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Despite all the improvements achieved over the last decade, the use of immune checkpoint inhibitors (ICIs) has been associated to a wide range of adverse drug events, which are frequently markedly different from those observed with cytotoxic chemotherapy and targeted therapies, such as sorafenib.We performed a meta-analysis with the aim to compare grade 3/4 treatment-related adverse events (TRAEs), grade 5 TRAEs, serious TRAEs, and TRAEs leading to discontinuation in ICIs versus sorafenib across phase III clinical trials of first-line treatment for advanced hepatocellular carcinoma (HCC).Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Patients treated with ICIs showed higher risk of serious TRAEs (OR 1.48, 95% CI = 1.16-1.9) while sorafenib treatment was associated with higher risk of TRAEs leading to discontinuation (OR 0.65, 95% CI = 0.48-0.89). No differences in grade 3/4 TRAEs and grade 5 TRAEs.Beyond activity and efficacy, careful consideration should be given to toxicity while choosing the appropriate first-line treatment in HCC.

Background: First-line therapies based on immune-checkpoint inhibitors (ICIs) significantly improved survival of metastatic renal cell carcinoma (mRCC) patients. Cabozantinib was shown to target kinases involved in immune-escape and to prolong survival in patients pre-treated with tyrosine-kinase-inhibitors (TKIs). The impact of ICIs combinations in first line on subsequent therapies is still unclear. Methods: This is an open label, multicenter, single arm, phase II study designed to assess activity, safety and efficacy of cabozantinib in mRCC patients progressed after an adjuvant or first line anti-Programmed Death (PD)-1/PD-Ligand (PD-L) 1-based therapy. Primary endpoint was progression free survival (PFS), secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. Results: 31 patients were included in the analysis. After a median (m) follow-up of 11.9 months, mPFS was 8.3 months (90%CI 3.9-17.4) and mOS was 13.8 months (95%CI 7.7-29.0). ORR was 37.9% with an additional 13 patients achieving disease stability. Grade 3-4 adverse events occurred in 47% of patients, including more frequently creatine phosphokinase (CPK) serum level elevation, neutropenia, hyponatremia, diarrhea, hand-food syndrome, oral mucositis and hypertension. Conclusions: The BREAKPOINT trial met its primary endpoint showing that cabozantinib as second line therapy after ICIs was active in mRCC. Safety profile was manageable. Trial registration number: NCT03463681 - A Study of CaBozantinib in Patients With Advanced or Unresectable Renal cEll cArcinoma (BREAKPOINT) - https://clinicaltrials.gov/ct2/show/NCT03463681

Hepatocellular carcinoma (HCC) represents the most frequent type of primary liver tumor. Most HCC patients present with advanced disease at diagnosis and the recurrence rate after surgery remains high. Treatment options for advanced HCC are limited, with sorafenib representing the only systemic agent approved for treatment of advanced HCC in more than a decade. However, in recent years new molecular targeted therapies and immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced HCC. In particular, combinations of ICIs with antiangiogenic drugs, or with other ICIs, represent one of the most promising strategies. Herein we provide a comprehensive overview of the main therapeutic advances in the systemic treatment of HCC, focusing on the most relevant ongoing clinical trials.

Hepatocellular carcinoma (HCC) remains a frequently diagnosed malignancy worldwide, still representing an important cause of cancer-related death. Recent years have seen the emergence of novel systemic treatments for HCC patients, including immune checkpoint inhibitors (ICIs). Nonetheless, several questions regarding HCC immunotherapy remain unanswered, especially in terms of biochemical predictors of response.In the current paper, we will discuss available evidence regarding predictive biomarkers of response to HCC immunotherapy. A literature search was conducted in January 2022 of Pubmed/Medline, Cochrane library, and Scopus databases.The identification of predictive biomarkers represents an unmet need in HCC patients receiving ICIs. The HCC medical community is called to further efforts aimed to elucidate the effective role of PD-L1 expression, TMB, MSI, gut microbiota, and other emerging biomarkers.

The 2021 has seen the publication of two practice-changing trials on second-line fluoropyrimidine-based doublet chemotherapy for advanced biliary tract cancer (BTC) patients. Herein, we conducted a meta-analysis aimed at assessing the overall survival (OS), disease control rate (DCR), and overall response rate (ORR) in ABC-06 and NIFTY trials. We retrieved all the relevant trials through PubMed/Medline, Cochrane library, and EMBASE; additionally, proceedings of the main international oncological meetings were also searched for relevant abstracts. Outcomes of interest included OS, DCR, and ORR. Hazard Ratios (HRs) and their 95% Confidence Intervals (CIs) for OS, and Odds Ratios (ORs) and 95% CIs for DCR and ORR, were extracted. According to our results, fluoropyrimidine-based doublet chemotherapy significantly decreased the risk of death (HR, 0.63; 95% CI, 0.49���0.8) compared with control treatment. In addition, higher DCR and ORR were observed in BTC patients receiving fluoropyrimidine-based combinations. Although ABC-06 and NIFTY have recently established fluoropyrimidine-based doublet chemotherapy as the standard of care, the role of second-line chemotherapy remains the object of debate in the BTC medical community. Further studies are required to clarify the role of second-line fluoropyrimidine-based chemotherapy in some ���neglected��� populations, including BTC patients with poor ECOG-PS.

