Combination of Targeted Therapy with Chemo in 1st Line in Patients with Left-Sided wtRAS mCRC
The preferred targeted therapy added to the combination with standard chemotherapy (CHT) for left-sided metastatic colorectal cancer (mCRC) with non-mutated RAS oncogene should be an antibody against the epidermal growth factor receptor (anti-EGFR), not against the vascular endothelial growth factor (anti-VEGF). This is based on a direct comparison of anti-EGFR panitumumab and anti-VEGF bevacizumab in the Japanese phase III PARADIGM study. The results were presented at the ASCO 2022 annual meeting.
Methodology, Course, and Objectives of the Study
The multicenter randomized open-label PARADIGM study conducted in Japan is the first prospective evaluation carried out to test the superiority of panitumumab (PAN) over bevacizumab (BEV) in combination with the standard first-line CHT doublet in patients with mCRC with non-mutated (wt – wild-type) RAS oncogene and left-sided primary tumors. Patients with wtRAS mCRC who had not previously used CHT were included and, as part of the study, received PAN + modified FOLFOX regimen (mFOLFOX6) or BEV + mFOLFOX6.
Overall survival (OS) as the primary endpoint was first tested in patients with left-sided tumors, then in the total study population. Key secondary endpoints included progression-free survival (PFS), response rate (RR), and R0 resection rates.
Results
From May 2015 to June 2017, 823 patients were randomized, of whom 802 met the criteria for evaluation. The PAN arm consisted of 400 patients, of which 312 had left-sided tumors. The BEV arm included 402 patients, of which 292 had left-sided tumors.
PAN significantly prolonged OS compared to BEV in the left-sided tumor population (median OS 37.9 vs. 34.3 months; hazard ratio [HR] 0.82; p = 0.031) and also in the total population (median OS 36.2 vs. 31.3 months; HR 0.84; p = 0.030). This difference appears to be driven by the left-sided tumor population based on exploratory analysis, as PAN did not improve OS in patients with right-sided tumors (median OS on PAN vs. BEV was 20.2 vs. 23.2 months; HR 1.09; 95% confidence interval [CI] 0.79–1.51). The length of PFS was similar between the arms, but PAN improved RR and R0 resection rates more than BEV.
No new safety signals were observed. As expected, skin toxicity (e.g., acneiform dermatitis, paronychia) and hypomagnesemia occurred more frequently with PAN (as an EGFR inhibitor) than with BEV.
Conclusion and Discussion
The study indicated that the combination of PAN + mFOLFOX6 appears to be an appropriate first-line treatment standard for patients with left-sided wtRAS mCRC.
Commenting on the results, the main author of the study, Dr. Takayuki Yoshino from the National Cancer Center Hospital East in Chiba, mentioned that it has long been believed that the sequence of therapy in mCRC does not matter, as long as patients have access to specific drugs at some point during therapy. However, he stated that this study shows that in wtRAS and left-sided mCRC, the choice of initial biological combined with chemotherapy does matter, and that the combination of panitumumab + FOLFOX shows superiority over bevacizumab + FOLFOX in initial treatment. Even though PARADIGM was conducted in Japan, he believes that its results are also applicable to non-Asian patients. The findings from the PARADIGM study 'highlight the importance of testing for RAS at initial diagnosis of metastatic disease in left-sided colorectal cancer and tailoring initial therapy to its results.'
Prof. Chiara Cremolini from the University of Pisa added that, in her opinion, the conclusions of the PARADIGM study support the combination of panitumumab + mFOLFOX6 as the first-line therapy for patients with microsatellite-stable wtRAS and left-sided disease, regardless of the treatment intent. 'When our patients are concerned about adverse effects associated with anti-EGFR treatment, especially rashes, we can inform them based on the results of the PARADIGM study that choosing a doublet with bevacizumab would be associated with an average loss of 3.6 months in overall survival and a disadvantage in terms of treatment activity,' she said. She emphasized that this initial therapy is not suitable for all patients with left-sided tumors (it is not suitable in the case of dMMR/MSI-H, where immunotherapy is chosen, and for patients with BRAF mutation, where bevacizumab is preferred). It remains unclear whether the CHT doublet + anti-EGFR is more advantageous than the CHT triplet (FOLFOXIRI) + bevacizumab; according to Prof. Cremolini, for right-sided tumors, FOLFOXIRI + bevacizumab is currently the preferred first-line regimen if feasible. She expressed confidence that, based on comprehensive molecular profiling, a more precise selection of patients with tumors sensitive to anti-EGFR therapy is possible, which 'could lead to earlier and clearer separation of overall survival curves than observed in the left-sided wtRAS tumor subgroup.'
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Sources:
1. Yoshino T., Watanabe J., Shitara K. et al. 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. ASCO Annual Meeting II. J Clin Oncol 2022; 40 (17_suppl): LBA1, doi: 10.1200/JCO.2022.40.17_suppl.LBA1.
2. Helwick C. In metastatic RAS wild-type left-sided colorectal cancer, panitumumab proves superior to bevacizumab. The ASCO Post, 2022 Jul 10. Available at: https://ascopost.com/issues/july-10-2022/in-metastatic-ras-wild-type-left-sided-colorectal-cancer-panitumumab-proves-superior-to-bevacizumab
3. Helwick C. Chiara Cremolini, MD, PhD, comments on findings from the PARADIGM trial. The ASCO Post, 2022 Jul 10. Available at: https://ascopost.com/issues/july-10-2022/epov-chiara-cremolini
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