Safety evaluation of Datopotamab deruxtecan for triple-negative breast cancer: a meta-analysis.

BACKGROUND: TROP-2 is emerging as a valid and fruitful strategy in triple-negative breast cancer (TNBC) patients, and several agents are currently under evaluation, including Datopotamab deruxtecan (Dato-DXd). RESEARCH DESIGN AND METHODS: Herein, we performed a meta-analysis aimed to evaluate any grade adverse events, grade 3-4 adverse events, dose reduction, and serious adverse events in TNBC patients treated with Dato-DXd in clinical trials. RESULTS: The pooled results suggests that Dato-DXd is associated with a favorable safety profile: while any grade treatment-related toxicities were common, grade 3-4 events were not particularly frequent and mainly represented by stomatitis (13.88%; 95% CI, 10.68 - 17.09). CONCLUSIONS: These findings may help to comprehensively define the safety profile of Dato-DXd and to assist in the design of future clinical trials in this setting.

Immune-Based Combination Therapies for Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the fourth most frequent cause of cancer-related death worldwide. HCC frequently presents as advanced disease at diagnosis, and disease relapse following radical surgery is frequent. In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced HCC, particularly with the introduction of atezolizumab/bevacizumab as the new standard of care for first-line treatment. Recently, dual immune checkpoint blockade with durvalumab plus tremelimumab has also emerged as an effective first-line treatment for advanced HCC and most of the research is currently focused on developing combination treatments based mainly on ICIs. In this review, we will discuss the rationale and ongoing clinical trials of immune-based combination therapies for the treatment of advanced HCC, also focusing on new immunotherapy strategies such as chimeric antigen receptor T cells (CAR-T) and anti-cancer vaccines.

Treatment-related adverse events of first-line immunotherapy versus sorafenib for advanced hepatocellular carcinoma: a meta-analysis.

BACKGROUND: 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. RESEARCH DESIGN AND METHODS: 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). RESULTS: 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. CONCLUSIONS: Beyond activity and efficacy, careful consideration should be given to toxicity while choosing the appropriate first-line treatment in HCC.

A multicenter phase 2 single arm study of cabozantinib in patients with advanced or unresectable renal cell carcinoma pre-treated with one immune-checkpoint inhibitor: The BREAKPOINT trial (Meet-Uro trial 03).

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.

Concomitant Drugs Prognostic Score in Patients With Metastatic Renal Cell Carcinoma Receiving Ipilimumab and Nivolumab in the Compassionate Use Program in Italy: Brief Communication.

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% (P<0.0001), 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.

Pemigatinib in Intrahepatic Cholangiocarcinoma: A Work in Progress.

Cholangiocarcinoma (CCA) is the second most frequent primary liver cancer, following hepatocellular carcinoma (HCC). Progress in the molecular understanding of CCA has led to the development of several agents, including FGFR inhibitors, such as pemigatinib, whose approval has marked a new era in this hepatobiliary malignancy. However, a number of questions remain unanswered, including the development of secondary resistance and the role of combination therapies, including FGFR inhibitors. Herein, we specifically focus on the current challenges and future research directions of pemigatinib use in CCA patients.

Advances in novel systemic therapies for advanced hepatocellular carcinoma.

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.

Pathological Complete Response to Neoadjuvant Chemoimmunotherapy for Early Triple-Negative Breast Cancer: An Updated Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have made a breakthrough in the systemic treatment for metastatic triple-negative breast cancer (TNBC) patients. However, results of phase II and III clinical trials assessing ICIs plus chemotherapy as neoadjuvant treatment were controversial and conflicting. We performed a meta-analysis aimed at assessing the Odds Ratio (OR) of the pathological complete response (pCR) rate in trials assessing neoadjuvant chemoimmunotherapy in TNBC. According to our results, the use of neoadjuvant chemoimmunotherapy was associated with higher pCR (OR 1.95; 95% Confidence Intervals, 1.27-2.99). In addition, we highlighted that this benefit was observed regardless of PD-L1 status since the analysis reported a statistically significant and clinically meaningful benefit in both PD-L1 positive and PD-L1 negative patients. These findings further support the exploration of the role of ICIs plus chemotherapy in early-stage TNBC, given the potentially meaningful clinical impact of these agents. Further studies aimed at more deeply investigating this emerging topic in breast cancer immunotherapy are warranted.