This is a retrospective analysis on the safety and activity of compassionate Ipilimumab and Nivolumab (IPI-NIVO) administered to patients with metastatic Renal Cell Carcinoma (mRCC) with intermediate or poor International Metastatic RCC Database Consortium (IMDC) score as a first-line regimen. IPI was infused at 1 mg/kg in combination with Nivolumab 3 mg/kg every three weeks for four doses, followed by maintenance Nivolumab (240 or 480 mg flat dose every two or four weeks, respectively) until disease progression or unacceptable toxicity. A total of 324 patients started IPI-NIVO at 86 Italian centers. Median age was 62 years, 68.2% IMDC intermediate risk. Primary tumor had been removed in 65.1% of patients. Two hundred and twenty patients (67.9%) completed the four IPI-NIVO doses. Investigator-assessed overall response rate was 37.6% (2.8% complete). Twelve-month survival rate was 66.8%, median progression-free survival was 8.3 months. Grade 3 or 4 treatment-related adverse events occurred in 67 patients (26.9%). IMDC intermediate risk, nephrectomy, BMI ≥ 25 kg/m2, and steroid use for toxicities correlated with improved survival, while age < 70 years did not. IPI-NIVO combination is a feasible and effective regimen for the first-line treatment of intermediate-poor IMDC risk mRCC patients in routine clinical practice.

Stage I–III triple-negative breast cancer accounts for approximately 15–20% of new diagnoses of early breast cancer. Novel systemic treatment options have recently been assessed as part of the neoadjuvant approach, such as the addition of immune checkpoint inhibitors to cytotoxic chemotherapy. However, several questions remain unanswered, including the identification of predictors of response to immunotherapy in this setting, and further efforts aimed at identifying reliable predictors and clarifying the effective role of PD-L1 status, tumor mutational burden, tumor-infiltrating lymphocytes and other biomarkers are warranted. Herein we will provide an overview of recent clinical studies of neoadjuvant immune checkpoint inhibitors in patients with triple-negative breast cancer, especially focusing on the recently presented and published KEYNOTE-522, IMpassion031 and GeparNUEVO trials.

A concomitant drug-based score was developed by our group and externally validated for prognostic and predictive purposes in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). The model considers the use of three classes of drugs within a month before initiating ICI, assigning score 1 for each between proton pump inhibitor and antibiotic administration until a month before immunotherapy initiation and score 2 in case of corticosteroid intake. In the present analysis, the drug score was validated in a prospective population of 305 patients with metastatic renal cell carcinoma treated with ipilimumab plus nivolumab in the first-line setting. The value of the model in predicting overall survival and progression-free survival was statistically significant and clinically meaningful, with an overall survival rate at 12 months of 73% vs. 44% (P0.0001), and median progression-free survival of 11.6 (95% CI: 9.1-14.1) months versus 4.8 (95% CI: 2.7-7.0) months (P=0.002), respectively, for patients belonging to the favorable group (score 0-1) versus the unfavorable (score 2-4). Further development will be represented by the gut microbiome analysis according to the drug-based model classification and to the outcome of patients to ICI therapy to demonstrate the link between drug exposure and immune sensitivity.

Background. Immune checkpoint inhibitors (ICIs) have recently represented a breakthrough in urothelial carcinoma (UC). Proton pump inhibitors (PPIs) are routinely used for extended time periods in UC patients, with these agents having potentially and frequently undervalued effects on ICIs efficacy. Methods. We performed a meta-analysis aimed at investigating the impact of concomitant PPI administration on progression-free survival (PFS) and overall survival (OS) among patients receiving immunotherapy for metastatic UC. Results. Two studies encompassing a total of 1015 patients were included. The pooled Hazard Ratios (HRs) for OS and PFS were 1.55 (95% CI, 1.31–1.84) and 1.43 (95% CI, 1.23–1.66), respectively, suggesting that the administration of PPIs was negatively associated with PFS and with OS in UC patients treated with ICIs. Conclusions. The current meta-analysis represents the first study to provide a systematic evaluation of the impact of concomitant PPI use in UC patients treated with ICIs. Further studies are warranted on this topic to clarify the relationship between gut microbiome, antiacid exposure, and cancer immunotherapy. In the current era of medical oncology, progress in this setting will require the collaboration of basic science and clinical research to optimize systemic treatment and to improve the outcomes of UC patients receiving ICIs.

