1. Froelich, Warren

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In what's been described as the "world's first prospective trial" of its kind, a team of researchers from Japan found that the addition of panitumumab instead of bevacizumab to a standard doublet-chemotherapy significantly extended overall survival among newly diagnosed patients with RAS wild-type (non-mutated) left-sided metastatic colorectal cancer.

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According to results presented during the 2022 American Society of Oncology Annual Meeting, colorectal cancer patients with RAS wild-type (WT) left-sided tumors treated with the panitumumab regimen had an overall survival of 37.9 months from the start of the trial compared to 34.3 months for patients receiving bevacizumab-an 18 percent lower risk of death (Abstract LBA1).


"These results establish a standard first-line combination regimen for patients with RAS WT (wild-type) left-sided metastatic colorectal cancer," said lead author Takayuki Yoshino, PhD, Chief of the Department of Gastrointestinal Oncology and Deputy Director of the National Cancer Hospital East in Kashiwa, Japan, who presented results during an ASCO press briefing.


Added Cathy Eng, MD, ASCO expert in gastrointestinal cancers: "These findings emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing, especially for the status of the RAS gene, which is critical for colorectal cancer patients at the time of diagnosis of metastatic disease."


Ongoing Research

Colorectal cancer is the third most diagnosed cancer worldwide with an estimated 1.9 million new cases diagnosed in 2020. About 36 percent of these patients have metastatic cancer at diagnosis, with a 5-year survival rate generally less than 20 percent. For more than a decade, studies have failed to demonstrate superior benefit for any treatment over standard of care among newly diagnosed metastatic RAS wild-type colorectal cancer, researchers noted.


That said, some retrospective studies recently have suggested that colorectal cancer patients with left-sided tumors experience longer overall survival than those with right-sided tumors. These previous studies also demonstrated a longer overall survival when patients with RAS WT and left-sided tumors were treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, such as panitumumab compared to anti-vascular endothelial growth factor (VEGF) agents including bevacizumab. The RAS gene is one of the most commonly mutated genes in colorectal cancer; wild-type RAS means the gene exists in its natural or non-mutated form.


To date, findings from these retrospective trials have left physicians with limited, and at times confounding, knowledge about the best course of treatment for this subset of colorectal cancer patients, spurring a controversy in the community about which regimen is best.


"Granted, this [study] is specifically for the left side, but it's also been an area of controversy especially in the United States because we have not necessarily had a prospective trial," said Eng, in response to a question during the ASCO press briefing. "We have looked at several of the other trials that were not specifically powered for the left-sided tumors. So, this [study] adds quite a bit to the literature, and I think we are quite excited about the possibilities of increasing the survival of our Stage IV patients."


The study presented by Yoshino is the world's first prospective trial to test the comparative effectiveness of the two regimens. Overall survival served as the primary endpoint, with progression-free survival, response rate, and curative resection rate as secondary endpoints.


Between May 2015 and June 2017, some 823 patients in Japan with RAS WT metastatic colon cancer were randomly assigned to one of two treatment arms-a modified FOLFOX6 doublet chemotherapy with the addition of panitumumab or bevacizumab. Modified FOLFOX6 is a combination chemotherapy regimen that includes drugs leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin.


Some 604 of patients in this Phase III trial had left-sided tumors which are commonly found in the splenic flexure, descending sigmoid colon, and/or rectum. The others were right-sided tumors, which arise in the cecum, ascending colon, hepatic flexure, and/or transverse colon.


With a follow-up of 61 months, the study showed that the addition of panitumumab to doublet-chemotherapy was associated with a significant improvement in overall survival in patients with left-sided tumors compared to bevacizumab at 37.9 months versus 34.3 months with a hazard ratio of 0.82 (p=.031). No significant difference was revealed between the two arms for progression-free survival, where tumor size was stable or shrinking-13.7 months for the panitumumab region versus 13.2 months with the bevacizumab treatment.


Adverse events were consistent with reports from previous studies. However, there was a significant difference in response rate in patients with left-sided tumors, representing the percentage of patients with cancer that shrinks or disappears after treatment-80.2 percent for those receiving panitumumab compared to 68.6 percent with bevacizumab. Curative resection rates, which indicate that no tumor remains in the body, also showed a wide statistical gap-18.3 percent for those on panitumumab versus 11.6 percent for bevacizumab.


Researchers suggest these somewhat confounding results may point to some long-term benefit of early anti-EGFR therapy for patients with left-sided tumors, but more studies will be needed to better understand the biology behind these findings. As for next steps, Yoshino said he and colleagues are performing an analysis of pre-treatment and post-treatment plasma and tissue samples from patients in the study to better define predictive biomarkers needed to guide future treatments.


"This trial demonstrates that, if gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior to initial treatment with bevacizumab plus mFOLFOX6 chemotherapy for those people with left-sided tumors," Yoshino noted.


Warren Froelich is a contributing writer.