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Addition of an EGFR Antibody to Fluorouracil/Folinic Acid Maintenance Therapy in RAS Wild-Type mCRC

Findings from the PANAMA study (AIO KRK 0212)
22 Sep 2021
Anticancer agents & Biologic therapy;  Gastrointestinal cancers

The findings from the first randomised study that evaluated the addition of an epidermal growth factor receptor (EGFR) antibody to fluorouracil/folinic acid maintenance therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC) show that panitumumab adds efficacy to fluorouracil/folinic acid as maintenance therapy in terms of progression-free survival (PFS). Moreover, overall survival (OS) numerically favours this combination over fluoruracil/folinic acid alone without reaching statistical significance. More patients achieved objective tumour responses (ORR) during maintenance with fluorouracil/folinic acid plus panitumuamb as compared with fluorouracil/folinic acid alone. The results are published by Prof. Dominik Paul Modest of the Department of Hematology, Oncology, and Tumorimmunology, Charité-Universitätsmedizin Berlin and the PANAMA study (AIO KRK 0212) investigators on 17 September 2021 in the Journal of Clinical Oncology.

The authors wrote in the study background that previously untreated patients with microsatellite stable mCRC are typically treated with combinations of fluorouracil/folinic acid plus either oxaliplatin (FOLFOX) or irinotecan or with all three agents. Additionally, monoclonal antibodies targeting either the EGFR or the vascular endothelial growth factor (VEGF) are added to these chemotherapy backbones.

Whereas anti-EGFR antibodies are typically used in patients with RAS wild-type mCRC and primaries located between the splenic flexure and rectum, all other patients are candidates for anti–VEGF therapy with bevacizumab. Chemotherapy, in particular oxaliplatin-based regimens, is associated with toxicities that frequently impair the tolerability and the continuation of treatment.

In the pre-antibody era, maintenance therapy with fluoropyrimidines was established following induction therapy with fluoropyrimidines and oxaliplatin. A recent study suggested that maintenance therapy with fluorouracil/folinic acid plus panitumumab was superior in terms of PFS compared with panitumumab alone.

The PANAMA study was designed to evaluate the efficacy of panitumumab during maintenance therapy with fluorouracil/folinic acid in patients with RAS wild-type mCRC in a randomised, controlled, open-label, phase II study. Patients with complete or partial remission or stable disease after 6 cycles of FOLFOX plus panitumumab were randomly assigned to either continuation of therapy with fluorouracil/folinic acid plus panitumumab or fluorouracil/folinic acid alone.

The primary objective was to demonstrate superiority of PFS defined as time from random assignment until progression or death in favour of fluorouracil/folinic acid plus panitumumab with a hazard ratio (HR) of 0.75, a power of 80%, and a significance level of 10%. Secondary endpoints included OS, ORR of maintenance therapy, and toxicity. 

Overall, 248 patients were randomly assigned and received maintenance therapy with either fluorouracil/folinic acid plus panitumumab (125 patients) or fluorouracil/folinic acid alone (123 patients).

At data cut-off, with 218 events, PFS of maintenance therapy was significantly improved with fluorouracil/folinic acid plus panitumumab, 8.8 months versus 5.7 months (HR 0.72; 80% confidence interval [CI] 0.60 to 0.85; p = 0.014).

With event rate of 54%, OS numerically favoured the fluorouracil/folinic acid plus panitumumab arm, 28.7 months versus 25.7 months (HR 0.84; 95% CI 0.60 to 1.18; p = 0.32).

The ORR was 40.8% in patients receiving fluorouracil/folinic acid plus panitumumab versus 26.0% in patients receiving fluorouracil/folinic acid alone (odds ratio 1.96; 95% CI 1.14 to 3.36; p = 0.02).

The most frequent adverse events of grade ≥3 during maintenance therapy was skin rash (7.2%).

The authors concluded that in RAS wild-type mCRC, maintenance therapy with fluorouracil/folinic acid plus panitumumab induced a significantly superior PFS compared with fluorouracil/folinic acid alone. If active maintenance therapy is aspired following induction therapy with FOLFOX plus panitumumab, fluorouracil/folinic acid plus panitumumab appears to be the most favourable option.

Longer follow-up and future studies may help to understand to which extent maintenance therapy including anti-EGFR antibodies affects OS.

The legal funder (sponsor) of the study was the AIO Studien gGmbH, Berlin, Germany. Amgen Inc supported the study with medication and a research grant to the AIO Studien gGmbH, Thousand Oaks, CA.

Reference

Modest PD, Karthaus M, Fruehauf S, et al. Panitumumab Plus Fluorouracil and Folinic Acid Versus Fluorouracil and Folinic Acid Alone as Maintenance Therapy in RAS Wild-Type Metastatic Colorectal Cancer: The Randomized PANAMA Trial (AIO KRK 0212). JCO; Published online 17 September 2021. DOI: 10.1200/JCO.21.01332

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