Compassionate Use Program of Ipilimumab and Nivolumab in Intermediate or Poor Risk Metastatic Renal Cell Carcinoma: A Large Multicenter Italian Study.

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.

The Impact of Concomitant Proton Pump Inhibitors on Immunotherapy Efficacy among Patients with Urothelial Carcinoma: A Meta-Analysis.

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.

Current and Future Role of Neoadjuvant Chemoimmunotherapy for Early Triple-Negative Breast Cancer: Which Way to Go Forward.

Immunotherapy has revolutionized previous triple-negative breast cancer (TNBC) treatment algorithms, prompting researchers and clinicians to consider the expansion of the role of immunotherapy in other settings, including the earlier stage of the disease (e.g., as neoadjuvant and adjuvant therapy). The role of chemoimmunotherapy have been assessed in some recently presented and published clinical trials, including the KEYNOTE-522, the IMpassion031, and the GeparNUEVO. In the current Editorial, we will provide a critical snapshot of these studies, exploring strengths and limitations of neoadjuvant chemotherapy in early TNBC.

Adenosine pathway inhibitors: novel investigational agents for the treatment of metastatic breast cancer.

INTRODUCTION: The adenosine pathway has been suggested to play a key role in several carcinogenetic processes, with the metabolism of adenosine-5'-triphosphate (ATP) and its derivatives reported to be dysregulated in breast cancer. Preclinical evidence has supported the role of adenosine in the pathogenesis of this malignancy as well as the development of selective adenosine pathway inhibitors. AREAS COVERED: The paper overviews the evidence regarding the use of adenosine pathway inhibitors in breast cancer; a literature search was conducted in January 2022 of Pubmed/Medline, Cochrane library, and Scopus databases. EXPERT OPINION: The adenosine pathway regulates inflammation, apoptosis, metastasis, and cell proliferation in breast cancer cells, and adenosine pathway inhibitors have yielded encouraging results in early-phase clinical trials. Well-designed, multicenter studies focused on monotherapies and combination therapies (which include immune checkpoint inhibitors) are warranted in this setting.

KEYNOTE-522, IMpassion031 and GeparNUEVO: changing the paradigm of neoadjuvant immune checkpoint inhibitors in early triple-negative breast cancer.

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.

Which role for predictors of response to immune checkpoint inhibitors in hepatocellular carcinoma?

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Impact of Proton Pump Inhibitors and Histamine-2-Receptor Antagonists on Non-Small Cell Lung Cancer Immunotherapy: A Systematic Review and Meta-Analysis.

(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.

Systemic Treatment for Metastatic Biliary Tract Cancer: State of the Art and a Glimpse to the Future.

Recent years have seen some breakthroughs in the therapeutic landscape of advanced biliary tract cancer (BTC). Firstly, a better understanding of the molecular background of BTC has led to important improvements in the management of these hepatobiliary malignancies, with the advent of targeted agents representing an unprecedented paradigm shift, as witnessed by the FDA approval of pemigatinib and infigratinib for FGFR2-rearranged and ivosidenib in IDH1-mutant cholangiocarcinoma. In addition, several novel treatments are under assessment, including immune checkpoint inhibitors and combination chemotherapies. In the current review, we provide an overview of systemic treatment for metastatic BTC, summarizing recent clinical data on chemotherapy as well as the main results of targeted therapies and immunotherapy.

Fluoropyrimidine-based doublet chemotherapy as second-line treatment for advanced biliary tract cancer: a meta-analysis of ABC-06 and NIFTY.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.