Background

TACE is the current standard of care for patients with unresectable intermediate-stage HCC. In a previous phase II study we found HAIC with FOLFOX yielded a higher treatment response versus TACE in patients with large unresectable HCC. Here we report results from a phase III trial of HAIC with FOLFOX versus TACE.

Methods

In this randomised, multi-centre, open-label trial, adults (≥18 years) with a primary unresectable HCC tumour with a largest diameter ≥7 cm, without macrovascular invasion or extrahepatic spread were randomised 1:1 to HAIC (oxaliplatin 130 mg/m², leucovorin 400 mg/m², fluorouracil bolus 400 mg/m² on day 1, and fluorouracil infusion 2400 mg/m² for 24 hours, every 3 weeks via repeated catheterization) or TACE (50 mg of epirubicin, 50 mg of lobaplatin, and lipiodol and polyvinyl alcohol particles). The primary endpoint was overall survival (OS) and secondary endpoints were objective response rate (ORR) using RECIST, progression-free survival (PFS) and safety. Treatment response was also assessed using mRECIST. Treatment outcomes were evaluated in an intention-to-treat population and safety was assessed in patients who received ≥1 cycle of study treatment.

Results

A total of 315 patients were randomised to HAIC (n=159) or TACE (n=156). The cut-off for the present analysis was April 2020 and patient follow-up is on-going. Median OS was higher for patients receiving HAIC versus TACE: 23.1 months (95% CI, 18.23–27.97) versus 16.07 months (95% CI, 14.26–17.88); hazard ratio (HR), 0.58 (95% CI, 0.45−0.75; P <0.001). Compared with the TACE group, patients in the HAIC group had a higher ORR (RECIST: 45.9 [73] vs. 17.9% [28], P <0.001; mRECIST: 48.4 [77] vs. 32.7% [51], P=0.004), and a longer median PFS (9.63 [95% CI, 7.40−11.86] vs. 5.40 [95% CI, 3.82−6.98] months; P <0.001). More patients in the HAIC group underwent subsequent resection compared with the TACE group (23.8 [38] vs. 11.5% [18], P=0.004). The incidence of serious adverse events was higher in the TACE group versus the HAIC group (30 vs 19%, P=0.03).

Conclusions

HAIC with FOLFOX significantly improved OS compared with TACE in patients with unresectable HCC.

Clinical trial identification

NCT02973685.

Legal entity responsible for the study

Shi Ming.

Funding

National Natural Science Foundation of China, Ministry of Science and Technology of the People's Republic of China.

Disclosure

All authors have declared no conflicts of interest.

Background

GEM and Nab-P is a standard first line therapy for mPDAC based on the MPACT Trial. D is a human monoclonal antibody (mAb) that inhibits binding PD-L1 to its receptor. T is a mAb directed against CTLA-4. PA.7 is designed to evaluate whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases treatment efficacy.

Methods

This randomized phase II study (NCT02879318) assessed the efficacy and safety of GEM, Nab-P, D, and T (arm A) vs GEM and Nab-P (arm B) in patients (pts) with mPDAC (n=191). Pts with untreated mPDAC and good performance status (ECOG PS 0-1) were eligible. A safety run in was conducted for 11 pts receiving GEM, Nab-P, D and T. The study then randomized 180 pts in a 2:1 ratio to receive GEM (1000mg/m2 D1, 8, 15); Nab-P (125mg/m2 D1, 8, 15); D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles vs. GEM and Nab-P alone. The primary endpoint is overall survival (OS); secondary endpoints include progression free survival (PFS), safety, overall response rate (ORR) and quality of life.

Results

180 pts were randomized (119 to arm A and 61 to arm B) between April 2017 and July 2018. Baseline characteristics were well balanced. With a median (med) follow-up of 28.5 months (mo) there was no significant difference in OS (med 9.8 mo in arm A vs. 8.8 mo in arm B, Hazard Ratio (HR)=0.94, 90% confidence interval (CI) 0.71-1.25, p=0.72). There was no significant difference in PFS (med 5.5 mo vs 5.4 mo respectively, HR=0.98, 90% CI 0.75-1.29, p=0.91). ORR was not significantly different, 30.3% vs. 23.0% respectively (Odds Ratio=1.49, 90% CI 0.81-2.72, p=0.28). Disease control rate (DCR) was 70.6% vs 57.4% respectively (difference=13.2%, 90% CI 0.7-25.7%, p=0.096). The only significant difference in grade 3 or greater adverse events was lymphopenia (38% vs 20% respectively, p=0.02).

