Publications
322 results found
van de Haar J, Ma X, Ooft SN, et al., 2023, Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer., Nat Med, Vol: 29, Pages: 605-614
Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73-1.20; P = 0.85). In contrast, patients with KRASG13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15-0.55; P < 0.001). In isogenic cell lines and patient-derived organoids, KRASG12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.
Pinato DJ, Cortellini A, 2023, Antibiotic Therapy: The Cornerstone of Iatrogenic Resistance to Immune Checkpoint Inhibitors., J Clin Oncol
Pinter M, Pinato DJ, Ramadori P, et al., 2023, NASH and Hepatocellular Carcinoma: Immunology and Immunotherapy., Clin Cancer Res, Vol: 29, Pages: 513-520
The last 10 years have revolutionized our basic understanding of nonalcoholic fatty liver disease and consequent liver cancer. It has become clear that several innate and adaptive immune cells play an important role in initiating, maintaining, or exacerbating nonalcoholic steatohepatitis (NASH)-a disease that has been recently defined as autoaggressive. Despite improved disease management aimed at reducing the progression of fibrosis, NASH is set to become a leading cause for hepatocellular carcinoma (HCC). Preliminary data from preclinical studies suggest that immunotherapy efficacy may be reduced in NASH-related HCC compared with viral HCC; however, conclusive evidence supporting clinical translation of these findings is lacking. Comprehensive clinical and immunologic phenotyping of mechanisms linking NASH progression with carcinogenesis and therapeutic resistance is key to prevent progression to cirrhosis, improve monitoring and stratification of NASH according to predicted cancer risk, and ultimately increase survival of patients with NASH-HCC. In this review, we summarize the state of the art in the field of NASH and NASH-HCC with focus on immunobiology. We discuss preclinical and clinical findings underpinning NASH as an immunologically distinct pro-tumorigenic disease entity, and explore areas of potential therapeutic vulnerabilities in NASH-associated HCC.
Tagliamento M, Gennari A, Lambertini M, et al., 2023, Pandemic Phase-Adjusted Analysis of COVID-19 Outcomes Reveals Reduced Intrinsic Vulnerability and Substantial Vaccine Protection From Severe Acute Respiratory Syndrome Coronavirus 2 in Patients With Breast Cancer., J Clin Oncol
PURPOSE: Although representing the majority of newly diagnosed cancers, patients with breast cancer appear less vulnerable to COVID-19 mortality compared with other malignancies. In the absence of patients on active cancer therapy included in vaccination trials, a contemporary real-world evaluation of outcomes during the various pandemic phases, as well as of the impact of vaccination, is needed to better inform clinical practice. METHODS: We compared COVID-19 morbidity and mortality among patients with breast cancer across prevaccination (February 27, 2020-November 30, 2020), Alpha-Delta (December 1, 2020-December 14, 2021), and Omicron (December 15, 2021-January 31, 2022) phases using OnCovid registry participants (ClinicalTrials.gov identifier: NCT04393974). Twenty-eight-day case fatality rate (CFR28) and COVID-19 severity were compared in unvaccinated versus double-dosed/boosted patients (vaccinated) with inverse probability of treatment weighting models adjusted for country of origin, age, number of comorbidities, tumor stage, and receipt of systemic anticancer therapy within 1 month of COVID-19 diagnosis. RESULTS: By the data lock of February 4, 2022, the registry counted 613 eligible patients with breast cancer: 60.1% (n = 312) hormone receptor-positive, 25.2% (n = 131) human epidermal growth factor receptor 2-positive, and 14.6% (n = 76) triple-negative. The majority (61%; n = 374) had localized/locally advanced disease. Median age was 62 years (interquartile range, 51-74 years). A total of 193 patients (31.5%) presented ≥ 2 comorbidities and 69% (n = 330) were never smokers. In total, 392 (63.9%), 164 (26.8%), and 57 (9.3%) were diagnosed during the prevaccination, Alpha-Delta, and Omicron phases, respectively. Analysis of CFR28 demonstrates comparable estimates of mortality across the three pandemic phases (13.9%, 12.2%, 5.3%, respectively; P = .182). Nevertheless, a significant improvement in outcome measures of COVID-19 severity across the three pande
