VELO supports liquid biopsy-guided anti-EGFR rechallenge therapy in mCRC

In the phase II VELO trial, third-line (3L) treatment with the anti-EGFR* monoclonal antibody (mAb) panitumumab and standard of care (SoC) improved progression-free survival (PFS) in patients with refractory RAS wild-type metastatic colorectal cancer (WT mCRC).

“Current 3L therapies for mCRC have limited efficacy. Rechallenge with EGFR inhibitors for RAS WT mCRC may be valuable for these patients,” said the researchers.

VELO met its primary endpoint. “Panitumumab + trifluridine/tipiracil as anti-EGFR rechallenge therapy for refractory RAS WT mCRC increased PFS at 6 and 12 months compared with SoC alone,” they said.

Treatment with panitumumab-SoC conferred longer PFS compared with SoC alone (median 4.0 vs 2.5 months), with a 52-percent reduction in the risk of disease progression (HR, 0.48; p=0.007). PFS rates were higher in the combination vs SoC-only arm, both at 6 (35.5 percent vs 9.7 percent; p=0.02) and 12 months (12.9 percent vs 0 percent; p=0.04). [JAMA Oncol 2023;9:966-970]

Confirmed partial response (PR) occurred in about 10 percent of panitumumab-SoC recipients. Disease control rates (PR + complete response [CR] + stable disease) of ≥4 months were nearly doubled in the combination vs SoC-only arm (74.2 percent vs 38.7 percent; p=0.009).

The incidence of grade 3/4 adverse events (AEs) was nearly twice as high with the experimental regimen vs SoC alone (51.6 percent vs 29.0 percent), as were dose reductions (51.6 percent vs 29.0 percent; p=0.07). No treatment-related deaths nor treatment discontinuations owing to AEs were reported.

Subgroup analysis

In participants with pretreatment plasma RAS/BRAF WT ctDNA**, panitumumab-SoC led to longer median PFS (4.5 vs 2.6 months; HR, 0.48; p=0.02) and higher disease control rate (80.7 percent vs 47.8 percent) compared with SoC alone. PFS rates were also higher with the combo regimen vs SoC alone, but the significant between-arm difference seen at month 6 (38.5 percent vs 13.0 percent; p=0.047) disappeared by month 12 (15.4 percent vs 0 percent; p=0.052).

Among those with pretreatment plasma RAS variant ctDNA, the addition of panitumumab to SoC did not confer any advantage over Soc alone (HR, 0.72; p=0.29).

A ctDNA liquid-biopsy extended mutation analysis was conducted in a subset of patients with baseline plasma RAS/BRAF WT ctDNA. In 15 of 23 panitumumab recipients whose tumours were WT for KRAS, NRAS, BRAFV600E, EGFR, ERBB2, MAP2K1, and PIK3CA, median PFS was 6.4 months. Of these, two had PR, another two had disease progression, while 11 had stable disease.

Improved clinical activity

Anti-EGFR mAbs plus cytotoxic drugs are the cornerstone of RAS WT mCRC treatment. [CA Cancer J Clin 2022;72:372-401; Ann Oncol 2023;34:10-32] However, acquired resistance mechanisms (including KRAS or NRAS alterations) are tied to treatment failure despite their reported efficacy. [Clin Cancer Res 2019;25:6899-6908; Nat Rev Clin Oncol 2021;18:506-525; Ann Oncol 2020;31:30-40]

The study included 62 individuals with refractory RAS WT mCRC who had PR or CR to first-line chemo plus an anti-EGFR mAb and anti-EGFR drug-free interval of ≥4 months during second-line therapy. Participants were randomized 1:1 to receive SoC either alone (median age 66 years, 55 percent male) or with panitumumab (median age 65 years, 61 percent male).

“Despite the limitations of a small trial, we [managed to provide] evidence of improved clinical activity with anti-EGFR rechallenge therapy compared with SoC,” said the researchers.

“The findings support the clinical utility of liquid biopsy-guided anti-EGFR rechallenge therapy for refractory RAS WT mCRC [and] of pretreatment plasma ctDNA for patient selection,” the researchers concluded.

They called for larger phase III trials to validate the clinical efficacy of this approach. A number of anti-EGFR rechallenge trials are underway. [Clin Colorectal Cancer 2021;20:314-317; Front Oncol 2022;12:940523]