Over the last decade, several chemotherapy and biologics combinations have demonstrated an improvement on survival for RAS wild-type metastatic colorectal cancer (mCRC). However, the best systemic treatment in the first-line setting remains uncertain.

Findings from the first randomized study designed to evaluate 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) demonstrates that panitumumab (Vectibix®; Amgen) adds efficacy to fluorouracil/folinic acid as maintenance therapy in terms of progression-free survival (PFS).

Furthermore, overall survival (OS) numerically favors this combination over fluorouracil/folinic acid alone without reaching statistical significance.

The study, funded* by the AIO Studien gGmbH, Berlin, Germany, shows that more patients achieved objective tumor responses (ORR) during maintenance with fluorouracil/folinic acid plus panitumumab as compared with fluorouracil/folinic acid alone. The results of the study were published in the Journal of Clinical Oncology by Professor Dominik Paul Modest of the Department of Hematology, Oncology, and Tumorimmunology, Charité-Universitätsmedizin Berlin, Germany, and the PANAMA study (AIO KRK 0212) investigators on September 17, 2021.[1]

Chemotherapy backbone
The authors wrote 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.

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Anti-EGFR antibodies are, in contrast, 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.

Efficacy of panitumumab
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 randomized, 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.

Objective
The primary objective was to demonstrate the superiority of PFS defined as the time from random assignment until progression or death in favor 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.

Treatment
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).

FOLFOX plus Pmab was given once every two weeks for six cycles with oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, fluorouracil 2,400 mg/m2 (one dose administered over 48 hours) plus Pmab 6 mg per kg body weight. To prevent patients from Pmab-induced acneiform rash, the investigators recommended the use doxycycline as prophylaxis for the first 6 weeks and reactively if needed beyond this interval.[1]

Study results
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 event of grade ≥3 during maintenance therapy was skin rash (7.2%).

Follow-up
Based on the study results, 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 required following induction therapy with FOLFOX plus panitumumab, fluorouracil/folinic acid plus panitumumab appears to be the most favorable option.

The investigators recommend a longer follow-up and future studies to help to understand to which extent maintenance therapy including anti-EGFR antibodies affects OS.

Note
* Amgen supported the study with medication and a research grant to the AIO Studien gGmbH, Thousand Oaks, CA. However, the company had no role in the design and conduct of the trial; collection, management, analysis, and interpretation of the data; or the decision to submit the manuscript for publication.

Clinical trials
Maintenance Therapy With 5-FU/FA Plus Panitumumab vs. 5-FU/FA Alone After Prior Induction and Re-induction After Progress for 1st-line Treatment of Metastatic Colorectal Cancer (PanaMa) – NCT01991873

Highlights of Prescribing Information
Panitumumab (Vectibix®; Amgen) [Prescribing Information]

Reference
[1] Modest DP, Karthaus M, Fruehauf S, Graeven U, Müller L, König AO, Fischer von Weikersthal L, Caca K, Kretzschmar A, Goekkurt E, Haas S, Kurreck A, Stahler A, Held S, Jarosch A, Horst D, Reinacher-Schick A, Kasper S, Heinemann V, Stintzing S, Trarbach T. 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). J Clin Oncol. 2021 Sep 17:JCO2101332. doi: 10.1200/JCO.21.01332. Epub ahead of print. PMID: 34533973.[Article]

Featured image: Dictionary definition of Colorectal cancer. Photo Courtesy: © 2016 – 2021 Fotolia/Adobe. Used with permission.

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