- Hanneke W. Van Laarhoven (Amsterdam, Netherlands)
- Florian Lordick (Leipzig, Germany)
- Russell Petty (Dundee, Scotland, United Kingdom)
- Ana C. Raimundo (Porto, Portugal)
673PD - Nab-paclitaxel (Nab) plus gemcitabine (G) is more effective than G alone in locally advanced, unresectable pancreatic cancer (LAUPC): The GAP trial, a GISCAD phase II comparative randomized trial (ID 3222)
- Stefano Cascinu (Modena, Italy)
Abstract
Background
The role of a combination therapy is defined in metastatic pancreatic cancer but not in LAUPC. Lacking dedicated randomized trials, evidence mostly comes from retrospective or phase II studies. G alone remains the standard option following a subgroup LAUPC analysis of a GERCOR/GISCAD trial (J Clin Oncol 2005).
Methods
GAP is a multicentre, open-label, randomized, comparative phase II trial testing the efficacy of NabG vs G. Patients ≤75 years, PS 0-1, were randomized 1:1 to Nab/G (Nab 125 mg/mq plus G 1000 mg/mq on days 1, 8 and 15 every 28 days for 3 cycles) or G (same schedule and doses). Patients not progressing after 3 cycles had to receive capecitabine plus radiotherapy for 5 weeks. Disease progression rate (DPR) according to RECIST 1.1 after 3 cycles of chemotherapy is the primary endpoint. With 80% power in detecting a reduction of DPR from 40% to 20%, one-tailed alpha=0.05, 124 patients were required. Progression-free survival (PFS) is a secondary endpoint; with 109 events the study has 80% power, with one-tailed alpha=0.05, to detect a 0.62 hazard ratio of PFS.
Results
124 patients were enrolled in this trial (4 withdrew consent after randomization in the G arm). Most of the patients were PS 0 (65.8%), and women (56.7%). The study met its primary endpoint DPR, with a reduction from 45.6% with G to 25.4% with Nab/G. There was no unexpected toxicity. One patient died during treatment with G due to a stroke. 673PDArm Patients DPR One-tail chi square Median PFS (102 events) HR of PFS Progression at distant site Median OS (82 events) HR of OS G 57 26 (45.6%) P = 0.01 5.1 mos 0.71 (90% CI 0.51-0.99) 18/26 10.7 mos 0.65 (90% CI 0.44-0.94) NabG 63 16 (25.4%) 7.6 mos 6/16 13.1 mos
Conclusions
NabG reduces the rate of LAUPC patients who progress after 3 cycles of chemotherapy compared with G, especially in terms of distant relapses, positively affecting PFS and overall survival. Nowadays it should be the therapeutic option in this setting.
Clinical trial identification
NCT02043730; 2013-002973-23.
Legal entity responsible for the study
Fondazione GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente).
Funding
Celgene.
Disclosure
S. Cascinu: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier; Advisory / Consultancy: Amgen; Research grant / Funding (self), Travel / Accommodation / Expenses: Celgene; Honoraria (self): Sanofi; Research grant / Funding (self): Eisai. R. Bianco: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Italfarmaco; Advisory / Consultancy: AstraZeneca. D. Ferrari: Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bristol-Meyers Squibb; Travel / Accommodation / Expenses: Roche. L. Cavanna: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Celgene. G.D. Beretta: Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Servier; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Taiho Pharmaceutical. A. Sobrero: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Serono; Advisory / Consultancy: Servier; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Takeda; Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Bristol-Meyers Squibb. A. Morabito: Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Ipsen; Honoraria (self): Delphi Diagnostics; Honoraria (self): Servier; Research grant / Funding (institution): Celgene. M.C. Piccirillo: Advisory / Consultancy: Glaxo; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Bayer; Honoraria (self): MSD; Research grant / Funding (institution): Roche. All other authors have declared no conflicts of interest.
674PD - Perioperative FLOT + anti-PD-L1 avelumab (FLOT-A) chemo-immunotherapy in resectable oesophagogastric adenocarcinoma (OGA): Safety and biomarker data from the ICONIC trial safety run-in (ID 5184)
- Michael Davidson (London, United Kingdom)
Abstract
Background
ICONIC is a single arm phase 2 trial investigating the safety and efficacy of 4 cycles pre-operative and 4 cycles post-operative FLOT-A in resectable OGA. We report results from the safety run-in phase and early translational biomarker data.
Methods
Eligible pts were enrolled into the 3 + 3 design dose finding stage. Standard dose FLOT was administered with 10mg/kg iv avelumab q2 weeks (dose level 0). Dose limiting toxicities (DLTs) were assessed for 28d. Biopsies were taken at baseline and post cycle 2.
Results
At data cut-off (12/4/19) 6 pts were enrolled and completed pre-operative treatment. 1/6 pts experienced a DLT (chest pain during 5FU infusion), and dose level 0 was established as the safe dose for the efficacy stage of the trial. During pre-operative FLOT-A all pts experienced at least one grade 1-2 adverse event (AE), most commonly diarrhoea (5/6 pts), fatigue, nausea, peripheral neuropathy and hypokalaemia (all 4/6 pts); 3/6 pts experienced at least one grade 3-4 AE: neutropenia and elevated liver enzymes (1 pt), thrombotic event (1 pt) and cardiac chest pain (1 pt). 4/6 pts reported any grade chest pain and underwent cardiac work up: 1 episode was due to PE, 1 of likely GI origin and 2 cardiac in nature, which then recurred in one pt who was re-exposed to FLOT without avelumab. 3/6 pts completed 4 cycles pre-operative FLOT-A: 1 pt discontinued avelumab due to diarrhoea, 2 pts discontinued FLOT-A due to cardiac chest pain and switched to a regimen without 5FU. 5 pts have undergone surgery at data cut-off, without unexpected complications. Immunofluorescence shows changes of CD8-, memory- and regulatory T cell infiltrates between baseline and on-treatment biopsies, and detailed results will be presented.
Conclusions
This is the first data showing that FLOT can be combined with a PD-L1-inhibitor with FLOT-A having a manageable safety profile at dose level 0 (standard dose FLOT + 10mg/kg avelumab). As chest pain of variable aetiologies was observed in 4/6 patients this will be closely monitored and assessed during the efficacy phase. No unexpected complications have been observed during surgery following FLOT-A treatment.
Clinical trial identification
2016-003306-13.
Legal entity responsible for the study
Royal Marsden Hospitals NHS Foundation Trust.
Funding
Royal Marsden Hospital NHS Foundation Trust Institute of Cancer Research, Merck Pharmaceuticals.