Conclusions

The addition of dual immune checkpoint inhibitors to Gem and Nab-P did not result in a significant improvement in OS, PFS, or ORR. There is a trend to improved DCR. Correlative analyses to assess biomarkers that may predict immune sensitivity in this setting are underway.

Clinical trial identification

NCT02879318.

Legal entity responsible for the study

Canadian Cancer Trials Group.

Funding

AstraZeneca.

Disclosure

D.J. Renouf: Advisory/Consultancy: Celgene; Advisory/Consultancy: Servier; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Taiho; Advisory/Consultancy: Bayer; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen. J.J. Knox: Research grant/Funding (self): AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): Merck; Research grant/Funding (self): Ipsen; Advisory/Consultancy, Research grant/Funding (self): Roche; Advisory/Consultancy: Eisai. M. Tehfe: Honoraria (institution), Research grant/Funding (self): Celgene; Honoraria (self), Advisory/Consultancy: AstraZeneca. N. Aucoin: Advisory/Consultancy: Celgene; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: BMS; Advisory/Consultancy: Amgen; Advisory/Consultancy: Pfizer. R. Ramjeesingh: Honoraria (self), Advisory/Consultancy: Celgene; Honoraria (self): Astrazeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Advisory/Consultancy: Servier. All other authors have declared no conflicts of interest.

Background

Gemcitabine and nab-paclitaxel (NPG) is one of the standard 1st therapies for metastatic pancreatic cancer (mPC). Nevertheless, only few data exist on health-related quality of life (QoL) in mPC. receiving first-line systemic chemotherapy.

Methods

The QOLIXANE-PARAGON study is a prospective, non-interventional, multicenter sub-study of the PARAGON- registry, conducted in Germany and transitioned into a permanent registry for pancreatic cancer pts considering all types of treatments.

This report focuses on the pts enrolled into the QOLIXANE portion of the study, treated with NPG in 1^st line. Pts were recruited from 95 German centers. QoL was prospectively measured via EORTC-C30 questionnaires (at baseline and every month thereafter): therapy and efficacy parameters were prospectively collected. QoL and efficacy endpoints were analyzed in the intention-to-treat population (ITT). Main objectives were the rate of patients without deterioration of Global Health Status/QoL (GHS/QoL) at 3 and 6 months.

Results

600 pts were enrolled. MPFS was 5.85 months (95% CI, 5.23 to 6.25). MOS was 8.91 mo (95% CI, 7.89 to 10.19). The mOS in ECOG 0 pts. was significantly better (11.18 mo; p = 0.027) than in ECOG 1 pts. (mOS 8.52 mo) and ECOG 2 (mOS 4.80 mo; p <0.0001). Worst mOS was seen in ECOG 3 (mOS 2.94 mo). The KM-analysis showed that 61% and 41% of pts had maintained QoL/GHS after 3 and 6 months, respectively. Median time to deterioration of QoL/GHS was 4.68 months (95% CI, 4.04 to 5.59). Mean QoL/GHS improved from 46.1 (SD 22.7) at baseline to 52.8 (SD 21.3) after 6 months. In the QoL response analysis, 34.6%, 37.4% and 28% of evaluable pts had improved, stable and worse QoL/GHS after 3 months, respectively. In the Cox regression analysis, GHS/QoL scores strongly predicted survival with a HR of 0.86 (p<0.0001).

Conclusions

QoliXane is the largest study on QoL in mPC and shows that time to deterioration of QoL is short, reflecting the aggressive nature of mPC. Nevertheless, a relevant group of mPC in 1^st line have improved or maintained QoL after 3 and 6 months, indicating that QoL is a predictor of pts outcome.

