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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.

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

The results of the phase III ClarIDHy trial have led to US FDA approval of ivosidenib as a therapeutic option for patients with locally advanced or metastatic cholangiocarcinoma (CCA) harboring isocitrate dehydrogenase 1 (IDH1) mutations.In this study, we report the first real-world experience including eight patients with previously treated locally advanced or metastatic IDH1-mutated CCA treated with ivosidenib.Patients treated with ivosidenib as second and third line for advanced CCA were collected with the aim of evaluating the survival outcomes. A molecular study has been performed by next-generation sequencing assay.After a median follow up of 9.4 months, median progression-free survival (PFS) from the start of treatment with ivosidenib was 4.4 months (95% confidence interval [CI] 3.3-5.8), whereas median overall survival (OS) was not reached. The disease control rate was 62.5%, with two patients achieving a partial response (25%); 12.5% of patients experienced a treatment-related adverse event (AE), but no grade 3 or higher AEs were reported. The observed grade 2 AEs were prolonged QT interval and hypomagnesemia (25% of the sample). Molecular profiling was performed on six of eight patients, highlighting TP53, BAP1, CDKN2A and CDKN2B as the most common co-altered genes in these patients.Efficacy outcomes were consistent with those reported in the ClarIDHy trial. Real-world experiences on larger samples are needed in order to confirm our results.

Supplementary Figure from Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients

The majority of metastatic colorectal cancers (mCRC) are mismatch repair (MMR) proficient and unresponsive to immunotherapy, whereas MMR-deficient (MMRd) tumors often respond to immune-checkpoint blockade. We previously reported that the treatment of colorectal cancer preclinical models with temozolomide (TMZ) leads to MMR deficiency, increased tumor mutational burden (TMB), and sensitization to immunotherapy. To clinically translate these findings, we designed the ARETHUSA clinical trial whereby O6-methylguanine-DNA-methyltransferase (MGMT)–deficient, MMR-proficient, RAS-mutant mCRC patients received priming therapy with TMZ. Analysis of tissue biopsies and circulating tumor DNA (ctDNA) revealed the emergence of a distinct mutational signature and increased TMB after TMZ treatment. Multiple alterations in the nucleotide context favored by the TMZ signature emerged in MMR genes, and the p.T1219I MSH6 variant was detected in ctDNA and tissue of 94% (16/17) of the cases. A subset of patients whose tumors displayed the MSH6 mutation, the TMZ mutational signature, and increased TMB achieved disease stabilization upon pembrolizumab treatment. Significance: MMR-proficient mCRCs are unresponsive to immunotherapy. We provide the proof of concept that inactivation of MMR genes can be achieved pharmacologically with TMZ and molecularly monitored in the tissue and blood of patients with mCRC. This strategy deserves additional evaluation in mCRC patients whose tumors are no longer responsive to standard-of-care treatments. See related commentary by Willis and Overman, p. 1612. This article is highlighted in the In This Issue feature, p. 1599

Atezolizumab plus bevacizumab (AtezoBev) is the standard of care for first-line treatment of unresectable HCC. No evidence exists as to its use in routine clinical practice in patients with impaired liver function.In 216 patients with HCC who were consecutively treated with AtezoBev across 11 tertiary centers, we retrospectively evaluated treatment-related adverse events (trAEs) graded (G) according to Common Terminology Criteria for Adverse Events v5.0, including in the analysis all patients treated according to label (n = 202, 94%). We also assessed overall survival (OS), progression-free survival (PFS), overall response (ORR), and disease control rates (DCR) defined by Response Evaluation Criteria in Solid Tumors v1.1. Disease was mostly secondary to viral hepatitis, namely hepatitis C (n = 72; 36%) and hepatitis B infection (n = 35, 17%). Liver function was graded as Child-Pugh (CP)-A in 154 patients (76%) and CP-B in 48 (24%). Any grade trAEs were reported by 143 patients (71%), of which 53 (26%) were G3 and 3 (2%) G4. Compared with CP-A, patients with CP-B showed comparable rates of trAEs. Presence and grade of varices at pretreatment esophagogastroduodenoscopy did not correlate with bleeding events. After a median follow-up of 9.0 months (95% CI, 7.8-10.1), median OS was 14.9 months (95% CI, 13.6-16.3), whereas median PFS was 6.8 months (95% CI, 5.2-8.5). ORR and DCR were respectively 25% and 73%, with no difference across CP classes.This study confirms reproducible safety and efficacy of AtezoBev in routine practice. Patients with CP-B reported similar tolerability compared with CP-A, warranting prospective evaluation of AtezoBev in this treatment-deprived population.

