The optimal maintenance therapy for patients with RAS wild-type metastatic CRC is the subject of an ongoing debate. In this light, the PRODIGE 28-time UNICANCER study assessed the use of maintenance cetuximab following first-line therapy with FOLFIRI + cetuximab. Despite the fact that the study failed to meet its primary endpoint, it did reveal a clinically meaningful benefit in progression-free survival (PFS) with this approach warranting further randomized studies.
In patients with unresectable metastatic colorectal cancer (mCRC), who have achieved disease control after first-line doublet chemotherapy +/- bevacizumab, maintenance therapy with fluoropyrimidine +/- bevacizumab was shown to induce a significant PFS benefit. However, this did not translate into a significantly longer overall survival (OS). To date, few studies have investigated the role of maintenance therapy after first line therapy with an anti-EGFR based treatment regimen in patients with RAS wildtype mCRC.
In this light, the phase II PRODIGE 28-time UNICANCER study randomised 139 mCRC patients with controlled disease after FOLFIRI + cetuximab to either receive maintenance with biweekly cetuximab (Arm A; N= 67) or enter an observation phase (Arm B; N= 72) (see slide 1 for a detailed study design). The primary endpoint of the trial consisted of the PFS rate 6 months after initiation of the maintenance therapy, with overall response rate (ORR), time to strategy failure, PFS, OS, safety and quality of life as key secondary study objectives. During ASCO GI 2021, the PFS and ORR analysis of this trial were presented.
Cetuximab produced a 6-month PFS of 34.3%
Two thirds of patients in the study were male and approximately two thirds had a left sided tumour. About half of the patients had more than one metastatic site and the baseline CEA level was higher than 100 µg/L in 40% of participants. At randomization, 75% of patients in arm A had an objective response, while this was somewhat lower at 69% in Arm B.
At 6 months, 34.4% of patients in the cetuximab were found to be free of progression. This corresponds to a total of 23 patients which is markedly lower than the 34 cases that was foreseen in the statistical design. As such, the investigators argued that the hypothesis used in th study design was probably too optimistic. In the observation arm, only 6.9% of patients was progression-free at 6 months. With respect to the PFS after randomization (secondary endpoint), cetuximab maintenance was associated with a median PFS of 5.3 months as compared to 2.0 months for patients in the observation arm. The most common ≥grade 3 adverse events (AEs) (Arm A vs. B) included diarrhoea (6% vs. 1%), rash (2% vs. 0%) and hypomagnesemia (5% vs. 0%).
In summary, although this study failed to meet its primary objective, maintenance cetuximab did produce a clinically meaningful benefit in PFS. In combination with the favourable safety findings in this study, these results warrant further investigation of cetuximab maintenance in this setting. However, to date the optimal maintenance regimen remains to be defined.
Boige V et al., Maintenance treatment with cetuximab versus observation in RAS wild-type metastatic colorectal cancer: Results of the randomized phase II PRODIGE 28-time UNICANCER study. Presented at ASCO GI 2021; Abstract 15.