Search

Purpose: The aim of this study was to evaluate the effectiveness of CDK 4/6 inhibitors (CDK 4-6i) according to HER2 status (low/zero), and endocrine resistance/sensitivity, as well as the efficacy of second-line treatments, in a large real-world cohort., Methods: The GIM14/BIOMETA study (NCT02284581) is a retrospective/prospective study of the Gruppo Italiano Mammella evaluating treatment patterns and survival outcomes in patients with metastatic breast cancer (MBC). We retrieved data on patients with hormone receptor-positive/HER2-negative MBC receiving first-line CDK 4/6i., Results: Among 3832 patients enrolled in the GIM14-BIOMETA study, 701 were eligible. At a median follow-up of 24.80 months, no significant differences were found between HER2-zero and HER2-low subgroups in terms of first-line time to treatment discontinuation (TTD) (26.16 months [IQR 12.84-NR] vs. 27.60 months [IQR 12.12-64.44], p = 0.972) or overall survival (OS) (mOS>60 months for both groups, p = 0.398). Median TTD was 33.24 months (IQR 16.32-NR) for the endocrine sensitive subgroup, 19.92 months (IQR 8.88-51.24) for the secondary endocrine resistant subgroup and 17.40 months (IQR 7.44-24.72) for the primary endocrine resistant subset, respectively (p < 0.001). Among 239 patients receiving second-line treatment, no significant difference (p = 0.188) was found in terms of second-line TTD between those treated with capecitabine (6.11 months, IQR 2.96-11.47), taxane-based chemotherapy (5.06 months, IQR 2.99-9.99), everolimus plus exemestane (5.39 months, IQR 2.53-9.03) or fulvestrant (6.44 months, IQR 3.38-NR)., Conclusions: Endocrine therapy plus CDK 4/6i represents an effective treatment, regardless of HER2 status (low/zero). Second-line agents did not differ significantly in terms of TTD. Endocrine resistant cancers exhibit poor response to CDK 4/6i., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chiara Molinelli reports honoraria for consultancy and consulting fees from Daiichi Sankyo, travel support to attend conferences from Gilead, Menarini and fees for medical writing from Lilly and Seagen. Eva Blondeaux reports honoraria from Eli Lilly and research funding (to institution) from Gilead. Michelino De Laurentiis reports honoraria or consultation fees for speaker, consultancy or advisory roles from Eli Lilly, Seagen, Therapeutics, GSK, Roche, Novartis, Genetic, Pfizer, Pierre Fabre, MSD, Menarini Stemline, Sophos Biotech, Max Farma, Celltrion Healthcare, Gilead, Daiichi Sankyo; institutional financial interests, financial support for clinical trials or contracted research, from: Novartis, Pierre Fabre, Pfizer, Roche, Stemline Therapeutics. Alessandra Fabi reports consulting fees and honoraria from Roche, Novartis, Lilly, Pfizer, MSD, Gilead, Seagen, Astra Zeneca, Daiichi Sankyo. Support for attending meetings and/or travel from Novartis, Lilly, Pfizer, MSD. Grazia Arpino reports research and medical writing from AstraZeneca; advisory boards, travel grants, activities as a speaker, consultancy from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Exact Science, Novartis, Roche, Seagen, Viatris. Andrea Fontana reports advisory boards from Roche, Novartis, Eli Lilly, Pfizer, MSD, Pierre Fabre, Eisai, Gilead, Seagen, Astra Zeneca, Exact Sciences; consulting fees from Dompé Farmaceutici S.p.A. D.G. Research funding from Menarini, Seagen, Novartis, AstraZeneca; advisory boards, activities as a speaker, consultancy from Seagen, Novartis, Eli Lilly, Roche, Gilead, Pfizer, Eisai, Exact Sciences. Fabio Puglisi reports advisory role for and receiving speaker honoraria from Amgen, AstraZeneca, Daichii Sankyo, Celgene, Eisai, Eli Lilly, Exact Sciences, Gilead, Ipsen, Menarini, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Takeda, and Viatris. Travel grants from AstraZeneca, Daichii Sankyo, Novartis, Roche. Research grants (to his institution) from Astrazeneca, Eisai, Roche. Claudia Bighin reports personal fees from Roche, Novartis, Lilly, Gilead, and Daiichi. Matteo