The use of panitumumab plus mFOLFOX6 significantly improved overall survival in patients with RAS wild-type metastatic colorectal cancer that was classified as left-sided compared with patients who received mFOLFOX6 plus bevacizumab, according to findings presented during the Plenary Session by Yoshino et al at the 2022 ASCO Annual Meeting (Abstract LBA1). This is the first advance with a biologic agent over the standard of care in a decade for this type of newly diagnosed metastatic colorectal cancer.
From May 2015 to June 2017, 823 patients in Japan were randomly assigned to one of two treatment arms in the PARADIGM phase III clinical trial. Patients were followed for a median of 61 months. A total of 400 patients received panitumumab and 402 patients received bevacizumab. Both groups received mFOLFOX6 (modified leucovorin, fluorouracil, and oxaliplatin). Of 802 patients, 614 patients had left-sided primary tumors. The primary endpoint was overall survival, and key secondary endpoints included progression-free survival, response rate, and curative resection rate.
Patients with RAS wild-type metastatic colorectal left-sided tumors who received panitumumab lived for 37.9 months from the start of treatment in the trial compared with 34.3 months for those who received bevacizumab; they had an 18% lower risk of death. Progression-free survival was 13.7 vs 13.2 months, respectively, which was statistically equivalent in both groups. The response rate and the curative resection rate were both higher with panitumumab than with bevacizumab. For overall survival in right-sided tumors, there was no statistically significant difference between panitumumab and bevacizumab.
Adverse events were consistent with those previously reported.
“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. It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” said lead author Takayuki Yoshino, PhD, who is Chief of the Department of Gastrointestinal Oncology and Deputy Director of the National Cancer Center Hospital East, Kashiwa, Japan.
In the future, a large-scale biomarker analysis based on 750 DNA samples from patients will be conducted using pre- and posttreatment DNA samples. A more defined predictive biomarker as well as resistance mechanisms for both panitumumab and bevacizumab will be explored.
Findings Emphasize Importance of Tumor Location
No new drugs have demonstrated superior benefit over standard-of-care treatments for a decade in newly diagnosed metastatic RAS wild-type colorectal cancer. Previous studies have retrospectively analyzed data comparing anti-EGFR antibody drugs and bevacizumab. Those studies did not provide consistent results. However, PARADIGM is the largest study conducted to date to prospectively assess the impact of panitumumab in a randomized study that also assesses the impact of primary tumor location per sidedness. Results of the study suggest tumor location, along with gene testing, should be part of standard disease assessment, as it can impact treatment decision-making.
“This trial shows the longest survival ever reported in a first-line unresectable metastatic colorectal cancer prospective phase III trial. 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 all colorectal cancer patients at the time of diagnosis of metastatic disease,” said Cathy Eng, MD, FACP, FASCO, an ASCO expert in gastrointestinal cancers.
Disclosure: This study was funded by Japan Medical Affairs, Japan Oncology Business Unit, Takeda Pharmaceutical Company Ltd, Tokyo. For full disclosures of the study authors, visit coi.asco.org.
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