Disclosure
M. Davidson: Travel / Accommodation / Expenses: Celgene. N. Starling: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck; Honoraria (institution): AstraZeneca. I. Chau: Advisory / Consultancy: Eli-Lilly; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): Eli-Lilly; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Sanofi Oncology; Research grant / Funding (institution): Merck-Serono; Honoraria (institution): Eli-Lilly. D. Cunningham: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Merck-Serono; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Merrimack; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi. D. Morganstein: Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Roche. M.D. Forster: Research grant / Funding (institution): Merck; Honoraria (institution): Merck. M. Gerlinger: Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS. All other authors have declared no conflicts of interest.
Invited Discussant 673PD and 674PD (ID 6765)
- Hanneke W. Van Laarhoven (Amsterdam, Netherlands)
Q&A led by Discussant (ID 6771)
LBA45 - Health-related quality of life (HRQoL) impact of pembrolizumab (P) versus chemotherapy (C) as first-line (1L) treatment in PD-L1–positive advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (ID 4638)
- Eric Van Cutsem (Leuven, Belgium)
Abstract
Background
KEYNOTE-062 (NCT02494583) was a randomized, active-controlled, phase III clinical trial of 1L P or P+C versus C in patients with HER2–negative, advanced G/GEJ with PD-L1 combined positive score (CPS) ≥1. P showed noninferiority to C for overall survival (OS) in CPS ≥1 and clinically meaningful improvement for OS in CPS ≥10. We present results of prespecified HRQoL analyses for P versus C in the population with CPS ≥1.
Methods
The EORTC QLQ-C30 and EORTC QLQ-STO22 were administered at baseline, weeks 3, 6, 9, and 12, and every 6 weeks thereafter up to 1 year or end of treatment, whichever came first, and the 30-day posttreatment discontinuation follow-up visit. Data from patients receiving ≥1 dose of study treatment and completing ≥1 HRQoL assessment were analyzed. Least square mean (LSM) score change from baseline to prespecified week 18, 95% CI, and nominal P values were calculated. Time to deterioration (TTD) (≥10-point decline from baseline) was assessed by Kaplan-Meier method and Cox regression model. HRs, 95% CIs, and nominal P values are provided.
Results
The HRQoL population included 495 patients with PD-L1 CPS ≥1 (P, n = 252; C, n = 243). Compliance at week 18 was similar in both P and C arms for QLQ-C30 (87.9% and 81.9%, respectively) and QLC-STO22 (87.9% and 81.3%, respectively). There was no significant difference in LSM score change from baseline to week 18 between arms (–0.16; 95% CI, –5.01 to 4.69; P = 0.948) in global health status (GHS)/QoL. The LSM score change from baseline to week 18 for most QLQ-C30 and QLQ-STO22 subscales/items showed comparable but not statistically significant worsening in both treatment arms. TTD for GHS/QoL (HR, 0.96; 95% CI, 0.67-1.38; P = 0.826), appetite loss subscale in QLQ-C30 (HR, 0.83; 95% CI, 0.58-1.20; P = 0.314), and pain subscale in QLQ-STO22 (HR, 1.22; 95% CI, 0.78-1.91; P = 0.381) were similar between arms. Significantly longer TTD was observed for P than for C for the nausea/vomiting subscale in QLQ-C30 (HR, 0.61; 95% CI, 0.44-0.85; P = 0.003).
Conclusions
HRQoL was similar between P and C in 1L treatment in patients with advanced G/GEJ adenocarcinoma with CPS ≥1.
Clinical trial identification
NCT02494583; July 10, 2015.
Editorial acknowledgement
Medical writing and/or editorial assistance was provided by Amy McQuay, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA) and funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Legal entity responsible for the study
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD).
Funding
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
Disclosure
E. Van Cutsem: Advisory / Consultancy: Astellas, Astrazeneca, Bayer, Bristol-Myers Squibb, Celgene, Incyte, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier; Research grant / Funding (institution): Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Roche, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. A. Valderrama: Full / Part-time employment: Merck & Co., Inc.. Y. Bang: Advisory / Consultancy: AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serano , Bayer, BMS, Eli Lilly, Taiho, Daiich-Sankyo, Astellas, BeiGene, GreenCross, Samyang Biopharm, Hanmi, Genexine; Research grant / Funding (institution): AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serano, Bayer, BMS, GSK, Pfizer, Eli Lilly, Boehringer-Ingelheim, MacroGenics, Boston Biomedical, FivePrime, Curis, Taiho, Takeda, Ono, Daiichi Sankyo, Astellas, BeiGene, Green Cross, CKD Pharma, Genexi. C. Fuchs: Advisory / Consultancy: Agios, Bain Capital, Bayer, Celgene, Dicerna, Five Prime Therapeutics, Gilead Sciences, Eli Lilly, Genentech, KEW, Merck, Merrimack Pharmaceuticals, Pfizer, Sanofi, Taiho, and Unum Therapeutics; Leadership role, Shareholder / Stockholder / Stock options, Director for CytomX; unexercised stock options: CytomX Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options, unexercised stock options : Entrinsic Health. K. Shitara: Honoraria (self): Novartis; Honoraria (self): AbbVie; Honoraria (self): Yakult; Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Advisory / Consultancy, Research grant / Funding (institution): MSD; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Chugai Pharma; Research grant / Funding (institution): MediScience. Y.Y. Janjigian: Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Michael J Hennessey; Advisory / Consultancy: Jounce Therapeutics; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: ONO Pharma; Advisory / Consultancy: Merck & Co., Inc.; Advisory / Consultancy: Bristol-Myers Squibb. V. Shankaran: Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer. S. Stein: Advisory / Consultancy: Merck; Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: Genentech; Advisory / Consultancy: Exelixis; Advisory / Consultancy: QED. J.M. Norquist: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. U. Kher: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. S. Shah: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. M. Alsina: Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Servier. All other authors have declared no conflicts of interest.
LBA46 - Chemotherapy for frail and elderly patients (pts) with advanced gastroesophageal cancer (aGOAC): Quality of Life (QoL) results from the GO2 phase III trial (ID 5708)
- Peter Hall (Edinburgh, United Kingdom)
Abstract
Background
Many pts with aGOAC are elderly and/or frail. GO2 [ASCO 2019 #4006] found that lower dose OxaliplatinCapecitabine (OCap) led to non-inferior progression free survival, less toxicity and better patient-centred outcomes using a novel composite endpoint ‘Overall Treatment Utility’. QoL endpoints were chosen to reflect the balance between benefits and harms of the three dose levels and to help patients understand likely implications of treatment for shared decision making.