Lambertini reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD, Exact Sciences, Pierre Fabre, Menarini; speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo, Takeda, Menarini, AstraZeneca; travel Grants from Gilead, Daiichi Sankyo, Roche; research funding (to the Institution) from Gilead all outside the submitted work. Lucia Del Mastro reports grants from Eli Lilly, Novartis, Roche, Daiichi Sankyo, Seagen, AstraZeneca, Gilead, and Pierre Fabre; receiving consulting fees from Eli Lilly, Gilead, and Daiichi Sankyo; receiving speaker honoraria from Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Exact Sciences, Ipsen, GSK, and Agendia-Stemline; receiving travel grants from Roche, Pfizer, Eisai, Daiichi Sankyo, and AstraZeneca; and having an advisory role for Novartis, Roche, Eli Lilly, Pfizer, Daiichi Sakyo, Exact Sciences, Gilead, Pierre Fabre, Eisai, AstraZeneca, Agendia, GSK, and Seagen. All the other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Treatment options for advanced melanoma have increased with the US Food and Drug Administration approval of the anti-LAG3 plus anti-PD-1 relatlimab/nivolumab combination. To date, ipilimumab/nivolumab is the benchmark of overall survival, despite a high toxicity profile. Furthermore, in BRAF-mutant patients, BRAF/MEK inhibitors and the atezolizumab/vemurafenib/cobimetinib triplet are also available treatments, making the first-line therapy selection more complex. To address this issue, we conducted a systematic review and network meta-analysis of the available first-line treatment options in advanced melanoma., Methods: Randomised clinical trials of previously untreated, advanced melanoma were included if at least one intervention arm contained a BRAF/MEK or an immune-checkpoint inhibitor (ICI). The aim was to indirectly compare the ICIs combinations ipilimumab/nivolumab and relatlimab/nivolumab, and these combinations with all the other first-line treatment options for advanced melanoma (irrespective of BRAF status) in terms of activity and safety. The coprimary end-points were progression-free survival (PFS), overall response rate (ORR) and grade ≥3 treatment-related adverse events (≥ G3 TRAEs) rate, defined according to Common Terminology Criteria for Adverse Events., Results: A total of 9070 metastatic melanoma patients treated in 18 randomised clinical trials were included in the network meta-analysis. No difference in PFS and ORR was observed between ipilimumab/nivolumab and relatlimab/nivolumab (HR = 0.99 [95% CI 0.75-1.31] and RR = 0.99 [95% CI 0.78-1.27], respectively). The PD-(L)1/BRAF/MEK inhibitors triplet combinations were superior to ipilimumab/nivolumab in terms of both PFS (HR = 0.56 [95% CI 0.37-0.84]) and ORR (RR = 3.07 [95% CI 1.61-5.85]). Ipilimumab/nivolumab showed the highest risk of developing ≥ G3 TRAEs. Relatlimab/nivolumab trended to a lower risk of ≥ G3 TRAEs (RR = 0.71 [95% CI 0.30-1.67]) versus ipilimumab/nivolumab., Conclusion: Relatlimab/nivolumab showed similar PFS and ORR compared to ipilimumab/nivolumab, with a trend for a better safety profile., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof. Genova reported receipt of Grants from Italian Ministry of Health and BMS, and Honoraria from AstraZeneca, BMS, Eli Lilly, MSD, Roche, Sanofi, Takeda, ThermoFisher. Prof. Del Mastro reported receipt of speaker Honoraria from Roche, Novartis, Eli Lilly and MSD; Travel Grants from Roche, Pfizer and Celgene; participation on Advisory Board for Roche, Novartis, MSD, Pfizer, Ipsen, AstraZeneca, Genomic Health, Eli Lilly, Seattle Genetics, Eisai, Pierre Fabre, and Daiichi Sankyo. Prof. Lambertini reported receipt of personal fees (advisory role and/or speaker honoraria) from Roche, Takeda, Sandoz, Eli Lilly, Pfizer, AstraZeneca, Novartis Exact Sciences and Ipsen. Prof. Spagnolo reported receipt of Honoraria for presentations or lectures from Sanofi Genzyme, Roche, BMS, Novartis, Merk, Sun Pharma, MSD, Pierre Fabre; participation on Advisory Board for Novartis, Philogen