Clinical trial identification

NCT02691052.

Legal entity responsible for the study

Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest.

Funding

Celgene.

Disclosure

T.O. Götze: Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Advisory/Consultancy: MSD Oncology; Speaker Bureau/Expert testimony: Bayer; Advisory/Consultancy: Servier; Advisory/Consultancy: Roche; Research grant/Funding (self): Deutsche Forschungsgemeinschaft; Research grant/Funding (self): Gemeinsamer Bundesausschuss. R.D. Hofheinz: Honoraria (self), Advisory/Consultancy: Merck Serono; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Amgen; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: Sanofi; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squipp; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Honoraria (self), Speaker Bureau/Expert testimony: Lilly; Speaker Bureau/Expert testimony: Merck; Speaker Bureau/Expert testimony: Servier; Honoraria (self), Honoraria (institution): Medac; Honoraria (institution): Germany Cancer Aid. G.M. Siegler: Honoraria (self): medizinwelten services GmbH; Honoraria (self): Shire; Honoraria (self): Eisai; Honoraria (self), Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy: Janssen-Cilag; Research grant/Funding (institution): Servier; Research grant/Funding (institution): Beigene; Research grant/Funding (institution): Roche-Genentech; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Isofol Medical; Research grant/Funding (institution): Nutricia; Research grant/Funding (institution): Mologen; Research grant/Funding (institution): Sanofi; Travel/Accommodation/Expenses: Lilly. O. Waidmann: Advisory/Consultancy: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony: Celgene; Advisory/Consultancy: Eisai; Advisory/Consultancy, Investigator: Incyte; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Ipsen; Advisory/Consultancy, Investigator: Merck kGA; Advisory/Consultancy, Investigator: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Investigator: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Servier; Advisory/Consultancy: Shire; Travel/Accommodation/Expenses: Abbvie; Travel/Accommodation/Expenses: Gilead; Travel/Accommodation/Expenses: Merck Serono; Travel/Accommodation/Expenses: Medac; Advisory/Consultancy, Investigator: Basilea; Advisory/Consultancy, Investigator: Lilly. D. Pink: Full/Part-time employment: Helios Kliniken GmbH; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): Clinigen Group; Advisory/Consultancy, Research grant/Funding (institution): Roche; Research grant/Funding (institution): PharmaMar; Research grant/Funding (institution): Novartis pharma SAS. A. Vogel: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Novartis; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Amgen; Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy: Baxalta; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: EISAI; Advisory/Consultancy: BTG; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self): Sanofi; Honoraria (self): Delcath Systems; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): MSD; Honoraria (self): Janssen. T.J. Ettrich: Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Bayer; Advisory/Consultancy: Roche; Advisory/Consultancy: Lilly; Advisory/Consultancy: Eisai; Advisory/Consultancy: Safoni/Aventis; Advisory/Consultancy: MSD; Travel/Accommodation/Expenses: Ipsen; Research grant/Funding (self): Baxalta/Shire. C. Schönherr: Honoraria (self): Celgene. G. zur Hausen: Honoraria (self), Travel/Accommodation/Expenses: Celgene. S-E. Al-Batran: Advisory/Consultancy, Research grant/Funding (self): Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Celgene; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Lilly; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (self): Merck; Advisory/Consultancy, Speaker Bureau/Expert testimony: Nordic Bioscience; Advisory/Consultancy: Merck Sharp & Dohme; Speaker Bureau/Expert testimony: AIO gGmbH; Speaker Bureau/Expert testimony: Forum für Medizinische Fortbildung; Speaker Bureau/Expert testimony: MCI group; Shareholder/Stockholder/Stock options: Institut für Klinische Krebsforschung IKF GmbH; Research grant/Funding (self): Medac; Research grant/Funding (self): Hospira; Research grant/Funding (self): Sanofi; Research grant/Funding (self): German Cancer Aid; Research grant/Funding (self): German Research Foundation; Research grant/Funding (self): Federal Ministry of Education and Research; Research grant/Funding (self): Vifor Pharma. All other authors have declared no conflicts of interest.