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)

Abstract

PURPOSE The randomized PANAMA trial investigated the efficacy of panitumumab (Pmab) when added to maintenance therapy with fluorouracil and folinic acid (FU/FA) in patients with RAS wild-type metastatic colorectal cancer. METHODS Following first-line induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab, responding patients (stable disease or partial or complete remission) were randomly assigned (1:1, open-label) to maintenance treatment with either FU/FA plus Pmab or FU/FA alone. The primary objective was to demonstrate superiority of progression-free survival (PFS, time from random assignment until progression or death) in favor of FU/FA plus Pmab with a hazard ratio (HR) of 0.75, a power of 80%, and a significance level of 10%. Secondary end points included overall survival, objective response rate of maintenance therapy, and toxicity. Survival end points were analyzed by the Kaplan-Meier method and compared by log-rank test and Cox regressions. Dichotomous variables were compared by Fisher's exact test; odds ratios were indicated when appropriate. The trial is registered with ClinicalTrials.gov ( NCT01991873 ). RESULTS Overall, 248 patients were randomly assigned and received maintenance therapy with either FU/FA plus Pmab (125 patients) or FU/FA alone (123 patients). At data cutoff, with 218 events (of 218 needed), PFS of maintenance therapy was significantly improved with FU/FA plus Pmab (8.8 months v 5.7 months; HR, 0.72; 80% CI, 0.60 to 0.85; P = .014). Overall survival (event rate 54%) numerically favored the FU/FA plus Pmab arm (28.7 months v 25.7 months; HR, 0.84; 95% CI, 0.60 to 1.18; P = .32). Objective response rates were 40.8% in patients receiving FU/FA plus Pmab versus 26.0% in patients receiving FU/FA alone (odds ratio, 1.96; 95% CI, 1.14 to 3.36; P = .02). The most frequent Common Terminology Criteria for Adverse Event grade ≥ 3 event during maintenance therapy was skin rash (7.2%). CONCLUSION In RAS wild-type metastatic colorectal cancer, maintenance therapy with FU/FA plus Pmab induced a significantly superior PFS compared with FU/FA alone. If active maintenance therapy is aspired following induction therapy with FU/FA and oxaliplatin plus Pmab, FU/FA plus Pmab appears to be the most favorable option.

Post-Induction Management in Patients With Left-Sided RAS and BRAF Wild-Type Metastatic Colorectal Cancer Treated With First-Line Anti-EGFR-Based Doublet Regimens: A Multicentre Study

“…The median number of induction cycles was also balanced between the cohorts. These results are consistent with previously summarized literature data, as the maintenance (10)(11)(12) or intermittent (13,14) strategies have been mainly investigated in patients treated with an oxaliplatin-based chemotherapy backbone following a 6-to 12-cycle (i.e., about 3-6 months) induction in order to reduce the incidence of peripheral neuropathy. The higher proportion of patients treated with a FOLFIRI chemotherapy backbone up to disease progression, unacceptable toxicity, or patient decision in the non-maintenance compared to the maintenance cohorts, together with the higher incidence of non-hematological and hematological AEs, including diarrhea and neutropenia, emphasized the issue of dealing with irinotecanrelated cumulative toxicities and the need for comparative trials of post-induction management in this setting.…”

“…This survival benefit was associated with a higher incidence of hematological and non-hematological AEs, other than paronychia/nail disorders, which usually occur after several weeks of treatment with anti-EGFR, particularly in association with fluoropyrimidines ( 23 ). These results are consistent with the existing literature, corroborating the hypothesis that patients gain more in terms of PFS and OS from a maintenance approach than from a “stop-and-go” strategy ( 13 ), with an even greater benefit for FU/LV+anti-EGFR compared to anti-EGFR alone, particularly in patients affected by left-sided RAS / BRAF wild-type mCRC, at the price of a slightly higher incidence of manageable toxic effects ( 9 , 10 ).…”

“…This is in line with the scarce evidence previously discussed, as, to date, no evidence supports the use of 5FU/LV alone as maintenance after an anti-EGFR-based induction regimen. In this respect, in the randomized phase 2 PanaMa trial comparing 5FU/LV+panitumumab vs. 5FU/ LV alone as maintenance strategies in RAS wild-type mCRC, the PFS of maintenance therapy was significantly improved with 5FU/ LV+panitumumab (8.8 vs. 5.7 months), with a trend toward better OS (28.7 vs. 25.7 months) (10).…”

“…An anti-epidermal growth factor receptor (EGFR) agent (i.e., cetuximab or panitumumab) added to doublet chemotherapy is currently recommended as the first-line treatment option, particularly in left-sided RAS/BRAF wild-type mCRC (6)(7)(8). However, only few phase 2 studies investigating the role of maintenance (9)(10)(11)(12) or intermittent (13,14) strategies following anti-EGFR-based induction are available. The aim of this study was to retrospectively assess clinicians' attitude and the safety and effectiveness of anti-EGFR post-induction strategies in a "real-life" population of patients affected by unresectable leftsided RAS/BRAF wild-type mCRC.…”

The Role of Anti-EGFR Monoclonal Antibody in mCRC Maintenance Therapy

“…In contrast to the abovementioned anti-EGFR mAb maintenance study, the control group design of the PANAMA-AIO KRK0212 study ( Modest et al, 2022 ) orally reported at the 2021 ASCO annual meeting is more suitable for the clinical problem which hopes to solve, that is, whether there is an advantage to adding anti-EGFR mAb to maintenance therapy over fluoropyrimidine-based monotherapy maintenance modalities. This study is a multicenter, randomized, open phase III clinical study, which explored the difference in efficacy between 5-FU combined with panitumumab and 5-FU monotherapy maintenance after six cycles of first-line panitumumab plus oxaliplatin plus 5-FU in RAS wild-type patients.…”