, and Ipsen; research funding from Ipsen; travel, accommodations, and expenses from Ipsen, Roche, MSD, and AstraZeneca; and participation on a data safety monitoring board or advisory board with Roche, MSD, Bayer, Ipsen, and AstraZeneca. FB reports employment and stock or other ownership interests with Ipsen. SM reports employment with Exelixis; and stock and other ownership interests in Exelixis, Amgen, and Fibrogen. ZW reports employment and stock and other ownership interests with Exelixis. DC reports employment and stock and other ownership interests with Exelixis. RKK reports a consulting or advisory role with Agios (paid to institution), AstraZeneca (paid to institution), Exelixis (paid to institution), Ipsen (paid to institution), Merck (paid to institution), Kinnate, Regeneron, Tyra Biosciences, and Compass Therapeutics; research funding from Agios, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech/Roche, Loxo Oncology, Merck, Novartis, Partner Therapeutics, QED, Relay Therapeutics, Surface Oncology, and Taiho, all paid to institution; travel, accommodations, and expenses from AstraZeneca and Merck; and participation on a data safety monitoring board or advisory board with Genentech/Roche, Merck, and Relay Therapeutics. LR reports honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Incyte, Ipsen, Merck Serono, Roche, and Servier; a consulting or advisory role or participation on a data safety monitoring board with AstraZeneca, Basilea, Bayer, Bristol Myers Squibb, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, and Zymeworks; research funding from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Zymeworks, all paid to institution; a leadership or fiduciary role with the International Liver Cancer Association and the European Organisation for Research and Treatment of Cancer; and travel, accommodations, expenses from AstraZeneca. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Patients with hepatocellular carcinoma (HCC) and Child-Pugh B liver cirrhosis have poor prognosis and are underrepresented in clinical trials. The CELESTIAL trial, in which cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with HCC and Child-Pugh A liver cirrhosis at baseline, was evaluated for outcomes in patients who had Child-Pugh B cirrhosis at Week 8., Methods: This was a retrospective analysis of adult patients with previously treated advanced HCC. Child-Pugh B status was assessed by the investigator. Patients were randomised 2:1 to cabozantinib (60 mg once daily) or placebo., Results: Fifty-one patients receiving cabozantinib and 22 receiving placebo had Child-Pugh B cirrhosis at Week 8. Safety and tolerability of cabozantinib for the Child-Pugh B subgroup were consistent with the overall population. For cabozantinib- versus placebo-treated patients, median OS from randomisation was 8.5 versus 3.8 months (HR 0.32, 95% CI 0.18-0.58), median PFS was 3.7 versus 1.9 months (HR 0.44, 95% CI 0.25-0.76), and best response was stable disease in 57% versus 23% of patients., Conclusions: These encouraging results with cabozantinib support the initiation of prospective studies in patients with advanced HCC and Child-Pugh B liver function., Clinical Trial Registration: NCT01908426., (© 2022. The Author(s).)

