The treatment landscape of advanced hepatocellular carcinoma (HCC) has broadened with immune checkpoint inhibitors (ICIs) setting a novel standard of care. With the increased number of therapies ...either in first or in further line, disentangling the possible treatment sequences has become much more complex. Yet, all the second-line therapies have been evaluated after sorafenib. After ICIs, offering multikinase inhibitors is a widespread approach, either shifting forward sorafenib or lenvatinib, or choosing among regorafenib or cabozantinib, already approved in the refractory setting. Under specific circumstances, ICIs could be maintained beyond disease progression in patients with proven clinical benefit, as supported by some data emerging from phase III clinical trials with immunotherapy in HCC. Rechallenge with ICIs is an additional attractive alternative, although requiring careful and individual evaluation as efficacy and safety of such a strategy have not been yet clarified. Still, a considerable number of patients displays primary resistance to ICIs and might benefit from antiangiogenics either alone or in addition to ICIs instead. Hopefully, the ongoing clinical trials will enlighten regarding the most effective treatment pathways. The identification of predictive correlates of response to immunotherapy will help treatment allocation at each stage, thus representing an urgent matter to address in HCC research. With programmed death ligand 1 expression, tumor mutational burden, and microsatellite status being inadequate biomarkers in HCC, patient characteristics, drug safety profile, and regulatory approval remain key elements to acknowledge in routine practice. Despite the tissue remaining a preferred source, biomarkers discovery could take advantage of liquid biopsy to overcome the matter of tissue availability and track tumor changes. Lastly, tumor genetic phenotypes, tumor microenvironment features, gut microbiome, and markers of immune response and systemic inflammation are all potential emergent predictors of response to ICIs, pending validation in the clinical setting.
The therapeutic landscape of advanced hepatocellular carcinoma (HCC) has become notably complex in recent years. With this review, we aimed to put the most recent findings in perspective and tried to ...delineate the rapidly changing treatment algorithm.
The combination of atezolizumab and bevacizumab has become the new first-line standard of care treatment for unresectable HCC after the positive results of the phase 3 IMbrave150 study. Nivolumab monotherapy failed to demonstrate advantage versus sorafenib in the CheckMate 459 trial, while two different therapeutic strategies (sintilimab and bevacizumab biosimilar and donafenib) outperformed sorafenib in two phase 2/3 studies conducted in the Chinese population. Several immunotherapy combinations are currently under study in large phase 3 trials after promising results in earlier phase studies. About further lines of treatment, the combination of ipilimumab and nivolumab was approved for sorafenib-pretreated patients after the positive results of the phase 1/2 CheckMate 040 study and apatinib was proven effective in the Chinese population in a phase 2/3 study, while pembrolizumab as monotherapy did not show statistically significant superiority when compared with placebo in the KEYNOTE-240 study.
Because of the growing complexity of advanced HCC treatment, the implementation of predictive biomarkers of response is eagerly needed.
IMbrave150 has established the superiority of atezolizumab plus bevacizumab over sorafenib in patients with unresectable hepatocellular carcinoma (HCC).
We generated a prospectively maintained ...database including patients treated with atezolizumab plus bevacizumab for unresectable HCC across Europe, Asia and USA. Clinico-pathologic characteristics were assessed for their prognostic influence on overall survival (OS) and progression-free survival (PFS) in univariable and multivariate analyses. Overall response rate by RECIST v1.1 and treatment-related adverse events (TRAEs) per CTCAE v.5.0 were reported.
Out of 433 patients, 296 Child-Pugh A and ECOG performance status01 patients received atezolizumab plus bevacizumab in first line and were included. Patients were mostly male (82.7%), cirrhotic (75%) with history of viral hepatitis (65.9%). Overall, 68.9% had Barcelona Clinic Liver Cancer C-stage HCC with portal vein tumour thrombosis (PVTT, 35%) and extrahepatic spread (EHS, 51.7%). After a median follow-up of 10.0 months (95% confidence interval (CI): 9.4–10.4), median OS and PFS were 15.7 (95% CI: 14.5-NE) and 6.9 months (95% CI: 6.1–8.3), respectively. In the response-evaluable patients (n = 273), overall response rate was 30.8%. Overall, 221 patients (74.6%) developed TRAEs, with 70 (23.6%) reporting grade 3 or higher TRAEs; 25 (8.4%) patients had bleeding events. OS was independently associated with baseline Albumin-bilirubin (ALBI) grade and PVTT. Shorter PFS was associated with AFP≥ 400 ng/ml, worse ALBI and presence of EHS.