Methods
Eligible pts unsuitable for full-dose 3-drug chemotherapy due to frailty, but fit for OCap. Baseline assessment included QoL; symptoms; functional scales; comorbidity; frailty. Randomization was 1:1:1 to dose Level (Lvl) A (Ox 130 mg/m2d1, Cap 625 mg/m2bd d1-21, q21d), B (80% Lvl A doses) or C (60% Lvl A doses) until progression or decision to stop. An alternative randomisation option where chemo benefit was considered uncertain (‘uc’) was between OCap Lvl C and Best Supportive Care (BSC). QoL (EQ-VAS) was measured weekly during chemotherapy. QoL (EQ-5D), Fatigue (EORTC QLQ-C30 Fatigue scale) were measured 9-weekly for 1 year. QoL endpoints were analysed descriptively as pre-defined in the statistical analysis plan.
Results
558 pts were enrolled, 2014-17, 61 UK centres, of which 45 pts were in the uc randomisation. LBA46 a. higher=better; b. higher=worse; c. TDF=Time to deterioration in fatigue Longitudinal QoL and Fatigue over the one year follow-up period were very similar between arms. Cancer symptoms also improved to a similar extend in each arm.Lvl A Lvl B Lvl C Lvl C (‘uc’) BSC (‘uc’) Pts 170 171 173 23 22 Median Age 76 76 77 79 79 % PS ≥ 2 31 32 31 57 68 % Severely Frail 61 56 58 70 68 9 wk Δ QLQ QoLa +0.4 +5.3 +4.9 na na 9 wk Δ EQ-5D QoLa -0.01 +0.06 +0.8 -0.19 -0.35 9 wk Δ EQ-VAS QoLa +8.6 +3.4 +5.4 +2.7 +0.2 9 wk Δ Fatigueb +8.6 +3.4 -0.6 +4.0 +15.1 Median TDFc (mths) 7.1 5.4 6.5 na na
Conclusions
GO2 is the largest RCT to date investigating frail and/or elderly aGOAC pts, and should guide future treatment. Lower doses led to more rapid improvements in QoL and fatigue without compromising disease control or survival.
Clinical trial identification
EudraCT: 2013-000009-21; ISRCTN44687907 Rec No: 13/YH/0229.
Legal entity responsible for the study
University of Leeds.
Funding
Cancer Research UK.
Disclosure
All authors have declared no conflicts of interest.
675PD - POLO: Health-related quality of life (HRQoL) of olaparib maintenance treatment versus placebo in patients with a germline BRCA mutation and metastatic pancreatic cancer (mPC) (ID 4511)
- Pascal Hammel (Clichy, France)
Abstract
Background
In the Phase III POLO trial (NCT02184195) patients (pts) with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and mPC derived a statistically significant and clinically meaningful progression-free survival benefit from maintenance olaparib compared with placebo. HRQoL assessment was a predefined secondary objective.
Methods
Pts with a gBRCAm and mPC whose disease had not progressed during first-line platinum-based chemotherapy were randomized to receive maintenance olaparib tablets (300 mg bid) or placebo. Pts completed the EORTC QLQ-C30 questionnaire at baseline and every 4 wks until discontinuation, with calculated scores ranging from 1–100. A change of ≥ 10 points was predefined as clinically meaningful improvement (increase) or deterioration (decrease) for global HRQoL and physical function score. Overall adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TCMD) was analysed using a log-rank test.
Results
Analyses were conducted in 89/92 olaparib pts and 58/62 placebo pts with evaluable baseline forms (overall compliance was 96.6% and 94.8%). There was no difference between arms for global HRQoL score (Table). The adjusted mean difference for physical function scale did not reach the threshold considered to be clinically meaningful. Global HRQoL and physical function remained relatively stable over time. There was no difference in TCMD for olaparib versus placebo for global HRQoL (median 21.2 vs 6.0 mo, respectively; hazard ratio 0.72 [95% CI 0.41–1.27]) or physical function (medians not reached, 1.38 [0.73–2.63]). 675PD Pts had to have baseline and ≥1 post-baseline assessment NC, not calculated due to insufficient numbers of values; SE, standard errorGlobal HRQoL Physical function Maintenance olaparib Placebo Maintenance olaparib Placebo Absolute score, mean (n) Baseline 70.4 (89) 74.3 (58) 83.3 (89) 84.9 (58) Week 12 73.6 (66) 74.1 (36) 84.4 (67) 85.4 (36) Week 24 73.4 (41) NC 87.4 (43) NC Week 48 79.0 (23) NC 89.6 (23) NC Overall change from baseline* Adjusted mean ± SE (n) −1.2±1.4 (84) 1.3±1.9 (54) −2.1±1.3 (84) 2.4± 1.7 (54) Between group difference (95% CI) −2.5 (−7.3, 2.3) −4.5 (−8.7, −0.2) P value 0.31 0.04
Conclusions
HRQoL was preserved during maintenance olaparib treatment with no meaningful difference versus placebo. Findings support the observed clinical benefit of maintenance olaparib in pts with a gBRCAm and mPC.
Clinical trial identification
NCT02184195.
Editorial acknowledgement
Debbi Gorman, from Mudskipper Business, Ltd, funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A.
Legal entity responsible for the study
AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A.
Funding
AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A.
