Panitumumab plus FOLFOX: the new standard of care for left-sided, RAS wildtype metastatic colorectal cancer

Results of the randomised phase III PARADIGM trial show that panitumumab plus FOLFOX leads to a longer overall survival, a higher objective response rate (ORR), and a higher chance for a curative resection, compared to bevacizumab plus FOLFOX in patients with left-sided RAS wildtype metastatic colorectal cancer (mCRC). As such, panitumumab and not bevacizumab should be the preferred targeted therapy to use upfront, in combination with FOLFOX, in this setting.

Introduction

For patients with RAS wild type mCRC, adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves the median overall survival (OS) to about 30 months. As a result, the VEGF inhibitor bevacizumab, and the EGFR inhibitors panitumumab and cetuximab are all recommended options for use in combination with doublet chemotherapy in the first-line setting. To date, however, there is a lack of convincing head-to-head data that can help to differentiate between the targeted therapies. The latter is of particular relevance in the context of tumor sidedness, a disease characteristic that can have a dramatic influence on the response to treatment. In fact, genomic and phenotypic features that are believed to be associated with intrinsic resistance to anti-EGFR agents (e.g., RAS or BRAF mutations, alterations in the MAPK and PI3K/PTEN/AKT signaling pathways, etc.) are much more prevalent among right-sided tumors. In line with this finding, several retrospective analyses have suggested that anti-EGFR therapy is superior to VEGF therapy in the first-line treatment of left-sided mCRC patients with wildtype RAS. Nevertheless, bevacizumab continues to be widely used in this population because of the lack of prospective data. To finally put this issue to bed, the prospective, randomized phase III PARADIGM study was set up.

Study design

In PARADIGM, a total of 823 patients with unresectable, RAS wildtype mCRC who did not receive prior chemotherapy were randomly assigned to receive panitumumab or bevacizumab both in combination with mFOLFOX6. OS was the primary endpoint of this trial and was hierarchically tested in patients with left-sided tumors, followed by those in the full-analysis set (FAS) population. Key secondary objectives of PARADIGM included progression-free survival (PFS), ORR, and curative resection (R0) rate. The median follow-up for the presented analysis was 61 months.

Results

Overall, the patient and disease characteristics were comparable between the left-sided population and the overall study cohort. In the left-sided population, about 56% of patient was aged 65-79 years, four out of five patients had an ECOG performance status of 0 and half of patients had 2 or more metastatic sites. As could be expected, the most common site of metastasis was the liver (~70%). In the left-sided cohort, panitumumab + mFOLFOX6 was associated with a significant OS benefit compared to bevacizumab + mFOLFOX6, with a median OS of 37.9 and 34.3 months, respectively (HR[95%CI]: 0.82[0.68-0.99]; p= 0.031). At 60 months, this difference translated into an absolute OS benefit of 11% in favor of the panitumumab-mFOLFOX6 regimen (32% vs. 21%). Among the whole group of patients, the results also significantly favored panitumumab over bevacizumab in terms of OS, with a median OS of 36.2 and 31.3 months for panitumumab-mFOLFOX6 and bevacizumab-mFOLFOX6, respectively (HR[95%CI]: 0.84[0.72-0.98]; p= 0.030). However, this difference appears to be driven by the left-sided population, as no OS improvement was seen for patients with right-sided tumors in an exploratory analysis (median OS: 20.2 vs. 23.2 months; HR[95%CI]: 1.09[0.79-1.51]).

No difference was seen between both arms in terms of PFS. In contrast, however, panitumaumab-mFOLFOX6 did induce a higher ORR compared to bevacizumab, both in the left sided cohort (80.2% vs. 68.6%) as in the entire study population (74.9% vs. 67.3%). Finally, the panitumumab-containing regimen also proved to be associated with a higher R0 rate compared to bevacizumab-mFOLFOX6 (18.3% vs. 11.6% in left-sided mCRC patients, 16.5% vs. 10.9% in entire study cohort).

With respect to safety, no unexpected signals were reported. As could be expected, panitumumab did produce more skin, nail, and mucosal toxicities (e.g., acne-like dermatitis, stomatitis, paronychia, and dry skin) than bevacizumab.

Conclusions

Based on the results of PARADIGM, panitumumab and not bevacizumab should be the preferred targeted therapy to combine with FOLFOX in the first line treatment of patients with left-sided, RAS wild-type mCRC. In this setting, panitumumab conferred a 3.6-month median OS advantage over the VEGF inhibitor, yielding the longest ever median OS reported in a prospective phase 3 trial in first-line mCRC.

Reference

Yoshino T, et al. Panitumumab (PAN) plus mFOLFOX6 versus bevacizumab (BEV) plus mFOLFOX6 as first-line treatment in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC): Results from the phase 3 PARADIGM trial. Presented at ASCO 2022; Abstract LBA1.