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A Lack of Resistance Gene Alterations in Baseline ctDNA Associated with Prolonged OS After First-Line Treatment with Panitumumab plus Chemotherapy in Patients with RAS wt mCRC

Findings from an exploratory preplanned biomarker analysis of the PARADIGM study
16 Feb 2024
Targeted Therapy;  Molecular Oncology
Colon and Rectal Cancer

In a prespecified exploratory biomarker analysis of the randomised, open-label, phase III PARADIGM study, the Japanese researchers investigated the potential prognostic and predictive role of hyperselecting patients for anti-EGFR treatment based on detection of a broad array of genetic alterations in plasma circulating tumour DNA (ctDNA) in patients with RAS wild-type (wt) unresectable metastatic colorectal cancer (mCRC).

This first report of negative hyperselection using ctDNA in a large phase III study population suggests that negative hyperselection using a validated and adequately sensitive plasma ctDNA assay may inform appropriate selection of patients for panitumumab treatment regardless of tumour sidedness (left versus right). For patients meeting negative hyperselection criteria, overall survival (OS) was prolonged with panitumumab plus mFOLFOX6 compared with bevacizumab plus mFOLFOX6 in patients with left-sided primary tumours according to Dr. Kohei Shitara of the Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East in Kashiwa and Department of Immunology, Nagoya University Graduate School of Medicine in Aichi, Japan, and colleagues who published the findings on 12 February 2024 in the Nature Medicine.

The authors wrote in the background that previously reported the phase III PARADIGM study, conducted in patients with unresectable RAS wt mCRC, demonstrated longer OS with first-line panitumumab plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 in patients with left-sided primary tumours with a median OS of 37.9 versus 34.3 months (hazard ratio [HR] 0.82; p = 0.03) and in the overall patient population, 36.2 versus 31.3 months (HR 0.84; p = 0.03). Exploratory analyses showed poorer survival (20.2–23.2 months) in patients with tumours originating from the right colon side.

Decision to initiate anti-EGFR treatment should be guided by the primary tumour location and testing for BRAF, KRAS and NRAS mutations and deficient mismatch repair or microsatellite instability. Several other less common molecular alterations have been linked to primary resistance to EGFR inhibitors, including mutations in PTEN and EGFR extracellular domain, amplifications of HER2 and MET, and fusions of ALK, RET and NTRK1. Testing for a combination of multiple molecular markers has the potential to guide more precise treatment selection for patients with mCRC.

To allow for molecular negative hyperselection of patients most likely to benefit from anti-EGFR treatment, previous studies have worked towards establishing a testing panel that includes a broad array of rare genomic alterations linked to primary resistance to EGFR inhibition. These studies demonstrated that detection of any of the panel-prespecified genetic alterations in tumour biopsy samples, as well as primary tumour sidedness, were predictive of clinical outcomes on anti-EGFR therapy. Genotyping of tumours based on testing of ctDNA is a minimally invasive alternative to tissue biopsy.

In this prespecified exploratory biomarker analysis of the phase III PARADIGM study (overall study population, 802 patients), the research team tested ctDNA in baseline plasma samples from 733 patients with RAS wt mCRC to investigate the utility of ctDNA-based negative hyperselection for predicting treatment outcomes with mFOLFOX6 combined with either panitumumab or bevacizumab. They evaluated the association between ctDNA gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions.

The study team reported that OS was prolonged with panitumumab plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (negative hyperselected) with a median in the overall population of 40.7 versus 34.4 months (HR 0.76, 95% confidence interval [CI] 0.62–0.92), but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel, 19.2 versus 22.2 months (HR 1.13, 95% CI 0.83–1.53), regardless of tumour sidedness.

Higher rates of antitumour response (83.3% versus 66.5%), curative resection (19.8% versus 10.6%) and greater depth of response (median, −60.2% versus −43.6%) with panitumumab versus bevacizumab may have contributed to the improved OS in this negative hyperselected left-sided population.

The prevalence of any genetic alteration associated with resistance was higher among patients with right-sided (49.7%) versus left-sided (26.0%) primary. Even in the patients with right-sided primary tumours, negative hyperselected patients showed numerically longer OS, 38.9 versus 30.9 months (HR 0.82, 95% CI 0.50–1.35), as well as evidence of improved response rate (71.4% versus 66.6%) and depth of response (median, −56.4% versus −39.4%) with panitumumab versus bevacizumab. The wide 95% CIs for the HR in this correlation may be attributed to the low number of patients with right-sided tumours in the study population.

The authors commented that their results suggest that the primary tumour location may not be the sole determinant and support the notion that primary tumour location serves as a clinical surrogate marker reflecting the intricate molecular landscape of primary resistance to anti-EGFR antibodies. Although exploratory, these findings suggest that even certain patients with right-sided CRC may benefit from first-line anti-EGFR antibodies with chemotherapy if negative hyperselection is feasible. Further investigations are needed to confirm whether treatment with anti-EGFR antibody is truly beneficial for negatively hyperselected patients with right-sided mCRC.

The authors concluded that negative hyperselection based on ctDNA testing using a comprehensive panel of gene alterations associated with resistance to anti-EGFR treatment allows for the identification of patients with mCRC who may derive benefit from first-line treatment with panitumumab combined with chemotherapy.

The study was sponsored by Takeda Pharmaceutical Company Ltd. 


Shitara K, Muro K, Watanabe J, et al. Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer. Nature Medicine; Published 12 February 2024. DOI: https://doi.org/10.1038/s41591-023-02791-w

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