Disclosure
P. Hammel: Research grant / Funding (institution): Celgene; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution), Non-remunerated activity/ies: Erythec; Honoraria (self), Research grant / Funding (institution): Halozyme. H.L. Kindler: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Aldeyra Therapeutics; Advisory / Consultancy: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer-Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Erytech; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Ipsen Pharmaceuticals; Advisory / Consultancy: Kyowa; Advisory / Consultancy, Travel / Accommodation / Expenses: Paredox Therapeutics; Research grant / Funding (institution): Aduro; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Polaris; Research grant / Funding (institution): Verastem. M. Reni: Honoraria (self), Research grant / Funding (institution), Non-remunerated activity/ies: Celgene; Honoraria (self): Baxalta; Honoraria (self): Shire; Honoraria (self): Eli-Liily; Honoraria (self): Pfizer; Honoraria (self): Novocure; Honoraria (self): Novartis; Advisory / Consultancy, Steering committee member: AstraZeneca; Advisory / Consultancy, Steering committee member: Boston Pharmaceuticals. E. Van Cutsem: Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Advisory / Consultancy, Research grant / Funding (institution): Merck KGaA; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Servier; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bristol-Myers Squibb. T. Macarulla Mercade: Advisory / Consultancy: Genzyme; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi Aventis; Advisory / Consultancy: Shire; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Baxalta; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Travel / Accommodation / Expenses: H3 Biomedicine; Advisory / Consultancy: QED Therapeutics; Research grant / Funding (institution): Agios pharmaceuticals, Aslan pharmaceuticals; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Halozyme, Inc, Immunomedics, Merrimack, Millennium; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Novartis Farmaceutica S.A.; Research grant / Funding (institution): Novocure GmBH; Research grant / Funding (institution): Oncomed, Pharmacyclics; Research grant / Funding (institution): Pfizer S.L.U.; Travel / Accommodation / Expenses: Merck. M.J. Hall: Research grant / Funding (institution), Travel / Accommodation / Expenses, Non-remunerated activity/ies: AstraZeneca; Travel / Accommodation / Expenses, Non-remunerated activity/ies, Non-remunerated activities relate to collaborative research: Caris Life Sciences; Non-remunerated activity/ies, Collaborative research: Myriad; Non-remunerated activity/ies, Collaborative research: Ambry; Non-remunerated activity/ies, Collaborative research: Invitae; Non-remunerated activity/ies, Collaborative research: Foundation Medicine; Non-remunerated activity/ies: Merck. J.O. Park: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Celgene; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Shire; Advisory / Consultancy: Merck; Advisory / Consultancy: Sereno. D. Arnold: Honoraria (self): AstraZeneca; Honoraria (self), Non-remunerated activity/ies: Bayer; Honoraria (self), Non-remunerated activity/ies: Bristol-Myers Squibb; Honoraria (self): Biocompatibles; Honoraria (self): Eli Lilly; Honoraria (self), Non-remunerated activity/ies: Merck Sharpe & Dohme; Honoraria (self), Non-remunerated activity/ies: Servier; Honoraria (self), Non-remunerated activity/ies: Sanofi; Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self): Terumo; Honoraria (self): Sirtex. D. Oh: Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech/ Roche; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bayer; Advisory / Consultancy: Taiho; Advisory / Consultancy: Aslan; Advisory / Consultancy: Halozyme. A. Reinacher-Schick: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Baxalta; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Research grant / Funding (institution): Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy: Merck Sharpe & Dohme; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Servier; Research grant / Funding (institution): AstraZeneca. G. Tortora: Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis. H. Algül: Honoraria (self): Celgene; Honoraria (self), Travel / Accommodation / Expenses: Servier; Research grant / Funding (institution): Chugai. E.M. O’Reilly: Advisory / Consultancy, Including spouse: 3DMedcare, Boston Scientific, CytomX, Daiichi, Debio, Delcath, Exelixis, Alignmed, Antengene, Aptus, Beigene, Bioline, Bridgebio, Carsgen, Aslan, Genoscience, Hengrui Inovio, LAM, Loxo, Mina, Novella, Onxeo, PCI Biotech, Pieris, QED, Redhill, Silenseed,; Research grant / Funding (institution), Including spouse: Actabiologica, Incyte, Array, Celgene, Mabvax, Oncoquest, Polaris, Puma; Advisory / Consultancy, Research grant / Funding (institution), Including spouse: Agios, Halozyme, Casi; Advisory / Consultancy, Including spouse: Amgen; Advisory / Consultancy, Including spouse: Astellas; Advisory / Consultancy, Research grant / Funding (institution), Including spouse: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Including spouse: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Including spouse: BMS; Advisory / Consultancy, Including spouse: Eisai; Research grant / Funding (institution), Including spouse: Genentech; Advisory / Consultancy, Including spouse: Ipsen; Advisory / Consultancy, Including spouse: Jazz; Advisory / Consultancy, Including spouse: Janssen; Advisory / Consultancy, Including spouse: Kyowa Kirin; Advisory / Consultancy, Research grant / Funding (institution), Including spouse: Lilly; Advisory / Consultancy, Including spouse: Merck; Research grant / Funding (institution), Including spouse: Novartis; Advisory / Consultancy, Including spouse: Pfizer; Research grant / Funding (institution), Including spouse: Roche; Advisory / Consultancy, Including spouse: Sanofi; Advisory / Consultancy, Including spouse: Sillajen, Sobi, Targovax, Tekmira, Twoxar, Vicus, Yakult, Yiviva. D. McGuinness: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. K.Y. Cui: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. S. Joo: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. H.K. Yoo: Full / Part-time employment: AstraZeneca. N. Patel: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. T. Golan: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck Sharp & Dohme Corp; Honoraria (self): AbbVie; Honoraria (self): Teva. All other authors have declared no conflicts of interest.
676PD - Health-related quality of life (HRQoL) impact of pembrolizumab (pembro) versus best supportive care (BSC) in previously systemically treated patients (pts) with advanced hepatocellular carcinoma (HCC): KEYNOTE-240 (ID 4623)
- Philippe Merle (Lyon, CEDEX 4, France)
Abstract
Background
KEYNOTE-240 (ClinicalTrials.gov: NCT02702401) is a double-blind, randomized, placebo-controlled, phase 3 trial that evaluated pembro 200 mg every 3 weeks compared with BSC in pts with advanced HCC who were previously systemically treated. Pembro reduced the risk of death by 22% and improved progression-free survival over BSC in pts with advanced HCC, although significance was not reached per prespecified statistical criteria. Here we present the results of prespecified exploratory HRQoL analyses.
Methods
The EORTC QLQ-C30 and EORTC QLQ-HCC18 questionnaires were administered electronically at baseline; weeks 3, 6, 9, 12, and 18; every 9 weeks thereafter up to 1 year or end of treatment; and at the 30-day safety follow-up visit. Least squares mean (LSM) score changes from baseline to week 12 (prespecified) were compared using constrained longitudinal data analysis model including treatment by study visit interaction and stratification factors as covariates. Time to deterioration (TTD) (≥10-point decline from baseline) was estimated by Kaplan-Meier method, and the magnitude of the treatment difference (hazard ratio) between treatment arms was assessed by a stratified Cox proportional hazards model.
Results
Pts receiving ≥1 dose of study treatment and completing ≥1 HRQoL assessment were included in the analysis. The HRQoL population included 398 pts (271 pembro; 127 BSC). HRQoL compliance at week 12 was 90.0% for pembro and 89.3% for BSC. From baseline to week 12, there was no statistically significant difference in LSM between the 2 arms for global health status (GHS)/QoL score (-1.19; 95% CI, -5.35, 2.97; P = 0.573). The GHS/QOL scores remained stable over time for both arms. TTD for prespecified symptoms of abdominal swelling (HR, 1.08; 95% CI, 0.76, 1.54; P = 0.6552), fatigue (HR, 0.98; 95% CI, 0.71, 1.20; P = 0.2795), and pain (HR, 0.97; 95% CI, 0.74, 1.27; P = 0.4078) from EORTC QLQ-HCC18 were similar between the 2 arms.
Conclusions
Over 12 weeks, pts treated with pembro had similar HRQoL compared to pts receiving BSC. Along with efficacy and safety results from KN240, these data support the benefit of pembrolizumab in HCC pts.
Clinical trial identification
NCT02702401; Release date: March 8, 2016.