Supplementary Tables S1-S4 from Clinical Usefulness of EGFR Gene Copy Number as a Predictive Marker in Colorectal Cancer Patients Treated with Cetuximab: A Fluorescent In situ Hybridization Study

Purpose: To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. The value of testing KRAS mutation status, in addition to EGFR GCN, was also explored.Experimental Design: FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done, recording individual GCN per cell and using different samples per tumor. Performances of published cutoff points and different summaries of EGFR GCN distribution were assessed for response prediction.Results: In our data set, two published cutoff points performed less well than in their training set, yielding positive predictive values and negative predictive values between 40.0% and 48.3% and between 81.0% and 86.5%, respectively. Among summaries of GCN distribution explored, mean and right-tailed distribution of GCN yielded the highest performances. A mean EGFR GCN ≥2.83 provided an area under the curve of 0.71. Important heterogeneity of repeated measures of mean EGFR GCN was observed within tumors (intraclass correlation, 0.61; within-class SD, 0.40), leading to potential misclassifications of FISH status in 7 of 18 (38.8%) patients if a cutoff point were used. In multivariable analysis, EGFR GCN testing provided significant information independent of the KRAS status to predict response (P = 0.016) and overall survival (P = 0.005).Conclusions: We confirm the association between increased EGFR GCN and outcome after cetuximab. However, because of reproducibility concerns, any decision making based on published cutoff points is not warranted.

Combining multikinase inhibitors (MKIs) with immune checkpoint inhibitors (ICIs) in advanced hepatocellular carcinoma (HCC) has a strong biological rationale. Among MKIs, cabozantinib seems an ideal partner for ICIs, playing a potentially synergistic role via a spectrum of immunomodulatory actions.This paper discusses the preclinical rationale for combining cabozantinib and atezolizumab in advanced HCC. It examines the mechanism of action of these agents and highlights their synergistic activitiesThe eventual approval of novel combinations for advanced HCC will require careful patient selection and a refinement of study design for future trials. Regarding the search for predictive biomarkers, etiology and extent of disease may predict response to therapy. Moving cabozantinib to first-line, treatment sequencing should consider possible cross-resistance not only to ICIs but also to other MKIs. Finally, the response rates of such combinations may pave the way for their evaluation as peri-operative therapies.

Background and Rationale: Immune checkpoint inhibitor (ICI) therapy is an expanding therapeutic option for hepatocellular carcinoma (HCC). Antibiotics (ATB) taken prior to or early during ICI therapy can impact immunotherapy efficacy across indications; however, the effect of ATB is undefined in HCC. Methods: In a large international cohort of 450 ICI recipients from Europe, North America, and Asia, we categorized patients according to timing of ATB focusing on exposure within −30 to +30 days from ICI (early immunotherapy period [EIOP]). EIOP was evaluated in association with overall survival (OS), progression-free survival (PFS), and best radiologic response using RECIST 1.1 criteria. Results: Our study comprised mostly cirrhotic (329, 73.3%) males (355, 79.1%) with a Child-Turcotte Pugh class of A (332, 73.9%), receiving ICI after 1 therapy line (251, 55.9%) for HCC of Barcelona clinic liver cancer stage C (325, 72.4%). EIOP (n = 170, 37.9%) was independent of baseline clinicopathologic features of HCC and correlated with longer PFS (6.1 vs. 3.7 months, log-rank p = 0.0135). EIOP+ patients had similar OS, overall response, and disease control rates (DCRs) compared to EIOP. The effect of EIOP persisted in landmark time analyses and in multivariable models, confirming the independent predictive role of EIOP in influencing PFS following adjustment for covariates reflective of tumor burden, liver function, and ICI regimen administered. In patients receiving programmed cell death-1 receptor/ligand inhibitors monotherapy, EIOP was also associated with higher DCRs (61.4% vs. 50.9%, p = 0.0494). Conclusions: Unlike other oncological indications, ATB in the 30 days before or after ICI initiation is associated with improved benefit from immunotherapy, independent of disease and treatment-related features. Evaluation of the immune microbiologic determinants of response to ICI in HCC warrants further investigation.

