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. 2020 Oct 2;21(10):891-898.
doi: 10.1080/15384047.2020.1798695. Epub 2020 Oct 7.

Frequency of S492R mutations in the epidermal growth factor receptor: analysis of plasma DNA from patients with metastatic colorectal cancer treated with panitumumab or cetuximab monotherapy

Timothy Price  1 , Agnes Ang  2 , Michael Boedigheimer  2 , Tae Won Kim  3 , Jin Li  4 , Stefano Cascinu  5 , Paul Ruff  6 , Attili Satya Suresh  7 , Anne Thomas  8 , Sergei Tjulandin  9 , Marc Peeters  10
Affiliations

Frequency of S492R mutations in the epidermal growth factor receptor: analysis of plasma DNA from patients with metastatic colorectal cancer treated with panitumumab or cetuximab monotherapy

Timothy Price et al. Cancer Biol Ther. .

Abstract

Background: Antibodies against epidermal growth factor receptor (EGFR), panitumumab, a fully human monoclonal antibody, and cetuximab, a human/mouse chimeric monoclonal antibody, have shown clinical efficacy in metastatic colorectal cancer (mCRC). In the phase 3 noninferiority ASPECCT (ClinicalTrials.gov, NCT01001377) study, panitumumab was demonstrated to be noninferior to cetuximab and provided a similar overall survival benefit for patients with chemotherapy-refractory wild-type KRAS exon 2 mCRC. However, some patients eventually develop resistance to anti-EGFR therapy. EGFR p.S492R mutation was previously identified as conferring resistance to cetuximab, but not to panitumumab.

Methods: This biomarker study analyzed plasma samples from ASPECCT collected at both baseline and posttreatment.

Results: No EGFR p.S492R mutations were identified at baseline; however, after treatment the EGFR p.S492R mutation was detected in 1% of patients treated with panitumumab versus 16% of those treated with cetuximab, supporting that, in a large population, this mutation is more likely to be induced by cetuximab than by panitumumab. There were, however, no significant differences in progression-free survival or overall survival between patients who were wild-type compared with those with the S492R mutation within the cetuximab arm or the overall population.

Conclusions: These results may support targeting treatment to small patient subgroups based on the presence of emerging EGFR mutations and provide a molecular rationale for rechallenging with a different anti-EGFR agent in patients who develop resistance. Prospective studies are needed to evaluate the efficacy of panitumumab in the EGFR p.S492R mutant population.

Keywords: Colorectal cancer; anti–epidermal growth factor receptor; cetuximab; gene mutations; panitumumab; resistance.

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Figures

Figure 1.
Figure 1.
Binding of panitumumab and cetuximab to wild-type and mutant (p.S492R) EGFR
Figure 2.
Figure 2.
Patient disposition
Figure 3.
Figure 3.
Progression-free survival for patients with or without the EGFR p.S492R mutation for (a) all patients, (b) patients treated with cetuximab
Figure 4.
Figure 4.
Overall survival for patients with or without the EGFR p.S492R mutation for (a) all patients, (b) patients treated with cetuximab
See this image and copyright information in PMC

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