Editorial acknowledgement
Harleigh E. Willmott, CMPP (ApotheCom, Yardley, PA, USA, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Legal entity responsible for the study
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosure
P. Merle: Advisory / Consultancy, Leadership role, Research grant / Funding (institution): Onxeo; Advisory / Consultancy: Bayer; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy: Eisai; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS. A.S. Kulkarni: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme Corp. A. Cheng: Honoraria (self): Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: IQVIA; Advisory / Consultancy: Bayer Schering Pharma; Advisory / Consultancy: BMS; Advisory / Consultancy: Exilixis; Advisory / Consultancy: Nucleix Ltd; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer Yakuhin, Ltd.; Speaker Bureau / Expert testimony: Amgen Taiwan. M. Kudo: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self): Bayer; Honoraria (self), Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Ono; Advisory / Consultancy: BMS; Advisory / Consultancy: Eli Lilly; Research grant / Funding (institution): EA Pharma; Research grant / Funding (institution): Gilead; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Otsuka; Research grant / Funding (institution): Taiho. M. Bouattour: Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer Pharma; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Sirtex Medical; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen. H.Y. Lim: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Eisai. V. Breder: Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Eisai; Travel / Accommodation / Expenses: BioCad. J. Edeline: Honoraria (self), Honoraria (institution), Research grant / Funding (self): BTG; Honoraria (self): Eisai; Honoraria (self): Ipsen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Bayer; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Servier; Travel / Accommodation / Expenses: Roche. S. Ogasawara: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Merck Sharp & Dohme Corp.; Advisory / Consultancy: Chugai Pharma; Advisory / Consultancy: AstraZeneca. T. Yau: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: BMS. M. Garrido: Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Speaker Bureau / Expert testimony: MSD; Research grant / Funding (institution): Pfizer. B. Daniele: Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self): Lilly; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Travel / Accommodation / Expenses: BMS; Honoraria (self): MSD; Advisory / Consultancy: Eisai; Advisory / Consultancy: Incyte; Travel / Accommodation / Expenses: Sanofi. J. Norquist: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme Corp. E. Chen: Full / Part-time employment: Merck Sharp & Dohme Corp. A.B. Siegel: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme Corp. A.X. Zhu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly; Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme Corp.; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Bayer; Advisory / Consultancy: Exelixis. R.S. Finn: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Eisai; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Merck Sharp & Dohme Corp.; Advisory / Consultancy: Roche/Genentech; Speaker Bureau / Expert testimony: Novartis. All other authors have declared no conflicts of interest.
Invited Discussant LBA45, LBA46, 675PD and 676PD (ID 6767)
- Florian Lordick (Leipzig, Germany)
Q&A led by Discussant (ID 6773)
677PD - Comprehensive genomic profiling (CGP) of mixed hepatocellular cholangiocarcinomas (cHCC-CCA) (ID 3561)
- Karthikeyan Murugesan (Cambridge, United States of America)
Abstract
Background
cHCC-CCA is a rare primary liver carcinoma, with histologic features of both hepatocellular carcinomas (HCC) and liver cholangiocarcinomas (CCA). In order to elucidate their shared and distinctive biology, we used CGP to compare the genomic alterations (GA) of cHCC-CCA with those of HCC and CCA.
Methods
1269 HCC, 3965 CCA and 44 cHCC-CCA were assayed by hybrid capture based CGP on 0.8-1.1 Mb of the coding genome to identify GAs in exons and select introns in up to 404 genes, tumor mutational burden (TMB), microsatellite status (MSI) and % monoallelic genome (gLOH). Utilizing the significant differences in GAs, biomarkers, and demographics between HCC and CCAs (Fischer exact test, FDR < 0.05, only GAs with freq > 10% shown, Table), we built a random forest-based machine learning model to rank a cHCC-CCA specimen in the CCA-HCC spectrum (Out of Bag error rate = 12.6%, AUC = 0.94).
Results
Biomarkers exclusively associated with one disease type included IDH1 (15% in CCA vs 1% in HCC, p = 1e-57), TERT (4% in CCA vs 47% in HCC, p = 2e-273) and Hepatitis B virus (HBV, 0.8% in CCA vs 8.5% in HCC, p = 9e-42). 10/44 cHCC-CCA were classified as CCA-like (IDH1 = 4/10, HBV = 0/10, TERT = 0/10, median TMB = 0.9) and 21/44 cases as HCC-like (IDH1=0/21, HBV=5/21, TERT = 15/21, median TMB = 4). 13/44 cHCC-CCA featured ambiguous/conflicting CGP findings (IDH1=0/13, HBV=1/13, TERT = 0/13, median TMB = 4). 5/13 cHCC-CCA had a computational tumor purity < = 20% and a different 1/13 was highly contaminated, making classification difficult. 677PDHCC CCA GAs TERT, CTNNB1, MYC CDKN2A/B, KRAS, ARID1A, IDH1, BAP1, PBRM1, FGFR2 Biomarkers HBV +, low gLOH, intermediate TMB HBV -, high gLOH, low TMB Demographics Male, Younger patients, African & East Asian ancestry Female, Older patients, European ancestry
Conclusions
Using a machine learning model, the prevalence and mutual exclusivity of IDH1/2, FGFR2, TERT, CTNNB1 and other key GAs, suggest that the majority of cHCC-CCA cases fall into molecular subgroups either similar to CCA or HCC. These findings suggest that cHCC-CCA is not a true disease entity but may be a conglomerate of transformed CCA and HCC.
Legal entity responsible for the study
Foundation Medicine.
Funding
Foundation Medicine.
Disclosure
K. Murugesan: Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. M. Javle: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Leadership role, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder /: Rafael Pharmaceuticals; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Leadership role, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder /: Incyte; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Leadership role, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder /: Pieris Pharmaceuticals; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Leadership role, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder /: Merck; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Leadership role, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder /: Merck Serono; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Leadership role, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder /: Novartis; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Leadership role, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder /: Seattle Genetics; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Leadership role, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder /: QED Therapeutics; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Leadership role, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder /: Bayer; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Leadership role, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder /: BeiGene. A.B. Schrock: Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. N. Ngo: Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. G.M. Frampton: Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. B.M. Alexander: Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. V.A. Miller: Full / Part-time employment: Foundation Medicine. T. Bekaii-Saab: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Lilly; Advisory / Consultancy: Regeneron; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy: NCCN; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Sirtex Medical; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Glenmark; Advisory / Consultancy: Ipsen; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Incyte; Advisory / Consultancy: Imugene; Advisory / Consultancy: Immuneering. L.A. Albacker: Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. J.S. Ross: Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Foundation Medicine. S.M. Ali: Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Foundation Medicine; Advisory / Consultancy: Revolution Medicines; Leadership role: Incysus; Shareholder / Stockholder / Stock options: Exelixis; Shareholder / Stockholder / Stock options: Blueprint Medicines; Shareholder / Stockholder / Stock options: Agios; Shareholder / Stockholder / Stock options: Genocea Biosciences.
