FGFR2 gene aberrations (GA) include fusions and mutations/amplifications, with an estimated prevalence of approximately 15% and 5% in iCCA, respectively. While FGFR2 fusions are acknowledged ...oncogenic drivers, the oncogenic potential of FGFR2 mutations and amplifications is less well defined, due to ambiguous available preclinical and clinical data. In a non-comparative Phase 2a study (NCT01752920), the potent pan-FGFR inhibitor DZB was administered to iCCA pts expressing either FGFR2-fusion (N=29), FGFR2 mutations/amplifications (N=6) or no FGFR gene aberration (N=9). Here, we present a post-hoc analysis of outcomes of iCCA pts expressing FGFR mutations/amplifications (N=6) or no FGFR GA (N=9) as compared to previously reported data of iCCA pts (N=29) expressing FGFR2 fusions (Mazzaferro et al. 2018 BJC).
Pts received 300mg DZB QD PO. Eligibility criteria included a locally confirmed (FISH or NGS) testing of FGFR2 GA (fusions vs mutations/amplifications or no aberrations). Objective responses were determined per RECIST 1.1. Disease control rate (DCR) was defined by the summation of CR, PR and SD, and PFS, calculated from treatment initiation until disease progression or death.
The table shows the efficacy outcomes in the 3 patient groups. Types of drug-related adverse events were similar across groups. No new safety signals were identified.Table721PTableiCCA patient groupFGFR2 fusion N=29FGFR2 mutation/ amplification N=6No FGFR2 genomic aberration N=9Objective response rate (RECIST 1.1)6 (21%)0 (0%)0 (0%)DCR (PR or SD)24 (83%)4 (67%)2 (22%)Any target lesion diameter reduction18 (62%)4 (67%)0 (0%)Median (95% CI) Progression free survival (PFS), months5.76.71.5(4.0-9.2)(1.0-14.7)(0.7 – NA)% PFS at 3 months83%67%0%% PFS at 6 months47%50%0%
Anti-tumor efficacy of DZB as measured by DCR and PFS in iCCA patients harboring an FGFR2 GA seems to be similar for patients with FGFR2 fusions and FGFR2 mutations/amplifications, while patients without any detectable FGFR GA appear to derive no benefit from DZB treatment. While the influence of prognostic variables still has to be confirmed, the anti-tumor efficacy of DZB seen in pts with FGFR2 GA other than fusions warrant further clinical investigation.
Basilea Pharmaceutica International Ltd.
Basilea Pharmaceutica International Ltd.
S. Braun: Full / Part-time employment: Basilea Pharmaceutica Int. Ltd.; Shareholder / Stockholder / Stock options: Ipsen. B. El-Rayes: Advisory / Consultancy: Merrimack; Advisory / Consultancy: BTG; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Loxo; Honoraria (self), Advisory / Consultancy: RTI Health Solutions; Honoraria (self), Speaker Bureau / Expert testimony: Lexicon; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Cleave Biosciences; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): AVEO; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Hoosier Cancer Research Network; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): PPD; Research grant / Funding (institution): Merck; Research grant / Funding (institution): ICON Clinical Research. W.P. Harris: Advisory / Consultancy: Neo Therma; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): ArQule; Research grant / Funding (institution): Halozyme; Research grant / Funding (institution): Nordion; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Agios. N. Damjanov: Advisory / Consultancy: Bayer; Advisory / Consultancy: Amgen; Advisory / Consultancy: Celgene; Honoraria (self): Sirtex Medical. L. Rimassa: Advisory / Consultancy: Bayer; Advisory / Consultancy: Sirtex Medical; Advisory / Consultancy: Italfarmaco; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: ArQule; Advisory / Consultancy: Baxter; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Amgen; Advisory / Consultancy: Incyte; Advisory / Consultancy: Celgene; Advisory / Consultancy: Eisai; Advisory / Consultancy: Lilly; Honoraria (self): AstraZeneca; Honoraria (self): AbbVie; Honoraria (self): Gilead Sciences; Honoraria (self): Roche. F. Braiteh: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Clovis Oncology; Shareholder / Stockholder / Stock options: Agios; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Insys Therapeutics; Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Tesaro; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Incyte; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Regeneron; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lexicon; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Taiho Pharmaceutical; Travel / Accommodation / Expenses: Heron. S. Lonardi: Advisory / Consultancy, Research grant / Funding (self): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Servier. M. Engelhardt: Full / Part-time employment: Basilea Pharmaceutica Int. Ltd. M. Saulay: Full / Part-time employment: Basilea Pharmaceutica Int. Ltd. B. Schwartz: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: ArQule; Advisory / Consultancy: CIRM. W.L. Shaib: Research grant / Funding (institution): ArQule; Research grant / Funding (institution): Lilly. V. Mazzaferro: Advisory / Consultancy: Terumo Europe NV; Speaker Bureau / Expert testimony: Ipsen AB. K.P. Papadopoulos: Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): ArQule; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): ARMO BioSciences; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Curegenix; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): 3D Medicines; Research grant / Funding (institution): Formation Biologics; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Syros Pharmaceuticals; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): OncoMed. All other authors have declared no conflicts of interest.
