Abstract 2196
Background
Despite decades of research, performance of DPYD genotyping to predict FP toxicity (tox) is poorly documented. GPCO-UNICANCER and RNPGx groups initiated the FUSAFE MA on individual patient data (IPD) to assess the prognostic value of consensual deleterious DPYD variants on grade (G) 4-5 FP tox.
Methods
Eligibility criteria included unbiased recruitment of Caucasian patients (pts) without FP dose adjustment based on DPD status. Main endpoint was 12 weeks hematological or digestive G4-5 tox. Age, sex, body mass index (BMI), advanced stage (M- vs M+), FP drug (5FU vs capecitabine), FP administration (bolus±continuous vs continuous alone or p.o.) and associated anticancer drugs (AAD) were collected. Multivariable logistic models were applied. Performance was assessed by AUC and diagnostic indices maximizing Youden index.
Results
From the 18 identified eligible studies (10230 pts), 14 were included (9030 pts), with complete IPD collected for 6403 pts (84% colorectal, 16% M+, 66% 5FU, 80% AAD). G4-5 tox prevalence was 8% (518 events). DPYD variants *2A, D949V, *13 and HapB3 were carried by 0.9%, 1.2%, 0.2% and 3.9% of pts, respectively. The clinical model (M1) retained age, sex, BMI, FP-administration, AAD. Adding variants *2A/D949V/*13 (at least one mutated allele) significantly (p<.0001) improved the model (M2). Further adding HapB3 did not improve the model (p=.24, M3). M3-adjusted OR (95%CI) was 10.0 (6.9-14.7) for the 3 variants *2A/D949V/*13 and 2.1 (1.4-3.0) for HapB3. Similar results were observed on colorectal pts only, or when excluding bolus administration alone.Table:
569P
Model | AUC (area under the curve) | Sensitivity | Specificity | Positive predictive value | Negative predictive value |
---|---|---|---|---|---|
M1 | 0.725 | 69.7% | 65.4% | 15.1% | 96.1% |
M2 | 0.750 | 75.5% | 62.8% | 15.2% | 96.7% |
M3 | 0.752 | 76.4% | 61.9% | 15.0% | 96.8% |
Conclusions
This is the largest MA on DPYD genotyping and toxicity. It shows the relevance of clinical variables and of the 3 consensual DPYD variants. Despite its association with tox, HapB3 does not improve the discriminant ability to identify pts at risk of G4-5 toxicity.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Centre Antoine Lacassagne, Nice, France (Dr Marie-Christine Etienne-Grimaldi, coordinator).
Funding
French Cancer Institute (INCa) funding (PHRC-K 14-193 FUSAFE) and French Ligue Nationale Contre le Cancer.
Disclosure
V. Boige: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Travel / Accommodation / Expenses: Roche Genentech; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Ipsen; Advisory / Consultancy: Prestizia; Advisory / Consultancy: Eisai; Travel / Accommodation / Expenses: Sanofi. J. Taieb: Advisory / Consultancy: Amgen; Advisory / Consultancy: Lily; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: MSD; Advisory / Consultancy: Celgene; Advisory / Consultancy: Servier; Advisory / Consultancy: Sirtex; Advisory / Consultancy: Pierre Fabre. D. Meulendijks: Full / Part-time employment: AstraZeneca UK. C. Palles: Advisory / Consultancy: Oxford Cancer Biomarkers. U. Zanger: Licensing / Royalties: Robert Bosch GmbH. M. Boisdron-Celle: Speaker Bureau / Expert testimony, Leadership role, Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: ODPM. A. Marinaki: Full / Part-time employment: Viapath. E. Gross: Licensing / Royalties: Klinikum Rechts der Isar der Technischen Universitat Munchen. All other authors have declared no conflicts of interest.
Resources from the same session
3191 - The efficacy and safety of lenvatinib in patients who did not meet the inclusion criteria of the phase 3 trial (REFLECT trial) and those with BCLC Stage B hepatocellular carcinoma - A nationwide multicenter study in Japan-
Presenter: Azusa Sakamoto
Session: Poster Display session 2
Resources:
Abstract
1529 - Prognostic and predictive value of baseline alpha-fetoprotein (AFP) in patients with advanced hepatocellular carcinoma (HCC) treated with ramucirumab from two phase 3 studies (REACH, REACH-2)
Presenter: Andrew Zhu
Session: Poster Display session 2
Resources:
Abstract
2767 - Effect of second-line cabozantinib on health states for patients with advanced hepatocellular carcinoma (aHCC) after sorafenib: QTWiST analysis from the CELESTIAL study
Presenter: Nicholas Freemantle
Session: Poster Display session 2
Resources:
Abstract
2150 - Alpha-fetoprotein (AFP) response in patients with unresectable hepatocellular carcinoma (HCC) in the phase 3 RESORCE trial
Presenter: Jordi Bruix
Session: Poster Display session 2
Resources:
Abstract
3437 - Phase I/II trial of NBTXR3 activated by SBRT in patients with hepatocellular carcinoma or liver metastasis
Presenter: Marc Pracht
Session: Poster Display session 2
Resources:
Abstract
1758 - Efficacy and safety of ramucirumab (RAM) for advanced hepatocellular carcinoma (HCC) with elevated alpha-fetoprotein (AFP) following first-line sorafenib across age subgroups in two global phase 3 trials (REACH and REACH-2)
Presenter: Masatoshi Kudo
Session: Poster Display session 2
Resources:
Abstract
1192 - Ramucirumab in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha fetoprotein (AFP): An exposure–response analysis
Presenter: Josep Llovet
Session: Poster Display session 2
Resources:
Abstract
1600 - Outcomes of Hepatocellular Carcinoma (HCC) Patients Treated with Nivolumab: The Mount Sinai Hospital Experience.
Presenter: Sirish Dharmapuri
Session: Poster Display session 2
Resources:
Abstract
2364 - Pembrolizumab vs Chemotherapy in Patients With Advanced/Metastatic Adenocarcinoma (AC) or Squamous Cell Carcinoma (SCC) of the Esophagus as Second-Line Therapy: Analysis of the Chinese Subgroup in KEYNOTE-181
Presenter: Jia Chen
Session: Poster Display session 2
Resources:
Abstract
1933 - A national comparative effectiveness study to assess definitive chemoradiation regimens in proximal oesophageal squamous cell cancer
Presenter: Judith de Vos-Geelen
Session: Poster Display session 2
Resources:
Abstract