678PD - Outcomes based on plasma biomarkers for the phase III CELESTIAL trial of cabozantinib (C) versus placebo (P) in advanced hepatocellular carcinoma (aHCC) (ID 4537)
- Lorenza Rimassa (Rozzano, (MI), Italy)
Abstract
Background
C inhibits tyrosine kinases implicated in HCC progression and resistance to antiangiogenic therapy, including VEGFR, MET, and AXL. In the phase 3 CELESTIAL trial (NCT01908426), C significantly improved overall survival (OS) and progression-free survival (PFS) vs P in previously treated aHCC (Abou-Alfa, NEJM 2018). Here, we evaluate outcomes based on plasma biomarkers in CELESTIAL.
Methods
707 patients (pts) were randomized 2:1 to receive C (60 mg qd) or P. Pts were Child-Pugh A and ECOG PS ≤ 1, must have received prior sorafenib, and could have received up to 2 prior systemic regimens for HCC. Plasma samples were collected at baseline and on treatment for 674 pts and analyzed by Luminex assay (Assay Gate) for MET, AXL, VEGFR2, c-KIT, HGF, GAS6, VEGF-A, VEGF-C, PlGF, ANG2, IL-8, IGF-1, and EPO. OS and PFS were evaluated for low and high baseline biomarker levels dichotomized at the median. Prognostic factors were identified by comparing high vs low biomarker levels within each treatment arm, using the criterion that the HR 95% CI does not include 1.0. Biomarkers were considered predictive if p ≤ 0.05 for the interaction between treatment and subgroup.
Results
For low and high levels of all 13 biomarkers analyzed, hazard ratios favored C over P for both OS (Table) and PFS (all C vs P HRs<0.55; not shown). Analyses comparing high vs low biomarker levels identified MET, HGF, GAS6, ANG2, IL-8, and IGF-1 as possible prognostic factors for OS in both treatment arms; VEGF-A in the P arm only; and AXL and EPO in the C arm only (Table). No baseline biomarkers were found to be predictive of an OS benefit with C (p interaction >0.05). 678PDPlasma Biomarker C vs P, HR (95% CI) for OS High vs Low Biomarker, HR (95% CI) for OS Low Biomarker High Biomarker C P MET 0.75 (0.57–1.00) 0.79 (0.61–1.02) 1.64 (1.31-2.06) 1.63 (1.19-2.23) AXL 0.65 (0.49–0.86) 0.92 (0.71–1.19) 1.53 (1.22-1.92) 1.12 (0.82-1.53) VEGFR2 0.72 (0.55–0.95) 0.82 (0.63–1.08) 0.98 (0.78-1.23) 0.85 (0.62-1.16) c-KIT 0.66 (0.50–0.85) 0.87 (0.65–1.16) 0.95 (0.75-1.19) 0.75 (0.55-1.03) HGF 0.78 (0.59–1.04) 0.70 (0.54–0.91) 1.73 (1.38-2.18) 2.05 (1.50-2.82) GAS6 0.69 (0.52–0.93) 0.81 (0.63–1.05) 1.60 (1.27-2.01) 1.42 (1.04-1.94) VEGF-A 0.84 (0.65–1.09) 0.71 (0.53–0.94) 1.21 (0.96-1.52) 1.48 (1.08-2.03) VEGF-C 0.72 (0.54–0.95) 0.82 (0.63–1.07) 1.04 (0.83-1.31) 0.89 (0.65-1.22) PlGF 0.83 (0.64–1.07) 0.70 (0.52–0.94) 1.09 (0.86-1.38) 1.30 (0.94-1.78) ANG2 0.80 (0.60–1.07) 0.72 (0.56–0.93) 2.05 (1.62-2.58) 2.27 (1.65-3.13) IL-8 0.77 (0.58–1.02) 0.79 (0.61–1.02) 1.80 (1.43-2.27) 1.71 (1.25-2.34) IGF-1 0.72 (0.56–0.94) 0.82 (0.62–1.09) 0.68 (0.54-0.85) 0.60 (0.44-0.82) EPO 0.68 (0.51–0.90) 0.85 (0.65–1.10) 1.52 (1.21-1.91) 1.28 (0.94-1.75)
Conclusions
C treatment was associated with improved OS and PFS vs P in previously treated aHCC irrespective of baseline biomarker levels. Low baseline levels of MET, HGF, GAS6, VEGF-A, ANG2, and IL-8 and high levels of IGF-1 were identified as potential prognostic biomarkers for longer OS with P.
Clinical trial identification
NCT01908426.
Editorial acknowledgement
David Markby, Exelixis Inc.
Legal entity responsible for the study
Exelixis Inc.
Funding
Exelixis Inc.
Disclosure
L. Rimassa: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): AbbVie; Honoraria (self): Gilead; Honoraria (self), Honoraria paid for lectures: Roche; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Bayer; Advisory / Consultancy: Sirtex Medical; Advisory / Consultancy: Itafarmaco; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Research grant / Funding (institution): ArQule; Advisory / Consultancy: Baxter; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy: Amgen; Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Agios. R.K. Kelley: Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Agios; Advisory / Consultancy, Research grant / Funding (institution): BMS; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): QED; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Taiho. T. Meyer: Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy, Research grant / Funding (institution): BTG; Advisory / Consultancy: Celgene; Advisory / Consultancy: MSD; Research grant / Funding (institution): Bayer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bristol Meyers Squibb; Advisory / Consultancy: Boehringer Ingelheim. P. Merle: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self): Eisai; Honoraria (self): BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self): Lilly; Honoraria (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Onxeo. J. Park: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Advisory / Consultancy: Ono; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Genentech. J. Blanc: Honoraria (self): Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy: Eisai. H.Y. Lim: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Eisai. A. Tran: Leadership role: Investigator. A.E. Borgman-Hagey: Shareholder / Stockholder / Stock options, Full / Part-time employment: Exelixis Inc. D.O. Clary: Shareholder / Stockholder / Stock options, Full / Part-time employment: Exelixis Inc. E. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Exelixis Inc. A. Cheng: Advisory / Consultancy: Bayer Schering Pharma; Honoraria (self): Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Honoraria (self): Merck Sharp Dohme; Honoraria (self): Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: IQVIA; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Nucleix Ltd; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer Yakuhin, Ltd; Speaker Bureau / Expert testimony: Amgen Taiwan. A.B. El-Khoueiry: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: EMD Serono; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self): Novartis; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Research grant / Funding (self): Astex Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: CytomX Therapeutics. G.K. Abou-Alfa: Advisory / Consultancy: 3DMedcare; Advisory / Consultancy, Research grant / Funding (institution): Agios; Advisory / Consultancy: Alignmed; Advisory / Consultancy: Amgen; Advisory / Consultancy: Antengene; Advisory / Consultancy: Aptus; Advisory / Consultancy: Aslan; Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Beigene; Advisory / Consultancy: Bioline; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Boston Scientific; Advisory / Consultancy: Bridgebio; Advisory / Consultancy: Carsgen; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): Casi; Advisory / Consultancy: Cipla; Advisory / Consultancy: CytomX; Advisory / Consultancy: Daiichi; Advisory / Consultancy: Debio; Advisory / Consultancy: Delcath; Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy: Genoscience; Advisory / Consultancy, Research grant / Funding (institution): Halozyme; Research grant / Funding (institution): Hengrui; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy: Inovio; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Jazz; Advisory / Consultancy: Jansen; Advisory / Consultancy: Kyowa Kirin; Advisory / Consultancy: LAM; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Loxo; Advisory / Consultancy: Merck; Advisory / Consultancy: Mina; Advisory / Consultancy: Novello; Research grant / Funding (institution): Mabvax; Research grant / Funding (institution): Novartis; Advisory / Consultancy: Onxeo; Research grant / Funding (institution): OncoQuest; Advisory / Consultancy: PCI Biotech; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Pieris; Research grant / Funding (institution): Polaris Puma; Advisory / Consultancy, Research grant / Funding (institution): QED; Research grant / Funding (institution): Roche; Advisory / Consultancy: Redhill; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: Silenseed; Advisory / Consultancy: Sillajen; Advisory / Consultancy: Sobi; Advisory / Consultancy: Targovax; Advisory / Consultancy: Tekmira; Advisory / Consultancy: Twoxar; Advisory / Consultancy: Vicus; Advisory / Consultancy: Yakult; Advisory / Consultancy: Yiviva. All other authors have declared no conflicts of interest.
