The RAMTAS trial did not meet its primary endpoint of overall survival in the intention-to-treat population. However, adding ramucirumab to FTD/TPI selectively improved survival in heavily pretreated female patients and those with left-sided metastatic colorectal cancer, underscoring the need for treatment personalisation.
Patients with metastatic colorectal cancer (mCRC) who are refractory to chemotherapy treatment have limited therapeutic options. Currently, the standard treatment for these patients is treatment with trifluridine/tipiracil (FTD/TPI). In addition, the anti-angiogenic agents bevacizumab, aflibercept, ramucirumab, regorafenib and fruquintinib are effective in various lines of therapy in mCRC. The phase III RAMTAS study investigated the efficacy and safety of the IgG1 monoclonal antibody ramucirumab in combination with FTD/TPI compared with FTD/TPI monotherapy in heavily pretreated patients with mCRC.
In the randomised, multicentre, open-label, phase III RAMTAS study, patients with mCRC and disease progression or intolerance following prior treatment with oxaliplatin, irinotecan, fluoropyrimidine, anti-EGFR antibodies (if indicated) or anti-angiogenic agents but without prior treatment with FTD/TPI were eligible to participate. The included patients were randomised 1:1 between treatment with FTD/TPI plus ramucirumab (combination therapy group) or treatment with FTD/TPI alone (monotherapy group). Treatment with FTD/TPI was given in both groups at a dose of 35 mg/m2 taken orally on days 1 to 5 and days 8 to 12 for a 4-week cycle. Ramucirumab was administered intravenously at a dose of 8 mg/kg on days 1 and 15 during a 4-week cycle.
The primary endpoint was overall survival (OS). The main secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life (measured with the EQ-5D-5L and the EORTIC QLQ-C30 GHS questionnaires at the time points: baseline, 4, 8, 12 weeks) and safety.
In the period from December 2018 to January 2023, a total of 428 patients in 43 different German centres were randomised to the combination therapy group (N= 213, median age 61 years; 43.7% female; 62.4% RAS mutated; 70% left-sided tumour location) or the monotherapy group (N= 215, median age 63 years; 46.5% female; 60.9% RAS mutated; 64.2% left-sided tumour location). In total, 62.6% of enrolled patients received more than 2 prior treatments for mCRC and 87.6% received treatment with anti-angiogenic agents.
The median OS was numerically longer in the combination therapy group as compared to the monotherapy group (7.46 vs. 7.06 months) but this difference did not reach statistical significance (HR[95%CI]: 0.871[0.708-1.073]; p= 0.1941). However, subgroup analyses showed that women (9.3 vs. 7.8 months; HR[95%CI]: 0.71[0.52-0.98]) as well as patients with left-sided tumour location (8.2 vs. 6.9 months; HR[95%CI]: 0.77[0.60-1.00]) had improved OS in the combination therapy group compared to the monotherapy group. The median PFS was 2.37 months in the combination therapy group and 2.07 months in the monotherapy group and this difference was statistically significant (HR[95% CI]: 0.774[0.636-0.949 ]; p= 0.011]). The ORR was exactly the same in both groups at a rate of 1.9%. The DCR was statistically significantly different between the two groups with a higher percentage in the combination therapy group (39.4% vs. 31.6%; p= 0.0336) compared to the monotherapy group. Quality of life (both the EORTC QLQ-C30 GHS and the EQ-5D-5L) remained stable during treatment with comparable scores for both groups.
A total of 181 patients (85.8%) in the combination therapy group and 154 patients in the monotherapy group (73.7%) reported treatment-related adverse events (TRAEs). TRAEs of grade ≥3 or higher were more common in the combination therapy group (55.9% vs. 36.8%, p< 0.001) compared to the monotherapy group of which the most common were neutropenia (32.2% vs. 22.0%), leukopenia (10.4% vs. 10.5%), diarrhoea (2.8% vs. 2.4%), fatigue (2.4% vs. 0.5%) and nausea (0.9% vs. 1.0%). Dose reduction of ramucirumab occurred in 18.3% of patients in the combination therapy group. Dose reduction of FTD/TPI occurred more often in the combination therapy group than in the monotherapy group (40.8% vs. 24.2%; p= 0.0003).
The phase III RAMTAS study did not meet its primary endpoint of overall survival in the ITT population, however, subgroups with benefit were female patients and patients with left-sided tumours. In addition, PFS and DCR improved statistically significantly in favour of the combination therapy group, both in the ITT and most subgroups. Overall, ramucirumab in combination with FTD/TPI had a manageable safety profile, with no new safety signals identified. These findings support personalised treatment decisions in patients with refractory mCRC after multiple lines of treatment.
Reference
Kaspar-Virchow S, et al. Randomized phase III trial of ramucirumab in combination with TAS102 (Trifluridin/Tipiracil) vs. TAS102 monotherapy in heavily pretreated metastatic colorectal cancer: The RAMTAS/IKF643 trial of the German AIO (AIO-KRK-0316). Presented at ESMO 2024; Abstract LBA25.
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