－ Nature Medicine, a world-renowned journal on biomedicine, publishes results of a study on the association between genetic abnormalities in tumors and treatment response in patients taking part in the PARADIGM trial
－ Analysis of circulating tumor DNA in patients' blood may identify patients more likely to benefit from treatment with panitumumab compared to treatment selection based on the primary tumor site
Takeda today announced that a study on biomarker research associated with a Phase III clinical trial of panitumumab (generic name; product name: "Vectibix®") for the first-line treatment of unresectable advanced colorectal cancer, known as the "PARADIGM trial" (Panitumumab and RAS, Diagnostically useful Gene Mutation for mCRC), has been published in the biomedical journal Nature Medicine on February 12, 2024(US time). The study summarizes the results of biomarker research analyzing circulating tumor DNA (ctDNA) obtained from patients participating in the PARADIGM trial to investigate the correlation of baseline ctDNA with treatment efficacy.
The results of this follow-up study showed that, in a group who did not have 10 genetic mutations reported to be associated with resistance to anti-EGFR antibody drugs (KRAS, NRAS, BRAF (V600E), PTEN and EGFR extracellular domain mutations, HER2 and MET amplification, as well as ALK, RET, and NTRK1 fusions), overall survival was longer in the mFOLFOX6 + panitumumab combination therapy group than in the mFOLFOX6 + bevacizumab combination therapy group in both left and right sided tumors combined(panitumumab combination therapy group: 40.7 months, bevacizumab combination therapy group: 34.4 months, HR: 0.76 [95% CI: 0.62-0.92]).
The primary analysis of the PARADIGM trial showed a statistically significant improvement in overall survival in the panitumumab arm versus the bevacizumab arm in the RAS wild-type, left-sided primary tumor site population, hence treatment selection by primary tumor site is recommended in national and international guidelines for colorectal cancer treatment. The results of this follow-up study suggest that analysis of ctDNA extracted from patients' blood may identify patients who are more likely to benefit from treatment with panitumumab, rather than simply selecting the treatment by the site of the primary tumor. The safety profile of panitumumab in this analysis aligns closely with the findings reported in previously published clinical trial results.
"The results of the biomarker study associated with the PARADIGM trial will contribute significantly to the advancement of personalized treatment of colorectal cancer. Moreover, I am delighted that the results of this research have been published in Nature Medicine, an extremely important global journal that is focused on cutting-edge research. I truly hope that the results of this research will be applied in clinical practice and will lead to improved treatment outcomes for as many patients as possible," said Dr. Kohei Shitara, Chief of Department of Gastrointestinal Oncology, National Cancer Center Hospital East and lead author of the paper.
"We hope that panitumumab and other anti-EGFR antibody drugs will continue to serve as an important treatment option for colorectal cancer. We will keep striving to further contribute to patients with colorectal cancer," said Satoshi Uchida, Head of the Japan Oncology Business Unit at Takeda.
PARADIGM is a prospective, randomized, comparative clinical trial comparing the efficacy and safety of mFOLFOX6 plus anti-VEGF (bevacizumab) versus mFOLFOX6 plus anti-EGFR (panitumumab) in chemotherapy-naive patients with advanced unresectable colorectal cancer and wild-type for the RAS gene. The results of the trial showed that mFOLFOX6 plus panitumumab demonstrated a statistically significant improvement over mFOLFOX6 plus bevacizumab in terms of the primary endpoint of overall survival (OS), in both left-sided tumors and regardless of tumor sidedness (median OS for left sided tumors: 37.9 vs. 34.3, HR=0.82 [95.798% CI: 0.68-0.99], p=0.03, median OS forboth left and right sided tumor : 36.2 vs. 31.3, HR=0.84 [95% CI: 0.72-0.98], p=0.03).
Vectibix® is approved by the FDA for the treatment of unresectable advanced or recurrent mCRC. It was approved and launched in the U.S. in September 2006 and in Japan in 2010 as a monotherapy for patients with EGFR-expressing mCRC after disease progression following prior treatment with chemotherapy drugs including pyrimidine fluoride, oxaliplatin, and irinotecan.
The cornerstone of treatment for colorectal cancer is to completely remove the primary lesion (the tumor in the colon) and metastatic lesions (tumors in other locations) by surgery. However, if the tumor cannot be removed by surgery, or if the cancer recurs after surgery and the tumor cannot be removed, the disease is classified as "unresectable" colorectal cancer. This is not based on whether the tumor can technically be resected but whether the cancerous tissue can be completely removed, and recurrence of the cancer can be controlled for a long time. If the cancer is judged to be "unresectable," systemic chemotherapy is administered to control disease progression, prolong life and control cancer-related symptoms.
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