Different approaches are available after progression of disease (PD) to immune checkpoint inhibitors (ICI) for hepatocellular carcinoma (HCC), including continuation of ICI, treatment switching to tyrosine kinase inhibitors (TKIs) and cessation of anticancer therapy. We sought to characterise the relationship between radiologic patterns of progression and survival post-ICI, also appraising treatment strategies.We screened 604 HCC patients treated with ICIs, including only those who experienced PD by data cut-off. We evaluated post-progression survival (PPS) according to treatment strategy at PD and verified its relationship with radiologic patterns of progression: intrahepatic growth (IHG), new intrahepatic lesion (NIH), extrahepatic growth (EHG), new extrahepatic lesion (NEH) and new vascular invasion (nVI).Of 604 patients, 364 (60.3%) experienced PD during observation. Median PPS was 5.3 months (95%CI: 4.4-6.9; 271 events). At data cut-off, 165 patients (45%) received no post-progression anticancer therapy; 64 patients (17.6%) continued ICI beyond PD. IHG (HR 1.64 [95%CI:1.21-2.22]; p=0.0013) and nVI (HR 2.15 [95%CI:1.38-3.35]; p=0.0007) were associated with shorter PPS. Multivariate models adjusted for progression patterns, treatment line, and ALBI grade and ECOG-PS at PD confirmed receipt of ICI beyond PD with (HR 0.17, 95%CI 0.09-0.32; p0.0001), or without subsequent TKI (HR 0.39, 95%CI 0.26-0.58; p0.0001) as predictors of prolonged PPS versus no anticancer therapy.ICI-TKI sequencing is a consolidated option in advanced HCC. nVI and IHG predict poorer prognosis. Despite lack of recommendation, continuation of ICI beyond progression in HCC is adopted clinically: future efforts should appraise which patients benefit from this approach.

Simple Summary The investigation of predictive and prognostic markers is pivotal in patients affected by hepatocellular carcinoma treated with immune-checkpoint-inhibitors. Inflammation has a central role in hepatocellular carcinoma development and progression; however, its role in influencing outcomes in the context of immunotherapy has not been fully elucidated yet. In the following study, we investigated the prognostic role of bloods derived inflammatory markers and we found that they predict survival and response of patients treated with immunotherapy for advanced hepatocellular carcinoma. Abstract Systemic inflammation is a hallmark of cancer, and it has a pivotal role in hepatocellular carcinoma (HCC) development and progression. We conducted a retrospective study including 362 patients receiving immune check-point inhibitors (ICIs) across three continents, evaluating the influence of neutrophiles to lymphocytes ratio (NLR), platelets to lymphocytes ratio (PLR), and prognostic nutritional index (PNI) on overall (OS), progression free survival (PFS), and radiologic responses. In our 362 patients treated with immunotherapy, median OS and PFS were 9 and 3.5 months, respectively. Amongst tested inflammatory biomarkers, patients with NLR ≥ 5 had shorter OS (7.7 vs. 17.6 months, p < 0.0001), PFS (2.1 vs. 3.8 months, p = 0.025), and lower objective response rate (ORR) (12% vs. 22%, p = 0.034); similarly, patients with PLR ≥ 300 reported shorter OS (6.4 vs. 16.5 months, p < 0.0001) and PFS (1.8 vs. 3.7 months, p = 0.0006). NLR emerged as independent prognostic factors for OS in univariate and multivariate analysis (HR 1.95, 95%CI 1.45–2.64, p < 0.001; HR 1.73, 95%CI 1.23–2.42, p = 0.002) and PLR remained an independent prognostic factor for both OS and PFS in multivariate analysis (HR 1.60, 95%CI 1.6–2.40, p = 0.020; HR 1.99, 95%CI 1.11–3.49, p = 0.021). Systemic inflammation measured by NLR and PLR is an independent negative prognostic factor in HCC patients undergoing ICI therapy. Further studies are required to understand the biological mechanisms underlying this association and to investigate the predictive significance of circulating inflammatory biomarkers in HCC patients treated with ICIs.

