Liquid Biopsy Assay May Be Predictive of Survival With Rechallenging Anti-EGFR Treatment in mCRC

Yu Sunakawa, MD, PhD

RAS status detected in circulating tumor DNA (ctDNA) was associated significantly with clinical outcomes when patients with metastatic colorectal cancer (mCRC) were rechallenged with anti-EGFR monoclonal antibody (mAb) therapy of either cetuximab (Erbitux) or panitumumab (Vectibix), according to findings from a clinical study evaluating RAS mutational status in ctDNA using the OncoBEAM RAS CRC test kit in 2 Japanese multicenter, prospective studies.¹

"We found that the OncoBEAM RAS CRC assay was not only effective in monitoring the resistance to anti-EGFR therapy, but was also important in helping us determine the efficacy of the rechallenge treatment and therefore predict patients who would have favorable outcomes.Overall, our novel findings support the value of using the ultrasensitive OncoBEAM RAS liquid biopsy test in the clinical management of [patients with] CRC receiving anti-EGFR mAb as rechallenge treatment," stated Yu Sunakawa, MD, PhD, of the Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki, Japan, in a statement.²

This retrospective biomarker study used data from the phase 2 JACCRO CC-08 and CC-09 studies. For patients to be included in this analysis, they had to have histologically confirmed unresectable metastatic or recurrent adenocarcinoma of the colon or rectum, a KRAS exon 2 wild-type tumor with evaluable lesions, clinical benefit achieved from first-line combination therapy with an anti-EGFR monoclonal antibody with disease progression during the second- or third-line chemotherapy without the anti-EGFR agent, and an ECOG performance status of 0 or 2.¹

In order to detect the RAS mutational status in patients with mCRC, the study investigators utilized the OncoBEAM RAS CRC test. This test is expected to be a valuable tool in routine clinical practice for genotyping RAS in patients with mCRC.

Sixteen patients had evaluable blood samples and were enrolled to the study, of which the majority were men (12; 75.0%), and the median age of patients was 67.5 years (range, 43-79). Of the 6 patients with a RAS mutation, 4 were male (66.7%), and the median age was 63.5 years (range, 43-68), compared with 10 patients who did not harbor the RAS mutation, whose median age was 73 years (range, 60-79), and the majority were also male (8; 80.0%).

All patients had mutations in KRAS codon 12, as well as KRAS codon 61 with or without NRAS codon 61. The disease control rate in patients with mutations was 33.3% compared with 80.0% in those without mutations at baseline. The progression-free survival (PFS) was significantly shorter in patients with RAS mutations compared with those without, whereby the median PFS was 2.3 months (95% CI, 1.4-3.8) and 4.7 months (95% CI, 2.0-5.5), respectively (HR, 6.2; 95% CI, 1.6-30.5; log-rank P = .0042). Median overall survival (OS) was also significantly shorter in those harboring the RAS mutation as well, whereby the median was 3.8 (95% CI, 2.6-8.1) compared with 16.0 months (95% CI, 4.9-22.3) without the RAS mutation (HR, 12.4; 95% CI, 2.7-87.7; log-rank P = .0002).

One patient from the 10 without a RAS mutation acquired an NRAS codon 12 mutation 8 weeks after rechallenging treatment, and at disease progression, 6 patients (60%) acquired mutations as well, which included KRAS codon 61 (n = 3), KRAS codon 12 (n = 2), NRAS codon 61 (n = 2), and KRAS codon 146 (n = 1). Two of the 6 patients had at least 2 mutations simultaneously, and 2 had more mutations at progression.

The investigators noted that there was no association between the RAS status in ctDNA at disease progression and survival of the rechallenging therapy. Post-progression survival after the rechallenging treatment also appeared to be numerically shorter in patients with RAS mutations in ctDNA compared with those harboring no mutations of no statistical significance, where the median survival was 4.8 versus 7.2 months, respectively (HR, 2.22).

Overall, this study demonstrated favorable survival in terms of PFS and OS after rechallenging treatment with an anti-EGFR monoclonal antibody in patients without RAS mutations in ctDNA. There was also a significant difference in the disease control rate, which overall demonstrated that the RAS mutational status may be an effective predictor of response to rechallenging treatment.

These findings suggest that OncoBEAM RAS CRC assay may not be predictive of efficacy when rechallenging treatment in this population, but it may also assist in monitoring resistance or predicting outcomes. This assay uses BEAMing technology, which is an enhanced digital polymerase chain reaction method optimized for high sensitivity of blood-based mutation detection in mCRC.

“Genomic profiling by liquid biopsy after progression would be helpful for overcoming resistance or guiding adequate targeted therapies,” the study authors, led by Sunakawa, wrote. “In patients receiving anti-EGFR mAb as rechallenge treatment, OncoBEAM RAS CRC kits may be a tool for predicting prognosis after rechallenge therapy.”

In conclusion, the study confirmed that patients with mCRC harboring RAS mutations in ctDNA at baseline had shorter survival outcomes when they received rechallenging treatment with an anti-EGFR monoclonal antibody, even if the patient was sensitive to frontline therapy with an anti-EGFR agent and chemotherapy. The OncoBEAM RAS CRC assay may also be able to predict the efficacy of rechallenging treatment in this patient population as well, supporting the clinical utility of this liquid biopsy assay for rechallenging treatment in patients with mCRC with RAS wild-type tumors.

_References

_{1. Sunakawa Y, Nakamura M, Ishizaki M, et al. RAS mutations in circulating tumor DNA and clinical outcomes of rechallenge treatment with anti-EGFR antibodies in patients with metastatic colorectal cancer. JCO Precision Oncology. 2020;4:898-911. doi: 10.1200/PO.20.00109}

_{2. Sysmex Inostics’ OncoBEAM RAS CRC testing supports clinical outcome improvements for metastatic colorectal cancer patients rechallenged with anti-EGFR therapy. News release. Sysmex Inostics. August 27, 2020. Accessed September 1, 2020. https://prn.to/3lygKgK}