679PD - Large-scale analysis of CDH1 mutations define a distinctive molecular subset in gastric cancer (GC) (ID 3521)
- Jingyuan Wang (Los Angeles, CA, United States of America)
Abstract
Background
Though molecular classifications have been well studied, targeted therapies for GC are still limited. CDH1 mutations are characteristics of genomically stable GC and associated with poor prognosis. Herein, to understand the specific mutation profile and enriched pathways in CDH1-mutated (MT) GC could help to discover novel drug targets.
Methods
GC (N = 1596) were analyzed by next-generation sequencing (NGS) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutation, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. Gene fusions were evaluated using Archer (N = 253) or Whole Transcriptome Sequencing (WTS, N = 96).
Results
The overall mutation frequency of CDH1 was 9.7%. A significant association of CDH1 mutations with cancer types (GC, 12% vs gastroesophageal junction adenocarcinoma, 2%), sex (female, 13% vs male, 8%), Lauren subtypes (diffuse, 27% vs intestinal, 1%) and younger age (58 vs 62) were observed (p < 0.05). The most frequently mutated genes in CDH1-MT GC were ARID1A (55%), TP53 (44%), KMT2D (8%), RNF43 (7%), PIK3CA (6%). Compared to CDH1-wild type (WT) GC, mutations in ARID1A (55% vs 39%), WRN (3% vs 1%), POT1 (2% vs 0.1%), CDK12 (2% vs 0.6%) and FANCC (1.4% vs 0.2%) were significantly higher, while TP53 (44% vs 64%) and APC (2% vs 6%) were significantly lower in CDH1-MT GC (p < 0.05); Amplifications of KRAS and HER2 were significantly lower, while CRKL and IGF1R amplifications were significantly higher in CDH1-MT GC, compared to CDH1-WT GC (p < 0.05). For immune-related markers, CDH1-MT GC showed significantly lower rates of PD-L1 positivity (CPS score>0) (57% vs. 73%, p < 0.05). No significant difference of TMB and MSI-H were overserved between CDH1-MT/WT GC. RNA sequencing showed similar frequency of ARHGAP26 fusion (6% vs 7%) in CDH1-MT vs WT tumors.
Conclusions
This is the largest study to explore the distinct genomic landscape in CDH1-MT GC. It indicates CDH1-MT GC patients could potentially benefit from agents targeting WRN, POT1, CDK12 and IGF1R, while immunotherapy may be of lower efficacy in this cohort based on lower CPS score. Efficiency of these therapeutic targets and enriched pathways in CDH1-MT GC warrant further investigation.
Legal entity responsible for the study
Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
680PD - Genomic alterations predict clinical response to systemic chemotherapy and immune checkpoint blockade in biliary tract cancer (ID 1484)
- Min Hwan Kim (Seoul, Korea, Republic of)
Abstract
Background
Previous studies have identified several targetable oncogenic mutations in biliary tract cancer (BTC). However, reliable predictors of clinical response to therapeutic agents have not been established. This study aimed to identify predictors of clinical response to chemotherapy and immune checkpoint blockade in advanced BTC patients.
Methods
Genomic alterations in 54 patients with recurrent or metastatic BTC were investigated by targeted deep-sequencing for 524 key cancer genes using pre-treatment tumor tissues. The predictive value of genomic alterations, including mutational signatures, on response to chemotherapy and anti-PD-1/PD-L1 therapy, was assessed.
Results
Frequently altered genes included TP53 (50.0%), NOTCH1 (31.5%), KRAS (24.1%), KMT2C (22.2%), BAP1 (22.2%), and ERBB2 (22.2%). BAP1 deletion and NOTCH1 mutation were associated with a favorable response to chemotherapy. The homologous recombination deficiency (HRD)-associated signature (signature 3) was significantly higher in the responding patients to chemotherapy and a positive correlation between the HRD-signature and BAP1 deletion was observed, suggesting that HRD caused by BAP1 deletion may contribute to a favorable response to chemotherapy. A high proportion of signature 12 was associated with favorable overall and progression-free survival after chemotherapy. Among 19 patients treated with anti-PD-1/PDL1 therapy, the mismatch repair (MMR) deficiency–associated signatures (signatures 6, 15, 20, and 26) were significantly higher in the responding patients.
Conclusions
This study identified several predictors on therapeutic response of advanced BTC. BAP1 deletion and NOTCH1 mutation were predictors of a favorable response to chemotherapy. Furthermore, the mutational signatures associated with HRD and MMR significantly correlated with the response to chemotherapy and anti-PD-1/PD-L1 therapy, respectively.
Legal entity responsible for the study
The authors.