Objective: In the phase 3 CELESTIAL trial, cabozantinib improved overall survival (OS) and progression-free survival (PFS) compared with placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). This subgroup analysis evaluated cabozantinib in patients who had received sorafenib as the only prior systemic therapy., Methods: CELESTIAL randomised (2:1) patients with advanced HCC and Child-Pugh class A liver function to treatment with cabozantinib (60 mg daily) or placebo. Eligibility required prior treatment with sorafenib, and patients could have received ≤2 prior systemic regimens. The primary endpoint was OS. Outcomes in patients who had received sorafenib as the only prior therapy were analysed by duration of prior sorafenib (<3 months, 3 to <6 months and ≥6 months)., Results: Of patients who had received only prior sorafenib, 331 were randomised to cabozantinib and 164 to placebo; 136 patients had received sorafenib for <3 months, 141 for 3 to <6 months and 217 for ≥6 months. Cabozantinib improved OS relative to placebo in the overall second-line population who had received only prior sorafenib (median 11.3 vs 7.2 months; HR=0.70, 95% CI 0.55 to 0.88). This improvement was maintained in analyses by prior sorafenib duration with longer duration generally corresponding to longer median OS-median OS 8.9 vs 6.9 months (HR=0.72, 95% CI 0.47 to 1.10) for prior sorafenib <3 months, 11.5 vs 6.5 months (HR=0.65, 95% CI 0.43 to 1.00) for 3 to <6 months and 12.3 vs 9.2 months (HR=0.82, 95% CI 0.58 to 1.16) for ≥6 months. Cabozantinib also improved PFS in all duration subgroups. Safety data were consistent with the overall study population., Conclusion: Cabozantinib improved efficacy outcomes versus placebo in the second-line population who had received only prior sorafenib irrespective of duration of prior sorafenib treatment, further supporting the utility of cabozantinib in the evolving treatment landscape of HCC., Clinical Trial Number: NCT01908426., Competing Interests: Competing interests: RKK: consulting or advisory role—Agios (Inst); AstraZeneca (Inst); Bayer (Inst); Bristol-Myers Squibb (Inst); Genentech/Roche; Gilead; Target Pharmasolutions; Target Pharmasolutions (Inst); research funding—Adaptimmune (Inst); Agios (Inst); AstraZeneca (Inst); Bayer (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); EMD Serono (Inst); Exelixis (Inst); Lilly (Inst); MedImmune (Inst); Merck Sharp & Dohme (Inst); Novartis (Inst); Taiho Pharmaceutical (Inst); PM: consulting or advisory role—Bayer; Bristol-Myers Squibb; Ipsen; MSD; Onxeo; Roche. LB: honoraria—Bayer; Bracco Diagnostics; Brystol-Myers-Squibb; Guerbet; Lilly; Meda Pharmaceuticals; Sirtex Medical; consulting or advisory role—Bayer; Brystol-Myers-Squibb; Guerbet; Sirtex medical speakers' bureau—Bayer; Bracco Diagnostics; Brystol-Myers-Squibb; Guerbet; Lilly; Meda Pharmaceuticals; Sirtex Medical; research funding—ArQule; Bayer; Brystol-Myers-Squibb; Daiichi Synkyo; travel, accommodations, expenses—Bayer; Bracco Diagnostics; Guerbet; Lilly. SLC: grants—Merck Sharp & Dohme (Asia) Ltd; personal fees—AstraZeneca Hong Kong Limited, Bayer HealthCare Limited. ADB: speakers' bureau—Amgen; Bristol-Myers Squibb; Genentech/Roche; Lilly; Merck. JK: honoraria—Novartis; consulting or advisory role—Lilly; Merck; research funding— AstraZeneca; Merck. SC: personal fees—Ipsen. TY: personal fees—BMS, MSD, Ipsen, Exelxis, Eisai, Bayer; grants and personal fees—BMS; personal fees—MSD, Ipsen, Exelixis, Bayer. JCL: employment and stock holdings—Exelixis, Inc. SM: employment—Exelixis, Inc; stock holdings—Amgen; Exelixis; FibroGen; GlaxoSmithKline. ABE-K: honoraria—AstraZeneca; Bayer; Brystol-Myers-Squibb; Genentech; GlaxoSmithKline; consulting or advisory role—AstraZeneca; Brystol-Myers-Squibb; Genentech/Roche; speakers' bureau—Merrimack; research funding—Astex Pharmaceuticals; travel, accommodations, expenses—AstraZeneca; Bayer; Brystol-Myers-Squibb; Genentech; GlaxoSmithKline. A-LC: personal fees (advisory board, honoraria, travel expenses)—Ono Pharmaceutical; Exelixis; Nucleix Ltd.; Roche/Genentech; IQVIA; Merck Sharp Dohme; Bayer Yakuhin; Amgen Taiwan; Ispen; advisor/board member—Bayer