Fluorouracil-leucovorin plus panitumumab: the standard of care maintenance regimen for RAS wildtype metastatic colorectal cancer
In the PANAMA study, panitumumab-based maintenance after oxaliplatin discontinuation in RAS wildtype metastatic colorectal cancer (mCRC) demonstrated a significantly improved progression-free survival compared to fluorouracil-leucovorin (5-FU/LV) maintenance alone. As maintenance with 5-FU/LV plus panitumumab was also well tolerated, this regimen should be regarded as the preferred maintenance regimen in this setting.
Maintenance concepts in the context of anti-EGFR based 1st line therapies have long been a subject of scientific debate in the management of colorectal cancer patients. Studies indicate that while EGFR monoclonal antibodies do provide activity during this maintenance phase, chemotherapy with fluorouracil-leucovorin (5-FU/LV) appears to be a necessary component. Thus far, the optimal maintenance therapy following FP/oxaliplatin/EGFR-based induction therapy remained unclear. To address this issue, the PANAMA study is evaluating the concept of limiting the application of chemotherapeutic agents while continuing with a maintenance treatment including an anti-EGFR antibody.
The PANAMA study
The PANAMA trial is a randomised phase II trial of maintenance therapy with 5-FU/LV plus panitumumab vs. 5-FU/LV alone in RAS WT mCRC patients. Eligible patients were not previously treated for metastatic CRC disease and had an ECOG performance status of 0 or 1. In order to be eligible for the study, patients had to have measurable disease (per RECIST v.1.1 criteria) and an adequate organ function. Following induction therapy with six cycles of 5-FU/LV, oxaliplatin (FOLFOX) and panitumumab, patients were randomised (1:1) to maintenance therapy with 5-FU/LV plus panitumumab (N= 125) or 5-FU/LV alone (N= 123) until disease progression or death. For all patients that failed maintenance therapy, re-induction with FOLFOX plus panitumumab was possible. The primary endpoint of the PANAMA study was progression-free survival (PFS), defined as the time from randomisation to progression or death from any cause. Patients were stratified based on treatment efficacy and dosing parameters of induction therapy.
5-FU/LV plus panitumumab identified as the best maintenance option
Patient and disease characteristics were generally well balanced between the two study arms. Non-surprisingly, the majority of study participants was male and a previous resection of primary tumour was reported in 74.4% and 67.5% of patients in the 5-FU/LV plus panitumumab and 5-FU/LV alone arm, respectively. A left-sided primary tumour location was clearly predominant with approximately 80% of patients in both study arms having a left-sided tumour. Synchronous metastatic disease was reported in 80.0% of patients in both arms. At data cut-off, the median PFS significantly improved from 5.7 months in the 5-FU/LV arm to 8.8 months in the 5-FU/LV plus panitumumab arm (HR [80%CI]: 0.72 [0.60-0.85], p= 0.014). Exploratory PFS subgroup analyses suggested a relatively homogeneous magnitude of benefit in all analysed subgroups, which included subgroups for which less benefit from panitumumab could have been expected (e.g. right-sided primary tumour). Importantly, none of the investigated subgroups tended towards a favourable outcome with 5-FU/LV alone. Overall survival data are still immature, with 45% of events in each arm recorded. Nevertheless, a trend for a better outcome with panitumumab maintenance was observed (28.7 vs. 25.7 months, HR [95%CI]: 0.84 [0.60-1.18], p= 0.32). Best objective responses diagnosed during maintenance therapy were evaluated using the baseline image that was used for randomisation, which is the image after induction therapy. Interestingly, more patients in the 5-FU/LV plus panitumumab arm achieved objective responses as compared to the 5-FU/LV alone arm (ORR 40.8% vs. 26.0%, odds ratio of 1.96, p= 0.02).
Adverse events of interest during maintenance therapy were more frequent in the panitumumab arm and mainly affected panitumumab-specific events such as skin toxicity and electrolyte imbalances. However, the highest frequency of grade 3-4 events was skin rash at 7.2% in the panitumumab arm, suggesting a very moderate toxicity profile. Re-induction therapy occurred more frequently in the 5-FU/LV arm (N= 75) than in the 5-FU/LV plus panitumumab arm (N= 45). Of note, these re-inductions were also more effective in the 5-FU/LV arm compared to the 5-FU/LV plus panitumumab arm (ORR: 34.7 vs. 8.9%; PFS of 5.8 vs. 3.3 months, respectively).
Conclusion
In RAS WT mCRC, maintenance therapy with 5-FU/LV plus panitumumab appears to be superior to 5-FU/LV alone and should be regarded as the standard of care maintenance regimen following induction therapy with FOLFOX plus panitumumab. However, it is currently too early to determine the differential effects of maintenance therapy on OS in PANAMA. Maintenance therapy with 5-FU/LV plus panitumumab was well tolerated. Finally, the low frequency and moderate efficacy of re-induction following maintenance with 5-FU/LV plus panitumumab suggest that induction of a new treatment line rather than re-induction may be a more favourable option.
Reference
Modest DP, et al. Maintenance therapy with 5-fluoruracil/leucovorin (5FU/LV) plus panitumumab (pmab) or 5FU/LV alone in RAS wildtype (WT) metastatic colorectal cancer (mCRC) - the PANAMA trial (AIO KRK 0212). Presented at ASCO 2021; Abstract 3503.
