Benefit of Adding Panitumumab to Maintenance Therapy in mCRC with Non-mutated RAS Oncogene
PANAMA was the first randomized study evaluating the addition of an anti-EGFR antibody to maintenance therapy with fluorouracil and folic acid (FU/FA) in patients with previously untreated metastatic colorectal cancer (mCRC) with a non-mutated (wt − wild-type) RAS oncogene. The results suggest that upon achieving disease control after initial treatment with FOLFOX + panitumumab, the combination of panitumumab with FU/FA might be the most suitable for maintenance therapy.
Methodology, Course, and Goals of the Study
The aim of the PANAMA study was to assess the effectiveness of panitumumab added to FU/FA in the maintenance treatment of untreated wtRAS mCRC. Patients who achieved disease control—defined as complete remission (CR), partial remission (PR), or stable disease (SD)—after 6 cycles of induction therapy with FU/FA and oxaliplatin (FOLFOX) plus panitumumab in the first line were included. They were randomized to receive maintenance therapy with FU/FA + panitumumab or FU/FA alone under open conditions. Treatment continued until disease progression.
The primary goal was to demonstrate the superiority of the FU/FA + panitumumab combination in terms of progression-free survival (PFS), defined as a hazard ratio (HR) of ≥ 0.75, with 80% power and 10% significance level. Secondary parameters included overall survival (OS), objective response rate (ORR) to maintenance therapy (CR + PR), and therapy safety.
Administered Therapy
The induction treatment consisted of the FOLFOX regimen (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil 2400 mg/m2) + 6 mg/kg of panitumumab every 2 weeks for 6 cycles. To prevent acneiform rash, doxycycline was recommended for the first 6 weeks and later reactively for patients receiving panitumumab. In maintenance therapy, the frequencies and dosages of FU/FA and panitumumab were maintained after randomization.
Maintenance therapy continued until disease progression or unacceptable toxicity. Upon failure of maintenance therapy, reinduction with the FOLFOX + panitumumab regimen was administered to patients in both groups. The median duration of maintenance therapy was 5.2 months with FU/FA + panitumumab and 4.4 months with only FU/FA.
Evaluated Patient Population
Safety was assessed in 377 patients, of whom 248 achieved disease control through induction therapy and were randomized for maintenance therapy, forming the efficacy evaluation population. The median age in the safety analysis cohort was 65 years; 66% were male, 56.5% had an ECOG performance status of 0, 80% had synchronous metastases, 69% underwent surgery before induction therapy, 12% had radiotherapy, and 13% had adjuvant chemotherapy. Characteristics of the randomized maintenance therapy groups were balanced, except for a slightly higher incidence of peritoneal involvement and metastases in more than one organ in the FU/FA only arm. During induction, 80% of patients achieved partial or complete remission and 20% achieved stable disease.
Findings
Clinical Efficacy
A total of 123 patients received FU/FA alone and 125 received FU/FA + panitumumab in maintenance therapy.
- PFS was significantly longer in the panitumumab group compared with the FU/FA alone group (8.8 vs. 5.7 months; HR 0.72; 80% CI 0.60–0.85; p = 0.014).
- Adding panitumumab was also associated with a significantly higher ORR (40.8% with panitumumab vs. 26.0% with FU/FA alone; OR 1.96; 95% CI 1.14–3.36; p = 0.02).
- OS was numerically longer with panitumumab added to maintenance therapy (28.7 vs. 25.7 months; HR 0.84; 95% CI 0.60–1.18; p = 0.32).
- Reinduction therapy was required by 36% of patients receiving FU/FA + panitumumab and 61% of those receiving FU/FA alone.
Safety Profile
Adverse events that first occurred during maintenance therapy or were more severe compared to those during induction therapy were not frequent and rarely involved hematological effects. Grade ≥3 adverse events that emerged or worsened during maintenance therapy were reported in 43.2% of patients receiving panitumumab and 26.0% without panitumumab:
- For patients receiving panitumumab, the most common grade ≥3 adverse event was acneiform rash (7.2% cases), which did not occur in patients receiving FU/FA alone.
- Among other grade ≥3 adverse events affecting health-related quality of life and not occurring with FU/FA alone were nail disorders (4.8%), skin fissures (2.4%), and dry skin (2.4%) observed during maintenance therapy with panitumumab.
- Grade ≥3 infections emerging or worsening during maintenance therapy occurred in 4% of patients with panitumumab and 0.8% without it.
- Pain (3.2% with panitumumab vs. 4.9% without) and thrombotic events (0.8% with panitumumab vs. 2.4% without) were numerically less frequent in the panitumumab group.
Conclusion
The PANAMA study demonstrated that adding panitumumab to FU/FA in patients with wtRAS mCRC as part of maintenance therapy significantly prolongs progression-free survival. In patients in the first-line treatment who responded to 6 cycles of the FOLFOX regimen combined with panitumumab, maintenance therapy with FU/FA + panitumumab led to a median PFS of 8.8 months compared to 5.7 months with FU/FA alone.
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Source: Modest D. P., Karthaus M., Frühhauf 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). J Clin Oncol 2022 Jan 1; 40 (1): 72–82, doi: 10.1200/JCO.21.01332.
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