Funding
National R&D Program for Cancer Control, Republic of Korea.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 677PD, 678PD, 679PD and 680PD (ID 6769)
- Russell Petty (Dundee, Scotland, United Kingdom)
Q&A led by Discussant (ID 6772)
681PD - Low-dose aspirin and risk of gastric and oesophageal cancer: A population-based study (ID 1438)
- Luis Garcia Rodriguez (Madrid, Spain)
Abstract
Background
Evidence suggests that low-dose aspirin is associated with a 30–40% protective effect against colorectal cancer (CRC) yet its effect on other gastrointestinal cancers has been less studied. We aimed to quantify the association between use of low-dose aspirin and risk of gastric/ oesophageal cancer using a population-based primary care database in the United Kingdom – The Health Improvement Network.
Methods
Among persons aged 40–89 years from 2005–2015, ∼200,000 new users of low-dose aspirin (75–300 mg/day) were each matched to a non-user by age, sex, time since study entry and number of primary care visits in the previous year. Individuals were followed (max. 18 years) to identify incident cases of gastric/oesophageal cancer. Nested case–control analyses were conducted using 5000 controls for both sets of cancer cases frequency matched by age, sex and calendar year. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for current vs. non-use of low-dose aspirin using logistic regression. Current use was when low-dose aspirin use lasted to 0–90 days before the index date (event date for cases, random date for controls) and total duration of use before the index date was >1 year; non-use was no use of low-dose aspirin ever before the index date or use that ended ≥1 year before the index date.
Results
We identified 727 incident cases of gastric cancer and 1394 incident cases of oesophageal cancer. As shown in the table, compared with non-use, current use of low-dose aspirin was associated with a significant 54% reduced risk of gastric cancer and a significant 41% reduced risk of oesophageal cancer. Protective effects were seen for both cancers irrespective of total previous duration of low-dose aspirin use. 681PD Odds ratios (95% confidence intervals) for the association between use of low-dose aspirin (current vs non-use) and gastric/oesophageal cancer Adjusted by age, sex and primary care practitioner visits in the year before the index date.Gastric cancer Oesophageal cancer Cases N = 727 n (%) Controls N = 5000 n (%) Adjusted OR* (95% CI) Cases N = 1394 n (%) Controls N = 5000 n (%) Adjusted OR* (95% CI) Non-use of low-dose aspirin 442 (60.8) 2404 (48.1) 1.0 (reference) 829 (59.5) 2555 (51.1) 1.0 (reference) Current use of low-dose aspirin (with duration >1 year) 146 (20.1) 1407 (28.1) 0.46 (0.38-0.57) 331 (23.7) 1397 (27.9) 0.59 (0.51-0.69) Duration >1 to < 3 years 56 (7.7) 693 (13.9) 0.34 (0.25-0.46) 145 (10.4) 680 (13.6) 0.51 (0.41-0.62) Duration > =3 years 90 (12.4) 714 (14.3) 0.60 (0.47-0.77) 186 (13.3) 717 (14.3) 0.68 (0.56-0.82) Remaining current users of low-dose aspirin (i.e. patients with duration <1 year) 66 (9.1) 730 (14.6) 0.31 (0.23-0.42) 103 (7.4) 625 (12.5) 0.33 (0.26-0.42) Past use of low-dose aspirin (use that ended >90 days before the index date) 73 (10.0) 459 (9.2) 0.61 (0.46-0.80) 131 (9.4) 423 (8.5) 0.65 (0.52-0.81) Duration <1 year 34 (4.7) 283 (5.7) 0.42 (0.29-0.62) 65 (4.7) 268 (5.4) 0.49 (0.37-0.67) Duration > =1 year 39 (5.4) 176 (3.5) 0.92 (0.64-1.34) 66 (4.7) 155 (3.1) 0.92 (0.67-1.26)
Conclusions
Our results indicate that use of low-dose aspirin is associated with a significantly reduced risk of gastric and oesophageal cancer as supported by mechanistic data.
Editorial acknowledgement
Susan Bromley, EpiMed Communications Ltd (Oxford, UK).
Legal entity responsible for the study
Luis A Garcia Rodriguez.
Funding
Bayer AG.
Disclosure
L. Garcia Rodriguez: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer AG. P. Vora: Full / Part-time employment: Bayer AG. M. Soriano-Gabarró: Full / Part-time employment: Bayer AG. L. Cea Soriano: Research grant / Funding (institution): Bayer AG.
LBA47 - Randomized, open-label, perioperative phase II study evaluating nivolumab alone versus nivolumab plus ipilimumab in patients with resectable HCC (ID 6574)
- Ahmed Kaseb (Houston, United States of America)
Abstract
Background
In HCC, surgical resection is associated with high recurrence rates, and no effective neoadjuvant or adjuvant therapies currently exist. Immunotherapy using anti-PD-1 antibodies has shown promised but limited increase in survival in advanced disease. To maximize the benefit, we are studying the efficacy and safety of anti–PD-1 (nivolumab) and anti–CTLA-4 (ipilimumab) antibodies against HCC for resectable HCC.
Methods
This is a randomized phase II trial of nivolumab (Arm A) or nivolumab + ipilimumab (Arm B) as pre-operative treatment for patients (pts) with HCC who are eligible for surgical resection. Pts are given nivolumab 240 mg every 2 weeks (wks) for a total of 6 wks. Pt in Arm B are treated concurrently with ipilimumab 1 mg/kg every 6 wks. Surgical resection occurs within 4 wks after last cycle of therapy. Pts continue adjuvant immunotherapy for up to 2 years after resection. The primary objective is the safety/tolerability of nivolumab +/- ipilimumab. Secondary objectives include overall response rate, complete response rate and time to progression. Exploratory objectives include evaluating the pre- and post-treatment immunological changes in tumor tissues and peripheral blood.
Results
Twenty-six patients were enrolled at the time of this interim analysis, of which 20 have evaluable data.Most pts (55%) were between 60-70yo and male (75%).Seven pts were HCV-positive, 7 had HBV and 6 had no hepatitis. 20 patients proceeded with resection as planned but surgery was aborted for 3 patients (1 for frozen abdomen and 2 development of contralateral liver nodule). Three are still receiving preoperative therapy. Pathologic complete response (pCR) was observed in 5/20 evaluable patients – 2 in Arm A and 3 Arm B (25% pCR rate). Five patients in Arm B and 1 in Arm A experienced grade 3 or higher toxicity prior to surgery. No grade 4 or higher toxicity were observed.
Conclusions
We report a pCR rate of 25% for resectable HCC after preoperative immunotherapy in a randomized phase II pilot trial. Treatment was safe and surgical resection was not delayed. The study is ongoing. These promising results may contribute to a paradigm shift in the perioperative treatment of resectable HCC.
Legal entity responsible for the study
BMS Pharmaceuticals.
Funding
BMS Pharmaceuticals.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 681PD and LBA47 (ID 6770)
- Ana C. Raimundo (Porto, Portugal)