This global observational study confirms the reproducible safety and efficacy of atezolizumab plus bevacizumab in routine clinical practice. Within Child-Pugh-A criteria, the presence of PVTT and higher ALBI grade identify patients with poorer survival.
•Atezolizumab plus bevacizumab (A + B) is the standard of care for patients with unresectable hepatocellular carcinoma.•We report data from a large cohort of patients treated with A + B in real-life.•Effectiveness and safety of the combination is reproducible in daily practice.•Liver function and macro-vascular invasion is with overall survival.•Radiological response predicts better outcomes.
The coronavirus pandemic that has brought Italy (like many other countries) to its knees brings to the surface in a brutal way the criticality of the health policy choices taken by the government in ...the last thirty years, guided by the principle of subordination of the quality of care to cost efficiency. The priority has been to maximize profit by sacrificing the quality of care and health services. All this forces us to redefine the terms and categories with which we read and interpret today the issues related to the physical and mental health of citizens and the policies that govern it. Starting from this, the aim of this article is to reflect on the limits of contemporary health policies and the urgency of rethinking them in terms of a greater capacity to reconcile people’s needs with a better use of public resources. To this end, the article will focus on bottom-up health policy practices that try to guarantee, at the same time, the quality of care and a better use of health spending, through the analysis of the experience of the Solaris association in Rome working in the field of mental health.
Background and Aims
Combination atezolizumab/bevacizumab is the gold standard for first‐line treatment of unresectable hepatocellular carcinoma (HCC). Our study investigated the efficacy and safety ...of combination therapy in older patients with HCC.
Methods
191 consecutive patients from eight centres receiving atezolizumab and bevacizumab were included. Overall survival (OS), progression‐free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in older (age ≥ 65 years) and younger (age < 65 years) age patients. Treatment‐related adverse events (trAEs) were evaluated.
Results
The elderly (n = 116) had higher rates of non‐alcoholic fatty liver disease (19.8% vs. 2.7%; p < .001), presenting with smaller tumours (6.2 cm vs 7.9 cm, p = .02) with less portal vein thrombosis (31.9 vs. 54.7%, p = .002), with fewer patients presenting with BCLC‐C stage disease (50.9 vs. 74.3%, p = .002). There was no significant difference in OS (median 14.9 vs. 15.1 months; HR 1.15, 95% CI 0.65–2.02 p = .63) and PFS (median 7.1 vs. 5.5 months; HR 1.11, 95% CI 0.54–1.92; p = .72) between older age and younger age. Older patients had similar ORR (27.6% vs. 20.0%; p = .27) and DCR (77.5% vs. 66.1%; p = .11) compared to younger patients. Atezolizumab‐related (40.5% vs. 48.0%; p = .31) and bevacizumab‐related (44.8% vs. 41.3%; p = .63) trAEs were comparable between groups. Rates of grade ≥3 trAEs and toxicity‐related treatment discontinuation were similar between older and younger age patients. Patients 75 years and older had similar survival and safety outcomes compared to younger patients.
Conclusions
Atezolizumab and bevacizumab therapy is associated with comparable efficacy and tolerability in older age patients with unresectable HCC.