SunPharma, and MSD. The remaining authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) have revolutionised clinical practice in oncology in the last years, leading to a survival benefit in several tumour types. To investigate whether these benefits are associated with improved quality of life, we conducted a systematic review and meta-analysis comparing patient-reported outcomes (PROs) between ICIs and standard chemotherapy (CT) in patients with advanced solid tumours., Methods: Clinical trials comparing the efficacy of ICIs (either programmed death receptor-1 and programmed death-ligand 1 inhibitors or cytotoxic T-lymphocyte antigen 4 inhibitors, as single agent or in combination) versus CT were included. Trials evaluating treatment with ICIs plus CT versus CT alone were also included, whereas studies in which the control arm included other anticancer agents (such as targeted therapy and other ICIs) or placebo alone were excluded. The aim of our meta-analysis was to compare PROs in subjects treated with ICIs or ICIs plus CT (intervention) with those reported by patients receiving CT (control). The co-primary endpoints were time from baseline to first deterioration in PROs, defined as the time from baseline to the first clinically significant deterioration in PROs, and the changes in PROs from baseline to follow-up between ICI and CT treatment groups (PROSPERO registration number CRD42021247440)., Results: A total of 8341 patients from 17 randomised trials of ICI versus CT were included in the analysis. Treatment with ICI delayed clinical deterioration over standard CT in Global Health Status/QoL EORTC QLQ-C30 (hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.74-0.89), and in both EQ-5D utility index (HR 0.65; 95% CI, 0.52-0.82) and EQ-5D visual analogue scale (VAS; HR 0.70; 95% CI, 0.61-0.80). The difference in mean change between the ICI-treated group and the CT-treated group was 5.82 (95% CI, 4.11-7.53) in favour of ICI. Similarly, in the EQ-5D, the mean change differences favoured treatment with ICIs in both Utility Index and VAS, with differences of 0.05 (95% CI, 0.03-0.07) and 5.41 (95% CI, 3.39-7.43), respectively., Conclusions: ICIs are associated with higher levels of quality of life and longer time to clinical deterioration on several PROs scales compared with CT in different types of solid tumours., Competing Interests: Conflict of interest statement F.S. received honoraria for presentations or lectures from Sanofi, Roche, BMS, Novartis, Merk, SunPharma, MSD, Pierre Fabre, and served on advisory boards of Novartis, Philogen, SunPharma and MSD; M.L. received honoraria for advisory role for Roche, Lilly, Novartis and AstraZeneca and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Takeda outside the submitted work. All other authors disclosed no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) may cause potentially life-threatening adverse events (AEs), but the risk of cardiotoxicity has not been fully investigated. It is also unknown whether ICI combinations increase cardiotoxicity compared with single ICI. We aimed to assess the cardiotoxicity of ICI in a range of tumour types., Methods: This systematic review and meta-analysis was conducted according to PRISMA guidelines (PROSPERO registration number: CRD42020183524). A systematic search of PubMed, MEDLINE, Embase databases, and conference proceedings was performed up to 30 June 2020. All randomised clinical trials comparing ICI with other treatments (primary objective) or dual-agent ICI versus single-agent ICI (secondary objective) in any solid tumour were included. Pooled risk ratios (RRs) with 95% confidence intervals (95% CIs) for cardiotoxicity events were calculated using random effect models., Results: Eighty studies including 35,337 patients were included in the analysis (66 studies with 34,664 patients for the primary endpoint and 14 studies with 673 patients for the secondary endpoint). No significant differences in terms of cardiac AEs were observed