Immune checkpoint inhibitors (ICIs) are a key component of different stages of hepatocellular carcinoma (HCC) treatment, particularly in the first line of treatment. A lesson on the primary resistance which hampers their efficacy and activity was learned from the failure of the trials which tested them as first-line mono-therapies. Despite the combination of anti-PD(L)1 agents with anti-VEGF, anti CTLA4, or TKIs demonstrating relevant improvements in efficacy, the “doublets strategy” still shows room for improvement, due to a limited overall survival benefit and a high rate of progressive disease as best response. In this review, we discuss the results from the currently tested doublet strategies (i.e., atezolizumab+bevacizumab, durvalumab+tremelimumab with a mention to the newly presented ICIs/TKIs combinations), which highlight the need for therapeutic improvement. Furthermore, we examine the rationale and provide an overview of the ongoing trials testing the treatment intensification strategy with triplet drugs: anti-PD1+anti-CTLA4+anti-VEGF/TKIs and anti-PD1+anti-VEGF+alternative immunity targets. Lastly, we report on the alternative strategy to integrate ICIs into the new paradigm of immune therapeutics constituted by CAR-T and anti-cancer vaccines. This review provides up-to-date knowledge of ongoing clinical trials of the aforementioned strategies and critical insight into their mechanistic premises.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, with most patients diagnosed at advanced stages. First-line treatment based on a combined chemotherapy (FOLFIRINOX or gemcitabine plus nab-paclitaxel) provides limited benefits. Olaparib, a PARP inhibitor, has been approved as maintenance for PDAC patients harboring germline BRCA1/2 pathogenic mutations and previously treated with a platinum-based chemotherapy. BRCA1/2 germline testing is recommended, but also somatic mutations could predict responses to PARP inhibitors. Analysis of tumor tissues can detect both germline and somatic mutations and potential resistance alterations. Few data are available about BRCA1/2 testing on pancreatic tumor tissues, which often include limited biological material. We performed BRCA1/2 testing, by an amplicon-based Next Generation Sequencing (NGS) panel, on 37 consecutive PDAC clinical samples: 86.5% of cases were adequate for NGS analysis, with a success rate of 81.2% (median DNA input: 10 nanograms). Three BRCA2 mutations were detected (11.5%). Failed samples were all from tissue macrosections, which had higher fragmented DNA than standard sections, biopsies and fine-needle aspirations, likely due to fixation procedures. BRCA1/2 testing on pancreatic tumor tissues can also be feasible on small biopsies, but more cases must be analyzed to define its role and value in the PDAC diagnostic algorithm.

FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GN) are the most common chemotherapy regimens in first-line treatment of metastatic pancreatic cancer (PC). They have not been compared each other in a prospective trial, but only in retrospective studies, which can thus be affected by several biases. In order to overcome these biases, we took advantage of matching-adjusted indirect comparison (MAIC), that allows an indirect comparison by reducing cross-trial differences, and compared data from 268 patients treated with GN in a real-world setting with data from the 171 patients included in the FFX arm of the PRODIGE trial. Survival outcomes did not differ between the two populations. Overall survival was 11.1 months for both treatments (hazard ratio (HR) of FFX 1.10, 95% confidence interval (CI) 0.81–1.49; p = 0.527). Progression-free survival was 6.0 months with GN and 6.4 months with FFX (HR of FFX 1.11, 95% CI 0.82–1.50; p = 0.520). On the other hand, we observed a difference in the toxicity profiles: grade 3/4 anemia was more frequent with GN, whereas a higher occurrence of grade 3/4 vomiting and diarrhea was reported with FFX. FFX and GN show an equivalent efficacy but different safety profiles in the first-line therapy of metastatic pancreatic cancer. Searching for reliable predictive biomarkers is advised in order to improve therapeutic strategy in metastatic PC.