Background and Aims
Recent advances in systemic treatments for hepatocellular carcinoma (HCC) have driven the discussion on their possible role for downstaging advanced HCC prior to liver ...transplantation (LT) or for bridging to LT to prevent tumor progression and reduce the dropout risk. The aim of this study was to evaluate the outcome of patients treated with TKIs before LT.
Method
an online survey was sent to all centers affiliated to the ELITA/ELTR network between June and December 2022. Demographic and clinical data were retrospectively collected.
Results
Fifty-two patients, median age 60.5 years, receiving a LT between December 2006 and September 2022 were enrolled. Thirty patients (57.6%) were treated with TKI with a downstaging purpose, while 22 (42.3%) received TKI as a bridging treatment to LT. 34 patients (65%) received sorafenib, 15 lenvatinib (28%) and 3 patients (3%) a sequential therapy with sorafenib-regorafenib. Forty-eight patients (92%) received at least one locoregional treatment before LT. Only 12 patients (23%) were in Milan criteria at treatment start time. Twenty-nine patients were Milan-in at listing (55.7%). Nine patients had neoplastic portal vein thrombosis (17.3%). The five-year survival was 70% (Figure 1). After a median time of 7.7 months (5-12.7), 7 patients (13%) experienced HCC recurrence. The only factor associated with HCC recurrence was AFP (p 0.02) at LT-We observed only a single recurrence in one of the patients with neoplastic thrombosis. Twelve patients (23%) experienced vascular or early bleeding complications after LT. The type of TKIs or the time from the last dose to LT didn't influence the risk of post-LT complications.
Conclusions
This is the largest collected series of patients receiving TKIs pre-LT as downstaging/bridging therapy, with a very favourable long-term outcome (70 % at 5 years) even in patients with neoplastic vein thrombosis.
Background
Access to the liver transplant waitlist for patients with hepatocellular carcinoma (HCC) depends on tumour presentation, biology, and response to treatments. The Milan Criteria (MC) ...represent the benchmark for expanded criteria that incorporate additional prognostic factors. The purpose of this study was to determine the added value of skeletal muscle index (SMI) in HCC patients beyond the MC.
Method
Patients with HCC that were transplanted beyond the MC were included in this retrospective multicentre study. SMI was quantified using the Computed Tomography (CT) within 3 months prior to transplantation. Cox regression models were used to identify predictors of overall survival (OS). The discriminative performance of SMI extended Metroticket 2.0 and AFP models was also assessed.
Results
Out of 889 patients transplanted outside the MC, 528 had a CT scan within 3 months prior to liver transplantation (LT), of whom 176 (33%) were classified as sarcopenic. The median time between assessment of the SMI and LT was 1.8 months (IQR: 0.77–2.67). The median follow‐up period was 5.1 95% CI 4.7–5.5 years, with a total of 177 recorded deaths from any cause. In a linear regression model with SMI as the dependent variable, only male gender (8.55 95% CI 6.51–10.59, P < 0.001) and body mass index (0.74 95% CI 0.59–0.89, P < 0.001) were significant. Univariable survival analysis of patients with sarcopenia versus patients without sarcopenia showed a significant difference in OS (HR 1.44 95% CI 1.07 − 1.94, P = 0.018). Also the SMI was significant (HR 0.98 95% CI 0.96–0.99, P = 0.014). The survival difference between the lowest SMI quartile versus the highest SMI quartile was significant (log‐rank: P = 0.005) with 5 year OS of 57% and 71%, respectively. Data from 423 patients, describing 139 deaths, was used for multivariate analysis. Both sarcopenia (HR 1.45 95% CI 1.02 − 2.05, P = 0.036) and SMI were (HR 0.98 95% CI 0.95–0.99, P = 0.035) significant. On the survival scale this translates to a 5 year OS difference of 11% between sarcopenia and no sarcopenia. Whereas for SMI, this translates to a survival difference of 8% between first and third quartiles for both genders.
Conclusions
Overall, we can conclude that higher muscle mass contributes to a better long‐term survival. However, for individual patients, low muscle mass should not be considered an absolute contra‐indication for LT as its discriminatory performance was limited.
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