Panitumumab Plus Trifluridine-Tipiracil Improves Outcomes in RAS Wild-type mCRC

Stefania Napolitano, MD, PhD

The combination of panitumumab (Vectibix) and standard-of-care (SOC) trifluridine-tipiracil rechallenge delivered a progression-free survival (PFS) benefit vs trifluridine-tipiracil alone in the third-line setting in patients with refractory RAS wild-type metastatic colorectal cancer (mCRC), meeting the primary end point of the phase 2 VELO trial (NCT05468892).¹

The median PFS was 4.0 months (95% CI, 2.8-5.3) in patients who received panitumumab plus trifluridine-tipiracil vs 2.5 months (95% CI, 1.4-3.6) in those who received trifluridine-tipiracil alone, translating to a 52% reduction in the risk of progression (HR, 0.48; 95% CI, 0.28-0.82; P = .007).

“Whereas the majority of RAS wild-type cancer cells are killed by chemotherapy plus cetuximab or panitumumab, a genetic selection of RAS-mutant cancer cells occurs with tumor progression,” lead study author Stefania Napolitano, MD, PhD, of the Department of Precision Medicine at the Università Degli Studi Della Campania “Luigi Vanvitelli” in Napoli, Italy, and colleagues, wrote in a paper of the data, published in JAMA Oncology. “A subsequent treatment, such as chemotherapy plus antiangiogenic drugs, could cause the disappearance of RAS-mutant clones and potentially restore sensitivity to anti-EGFR drugs.”

Single-arm phase 2 studies, including the phase 2 CHRONOS trial (NCT03227926), have demonstrated the efficacy of anti-EGFR rechallenge therapies. In CHRONOS, patients with RAS, BRAF, and EGFR wild-type mCRC received an anti-EGFR rechallenge with panitumumab experienced a 30% partial response (PR) rate and a 63% disease control rate (DCR), including 2 unconfirmed responses.²

The open-label, unmasked VELO trial aimed to determine the efficacy of adding panitumumab to trifluridine-tipiracil in the third line in patients with RAS wild-type mCRC.¹ VELO was conducted in 7 centers in Italy from June 2019 to April 2022 and enrolled 62 patients with refractory RAS wild-type mCRC who had achieved a PR or complete response (CR) to first-line chemotherapy plus an EGFR inhibitor and had an EGFR drug-free interval of at least 4 months during their second line of therapy.

Patients were randomized 1:1 to receive panitumumab plus trifluridine-tipiracil (arm B, n = 31) or trifluridine-tipiracil alone (arm A, n = 31).

The primary end point of this trial was PFS. Key secondary end points were objective response rate, incidence of adverse effects (AEs), overall response rate, and overall survival.

In arm B, 61.3% (n = 19) of patients were male, and patients had a median age of 65 years (range, 39-81). In arm A, 54.8% of patients were male, and patients had a median age of 66 years (range, 32-82). Liquid biopsy found no BRAF V600E alterations in any patients. A total of 83.9% (n = 26) and 74.2% (n = 23) of patients in arms B and A, respectively, had RAS or BRAF wild-type ctDNA. Patients in arms B and A had a median of and 4 (range, 1-26) and 2 (range, 1-10) treatment cycles, respectively.

Three patients, all in arm B, achieved a confirmed PR. The DCRs of at least 4 months were 74.2% and 38.7% in arms B and A, respectively (P = .009). The 6-month PFS rates were 35.5% and 9.7% in arms B and A, respectively (P = .02), and the 12-month PFS rates were 12.9% and 0% in arms B and A, respectively (P = .04).

In patients with RAS or BRAF wild-type ctDNA in plasma prior to treatment, the median PFS was 4.5 months (95% CI, 2.2-6.8) in arm B and 2.6 months (95% CI, 1.0-4.3) in arm A (HR, 0.48; 95% CI, 0.26-0.89; P = .02). In these patients, the DCRs were 80.7% and 47.8% in arms B and A, respectively. The 6-month PFS rates were 38.5% in arm B and 13.0% in arm A (P = .047). The 12-month PFS rates were 15.4% in arm B and 0% in arm A, however, the PFS difference at 12 months was not significant. In patients with pretreatment ctDNA containing RAS variants, the investigators observed no advantage with the panitumumab/trifluridine-tipiracil combination (HR, 0.72; 95% CI, 0.15-1.75; P = .29).

Before the study treatment, 88.5% (n = 23) of patients in arm B and 69.6% (n = 16) of patients in arm A with RAS or BRAF wild-type ctDNA had available next-generation sequencing (NGS) liquid biopsy findings. This NGS analysis showed that the most frequently mutated genes in the EGFR pathway were KRAS, PIK3CA, BRAF, MAP2KI, and EGFR, and that the most frequently mutated tumor suppressor genes were TP53, APC,ARID1A, and SMAD4. In total, 91.3% (n = 42/46) and 93.5% (n = 43/46) of patient samples in arms A and B, respectively, had APC and TP53 alterations.

A liquid biopsy extended mutation analysis of ctDNA by FoundationOne Liquid CDx, which profiled 324 genes, was performed in the subgroup of patients with baseline RAS or BRAF wild-type ctDNA. In arm B, 23 patients had wild-type KRAS, NRAS, BRAF V600E, EGFR, ERBB2, MAP2K1, and PIK3CA, 65.2% (n = 15) of whom had a median PFS of 6.4 months (95% CI, 3.7-9.2). Of these 15 patients, 13.3% (n = 2) achieved a PR, 73.3% (n = 11) had stable disease, and 13.3% (n = 2) had disease progression as their best response. Of the 11 patients in arm B with RAS or BRAF wild-type ctDNA who had available FoundationOne Liquid CDx findings both prior to treatment and at disease progression, 54.5% (n = 6) had at least 1 EGFR pathway sequence variation at progression.

In total, 51.6% (n = 16) of patients in arm B and 29.0% (n = 9) of patients in arm A experienced grade 3/4 AEs. No patients discontinued treatment because of AEs, and no treatment-related deaths occurred. In arms A and B, respectively, 29.0% (n = 9) and 51.6% (n = 16) of patients required dose reductions (P = .07).

The investigators report the small size of the subgroup analysis, which was influenced by the COVID-19 pandemic, as a key limitation of the VELO trial.

“We provided evidence of improved clinical activity of anti-EGFR rechallenge therapy compared with the SOC,” the study authors concluded. “These findings also support the use of pretreatment plasma ctDNA for patient selection.”

References

1. Napolitano S, De Falco V, Martini G, et al. Panitumumab plus trifluridine-tipiracil as anti-epidermal growth factor receptor rechallenge therapy for refractory RAS wild-type metastatic colorectal cancer: a phase 2 randomized clinical trial. JAMA Oncol. Published online May 18, 2023. doi:10.1001/jamaoncol.2023.0655
2. Sartore-Bianchi A, Pietrantonio F, Lonardi S, et al. Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial. Nat Med. 2022; 28(8):1612-1618. doi:10.1038/s41591-022-01886-0