(1) Background: In recent years, immunotherapy has revolutionized the treatment landscape of non-small cell lung cancer (NSCLC), representing a therapeutic breakthrough in this field. Antacid agents such as proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) are commonly prescribed for extended periods in NSCLC patients, and these drugs have the potential to modify the efficacy of immune checkpoint inhibitors (ICIs). (2) Materials and Methods: Herein, we conducted a systematic review and meta-analysis to investigate the impact of PPIs and H2RAs on progression-free survival (PFS) and overall survival (OS) among patients receiving immunotherapy for metastatic NSCLC. Effect measures for OS were Hazard Ratios (HRs) and 95% Confidence Intervals (CIs), which were extracted from available studies. Forest plots were used to assess HRs to describe the relationship between treatment and OS in the specified cohorts of patients. (3) Results: Six studies were included in the analysis, involving 2267 patients. The pooled HRs for OS and PFS were 1.4 (95% CI, 1.25–1.58) and 1.29 (95% CI, 1.17–1.43), respectively, suggesting that PPIs and H2RAs administration was negatively associated with PFS and OS. (4) Conclusion: Concomitant antacid use could modify the activity of ICIs in NSCLC patients.

4569 Background: For many years, vascular endothelial growth factor (VEGF)-targeted therapy (tp) has been a milestone for metastatic renal cell carcinoma (mRCC). Recently, first line tp based on anti-PD-1/PD-L1 immune-checkpoint inhibitors (ICIs) plus tyrosine-kinase-inhibitors (IO-TKI) and anti-PD-1 plus anti-CTLA-4 combos (IO-IO) significantly improved survival of mRCC patients (pts). Prospective data are lacking to determine the efficacy of anti-VEGF tp after IO-IO or IO-TKI. Cabozantinib (Cabo) showed to prolong survival in mRCC pts pre-treated with TKIs and to target kinases involved in immune-escape. So, it may represent an ideal agent to be used sequentially after ICIs. Methods: This is an open label, single arm, multicenter, phase II study evaluating efficacy and safety of Cabo in mRCC pts who received an anti-PD-1/PD-L1-based adjuvant (adj) or first line tp. Cabo 60 mg/daily was administered until progressive disease (PD) or unacceptable toxicity. Primary endpoint was progression free survival (PFS) by Brookmeyer-Crowley test, secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. Exploratory endopoints were to investigate tissue PD-L1 expression, to assess the modulating activity of Cabo on local and systemic tumor immunity and to explore bone formation and reabsorption markers. Results: From July 2018, 49 pts were enrolled and 48 were included in the analysis. Median age was 62.5 years (range: 30-78), 63% of pts were male. At baseline, 26% of pts had a good Heng risk score, 47% intermediate and 28% a poor risk, while in 2% of pts the class of risk was undetermined. 74% of pts received an IO-IO combo as first line tp, 17% IO-TKI, 9% pts an adj IO monotherapy. Pts received a median of 10 cycles of Cabo (range 5-17 cycles). 25 pts (53%) are still on tp, 1 patient discontinued Cabo for AEs, 13 pts for radiological PD, 6 pts discontinued for clinical PD or death, while 2 pts for reasons other than AEs or PD. Among evaluable cases, 17 pts (43%) achieved a partial response and 15 pts (37%) stable disease. Complete responses were not observed. At a median (m) follow-up of 8.0 months (mo) (4.4-13.5 mo), 71% of pts were alive and mPFS was 9.3 mo (95% CI 7.1-29.0 mo). Grade (G) 3-4 adverse events (AEs) occurred in 34% of pts, including more frequently serum bilirubin increase, hypertension, calcium and sodium serum levels alterations and oral mucositis. G1-2 were observed in 61% of pts, including in most of cases diarrhoea, nausea, oral mucositis, disgeusia, hand-foot syndrome, fatigue and hypothyroidism. Due to AEs, transitory withholding of Cabo was observed in 53.5% of pts and for 23 pts (48%) dose reductions were needed. Conclusions: So far, Cabo tp after IO-IO or IO-TKI showed promising results and was well tolerated. Longer follow-up is needed for final OS and exploratory endpoints results. Clinical trial information: NCT03463681.