The incidence rate of hepatocellular carcinoma is growing and age at diagnosis is increasing; however, despite the unprecedented wealth of therapeutic options for advanced HCC, its optimal management in some categories, such as older adults, is yet to be defined. Even though age is not an exclusion criterion per se, most of the landmark trials enrolled a limited number of senior patients, raising some concerns on the potential benefit of active treatments in this group. The identification of more vulnerable patients remains a crucial issue in clinical practice. In fact, the suitability assessment for systemic therapy through performance status metrics might underestimate or conversely overestimate the fitness of older patients, failing to detect other relevant impairments. Thus, the assessment of frailty through geriatric screening scales is largely necessary. In addition, most of the available data relate to the use of sorafenib, while very little is known about the most recent therapeutic agents. Age subgroup analyses provided by many of the pivotal trials did not find significant efficacy or safety differences across ages; however, the most widely used cut-off age of 65 years may not be very informative for the current older population. Regarding immunotherapy, the clinical benefit reported with immune checkpoint inhibitors reassures their safe use in senior patients and supports further investigations to assess their efficacy in this population.

The international PRECONNECT Phase IIIb study demonstrated safety and efficacy of trifluridine/tipiracil in the management of patients with metastatic colorectal cancer. Post-hoc analyses in a national context are important because of the differences in disease management across countries. Post-hoc safety and efficacy analyses in the PRECONNECT Italian patient subset were conducted. Patients' quality of life was assessed from baseline to end of treatment. In Italy, 161 patients were enrolled. The median age was 64 years, with a performance status of 0–1. The most common hematological drug-related adverse events ≥grade 3 were neutropenia (41.0%) and anemia (13.7%). The median progression-free survival was reached at 3.0 months, with a disease control rate of 28.6%. The Quality of Life Questionnaire Core 30 score improved in 25.4% of the patients. Safety, efficacy and quality of life results confirmed trifluridine/tipiracil as a feasible and favorable treatment option for metastatic colorectal cancer patients.

Summary Recent years have seen significant progress in the systemic treatment of hepatocellular carcinoma (HCC), including the advent of immunotherapy. While several large phase III trials have provided the evidence for a multi-line treatment paradigm, they have focused on a highly selected group of patients by excluding potentially confounding comorbidities. As a result, high quality evidence for the systemic treatment of HCC in patients with various comorbidities is missing. This review summarises current knowledge on the use of approved medicines in patients with HIV, autoimmune disease, cardiovascular disease, diabetes, fibrolamellar HCC, mixed HCC-cholangiocarcinoma, decompensated cirrhosis (Child-Pugh B and C), a significant bleeding history, vascular invasion or portal vein thrombosis, as well as the elderly, those on haemodialysis, and those after solid organ transplantation. The article highlights relevant knowledge gaps and current clinical challenges. To improve the safety and efficacy of HCC treatment in these subgroups, future trials should be designed to specifically include patients with comorbidities.

Advanced hepatocellular carcinoma (HCC) management has become more complex as novel therapies have been proven effective. After sorafenib, the approval of other multikinase inhibitors (MKIs) and immune checkpoints inhibitors (ICIs) has considerably increased the number of systemic therapies available. Therefore, careful assessment and monitoring of response to systemic treatment are essential to identify surrogate endpoints of overall survival (OS) in clinical trials and reliable tools to gauge treatment benefit in clinical practice. Progression-free survival (PFS) and objective response rate (ORR) are early informative parameters of efficacy that are not influenced by further lines of therapy. However, none of them has shown sufficient surrogacy to be recommended in place of OS in phase 3 trials. With such a wealth of therapeutic options, the prime intent of tumor assessments is no longer limited to identifying progressive disease to spare ineffective treatments to non-responders. Indeed, the early detection of responders could also help tailor treatment sequencing. Tumor assessment relies on the Response Evaluation Criteria for Solid Tumors (RECIST), which are easy to interpret - being based on dimensional principles - but could misread the activity of targeted agents. The HCC-specific modified RECIST (mRECIST), considering both the MKI-induced biological modifications and some of the cirrhosis-induced liver changes, better capture tumor response. Yet, mRECIST could not be considered a standard in advanced HCC. Further prognosticators including progression patterns, baseline and on-treatment liver function deterioration, and baseline alpha-fetoprotein (AFP) levels and AFP response have been extensively evaluated for MKIs. However, limited information is available for patients receiving ICIs and regarding their predictive role. Finally, there is increasing interest in incorporating novel imaging techniques which go beyond sizes and novel serum biomarkers in the advanced HCC framework. Hopefully, multiparametric models grouping dimensional and functional radiological parameters with biochemical markers will most precisely reflect treatment response.

