Longest OS Seen to Date With Panitumumab/mFOLFOX in RAS Wild-Type Metastatic CRC

Improvement in overall survival shown in patients with RAS wild-type metastatic colorectal cancer treated with panitumumab, according to results from the phase 3 PARADIGM trial.

Panitumumab (Vectibix) plus chemotherapy demonstrated superiority to bevacizumab (Avastin) and chemotherapy in the front-line treatment of patients with RAS wild-type metastatic colorectal cancer (mCRC), according to results from the phase 3 PARADIGM trial (NCT02394795) presented in a press briefing at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.1

Results showed an improvement in overall survival (OS) in the panitumumab arm of the trial compared with the bevacizumab arm in both the left-sided primary tumor and overall mCRC populations.

“Panitumumab and the modified FOLFOX6 [regimen] demonstrated longer survival [than] ever reported in the first-line metastatic colorectal cancer phase 3 studies,” Takayuki Yoshino, MD, PhD, chief of the Department of Gastrointestinal Oncology and deputy director of the National Cancer Center Hospital East in Chiba, Japan, said during the press briefing.

Retrospective data pooled from 6 randomized trials (CRYSAL, FIRE-3, CALGB 80405, PRIME, PEAK, and 20050181) have suggested that patients with RAS wild-type mCRC who have primary left-sided disease (descending colon, sigmoid colon, rectosigmoid, and rectum) benefit more from anti-EGFR therapy in combination with chemotherapy than anti-VEGF therapy plus chemotherapy.2

“PARADIGM is the first prospective study to test the superiority of panitumumab over bevacizumab plus standard chemotherapy in patients with RAS wild-type [mCRC],” Yoshino explained.

Panitumumab was the first fully human EGFR-directed monoclonal antibody approved by the FDA for the treatment of patients with mCRC in September 2006. The FDA also approved an indication for panitumumab in June 2017 as treatment for patients with RAS wild-type mCRC.

PARADIGM was a randomized, open-label, multicenter phase 3 study that enrolled 823 patients with RAS wild-type mCRC who had unresectable disease and no prior chemotherapy. They were randomized 1:1 to receive either panitumumab and mFOLFOX6 (modified fluorouracil, leucovorin, and oxaliplatin) or bevacizumab and mFOLFOX6. All patients were treated until disease progression, intolerable toxicity, curative resection, or patient withdrawal.1

The primary end point was OS in the left-sided mCRC population, and if OS benefit was significant in this group, it would also be analyzed in the overall population of both left-sided and right-sided mCRC.

In the left-sided population, the median OS in patients receiving panitumumab and mFOLFOX6 (n = 312) was 37.9 months (95.798% CI, 34.1-42.6) compared with 34.3 months (95.798% CI, 30.9-40.3) in the bevacizumab and mFOLFOX6 arm (n = 292) (stratified HR, 0.82; 95.798% CI, 0.68-0.99; P = .031). As the P value was less than .04202, it was considered significant.

The median OS was 36.2 months (95% CI, 32.0-39.0) with panitumumab and chemotherapy compared with 31.3 months (95% CI, 29.3-34.1) with bevacizumab and chemotherapy (stratified HR, 0.84; 95% CI, 0.72-0.98; P = .030) among 802 evaluable patients with RAS wild-type mCRC in the overall trial. The P value was under .05, so the investigators considered the comparison significant as well.

According to Yoshino, these results established a standard first-line combination regimen for patients with RAS wild-type, left-sided metastatic colorectal cancer.

“It’s really important to keep in mind for our patients with surgically unresectable disease, the expected 5-year survival is still only at 15%. It’s only changed about 6% over the past 20 years. We are constantly looking for new breakthroughs, and this is one of the longest OS that have been reported, and the median follow-up is extremely long at 61 months,” stated ASCO Expert Cathy Eng, MD, FACP, FASCO, of the Vanderbilt-Ingram Cancer Center, in the briefing. “Granted, this is specifically for the left side, but it's been an area of controversy, especially here in the United States because we have not necessarily had a prospective trial. We have looked at several of our other trials that were not specifically powered for the left-sided tumors. So, this adds quite a bit to the literature, and I think we're quite excited about the possibilities of increasing the survival of our stage IV patients.”

Yoshino also noted that a multi-omics analysis (NCT02394834) studying plasma and tumor tissue samples from patients from the PARADIGM trial collected both before and after treatment to assess for potential biomarkers through DNA targeted sequencing, RNA targeted sequencing, immunohistochemistry, and multiplex immunofluorescence with artificial intelligence is ongoing. He said that results will be available for presentation at a future international meeting.

References
1. Yoshino T, Watanabe J, Shitara K, et al. Panitumumab plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 as first-line treatment in patients with RAS wild-type metastatic colorectal cancer: results from the phase 3 PARADIGM trial. J Clin Oncol. 2022;40(suppl 16):LBA1. doi:10.1200/JCO.2020.40.16_suppl.LBA1
2. Arnold D, Lueza B, Douillard JY, et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol. 2017;28(8):1713-1729. doi:10.1093/annonc/mdx175
3.FDA Approves Vectibix® (Panitumumab) For Use In Wild-Type RAS Metastatic Colorectal Cancer. News release. Amgen. June 29, 2017. Accessed June 5, 2022. https://bit.ly/3me0anZ