Background: In the field of oncological assistance, nowadays we have to deal with a complex scenario where patients got used to obtain a huge amount of information through internet or social media and to apply them in performing their health-related decisions. This landscape requires that clinicians become able to handle therapeutical approaches and adequate skills in communication tools to satisfy the current needs. Our project aimed to build a communication model based on clinical oncologists’ real experiences in order to find a simple way to share with patients all the innovative therapeutical opportunities today available in lung cancer. The final goal is to design a flexible and personalized model adaptable to clinician’s personal characteristics and to the specific patient he is facing. We applied both traditional educational tools and innovative techniques in order to make the results effective and applicable to support peer learning. Methods: The first step consisted in a Board synthesized the definition of the diagnostic process, the identification of treatment strategies and any potential communication barrier clinicians may face dealing with patients. The second step consisted in teamwork including a theoretical part and a training part. In the third step we produce five training videos and video interviews regarding communication praxis and a “Small communication manual”. The last step consisted in the publication of the produced material on website and its diffusion through the social media. Results: In medicine, the universal application of a single model of communication does not represent the optimal solution. By contrary, the availability of simple and practical suggestions to improve the communicative style could allow clinicians to abandon stereotyped formulas identically repurposed to all patients. The “from bottom to top” training, starting from real-life to take advantage of the clinician’s experience, give the clinicians the possibility to meditate about their own communicative style and to train in the context of a protected environment. Applying these rules, we design an effective communication model, based on healthcare humanization, which could represent a fundamental support for the patient in order to be gently driven by the clinician to the most appropriate therapeutical choice, balancing efficacy and quality of life. The relational training may improve the quality of clinician-patient communication and could be widespread to other clinicians through the media. Conclusions: Considering the innovative therapeutical options available, particularly for lung cancer patients, and the increasing access of health-related information through internet or social media the clinician-patient communication has become crucial to support the achievement of the most appropriate therapeutical choice for the patient, facing the intricate illness experience. Building a shareable and easy-to-apply communication model represents a challenge aimed to help clinicians and including technology not as a threat, but as a positive tool.

Aim: This retrospective analysis focused on the effect of treatment with EVE/EXE in a real-world population outside of clinical trials. We examined the efficacy of this combination in terms of PFS and RR related to dose intensity (5 mg daily versus 10 mg daily) and tolerability. Methods: 163 HER2-negative ER+/PgR+ ABC patients, treated with EVE/EXE from May 2011 to March 2016, were included in the analysis. The primary endpoints were the correlation between the daily dose and RR and PFS, as well as an evaluation of the tolerability of the combination. Secondary endpoints were RR, PFS, and OS according to the line of treatment. Patients were classified into three different groups, each with a different dose intensity of everolimus (A, B, C). Results: RR was 29.8% (A), 27.8% (B) (p = 0.953), and not evaluable (C). PFS was 9 months (95% CI 7–11) (A), 10 months (95% CI 9–11) (B), and 5 months (95% CI 2–8) (C), p = 0.956. OS was 38 months (95% CI 24–38) (A), median not reached (B), and 13 months (95% CI 10–25) (C), p = 0.002. Adverse events were stomatitis 57.7% (11.0% grade 3–4), asthenia 46.0% (6.1% grade 3–4), hypercholesterolemia 46.0% (0.6% grade 3–4), and hyperglycemia 35.6% (5.5% grade 3–4). The main reason for discontinuation/interruption was grade 2–3 stomatitis. Conclusions: No correlation was found between dose intensity (5 vs. 10 mg labeled dose) and efficacy in terms of RR and PFS. The tolerability of the higher dose was poor in our experience, although this had no impact on efficacy.

Interleukin 6 (IL-6) is an important survival and growth factor for myeloma cells and exerts its effects by activating several transduction pathways, including the Ras cascade. As farnesylation of the activated Ras oncogene product by protein farnesyltransferase (FTase) is a critical step for Ras functional activity, FTase has emerged as a potential target for the development of new anti-cancer agents. Based on our previous demonstration that IL-6-producing myeloma cells are refractory to drug-induced apoptosis, we have analysed the effect of manumycin, a natural FTase inhibitor, on IL-6-producing myeloma cells resistant to Fas-, dexamethasone- and doxorubicin-induced apoptosis. Treatment of myeloma cells with manumycin prevented cell proliferation and induced apoptosis. Western blotting experiments demonstrated that this effect was related to inhibition of the post-translational Ras processing.Further analysis showed that manumycin-induced apoptosis involved caspase-3. Activation of caspase-3, in fact, was observed in 6 h-treated myeloma cells expressing Apo 2.7 antigen, the marker of early apoptosis, whereas their treatment with cell-permeable DEVD-fmk, that irreversibly inhibits caspase-3 activity, prevented their apoptosis. Over-expression of caspase-3 was also demonstrated by reverse transcription-polymerase chain reaction. Finally, over-expression of Bcl-2 and its homologue Bcl-xL was observed in manumycin-treated cells as well as in control myeloma cells, implying that the Bcl-2 family is not involved. FTase inhibitors may thus be proposed as a potential pharmacological weapon, as they block the Ras pathway and induce the apoptosis of drug-resistant IL-6-producing myeloma cells.