The systemic treatment of advanced hepatocellular carcinoma (HCC) has significantly changed over the last years, with the introduction of two new standard-of-care first-line treatments (lenvatinib and the combination of atezolizumab and bevacizumab) and the success of several new agents in second line. In particular, after the approval of regorafenib, ramucirumab and cabozantinib, the landscape of second-line treatment has become notably complex, providing a serious challenge in clinical practice. In this review, we focus on cabozantinib, a multikinase inhibitor which was proven effective in improving overall and progression-free survival of patients previously treated with sorafenib in the randomized Phase III CELESTIAL trial. CELESTIAL is the only phase III study to have included patients in the third-line setting and cabozantinib efficacy was confirmed in several post hoc analyses, irrespective of alpha-fetoprotein levels, albumin-bilirubin score, age, and duration of previous sorafenib treatment. The safety profile of cabozantinib in the CELESTIAL trial was comparable with other multikinase inhibitors used for HCC and the most frequent grade ≥3 adverse events were diarrhea, palmar-plantar erythrodysesthesia, fatigue, hypertension, and aspartate aminotransferase increase. Tolerability did not differ between younger and older patients and quality of life was significantly improved compared to placebo during the treatment. In this review, we also make a particular mention to the use of cabozantinib in populations which are normally excluded from clinical trials, such as older patients and Child-Pugh B patients. Finally, we present the new treatment strategies in which cabozantinib is being tested, most notably the combination of cabozantinib and atezolizumab in the first-line setting in the phase III COSMIC-312 trial and the use of cabozantinib after progression on immune-checkpoint inhibitors.

To prevent damage from an immune response against autoantigens and toxins originating from the gut, the liver promotes an immune-tolerant milieu providing fertile ground for immune escape of cancer cells. Therefore, the use and evaluation of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) is a treatment rationale.In this article, we discuss the role of the dual ICIs blockade in advanced HCC, covering the biological basis for their combination, their mechanism of action, and the results of the early-phase studies testing nivolumab plus ipilimumab and durvalumab plus tremelimumab. Furthermore, we provide the results of the phase III HIMALAYA trial and an overview of the ongoing trials investigating the dual ICIs in different disease stages.The potential approval of the dual ICIs blockade strategies for advanced HCC will set the entry of antiangiogenic-free options, expanding the proportion of patients eligible for a first-line treatment. However, it will pose a series of clinical challenges with a sizable proportion of patients, namely Child-Pugh B, elderly, and immunocompromised patients, still marginalized. Also, given the rate of disease progression, identifying reliable predictive biomarkers is crucial to inform treatment choice and sequences. Finally, the compelling response rate of such combinations is paving the way for their evaluation in earlier stages.

Sorafenib is a multikinase inhibitor used to treat advanced hepatocellular carcinoma (HCC). Recently, a preclinical trial has shown that response to sorafenib is associated with a metabolic shift towards aerobic glycolysis. To test this observation in humans, we decided to conduct a proof-of-concept trial investigating the role of metabolic shift detected on [18F]FDG PET/CT in predicting survival and tumor response in HCC patients treated with sorafenib. We prospectively enrolled advanced HCC patients candidate to sorafenib and undergoing [18F]FDG PET/CT at baseline, at 24 h, and at day 7 following treatment start. Response evaluation was obtained after 8 weeks according to Response Evaluation Criteria in Solid Tumors (RECIST). All clinical variables and metabolic parameters (i.e., SUVmax; metabolic tumor volume, MTV; total lesion glycolysis, TLG; and their variations, Δ) were compared with those of treatment response and correlated to progression-free (PFS) and overall survival (OS). For this proof-of-concept trial, between August 2016 and August 2018, 13 patients (10 male, 3 female, median age 69) were enrolled. Considering the entire cohort, we demonstrated a significant negative correlation between ΔSUVmax at 24 h and 1 week (rho = − 0.733, p = 0.016). The metabolic shift, as expected, demonstrated median SUVmax, MTV, and TLG after 1 week lower in patients with a stable disease than a progressive disease (p = 0.019). Metabolic parameters and ECOG performance status (PS) resulted significantly correlated to PFS and OS at univariate analysis. On multivariate analysis, only median MTV at 1 week resulted as an independent prognostic factor for PFS (p = 0.033). As hypothesized, [18F]FDG PET/CT resulted in able to evaluate metabolic shift at 24 h and early treatment response already 1 week after treatment start. Moreover, metabolic parameters and ECOG PS resulted in predictive and prognostic factors to PFS and OS, with MTV at 1 week appearing as an independent predictive factor for PFS.

