Panitumumab Is Superior to Bevasizumab in Metastatic RAS-Wild Left-Sided Colorectal Cancer

Research in recent years has shown that cancers arising on the right and left sides of the large bowel have different genetic and clinical characteristics. This has raised the question: does choosing different drugs for treatment change disease outcomes?

The large bowel consists of two parts, the colon and rectum; it can also be classified in a different way as right and left. Genetic alterations (MSI-H and BRAF mutations, etc.) are more frequent in right-sided colon cancers. In most people with Lynch syndrome the tumor is in the right colon, and right-sided colon cancers are also more common in women. Right-sided colon cancers have characteristics similar to small-bowel cancers. Left-sided colon cancers are more common in men, and chromosomal instability is more frequent in tumors removed from the left colon; KRAS and p53 mutations also stand out in left-sided colon tumors.

The Right–Left Colon Difference in Choosing Targeted Drugs

Stage 4 colon cancer can be treated with newer-generation drugs called biological agents in addition to chemotherapy. Many studies examine bevasizumab (Altuzan), setuksimab (Erbitux) and panitumumab (Vectibix) to determine in which patients these targeted drugs work better.

RAS Mutation

First discovered in a mouse sarcoma caused by a viral infection and named after it (rat sarcoma), the RAS protein has three different types (KRAS, NRAS and HRAS). Attached to the inner cell membrane, this protein sends intracellular signals that cause cell proliferation when activated by an external stimulus. Of these three types, the KRAS protein can undergo a mutation that is encountered in many types of cancer.

This genetic mutation is present in 40% of metastatic colon cancers. We call colon cancers with this genetic mutation RAS-mutant, and those without it RAS-wild. RAS-mutant colon cancer patients do not appear to benefit much from certain targeted drugs (biological agents). Therefore, all patients with metastatic colorectal cancer need to be tested for this genetic alteration so that we can select the targeted drugs used in the fourth stage.

The PARADIGM Study That Attracted Attention at ASCO 2022

For left-sided RAS-wild type metastatic colorectal cancer, the phase III PARADIGM study, which directly compared bevasizumab and panitumumab, revealed which targeted drug is more effective; the result favors panitumumab.

When chosen as first-line treatment for metastatic colorectal cancer, panitumumab plus chemotherapy provided the longest overall survival ever reported in a prospective phase III study. This study, one of the most notable presentations at the 2022 ASCO Congress, was presented by Dr. Takayuki Yoshino from Japan.

Use of panitumumab, an inhibitor of the epidermal growth factor receptor (EGFR), increased overall survival by 3.6 months compared with bevasizumab, an inhibitor of the vascular endothelial growth factor receptor (VEGF). According to Dr. Yoshino, median overall survival was 37.9 months versus 34.3 months, respectively (hazard ratio [HR] = 0.82; P = 0.031).

Dr. Yoshino said, "It had long been believed that the sequence of treatment in metastatic colorectal cancer did not matter as long as patients had access to the drugs at some point in their treatment". "This trial shows that the first targeted drug chosen alongside chemotherapy matters for RAS-wild type and left-sided metastatic colorectal cancer, and that adding panitumumab to FOLFOX [florourasil, lökovorin, oksaliplatin] chemotherapy is superior to adding bevasizumab."

The PARADIGM study, in RAS-wild type metastatic colorectal cancer patients with left-sided tumors, is the first prospective (forward-looking) study comparing the superiority of panitumumab versus bevasizumab in combination with standard first-line chemotherapy. In the CALGB/SWOG 80405 and FIRE-3 studies, the EGFR inhibitor setuksimab was compared with bevasizumab, but there was no prospective evaluation according to tumor location. Retrospective analyses have shown that EGFR inhibitors are superior to VEGF treatment in the first-line setting for left-sided RAS-wild tumors, but in the absence of prospective data, bevasizumab continues to be widely used.

Study Details

This open-label, multicenter clinical trial conducted in Japan randomly assigned patients who had not previously received chemotherapy and had RAS-wild type tumors to panitumumab plus modified (m)FOLFOX6 or bevasizumab plus mFOLFOX6. Overall survival as the primary endpoint was tested hierarchically in patients with left-sided tumors, followed by evaluation in the entire patient group.

The analysis included 823 patients who met the basic eligibility criteria. The subgroup with left-sided tumors included 312 patients receiving panitumumab and 292 receiving bevasizumab. Overall survival in patients with left-sided disease was analyzed after 48 events during a median follow-up of 61 months.

Survival Advantage

For RAS-wild patients, panitumumab significantly improved overall survival versus bevasizumab in patients with both right-sided and left-sided colon cancer.

In patients with left-sided tumors, median overall survival was 37.9 months with panitumumab versus 34.3 months with bevasizumab (HR = 0.82; 95.798% confidence interval [CI] = 0.68-0.99, P = 0.031).

Median progression-free survival was similar, but the response rate and R0 (curative-intent) resection rates were better with panitumumab.

For all left-sided and right-sided tumors together, panitumumab also produced significantly better results; median overall survival was 36.2 months with panitumumab versus 31.3 months (HR = 0.84; 95% CI = 0.72-0.98, P = . 030). However, this difference appeared to be driven by the group with left-sided tumors, because panitumumab did not significantly improve overall survival in patients with right-sided tumors: for them, median overall survival was 20.2 months with panitumumab and 23.2 months with bevasizumab (HR = 1.09; 95% CI = 0.79–1.51).

Unexpectedly, panitumumab was associated with more skin, nail and mucosal toxicity than bevasizumab. These side effects are associated with EGFR inhibitors.

Dr. Yoshino emphasized that, although PARADIGM was conducted in Japan, there was no reason to believe these results did not apply to non-Asian patients. Large-scale biomarker analysis using plasma and tumor-tissue samples collected before and after treatment is currently ongoing.

In conclusion, the results from PARADIGM emphasize the importance of planning initial treatment at the first diagnosis of metastatic disease in left-sided colorectal cancer according to RAS testing.