Schering Pharma; Bristol-Myers Squibb; Eisai; Merck Serono; Novartis. TM: consulting or advisory role—Beigene; Bristol-Myers Squibb; BTG; Eisai; Ipsen; MSD; Tarveda Therapeutics; research funding—Bayer (Inst); BTG (Inst); Ipsen (Inst). GKA-A: grants and personal fees—Bayer, Exelixis, BMS, Eisai, Lilly, Merck; patent: Articles and methods for preventing and treating dermatologic adverse events, identified by International Patent Application No PCT/US2014/031545 filed on 24 March 2014, and priority application serial no: 61/804,907; filed: 25 March 2013 issued. All other authors report no conflicts of interest., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Purpose Cabozantinib, an inhibitor of tyrosine kinases including MET, vascular endothelial growth factor receptors, and AXL, increased progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients with advanced renal cell carcinoma (RCC) after previous vascular endothelial growth factor receptor-targeted therapy in the phase III METEOR trial. Because bone metastases are associated with increased morbidity in patients with RCC, bone-related outcomes were analyzed in METEOR. Patients and Methods Six hundred fifty-eight patients were randomly assigned 1:1 to receive 60 mg cabozantinib or 10 mg everolimus. Prespecified subgroup analyses of PFS, OS, and ORR were conducted in patients grouped by baseline bone metastases status per independent radiology committee (IRC). Additional end points included bone scan response per IRC, skeletal-related events, and changes in bone biomarkers. Results For patients with bone metastases at baseline (cabozantinib [n = 77]; everolimus [n = 65]), median PFS was 7.4 months for cabozantinib versus 2.7 months for everolimus (hazard ratio, 0.33 [95% CI, 0.21 to 0.51]). Median OS was also longer with cabozantinib (20.1 months v 12.1 months; hazard ratio, 0.54 [95% CI, 0.34 to 0.84]), and ORR per IRC was higher (17% v 0%). The rate of skeletal-related events was 23% with cabozantinib and 29% with everolimus, and bone scan response per IRC was 20% versus 10%, respectively. PFS, OS, and ORR were also improved with cabozantinib in patients without bone metastases. Changes in bone biomarkers were greater with cabozantinib than with everolimus. The overall safety profiles of cabozantinib and everolimus in patients with bone metastases were consistent with those observed in patients without bone metastases. Conclusion Cabozantinib treatment was associated with improved PFS, OS, and ORR when compared with everolimus treatment in patients with advanced RCC and bone metastases and represents a good treatment option for these patients.

Purpose: This study evaluated factors impacting QTc interval in a phase 3 trial of cabozantinib in progressive, metastatic, medullary thyroid cancer (MTC)., Methods: Electrocardiogram (12-lead ECG) measurements were obtained at screening, and at pre-dose, and 2, 4, and 6 h post-dose on Days 1 and 29 in a phase 3 study in patients with MTC treated with cabozantinib (140 mg/day). Central tendency analyses were conducted on baseline-corrected QTc values. Linear and nonlinear mixed-effects models were used to evaluate potential factors affecting the QTc interval, including serum electrolytes, patient demographics, and cabozantinib concentration., Results: Central tendency analysis showed that oral cabozantinib (140 mg/day) produced a 10-15 ms increase in delta-delta Fridericia corrected QT (∆∆QTcF) and delta-delta study-specific corrected QT (∆∆QTcS) on Day 29, but not on Day 1. Further analysis showed that QTcS provided a slightly more accurate QT correction than QTcF. Mixed-effects models evaluating serum electrolytes, age, sex, and cabozantinib concentration showed that decreased serum calcium and potassium could explain the majority of cabozantinib treatment-associated QTcS prolongation observed in this study., Conclusions: Cabozantinib treatment prolongs the ∆∆QTcF interval by 10-15 ms. There was the absence of a strong relationship between cabozantinib concentration and QTcS prolongation. Cabozantinib treatment effects on serum calcium and potassium best explain the QTcS prolongation observed in this study.