between ICI and non-ICI groups (RR 1.14, 95% CI 0.88-1.48, p = 0.326) nor between dual ICI and single ICI groups (RR 1.91, 95% CI 0.52-7.01, p = 0.329). Myocarditis incidence did not significantly differ between ICI and non-ICI groups (RR 1.11, 95% CI 0.64-1.92, p = 0.701) nor between dual ICI and single ICI groups (RR 1.10, 95% CI 0.31-3.87, p = 0.881). No differences were observed in subgroup analyses according to tumour type, setting of disease, treatment line, and type of treatment., Conclusion: The use of ICI as single or combination regimens is not associated with increased risk of cardiotoxicity., Competing Interests: Conflict of interest statement This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article. EA, MC, and MB have no conflicts of interest to declare. DEF funding for his ESMO fellowship (2018–2019) from Novartis and received honoraria from Janssen for speaking (outside the submitted work). ML acted as a consultant for Roche and Novartis and received honoraria from Theramex, Takeda, Roche, Lilly, Pfizer, and Novartis (outside the submitted work). NP acted as a consultant for Lilly and has received honoraria from Roche, Lilly, Novartis, and AstraZeneca (outside the submitted work). CP has received honoraria for speaking at educational meetings from Amgen, Ferring, Incyte, Ipsen, Novartis, Pfizer, and Roche (outside the submitted work). AHA received advisory role, speaker fees, and research funding for his institute from Roche, Lilly, Amgen, EISAI, BMS, Pfizer, Novartis, MSD, Genomic Health, Ipsen, AstraZeneca, Bayer, and Leo Pharma (outside the submitted work). AS is a member of the advisory boards at BMS, Servier, Gilead, Pfizer, Eisai, Bayer, and MSD; participated in conference at Takeda, Roche, AbbVie and Amgen, Celgene, AstraZeneca, Lilly, Sandoz, Novartis, BMS, Servier, Gilead, Pfizer, ArQule, and Eisai; and was a consultant at ArQule (outside the submitted work). MP was a board member (Scientific Board) at Oncolytics, Radius; was a consultant (honoraria) at AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Oncolytics, Periphagen, Pfizer, Roche, and Seattle Genetics; and received grants to her institute from AstraZeneca, Lilly, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, and Synthon (outside the submitted work). EdA received honoraria from and was a member of advisory board at Roche/GNE, Novartis, Seattle Genetics, Zodiacs, Libbs, and Pierre Fabre; received travel grants from Roche/GNE and GSK/Novartis; received grant for his institute from Roche/GNE, Astra-Zeneca, Novartis, and Servier (outside the submitted work)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Luminal A-like and luminal B-like subtypes have different sensitivity to (neo)adjuvant chemotherapy, but their role in predicting dose-dense (DD) efficacy in the high-risk setting is unknown. In this exploratory analysis of the Gruppo Italiano Mammella 2 (GIM2) trial, we investigated DD efficacy according to luminal-like subtypes., Methods: Patients with node-positive early breast cancer were randomised to receive either DD or standard-interval (SI) anthracycline-based chemotherapy followed by paclitaxel. In our analysis, luminal A-like cohort was identified as having a Ki67 < 20% and a progesterone receptor (PgR) ≥ 20%; luminal B-like cohort as having a Ki67 ≥ 20% and/or a PgR < 20%., Results: Out of 2003 patients enrolled in the GIM2 trial, 412 had luminal A-like and 638 luminal B-like breast cancer. After a median follow-up of 7.9 years, disease-free survival (DFS) was 80.8% (95% confidence interval [CI] 76.4-84.5) and 70.5% (66.5-74.2) in luminal A-like and luminal B-like cohorts; overall survival (OS) was 91.6% (88.2-94.1) and 85.1% (81.7-87.9), respectively. We found no significant interaction between treatment and luminal subtype (interaction p = 0.603 and 0.535 for DFS and OS, respectively). When DD efficacy was investigated separately in each cohort, luminal-B like cohort appeared to benefit more from the DD schedule both in terms of DFS (unadjusted hazard ratio [HR] 0.72 [95% CI 0.54-0.96]) and OS (unadjusted HR 0.61 [95% CI 0.40-0.94]), compared with the luminal A-like cohort (unadjusted HR for DFS 0.89 [95% CI 0.59-1.33]; unadjusted HR for OS 0.83 [95% CI 0.45-1.54])., Conclusions: No significant interaction between luminal-like subtype and treatment was observed. Patients in the luminal B-like cohort seemed to benefit more from DD schedule., Competing Interests: Conflict of interest statement L.D.M. declares honoraria from Roche, Pfizer, Ipsen, Eli Lilly, Eisai, Novartis, Takeda and MSD and Seattle Genetics; a consulting and advisory role for Roche and Eli Lilly and fees for travel, accommodation and expenses from Roche, Pfizer and Celgene outside the submitted work. M.L. served as a consultant for Teva and received speaker honoraria from Theramex outside the submitted work. O.G. received personal fees from Celgene, Eisai, Pfizer, Amgen, Eli Lilly and Novartis; travel and accommodation expenses from Celgene, Roche and Pfizer and research funding from Eisai outside the submitted work. F.P. received honoraria for advisory boards, activities as a speaker, travel grants, research grants from Agmen, Celgene, Eli Lilly, Ipsen, MSD, Novartis, Pierre-Fabre, Pfizer and Takeda and received research funding from Astrazeneca, Eisai and Roche outside the submitted work. M.D.L. declares consulting fees from Pfizer, Novartis, Eli Lilly, Roche, Eisai and Celgene outside the submitted work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

It has been demonstrated that the prognosis of ovarian cancer is influenced by the dose intensity of cytotoxic treatment. The impact of received dose intensity of platinum-based combination chemotherapy on disease outcome was analysed in 226 stage III-IV ovarian cancer patients entered into two prospective randomised trials. All patients received either cisplatin or carboplatin and cyclophosphamide with or without doxorubicin for six courses after primary surgery. The impact of the received dose intensity of each drug (RDI), the average received dose intensity of the treatment regimen (ARDI) and the relative total drug dose (RTD) on progression-free survival (PFS) and survival were analysed. In the 198 patients receiving the full six courses of treatment, RDI of cisplatin or carboplatin, ARDI and RTD were > 0.76 in 74.2, 61.1 and 65.1% of cases, respectively. Although the differences were not significant, pathological complete response was more frequently observed in the group of patients with ARDI < 0.75, whereas the partial response rate was higher in the ARDI > or = 0.76 group. Median survival and PFS were 19 and 13 months; 22 and 10 months; 23 and 13 months for the groups of patients receiving chemotherapy at a ARDI of < 0.75, > or = 0.76-0.99 and > 1.00, respectively (P = not significant). It appears that modest dose modifications and brief treatment delays during first-line platinum-based chemotherapy do not affect response rate, survival and PFS in advanced ovarian cancer patients.

87 patients with high risk of recurrence FIGO stage I and II ovarian carcinoma were treated with adjuvant chemotherapy consisting of cisplatin 50 mg/m2 plus cyclophosphamide 600 mg/m2 on day 1 every 28 days for 6 courses. Toxicity and efficacy of the regimen was evaluated after a median follow-up of 45 months. Treatment-related toxicity was mild and reversible, consisting chiefly of acute WHO grade 2 myelosuppression (10% of patients) and controllable grade 3 emesis (55%). No late toxicity was observed. Actuarial 7-year survival and relapse-free survival (RFS) were 76% and 61%, respectively; a statistically significant difference in outcome was observed for undifferentiated grade tumour (G1 vs. G2 vs. G3: P less than 0.01) but not for FIGO stage disease (stage I vs. stage II). In our opinion, short-term chemotherapy including the most active single agent, i.e. cisplatin, appears a tolerable and effective treatment which deserves further evaluation in large randomised trials.