Background: There are currently few data about the safety and effectiveness of chemotherapy for patients with metastatic non-small-cell lung cancer (NSCLC) who have progressed from prior immunotherapy. Methods: Data from patients with consecutive stage IIIB–IV, ECOG performance status (PS) 0–2, non-small-cell lung cancer (NSCLC) treated with combination or single-agent chemotherapy following progression on an earlier immunotherapy regimen were retrospectively gathered. Recorded were baseline attributes, outcome metrics, and toxicities. The neutrophil/lymphocyte (N/L) ratio’s predictive usefulness was examined through an exploratory analysis. Results: The analysis comprised one hundred subjects. The adeno/squamous carcinoma ratio was 77%/23%, the M/F ratio was 66%/34%, the ECOG PS was 0/1/≥2 47%/51%/2%, and the median PD-L1 expression was 50% (range 0–100). The median age was 67 (range 39–81) years. Prior immunotherapy included a single-agent treatment in 83% of cases, with pembrolizumab use being prevalent, and a median N/L ratio of four prior to chemotherapy. The overall median time-to-progression on previous immunotherapy was 6 months. After immunotherapy, just 33% of subjects underwent chemotherapy. A median of 4 (range 1–16) cycles of chemotherapy were administered; platinum doublets (primarily carboplatin) were delivered in only 31% of cases, vinorelbine accounted for 25%, taxanes for 25%, and gemcitabine for 8%. The median clinical benefit was 55%, while the overall response rate was 21%. The median overall survival was 5 months (range 1–22) and the median time to progression was 4 months (range 1–17). Subgroups with low and high N/L ratios were compared, but there was no discernible difference in survival. Conclusions: After immunotherapy, a small percentage of patients with advanced NSCLC had chemotherapy. Following immunotherapy advancement, chemotherapy demonstrated a moderate level of therapeutic effectiveness; no adverse concerns were noted. The effectiveness of chemotherapy following immunotherapy was not predicted by the baseline N/L ratio.

Background HCC-CC is the second most frequent subtype among rare pathological variants of HCC. Despite epidemiological, clinical, radiological and molecular peculiarities have been reported, neither dedicated treatment guidelines nor clinical trials are available for HCC-CC. Methods We retrospectively collected clinical and survival data from HCC-CC patients followed at our Institution from January 2015 to present. The primary aim of our study was to describe both patients’ baseline characteristics and outcomes in terms of progression-free survival (PFS) and overall survival (OS) according to disease stage and type of treatment. Estimations of time-to-event curves were generated by the Kaplan-Meier method. Results Among 138 HCC patients, 73 (52.9%) had a histologically confirmed diagnosis and 18 (13.0%) belonged to the HCC-CC subtype and were therefore included in the present analysis. Of the 18 HCC-CC patients, 16 (88.9%) were males and 2 females (11.1%), with a mean age at diagnosis of 67 years (range: 53-79). As for etiology, 9 (50.0%) cases recognized a dysmetabolic cause, 1 (5.5%) was HCV-related and 8 (44.5%) arose on healthy liver. All patients showed a preserved liver function (Child-Pugh A) at baseline. Regarding disease extension at diagnosis, 12 (66.7%) were in early stage (BCLC-A), 1 (5.5%) had intermediate (BCLC-B) and 5 (27.8%) advanced (BCLC-C) disease due to ECOG PS≥1. Sixteen patients (88.9%) underwent surgery as first treatment, while 1 case received liver transplantation and 1 received transarterial chemoembolization (TACE). At first evidence of progression, 4 patients were offered additional locoregional treatments: TACE in 2 cases, transarterial radioembolization and microwave ablation 1 case each. After a median interval of 9.1 months from initial curative-intent treatment, 10 (55.5%) patients progressed, 2 showing hepatic-only spread, 1 lung-only and and 7 ≥2 metastatic sites, i.e. liver (6), peritoneum (4), lung (2), skeletal, lymph nodes and skin (1 each). A systemic first-line therapy was administered to 7 metastatic patients, 6 of which were followed at our center: 4 received sorafenib and 2 received experimental treatment with durvalumab (1 patient) or lenvatinib plus pembrolizumab/placebo (1 patient). Disease progression was reported as best radiological response in 66.7% of cases. Notably, despite a median first-line PFS of 2.76 months (95% CI 1.38-5.03), most patients received subsequent systemic therapies (50% second-line, 20% third-line) and 20% were considered for surgery (peritonectomy with hypertermic intraperitoneal chemotherapy), reaching a survival rate of 100% and 60% at 6-months and 1-year respectively. Surgery was performed as only treatment in other 2 metastatic patients; of note, 1 of them underwent multiple excisions of extrahepatic localizations, reaching a 50.0 months survival at the time of analysis. Conclusion Our cohort of HCC-CC patients showed a predominantly non-viral etiology, a mainly early-stage at diagnosis with preserved liver function and a relatively favorable outcome even in metastatic patients, consistently with previously published data. Interestingly, we observed a poor efficacy of systemic treatment with tyrosine-kinase inhibitors, whereas surgery seemed to be effective even in the metastatic setting. Role of immune checkpoints inhibitors in HCC-CC should be further explored. Wider multicentric experiences are warranted to shed light on this not-so-rare HCC-subtype. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure The presenting author has declared no conflicts of interest.