Aim: Regorafenib may be active in different cancer types. This Phase II trial included patients with various refractory cancer types treated with regorafenib. Here, we report the results of the pancreatic adenocarcinoma cohort. Methods: The primary end point was progression-free survival (PFS) rate at 8 weeks; further investigation of regorafenib would be warranted with a PFS rate ≥50%. Results: A total of 20 patients were enrolled. The best response was stable disease in four patients (20%). The 8-week PFS rate was 25% with a median PFS of 1.7 months (95% CI: 1.5–2.0). A total of 13 patients (65%) experienced grade 3–4 treatment-related adverse events. Conclusion: The study did not meet its primary end point. Further investigation of regorafenib monotherapy in this setting is not recommended. Clinical Trial Registration: NCT02307500

Over the past ten years, sorafenib, a multikinase inhibitor, has been the standard of care for patients with unresectable hepatocellular carcinoma (HCC) and well-preserved liver function. Recently, lenvatinib, a different multikinase inhibitor, was shown to be non-inferior to sorafenib, in terms of survival, while all other agents previously tested failed to prove non-inferiority (or superiority) when compared to sorafenib. Similarly, in the second-line setting, most investigational drugs failed to provide better survival outcomes than placebo. However, in the last 2 years three positive phase III trials have been published in this setting. The RESORCE trial, a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib, showed better outcomes with regorafenib compared to placebo. More recently, the phase III CELESTIAL trial demonstrated the superiority of cabozantinib, a multikinase inhibitor targeting vascular endothelial growth factor receptor, MET, and AXL, vs placebo in the second- and third-line setting in patients progressing on or intolerant to sorafenib. The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels. Overall, the adverse events reported in these trials were in line with the known safety profiles of the tested agents. After nearly a decade of a certain degree of stagnation, we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.

Current guidelines recommend pre-therapeutic

The availability of immune checkpoint inhibitors (ICIs) for the management of advanced hepatocellular cancer (HCC) has changed the treatment paradigm. There are emerging questions regarding the efficacy of subsequent anticancer therapies. The primary aim of this retrospective, multicenter study was to examine the types of anticancer treatment received after ICIs and to assess the impact on post-ICI survival. We established an international consortium of 11 tertiary-care referral centers located in the USA (n = 249), Europe (n = 74), and Asia (n = 97), and described patterns of care following ICI therapy. The impact of subsequent therapy on overall survival (OS) was estimated using the Kaplan–Meier method and presented with a 95% confidence interval (CI). A total of 420 patients were treated with ICIs for advanced HCC after one line of systemic therapy (n = 371, 88.8%): 31 (8.8%) had died, 152 (36.2%) received best supportive care (BSC) following ICIs, and 163 patients (38.8%) received subsequent anticancer therapy. Tyrosine kinase inhibitors (TKIs, n = 132, 80.9%), in particular sorafenib (n = 49, 30.0%), were the most common post-ICI therapy followed by external beam radiotherapy (n = 28, 17.2%), further immunotherapy (n = 21, 12.9%), locoregional therapy (n = 23, 14.1%), chemotherapy (n = 9, 5.5%), and surgery (n = 6, 3.6%). Receipt of post-ICI therapy was associated with longer median OS compared with those who had received BSC (12.1 vs. 3.3 months; hazard ratio [HR]: 0.4 (95% CI: 2.7–5.0). No difference in OS was noted in those patients who received TKI before ICIs compared with those who received ICIs followed by TKI. Conclusion: Post-ICI therapy is associated with OS in excess of 12 months, suggesting a role for therapeutic sequencing. OS from TKI therapy was similar to that reported in registration studies, suggesting preserved efficacy following ICIs.