Scheiner B, Pinato DJ, 2023, Tumor-infiltrating Neutrophils: Gatekeepers in Liver Cancer Immune Control., Gastroenterology
Talbot T, D'Alessio A, Pinter M, et al., 2023, Progression patterns and therapeutic sequencing following immune checkpoint inhibition for hepatocellular carcinoma: An international observational study, International Liver Congress, Publisher: WILEY, Pages: S383-S383, ISSN: 1478-3223
Anpalakhan S, Huddar P, Behrouzi R, et al., 2023, The Effects of GCSF Primary Prophylaxis on Survival Outcomes and Toxicity in Patients with Advanced Non-Small Cell Lung Cancer on First-Line Chemoimmunotherapy: A Sub-Analysis of the Spinnaker Study, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 24
Wu YL, Fulgenzi CAM, D'Alessio A, et al., 2022, Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as Prognostic Biomarkers in Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab, CANCERS, Vol: 14
D'Alessio A, Pinato DJ, 2022, Dissecting the Tumor Microenvironment to Predict Immunotherapy Response in Hepatocellular Cancer., Gastroenterology, Vol: 163, Pages: 1712-1713
Cortellini A, Pinato D, 2022, Immune checkpoint inhibitor therapy and outcomes from SARS-CoV-2 infection in patients with cancer: a joint analysis of OnCovid and ESMO-CoCARE registries, Journal for ImmunoTherapy of Cancer, Vol: 11, Pages: 1-10, ISSN: 2051-1426
Background: As management and prevention strategies against Coronavirus Disease-19 (COVID-19) evolve, it is still uncertain whether prior exposure to immune checkpoint inhibitors (ICIs) affects COVID-19 severity in patients with cancer. Methods: In a joint analysis of ICI recipients from OnCovid (NCT04393974) and ESMO CoCARE registries, we assessed severity and mortality from SARS-CoV-2 in vaccinated and unvaccinated patients with cancer and explored whether prior immune-related adverse events (irAEs) influenced outcome from COVID-19.Findings: The study population consisted of 240 patients diagnosed with COVID-19 between January 2020 and February 2022 exposed to ICI within 3 months prior to COVID-19 diagnosis, with a 30-day case fatality rate (CFR30) of 23.6% (95%CI: 17.8-30.7%). Overall, 42 (17.5%) were fully vaccinated prior to COVID-19 and experienced decreased CFR30 (4.8% vs 28.1%, p=0.0009), hospitalization rate (27.5% vs 63.2%, p<0.0001), requirement of oxygen therapy (15.8% vs 41.5%, p=0.0030), COVID-19complication rate (11.9% vs 34.6%, p=0.0040), and COVID-19-specific therapy (26.3% vs 57.9%, p=0.0004) compared with unvaccinated patients. Inverse Probability of Treatment Weighting (IPTW)-fitted multivariable analysis, following a clustered-robust correction for the data source (OnCovid vs ESMO CoCARE), confirmed that vaccinated patients experienced a decreased risk of death at 30 days (adjusted oddsratio-aOR 0.08, 95%CI: 0.01-0.69).Overall, 38 patients (15.8%) experienced at least 1 irAE of any grade at any time prior to COVID-19, at a median time of 3.2 months (range: 0.13-48.7) from COVID-19 diagnosis. IrAEs occurred independently of baseline characteristics except for primary tumour (p=0.0373) and were associated with a significantly decreased CFR30 (10.8% vs 26.0%, p=0.0462) additionally confirmed by the IPTW-fitted multivariable analysis(aOR: 0.47, 95%CI: 0.33-0.67). Patients who experienced irAEs also presented a higher median absolute lymphocyte co
Vithayathil M, D'Alessio A, Fulgenzi CAM, et al., 2022, Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma, Liver International, Vol: 42, Pages: 2538-2547, ISSN: 1478-3223
Background and AimsCombination 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.Methods191 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.ResultsThe 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.ConclusionsAtezolizumab and bevacizumab therapy is associated with comparable efficacy and tolerability in older age patients with unresectable HCC.