Systemic inflammation is a key risk factor for hepatocellular carcinoma (HCC) progression and poor outcomes. Inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) and ...platelet-to-lymphocyte ratio (PLR) may have prognostic value in HCC treated with standard of care atezolizumab plus bevacizumab (Atezo-Bev). We conducted a multicenter, international retrospective cohort study of patients with unresectable HCC treated with Atezo-Bev to assess the association of NLR and PLR with overall survival (OS), progression-free survival (PFS), and objective response rates. Patients with NLR ≥ 5 had a significantly shorter OS (9.38 vs. 16.79 months, p < 0.001) and PFS (4.90 vs. 7.58 months, p = 0.03) compared to patients with NLR < 5. NLR ≥ 5 was an independent prognosticator of worse OS (HR 2.01, 95% CI 1.22−3.56, p = 0.007) but not PFS. PLR ≥ 300 was also significantly associated with decreased OS (9.38 vs. 15.72 months, p = 0.007) and PFS (3.45 vs. 7.11 months, p = 0.04) compared to PLR < 300, but it was not an independent prognosticator of OS or PFS. NLR and PLR were not associated with objective response or disease control rates. NLR ≥ 5 independently prognosticated worse survival outcomes and is worthy of further study and validation.
Background
Atezolizumab plus bevacizumab (Atezo/Bev) is first line-treatment for unresectable hepatocellular carcinoma (HCC). Body mass index (BMI) has demonstrated predictive value for response to ...immunotherapy in non-HCC cancer types. Our study investigated the effect of BMI on safety and efficacy of real-life use of Atezo/Bev for unresectable HCC.
Methods
191 consecutive patients from seven centres receiving Atezo/Bev were included in the retrospective study. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in overweight (BMI ≥ 25) and non-overweight (BMI < 25) patients. Treatment-related adverse events (trAEs) were evaluated.
Results
Patients in the overweight cohort (
n
= 94) had higher rates of non-alcoholic fatty liver disease (NAFLD) and lower rates of Hepatitis B compared to non-overweight cohort (
n
= 97). Baseline Child–Pugh class and Barcelona Clinic Liver Cancer stage were similar between cohorts, with lower rates of extrahepatic spread in the overweight group. Overweight patients had similar OS compared to non-overweight (median OS 15.1 vs. 14.9 months;
p
= 0.99). BMI did not influence median PFS (7.1 vs. 6.1 months;
p
= 0.42), ORR (27.2% vs. 22.0%;
p
= 0.44) and DCR (74.1% vs. 71.9%;
p
= 0.46). There were higher rates of atezolizumab-related fatigue (22.3% vs. 10.3%;
p
= 0.02) and bevacizumab-related thrombosis (8.5% vs. 2.1%;
p
= 0.045) in the overweight patients, but overall trAEs and treatment discontinuation were comparable between cohorts.
Conclusion
Atezo/Bev has comparable efficacy in overweight HCC patients, with an increase in treatment-related fatigue and thrombosis. Combination therapy is safe and efficacious to use in overweight patients, including those with underlying NAFLD.
Biliary tract cancers (BTCs) are aggressive tumors arising from different portions of the biliary tree and classified according to the anatomical location in intrahepatic (i) cholangiocarcinoma (CCA, ...iCCA), perihilar CCA (pCCA), and distal CCA (dCCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). Due to their silent behavior, BTCs are frequently diagnosed at advanced stages when the prognosis is poor. The available chemotherapeutic options are palliative and unfortunately, most patients will die from their disease between 6 and 18 months from diagnosis. However, over the last decade, amounting interest has been posed on the genomic landscape of BTCs and deep-sequencing studies have identified different potentially actionable driver mutations. Hence, the promising results of the early phase clinical studies with targeted agents against isocitrate dehydrogenase (IDH) 1 mutation or fibroblast growth factor (FGF) receptor(FGFR) 2 aberrations inintrahepatic tumors, and other agents against humanepidermal growth factor receptor (HER) 2 overexpression/mutations, neurotrophic tyrosine receptor kinase (NTRK) fusions or B-type Raf kinase (BRAF) mutations across different subtypes of BTCs, have paved the way for a “precision medicine” strategy for BTCs. Moreover, despite the modest results when used as monotherapy, beyond microsatellite instability-high (MSI-H) tumors, immune checkpoint inhibitors are being evaluated in combination with platinum-based chemotherapy, possibly further expanding the therapeutic landscape of advanced BTCs. This review aims to provide an overview of the approved systemic therapies, the promising results, and the ongoing studies to explore the current and future directions of advanced BTC systemic treatment.
