An anti-epidermal growth factor receptor (EGFR) agent, such as cetuximab or panitumumab, added to doublet chemotherapy is generally recommended as the first-line treatment option in left-sided RAS/BRAF wild-type (WT) metastatic colorectal cancer (CRC). But should all of these patients receive anti-EGFR therapy at first, or should they receive vascular endothelial growth factor (VEGF) inhibitors? This question was up for debate at the 2022 Great Debates & Updates in Gastrointestinal Malignancies.
VEGF Inhibitors
Not all of these patients should receive anti-EGFR therapy up front, stated Cathy Eng, MD, FACP, FASCO, Co-Leader of the Gastrointestinal Cancer Research Program of Vanderbilt-Ingram Cancer Center. "There is no perfect answer. We need to discuss the benefits and potential toxicities of therapies with our patients," she said.
To support her case for anti-VEGF therapy, Eng examined data from a handful of large randomized clinical trials treating metastatic CRC. The FIRE-3 trial of FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer, conducted in Germany, used the unique primary endpoint of response rate. The superior response and overall survival (OS) benefit associated with cetuximab was particularly beneficial for patients with symptomatic tumors or borderline-resectable metastases. This combination became the standard of care in Germany.
But Eng pointed out that, after more than 70 months, there was no difference in progression-free survival (PFS). The statistical benefit in OS was dependent on subsequent lines of therapy, she said.
The CALGB 80405 trial tested the effect of first-line chemotherapy combined with cetuximab or bevacizumab on OS in patients with KRAS WT advanced or metastatic CRC. The more common primary endpoint was OS, and while there was no difference in OS between the arms, the American researchers noted a difference in sidedness, leading to recommendation that patients with right-sided tumors should not receive anti-EGFR therapy. Again, the OS depended on subsequent lines of therapy, Eng noted.
In comparing the two trials, she mentioned a few salient points. "FIRE-3 had no PFS significant difference; OS was a secondary endpoint. It was not powered to compare cetuximab versus bevacizumab for left-sided RAS WT tumors. In the post-hoc analysis, in terms of sidedness, about one-third of patients in both arms did not receive oxaliplatin as second-line therapy, only 47 percent in the cetuximab group received bevacizumab in second line, and 41 percent in the bevacizumab group received anti-EGFR therapy and did not continue to bevacizumab, which is the standard of care in the U.S."
CALGB 80405 found no significant difference in PFS or OS, and also was not powered to compare cetuximab versus bevacizumab in these patients, she said. "A meta-analysis of PEAK, FIRE-3, and CALGB 80405 found no statistical difference in PFS in left-sided metastatic CRC tumors," she added.
In the DEEPER randomized Phase II study of FOLFOXIRI plus cetuximab versus FOLFOXIRI plus bevacizumab as the first-line treatment in metastatic CRC with RAS WT tumors, the majority (85%) of patients had left-sided tumors. "The depth of response was greater, but there was no difference in response rate or disease control rate," Eng said.
The Phase III PARADIGM trial compared panitumumab plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 as first-line treatment. The results suggested an OS benefit with panitumumab for left-sided tumors; there was no difference in PFS, and a slightly higher response rate. "It's unclear what maintenance regimen was provided," Eng stated. "Is the depth of response impactful enough to impact OS but not PFS?" The final publication of this trial is still pending.
She noted PARADIGM found significantly more toxicity with anti-EGFR therapy, and the CALGB 80405 study also found a reduction in quality of life (QOL). Anti-EGFR toxicities included electrolyte disturbance, diarrhea, dry skin/irritation, fissuring of distal fingertips, paronychia infection, sun hypersensitivity mucositis, and trichomegaly.
Eng concluded: "Not all patients with left-sided RAS WT should receive anti-EGFR therapy as first-line chemotherapy. The OS benefit appears to be dependent on all subsequent lines of therapy. There are several drawbacks of anti-EGFR therapy, including QOL, early development of acquired KRAS mutations, and RAS status not readily available for treatment planning."
In her clinic, Eng noted that "most patients defer anti-EGFR frontline therapy. I utilize anti-VEGF therapy in the majority of my patients, and I still can use it in subsequent lines of therapy."
EGFR Inhibitors
In support of anti-EGFR as frontline therapy, Namrata Vijayvergia, MD, Assistant Chief of Gastrointestinal Medical Oncology at Fox Chase Cancer Center, stated, "The OS benefit story repeats itself in multiple trials, including CALGB 80405, PEAK, FIRE-3, and PARADIGM. There is risk of rash and diarrhea that has to be balanced against improved OS and ORR."
She noted that testing lags behind significantly. "Bevacizumab is the easier choice as it can be started without any delay, but why settle for less? Anti-EGFR therapy may be more cost-effective. There is a slight worsening of quality of life, but that can be offset by improved OS and preserved QOL in the long term. I'm a strong believer of frontline anti-EGFR therapy for left-sided metastatic CRC."
Debate moderator David Ilson, MD, PhD, Medical Oncologist at Weill Cornell Medical College, Memorial Hospital, Memorial Sloan Kettering Cancer Center, commented: "There will be a shift in practice with arrival of the newest data. Current data show no improvement in PFS, and survival curves differ from year 2 to 3."
He noted that, in Europe, clinicians prefer anti-EGFR as the first-line therapy option in all metastatic CRC patients. "I would consider using anti-EGFR therapy upfront for patients with borderline operable disease who would be on treatment for a shorter duration, those with more symptoms, or those willing to tolerate more side effects," Ilson concluded.
Mark L. Fuerst is a contributing writer.