Objective: To determine the safety and efficacy of filgrastim (r-metHuG-CSF) in combination with intravenous antibiotics to reduce the rate of mortality in patients with pneumonia and sepsis., Design: This study was multicenter, double-blind, and randomized., Setting: Intensive care units PATIENTS Adult patients with bacterial pneumonia, either acquired or nosocomial, as confirmed by chest radiograph and positive culture or Gram-negative stain, and severe sepsis, defined as sepsis-induced hypotension or organ dysfunction., Interventions: Standard antibiotic therapy with or without filgrastim (300 microg/day) or placebo administered as a 30-min intravenous infusion. The study drug was started within 24 hrs of enrollment and was continued for 5 days or until the white blood cell count reached >75.0 x 10(9) cells/L., Measurements and Main Results: The primary end point was the occurrence of mortality through day 29; secondary end points included occurrence of subsequent organ dysfunction, time to discharge from intensive care unit, number of days on mechanical ventilatory support, and time to death. Study-related observations were recorded through day 10 and included vital signs, onset of organ dysfunction, clinical laboratory variables, and adverse events. Filgrastim increased the white blood cell count to a median peak of 31.7 x 10(9) cells/L from a baseline of 12.3 x 10(9) cells/L. The two groups were well matched and did not differ significantly with regard to severe adverse events, time to death, occurrence of end-organ dysfunction, days of intensive care unit hospitalization, or days on mechanical ventilatory support. Mortality was low in both treatment groups; the mortality rate in patients with adult respiratory distress syndrome was similar between the two groups., Conclusions: The addition of filgrastim to the antibiotic and supportive care treatment of patients with pneumonia complicated by severe sepsis appeared to be safe, but not efficacious in reducing mortality rates or complications from this infection.

This study assessed the safety and efficacy of filgrastim (r-metHuG-CSF [recombinant human methionine granulocyte colony-stimulating factor]), when combined with intravenous (IV) antibiotics, in the treatment of hospitalized adult patients with multilobar community-acquired pneumonia (CAP). Four hundred eighty patients were randomized to receive placebo (n=243) or filgrastim 300 microg/day (n=237), in addition to standard therapy. Treatment with study drug was continued for 10 days, until the peak white blood cell (WBC) count reached 75x109/L, until discharge from the hospital, until death, or until IV antibiotics were discontinued. Study-related observations continued through day 29. Filgrastim increased WBC counts (baseline median, 13.3x109/L; median peak, 43. 8x109/L). The 2 treatment groups were not statistically different with respect to the study end points; however, there was a trend toward reduction of mortality in patients with pneumococcal bacteremia. Although further studies will be required to validate this observation, filgrastim was safe and well tolerated when administered to patients with multilobar CAP.

Twenty-four healthy male volunteers received either placebo or 75, 150, or 300 microg filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) for 12 days to study effects on monocytes and lymphocytes. In all filgrastim-treated groups, tumor necrosis factor alpha (TNF-alpha), interleukin-12 (IL-12), and interferon gamma (IFN-gamma) release by whole blood in response to endotoxin (lipopolysaccharide) was reduced. IL-12 added in vitro to lipopolysaccharide-stimulated blood of filgrastim-treated donors restored IFN-gamma and TNF-alpha release, suggesting that the anti-inflammatory effect of granulocyte colony-stimulating factor is exercised through IL-12 suppression. Phytohemagglutinin- or anti-CD3 antibody-induced lymphocyte proliferation ex vivo was reduced by 60% from day 5 to day 15, after a 50% increase at day 2 with concomitant doubled IL-2 release. In vivo, filgrastim induced doubling of all T-cell populations by day 8. Filgrastim decreased proinflammatory cytokine production and lymphocyte proliferation ex vivo throughout prolonged treatment at all doses. This indicates that endogenous granulocyte colony-stimulating factor may counterregulate the inflammatory cytokine cascade and implies a potential indication for filgrastim in chronic inflammatory conditions.