Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

BACKGROUND & AIMS: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. METHODS: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. RESULTS: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. CONCLUSIONS: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. IMPACT AND IMPLICATIONS: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy

A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73–0.86) but not in female (pooled HR 0.85; 95% CI 0.70–1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59–1.04; 1.02, 95% CI 0.80–1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

BACKGROUND & AIMS: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. METHODS: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. RESULTS: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. CONCLUSIONS: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. IMPACT AND IMPLICATIONS: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy

Report from the Annual Conference of the British Society of Echocardiography, November 2016, Queen Elizabeth II Conference Centre, London.

Peer reviewedPublisher PD

Fish assemblage responses to flow seasonality and predictability in a tropical flood pulse system

Hydropower dams are looming in the Mekong Basin, affecting river flows that structure aquatic communities. Here, we quantitatively assessed flow seasonality and predictability in three sites located in three rivers displaying a gradient in flow alterations caused by upstream dams and investigated how fish assemblages responded seasonally and inter-annually to this gradient. By analyzing 7-yr daily fish and water monitoring data, we found that dams disturbed the natural flow seasonality and predictability. While the river displaying the lower seasonality-predictability was characterized by a distinct seasonal variation in assemblage composition with high species turnover, rivers with stronger flow seasonality-predictability exhibited broadly similar seasonal patterns in fish assemblage composition with low species turnover and regular annual peaks of fish migration. These results challenge the expectation of higher species turnover in systems displaying higher flow seasonality and predictability and may be partly due to the strong adaptation of fish assemblages to these specific systems. By enhancing our understanding of biological systems in the highly seasonal-predictable and aseasonal-unpredictable environments of the lower Mekong system, these findings suggest that hydropower-related pulsed flows that can mimic as far as possible natural pulsed flows are critical to reduce downstream effects on aquatic organisms

Long term outcomes of patients receiving Implantable Cardioverter Defibrillators in a contemporary implant population in the Essex region of the UK

Abstract Introduction Implantable cardioverter-defibrillators (ICD) reduce the risk of sudden cardiac death in patients who are at risk and amongst among heart failure (HF) patients with a reduced left ventricular ejection fraction (LVEF). Objective The aim of this study was to determine the differences in outcomes amongst patients in a contemporary ICD implant population based on primary or secondary indications and an ischaemic or non-ischaemic aetiology. The primary outcome was death or appropriate device therapy for a ventricular arrhythmia. The secondary outcome was inappropriate shock therapy. Purpose The study cohort included consecutive patients who had an ICD or CRT-D implanted at a high-volume regional referral centre in Essex between 2014 and 2015. The censor point for follow up was 31/12/2018. Cumulative incidences were analysed by the method of Kaplan–Meier and compared using the log-rank test. In addition, the relationship between several clinical variables were tested in a multivariate Cox model to predict long-term mortality and this is described with hazard ratios (HR) and 95% CI. Results 407 patients who received ICD treatment were followed up for a mean of 50±4 months. 63% had an Ischaemic cardiomyopathy and 60% had a primary prevention indication. Majority were men (81.5%), mean LVEF was (31±11) and mean age (71±11). The incidence of appropriate ICD therapy at 1-year post ICD insertion was 6.8% in all patients. This was significantly higher in patients with a secondary prevention indication compared to primary prevention (11.7% v 3.6% p=0.015) but similar in ischaemic compared to non-ischaemic patients (7.8% v 5.2% p=0.46). 1.9% patients had an inappropriate shock at 1 year and between group rate was similar. Overall 8.1% of patients did not survive beyond 1-year post implant with a mean time to death of 5.6±3.6 months. The cumulative incidence of the primary end-point at 1 year was similar in ischaemic and non-Ischaemic patients (7.8% v 8.6%; HR: 1.04, 95% CI 0.7–1.5, p=0.83) but was significantly higher at the end of study period in patients with an ischaemic aetiology (32.4% v 21%; HR: 1.59, 95% CI: 1.1–2.4, p=0.024) (Fig.1). In an adjusted Cox Hazard model, appropriate ICD therapy at 1 year (HR: 0.28, 95% CI: 0.17–0.47, p<0.001) and a secondary indication for ICD treatment (HR: 0.47, 95% CI: 0.31–0.73, p=0.001) were strongly associated with long-term mortality. Figure 1 Conclusions Our study highlights outcomes in a long-term follow up of ICD patients and in light of the debate around the DANISH trial, we have shown that at 1 year, the benefit of ICD therapy is comparable in non-ischaemic compared to ischaemic cardiomyopathies. Moreover, patients who had an ICD implanted for secondary prevention had a 3-fold mortality benefit at 1 year and had a higher rate of death. Appropriate ICD therapy and a secondary prevention indication predicted long term mortality