Fulgenzi CAM, Cheon J, D'Alessio A, et al., 2022, Reproducible safety and efficacy of atezolizumab plus bevacizumab for HCC in clinical practice: Results of the AB-real study., Eur J Cancer, Vol: 175, Pages: 204-213
BACKGROUND: IMbrave150 has established the superiority of atezolizumab plus bevacizumab over sorafenib in patients with unresectable hepatocellular carcinoma (HCC). METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Schettini F, Venturini S, Giuliano M, et al., 2022, Multiple Bayesian network meta-analyses to establish therapeutic algorithms for metastatic triple negative breast cancer, CANCER TREATMENT REVIEWS, Vol: 111, ISSN: 0305-7372
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- Citations: 2
Scheiner B, Pomej K, Pressiani T, et al., 2022, EFFICACY AND SAFETY OF IMMUNE CHECKPOINT INHIBITOR RECHALLENGE IN PATIENTS WITH HEPATOCELLULAR CARCINOMA, Publisher: WILEY, Pages: S1367-S1369, ISSN: 0270-9139
Cabibbo G, Celsa C, D'Alessio A, et al., 2022, COSMIC-312: mounting immunotherapy enigmas for hepatocellular carcinoma., Lancet Oncol, Vol: 23
Cortellini A, Aguilar-Company J, Salazar R, et al., 2022, Natural immunity to SARS-CoV-2 and breakthrough infections in vaccinated and unvaccinated patients with cancer, BRITISH JOURNAL OF CANCER, Vol: 127, Pages: 1787-1792, ISSN: 0007-0920
Fulgenzi CAM, D'Alessio A, Airoldi C, et al., 2022, Comparative efficacy of novel combination strategies for unresectable hepatocellular carcinoma: A network metanalysis of phase III trials, EUROPEAN JOURNAL OF CANCER, Vol: 174, Pages: 57-67, ISSN: 0959-8049
Fulgenzi CAM, D'Alessio A, Talbot T, et al., 2022, New Frontiers in the Medical Therapy of Hepatocellular Carcinoma, CHEMOTHERAPY, Vol: 67, Pages: 164-172, ISSN: 0009-3157
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- Citations: 5
Barsch M, Salie H, Schlaak AE, et al., 2022, T-cell exhaustion and residency dynamics inform clinical outcomes in hepatocellular carcinoma, JOURNAL OF HEPATOLOGY, Vol: 77, Pages: 397-409, ISSN: 0168-8278
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- Citations: 9
D'Alessio A, Fulgenzi CAM, Pinato DJ, 2022, Untitled Reply, HEPATOLOGY, Vol: 76, Pages: E82-E83, ISSN: 0270-9139
Johnson PJ, Pinato DJ, Kalyuzhnyy A, et al., 2022, Breaking the Child-Pugh Dogma in Hepatocellular Carcinoma comment, JOURNAL OF CLINICAL ONCOLOGY, Vol: 40, Pages: 2078-+, ISSN: 0732-183X
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- Citations: 2
D'Alessio A, Weinmann A, Galle P, et al., 2022, Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: a real-world study, JOURNAL OF HEPATOLOGY, Vol: 77, Pages: S376-S376, ISSN: 0168-8278
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- Citations: 11
Sharma R, Pillai A, Marron TU, et al., 2022, Patterns and outcomes of subsequent therapy after immune checkpoint inhibitor discontinuation in HCC, Hepatology Communications, Vol: 6, Pages: 1776-1785, ISSN: 2471-254X
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.
Takada K, Buti S, Bersanelli M, et al., 2022, Antibiotic-dependent effect of probiotics in patients with non-small cell lung cancer treated with PD-1 checkpoint blockade, EUROPEAN JOURNAL OF CANCER, Vol: 172, Pages: 199-208, ISSN: 0959-8049
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- Citations: 2
Munoz-Martinez S, Sapena V, Forner A, et al., 2022, Outcome of liver cancer patients with SARS-CoV-2 infection: An International, Multicentre, Cohort Study, LIVER INTERNATIONAL, Vol: 42, Pages: 1891-1901, ISSN: 1478-3223
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- Citations: 2
Cortellini A, Ricciuti B, Borghaei H, et al., 2022, Differential prognostic effect of systemic inflammation in patients with non-small cell lung cancer treated with immunotherapy or chemotherapy: A post hoc analysis of the phase 3 OAK trial, CANCER, Vol: 128, Pages: 3067-3079, ISSN: 0008-543X
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- Citations: 2
Marinelli B, Kim E, D'Alessio A, et al., 2022, Integrated use of PD-1 inhibition and transarterial chemoembolization for hepatocellular carcinoma: evaluation of safety and efficacy in a retrospective, propensity score-matched study, JOURNAL FOR IMMUNOTHERAPY OF CANCER, Vol: 10
Cortellini A, Salazar R, Gennari A, et al., 2022, Original Research Persistence of long-term COVID-19 sequelae in patients with cancer: An analysis from the OnCovid registry, EUROPEAN JOURNAL OF CANCER, Vol: 170, Pages: 10-16, ISSN: 0959-8049
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- Citations: 3
Fulgenzi CAM, D'Alessio A, Ogunbiyi O, et al., 2022, Novel immunotherapy combinations in clinical trials for hepatocellular carcinoma: will they shape the future treatment landscape?, EXPERT OPINION ON INVESTIGATIONAL DRUGS, Vol: 31, Pages: 681-691, ISSN: 1354-3784
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Serra C, Cossiga V, Serenari M, et al., 2022, Safety and efficacy of percutaneous radiofrequency ablation for hepatocellular carcinoma: a textbook outcome analysis, HPB, Vol: 24, Pages: 664-671, ISSN: 1365-182X
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