Purpose The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI); however, this relationship is undefined in patients with hepatocellular carcinoma (HCC). Patients and methods We derived a cohort of 406 patients with unresectable/advanced HCC receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. We tested whether the development of clinically significant trAE (i.e. graded ≥2, trAE2) predicted improved overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) following ICI. We established an international consortium of 10 tertiary-care referral centres located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to validate this association. Results In the FDA dataset of 406 patients, 325 (80%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 258, 64%), trAE2 were reported in 228 patients (56.1%). Development of trAE2 was associated with longer OS (16.7 versus 11.2 months) and PFS (5.5 versus 2.2 months) and persisted as an independent predictor of outcome after adjusting for viral aetiology, gender, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy. In a multi-institutional cohort of 357 patients with similar characteristics mostly treated with ICI monotherapy (n = 304, 85%), the development of trAE2 was associated with longer OS (23.3 versus 12.1 months) and PFS (9.6 versus 3.9 months). TrAE2 were confirmed predictors of improved OS (HR 0.43; 95% CI:0.25–0.75) and PFS (HR 0.48; 95% CI: 0.31–0.75), with multivariable analyses confirming their association with outcome independent of clinicopathologic features of interest. Additional time-varying multivariable analyses also indicated that trAEs were associated with a decreased risk of progression (HR 0.56, 95% CI: 0.46–0.67) in the FDA dataset and death (HR 0.55; 95% CI: 0.32–0.95) in the multi-institutional dataset. Conclusion Development of trAE2 correlates with improved outcomes in patients with HCC receiving ICI in clinical trials and in routine practice. Prospective studies aimed at understanding the underlying immunologic foundations of such relationships are warranted to identify predictive biomarkers of toxicity and response.

Introduction: The treatment of unresectable hepatocellular carcinoma (HCC) has radically changed after the approval of the combination of atezolizumab plus bevacizumab as first-line treatment. A st...

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment., In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.

The speed and spread of the COVID-19 pandemic has been affecting the entire world for the past several months. OncoAlert is a social media network made up of more than 140 oncology stakeholders: oncologists (medical, radiation, and surgical), oncology nurses, and patient advocates who share the mission of fighting cancer by means of education and dissemination of information. As a response to the COVID-19 pandemic, OncoAlert hosted The Round Table Discussions. We have documented this effort along with further discussion about the COVID-19 pandemic and the consequences on patients living with cancer to disseminate this information to our colleagues worldwide. ispartof: JCO GLOBAL ONCOLOGY vol:7 pages:455-463 ispartof: location:United States status: published

Aim: Cetuximab is used for the treatment of RAS wild-type metastatic colorectal cancer patients. Standard administration schedule is once a week; however, the bioequivalence of an every-other-week (EOW) schedule was demonstrated. Methods: We compared a base case scenario of 100% weekly administration to an EOW at 50 or 100%. Medical examinations, patient management and loss of productivity were considered. Results: Base case was estimated at €100.6 million versus €92.8 million and €84.9 million of EOW 50 and 100%, which showed a cost reduction of 8 and 16%, respectively. Indirect costs accounted for 65% in both scenarios. Conclusion: The adoption of an EOW administration schedule of cetuximab reduced direct and indirect costs substantially.

During the last 10 years, the multikinase inhibitor sorafenib has emerged as the only systemic treatment for unresectable hepatocellular carcinoma (HCC). More recently, data from the Phase III REFLECT trial showed that another multikinase inhibitor, namely, lenvatinib, was non-inferior to sorafenib in terms of overall survival (OS). In contrast, with respect to OS, previous randomized Phase III trials have been negative, and several agents tested have failed to prove non-inferiority (or superiority) when compared with sorafenib in a first-line setting. Furthermore, the REFLECT trial demonstrated that lenvatinib, in comparison with sorafenib, significantly increased progression-free survival, time to progression, and objective response rate. Overall, the incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was similar in the two treatment arms of the trial, with a higher incidence of serious TEAEs in the lenvatinib arm. Encouraging efficacy signals had already been reported for immune checkpoint inhibitors in HCC, and different synergisms have been postulated in the frame of interplay between vascular endothelial growth factor receptor-2 inhibitors and immunotherapy. Given these premises, future approaches are being developed in Phase I trials testing lenvatinib in combination with pembrolizumab or nivolumab. As the treatment landscape of HCC is expanding with novel agents being approved for patients who are intolerant or are progressing on prior sorafenib, we will discuss current challenges pertaining to the optimal sequencing of active agents in first- and second-line setting.