Current guidelines recommend pre-therapeutic
genotyping to guide irinotecan dosing, but the usefulness of this approach remains to be clarified. In 247 patients with advanced gastrointestinal cancers ...undergoing irinotecan-based chemotherapy, we prospectively performed
genotyping and we analyzed the incidence of severe neutropenia according to genotype-guided dose reductions. Overall, 28 (11.3%) and 92 (37.2%) patients were homozygous or heterozygous
carriers, respectively. Grade ≥ 3 neutropenia was reported in 39% of homozygous patients receiving an upfront dose reduction of irinotecan (median 40%, range 22-58%), in 20% of heterozygous or wild-type patients receiving full dose (OR
= 0.38; 95% CI: 0.14-1.03;
= 0.058), and in 15.3% of those receiving a reduced dose for clinical reasons (OR
= 0.28, 95% IC: 0.12-0.67;
= 0.004). Occurrence of severe neutropenia was inversely associated with dose reduction in
homozygous carriers (OR
= 0.62, 95% CI: 0.27-1.40,
= 0.249) and
heterozygous or wild-type patients (OR
= 0.87, 95% CI: 0.59-1.28,
= 0.478). Incidence of severe neutropenia was related to irinotecan doses and
polymorphisms. Upfront irinotecan dose reductions do not reduce the burden of grade ≥ 3 neutropenia in
homozygous carriers.
4065 Background: Perioperative chemotherapy (ChT) is a standard for operable gastroesophageal adenocarcinoma (GEA). The addition of immune checkpoint inhibitors (ICIs) has improved pathological ...complete response (pCR) with unclear survival advantages in an unselected population. In the advanced setting, PD-L1 is a validated biomarker of response to ICIs. We aimed to assess its predictive role in the early stages wherein remains unexplored. Methods: We conducted a systematic review of randomised clinical trials (RCTs) of neoadjuvant or peri-operative ChT +/- ICIs in non-metastatic GEA, published between 2006-2024. Biomarker-unselected phase 2/3 or phase 3 RCTs with an active comparator were selected. Odds ratios (ORs) for pathological response (defined as pCR, ypT0, or ypT≤1), the primary outcome of this meta-analysis, were extracted and analysed using a random-effect meta-analysis. Subgroup analysis (ICI-ChT versus ChT) was performed to estimate the pooled effect of peri-operative ICIs on pathological response. Sensitivity analyses were performed to account for between-study heterogeneity. We then extracted pCR data by PD-L1 (cutoffs 1, 5, 10) from phase 2 trials of neoadjuvant ICIs+ChT or chemoradiotherapy (CRT) published between 2006-2024. Weighted Pearson trial-level correlation and a meta-regression model were used to assess the relationship of PD-L1 with pCR. Results: Nine RCTs were eligible for the analysis, one of which had two experimental arms contributing to two comparisons. Of 5359 included patients, 1302 received ICI-ChT and 4057 systemic ChT. ICI-ChT showed a significant improvement in pathological response (pooled OR 2.90, 95% CI 1.81-4.63, p<0.001) with a larger effect compared to ChT-only trials (pooled OR 1.40, 95% CI 1.10-1.79, p=0.007). Results were consistent in sensitivity analyses of pCR-only, non-Asian, and since-FLOT studies. Fourteen studies were included in the phase 2 trials dataset (n=10 ICI+ChT and n=4 ICI+CRT) accounting for 708 patients receiving ICIs. PD-L1 showed a moderate positive correlation with pCR, stronger for higher cut-offs (weighted R for cut-offs 1, 5, and 10: 0.33, 0.51, and 0.65, respectively) and after exclusion of CRT trials (weighted R for cut-offs 5 and 10: 0.67 and 0.99, respectively). In a mixed-effect meta-regression model, PD-L1 ≥5 was a significant predictor of response (effect size ES: 0.71, 95% CI, 0.29-1.13, p=0.001), even after accounting for the backbone treatment (ChT versus CRT) (ES: 0.60, 95% CI, 0.20-1.00, p=0.003). Conclusions: Neoadjuvant ICI-ChT consistently improves pathological response in operable GEA, particularly in PD-L1-positive tumours. PD-L1 ≥5 appears a significant biomarker of pCR in non-metastatic GEA, supporting stratification by PD-L1 and biomarker-selected trials for evaluation at the individual patient level.
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