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. 2019 Feb 1;30(2):243-249.
doi: 10.1093/annonc/mdy509.

Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge

C M Parseghian  1 , J M Loree  2 , V K Morris  3 , X Liu  4 , K K Clifton  3 , S Napolitano  3 , J T Henry  3 , A A Pereira  3 , E Vilar  5 , B Johnson  3 , B Kee  3 , K Raghav  3 , A Dasari  3 , J Wu  3 , N Garg  6 , V M Raymond  7 , K C Banks  7 , A A Talasaz  7 , R B Lanman  7 , J H Strickler  8 , D S Hong  4 , R B Corcoran  9 , M J Overman  3 , S Kopetz  3
Affiliations

Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge

C M Parseghian et al. Ann Oncol. .

Abstract

Background: Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy.

Patients and methods: We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies.

Results: Our analysis showed that RAS and EGFR relative mutant allele frequency decays exponentially (r2=0.93 for RAS; r2=0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model.

Conclusion: These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation.

Keywords: anti-EGFR therapy; circulating tumor DNA; clonal decay; colorectal cancer.

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Figures

Figure 1.
Figure 1.
(A) Sum of exponential decay of median RAS and median EGFR rMAF (t1/2=4.4  ± 2.90 months, r2=0.94). (B) Exponential decay of the median RAS allele over time after discontinuation of anti-epidermal growth factor receptor (EGFR) therapy (t1/2=3.4 months; r2=0.93). (C) Exponential decay of the median EGFR allele over time after discontinuation of anti-EGFR therapy (t1/2=6.9 months; r2=0.94).
Figure 2.
Figure 2.
(A) Estimated exponential decay of the average of the RAS plus EGFR allele on an external cohort of patients (t1/2=4.3 months). (B) Estimated exponential decay of the RAS allele on an external cohort of patients (t1/2=3.7 months). (C) Estimated exponential decay of the EGFR allele on an external cohort of patients (t1/2=4.7 months). P = 0.11 for a difference between RAS and EGFR.
Figure 3.
Figure 3.
Comparison of the exponential decay of the median RAS plus EGFR rMAF in the MD Anderson Cancer Center (MDACC) cohort (t1/2=4.4 months) and validation cohort (t1/2=4.3 months).
Figure 4.
Figure 4.
Impact of time from prior anti- epidermal growth factor receptor (EGFR) on (A) progression-free survival and (B) response rates of metastatic colorectal cancer patients undergoing re-challenge with a second regimen containing an anti-EGFR agent. CI, confidence interval.
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