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.

Abstract

LBA1 Background: PARADIGM is the first prospective trial to test the superiority of PAN vs. BEV in combination with standard doublet first-line chemotherapy for patients (pts) with RAS WT mCRC and left-sided primary tumors. Methods: This open-label, multicenter trial in Japan (NCT02394795) randomly selected pts with chemotherapy-naive RAS WT mCRC to PAN + mFOLFOX6 or BEV + mFOLFOX6. Overall survival (OS) as primary endpoint was hierarchically tested in patients with left-sided tumors, followed by those in the full-analysis set (FAS) population. Key secondary endpoints included progression-free survival (PFS), response rate (RR), and curative resection (R0) rate. Results: From May 2015 to June 2017, 823 pts were randomized; 12 did not receive protocol treatment and 9 were excluded due to major deviation of inclusion criteria. A total of 400 pts received PAN and 402 pts received BEV as FAS; 312 and 292 pts had left-sided primary tumors, respectively. OS was analyzed after 448 OS events in left-sided pts with a median follow-up of 61 months. PAN significantly improved OS vs. BEV in both populations: left-sided (HR, 0.82; 95.798% CI, 0.68-0.99, p = .031, which crossed the boundary of significance [0.042]), and FAS (HR, 0.84; 95% CI, 0.72-0.98; p = .030, with < 0.05 as the boundary). Although PFS was comparable between treatment groups, RR and R0 resection rates were higher with PAN compared with BEV (Table). HR for OS in the right-sided population was 1.09. No new safety signal was observed. Conclusions: PAN significantly improved OS vs. BEV in combination with mFOLFOX6 in pts with RAS WT and left-sided mCRC, establishing a standard first-line combination regimen for this population. Clinical trial information: NCT02394795. [Table: see text]

Treatment outcome comparisons of first‐line targeted therapy in patients with KRAS wild‐type metastatic colorectal cancer: A nationwide database study

“…Furthermore, in the PARADIGM study, the secondary resection rate was 16.5% and 10.9% in the panitumumab and bevacizumab arms, respectively. 17 Our study indicated that anti-EGFR mAb plus chemotherapy led to significantly higher secondary resection rates, regardless of the primary tumor location, which was compatible with the results in the PARADIGM study. Because of the retrospective nature of our study, we could not adjust for other critical confounding factors, such as tumor size and metastatic site.…”

“…In the DEEPER trial, cetuximab in combination with triplet chemotherapy induced significantly deeper tumor responses compared with bevacizumab plus a chemotherapy triplet 35 ; however, the secondary resection rate was similar between the two arms. Furthermore, in the PARADIGM study, the secondary resection rate was 16.5% and 10.9% in the panitumumab and bevacizumab arms, respectively 17 . Our study indicated that anti‐EGFR mAb plus chemotherapy led to significantly higher secondary resection rates, regardless of the primary tumor location, which was compatible with the results in the PARADIGM study.…”

“…Our study results are compatible with those of the FIRE-3 and PARADIGM randomized clinical trial studies, which have demonstrated that patients who receive anti-EGFR mAb exhibit significantly longer OS than patients who receive bevacizumab in combination with a chemotherapy doublet. [7][8][9][10][11]17 However, the phase III CALGB 80405 study reported similar OS between patients who received either bevacizumab or cetuximab as the combination targeted therapy agents. 5,6,9 A pooled analysis of these studies indicated that anti-EGFR mAb as the first-line targeted agent for RAS wild-type mCRC significantly benefitted OS, especially in patients with left-sided mCRC.…”

Consensus Molecular Subtypes as Biomarkers of Fluorouracil and Folinic Acid Maintenance Therapy With or Without Panitumumab in RAS Wild-Type Metastatic Colorectal Cancer (PanaMa, AIO KRK 0212)

“…Third, the sample size in subgroups was limited and the hypothesis-generating results do not allow for definite conclusion. Validation of our findings in other-ideally bigtrials with randomized anti-EGFR antibody maintenance therapy or at least random assignment of the antibody within the regimen such as the PARADIGM trial 31 will add to the level of evidence. Fourth, a potential selection bias by pretreatment with Pmab 1 FOLFOX as induction treatment might have occurred, which subsequently might have led to selection of patients with favorable outcomes only-limiting the generalizability of the observations.…”

Tumor Biomarker Testing for Metastatic Colorectal Cancer: a Canadian Consensus Practice Guideline

“…Location of primary tumor has also been shown to impact prognosis and response to anti-EGFR therapy, with retrospective analyses from the Intergroup 80405, CRYSTAL, FIRE-3, PEAK, PRIME, and PARADIGM trials showing that patients with left-sided tumors, but not those with right-sided tumors, benefited from the addition of anti-EGFR therapy to their treatment (Yoshino, and , 2021). [43][44][45] Incorporation of cetuximab or panitumumab with FOLFIRI or FOLFOX are now standard of care first-line treatment options in Canada for patients with mCRC who have leftsided primary tumors and are RAS wild-type.…”