A randomised, multicentre, non-comparative, phase II PRODIGE 59-FFCD 1707-DURIGAST study showed that second-line FOLFIRI combined with immune checkpoint inhibitors (ICIs) has an acceptable safety profile and provides significant antitumour activity in a subgroup of about 20% of patients with advanced gastric/gastro-oesophageal junction (GEJ) cancer, even if the primary endpoint of progression-free survival (PFS) at 4 months was not met.
However, when the investigators designed the study, they did not know that long-term disease control would be a more relevant endpoint to evaluate ICI efficacy. The findings are reported by Dr. David Tougeron of the Department of Gastroenterology and Hepatology, Poitiers University Hospital in Poitiers, France and colleagues on 4 April 2024 in the JAMA Oncology.
The authors wrote in the background that the phase III CheckMate-649 showed that nivolumab plus chemotherapy is superior to chemotherapy alone in terms of overall survival (OS) and PFS in patients with a tumour with a PD-L1 combined positive score (CPS) of 5 or higher. The KEYNOTE-859 also reported positive results of pembrolizumab plus chemotherapy in tumour with PD-L1 CPS of 1 or higher.
Second-line chemotherapies (docetaxel, paclitaxel, irinotecan, or FOLFIRI), compared with best supportive care alone, have increased OS. Currently, the most widely used second-line treatment for gastric/GEJ adenocarcinoma is paclitaxel plus ramucirumab. The FOLFIRI regimen is also a treatment option in the second-line setting, especially in case of early recurrence after perioperative FLOT chemotherapy and in countries where ramucirumab is not reimbursed.
A recently published phase IB/II study with either durvalumab or tremelimumab alone, or in combination in patients with advanced gastric/GEJ adenocarcinoma demonstrated significant efficacy with a 6-month PFS of 20.0% and a 12-month OS of 38.8% in the durvalumab plus tremelimumab arm. The PRODIGE 59-FFCD 1707-DURIGAST randomised phase II study aimed to evalute the efficacy and safety of FOLFIRI with durvalumab with or without tremelimumab as the second-line treatment in patients with advanced gastric/GEJ adenocarcinoma.
The PRODIGE 59-FFCD 1707-DURIGAST was conducted from 27 August 2020 and 4 June 2021, at 37 centres in France and included patients with advanced gastric/GEJ adenocarcinoma who had disease progression after platinum-based first-line chemotherapy. Patients were randomised to receive FOLFIRI plus durvalumab (FD arm) or FOLFIRI plus durvalumab and tremelimumab (FDT arm). The efficacy analyses used a clinical cut-off date of 9 January 2023. The primary endpoint was PFS at 4 months according to RECIST v1.1 criteria evaluated by investigators.
A total, 96 patients were randomised, 48 in each arm. The median age was 59.7 years, 28 patients (30.4%) were women and 49 (53.3%) had GEJ tumours. Rate of PFS at 4 month was 44.7% (90% confidence interval [CI] 32.3-57.7) and 55.6% (90% CI 42.3-68.3) in the FD and FDT arms. The primary endpoint was not met. Median PFS was 3.8 and 5.4 months in the FD and FDT arms.
Objective response rates were 34.7% and 37.7%, and median OS was 13.2 and 9.5 months in the FD and FDT arms. Disease control beyond 1 year was 14.9% in the FD arm and 24.4% in the FDT arm.
Grade 3 to 4 treatment-related adverse events (TRAEs) were observed in 22 patients (47.8%) in each arm; 4 patients (8.7%) in the FD arm and 3 patients (6.5%) in the FDT arm definitively stopped treatment due to TRAEs. One patient (2.2%) in each arm definitively stopped durvalumab due to immune-related adverse events (irAEs). Two patients (4.3%) in the FDT arm definitively stopped tremelimumab due to irAEs.
Median time until deterioration in quality-of-life, defined as loss of more than 10 points in the EORTC QLQC30 score, was 7.4 months (95% CI 4.2-12.0) in the FD arm and 8.3 months (95% CI 4.7-14.8) in the FDT arm.
PD-L1 CPS of 5 or higher was observed in 18 tumours (34.0%) and PD-L1 tumour proportion score (TPS) of 1% or higher in 13 tumours (24.5%). Median PFS according to PD-L1 CPS was similar (3.6 months for PD-L1 CPS ≥5 versus 5.4 months for PD-L1 CPS <5) by contrast for PD-L1 TPS (6.0 months for PD-L1 TPS ≥1% versus 3.8 months for PD-L1 TPS <1%).
The authors wrote that this regimen deserves evaluation in a randomised phase III study comparing FOLFIRI combined with ICIs versus FOLFIRI alone in a selected subgroup of patients with favourable biomarkers that remain to be identified. This combination should be evaluated in second-line settings not only after oxaliplatin-based chemotherapy alone or combined with ICIs in the first-line setting, but also in cases of early recurrence or progression during perioperative FLOT combinations.
In an accompanied editorial article, Dr. Thierry Alcindor of the Department of Medical Oncology, Dana-Farber Cancer Institute in Boston, MA, US wrote that in the absence of any putative biomarker of long-term benefit being identified in this PRODIGE study, plans to proceed with a phase III study appear insufficiently justified. In addition, more and more patients receive ICI early in the course of their disease in combination with chemotherapy. ICI in combination with chemotherapy is also being investigated in the perioperative setting, with promising results.
It is likely that the question raised by this study will become less relevant, although investigators will probably look at the potential advantage of maintaining ICI while changing the chemotherapy backbone on progression after first-line treatment. One can also question the overall feasibility of administering dual ICI with combination chemotherapy in the second-line setting, given the common limitations in performance status and organ function in this patient population.
If it were to be redone, the study might contain a third arm, with FOLFIRI alone or with FOLFIRI combined with ramucirumab, which appears comparable to paclitaxel plus ramucirumab, widely considered the reference second-line treatment. Despite its shortcomings, this study provides few lessons in research methodology such as the choice of the study design and the selection of endpoints.
The Fédération Francophone de Cancérologie Digestive (FFCD) is the sponsor of the PRODIGE 59-FFCD 1707-DURIGAST trial. AstraZeneca provided financial support for the trial. FFCD funded the biobank and molecular analyses. AstraZeneca provided the study drugs.
References
- Tougeron D, Dahan L, Evesque L, et al. for the PRODIGE 59-FFCD 1707-DURIGAST Investigators/Collaborators. FOLFIRI Plus Durvalumab With or Without Tremelimumab in Second-Line Treatment of Advanced Gastric or Gastroesophageal Junction Adenocarcinoma The PRODIGE 59-FFCD 1707-DURIGAST Randomized Clinical Trial. JAMA Oncology; Published online 4 April 4 2024. doi:10.1001/jamaoncol.2024.0207
- Alcindor T. Immunotherapy in Gastric Cancer—Choosing Methods or Results. JAMA Oncology; Published online 4 April 2024. doi:10.1001/jamaoncol.2023.7262