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. 2022 Apr 21:12:852583.
doi: 10.3389/fonc.2022.852583. eCollection 2022.

Liquid Biopsy-Driven Cetuximab Rechallenge Strategy in Molecularly Selected Metastatic Colorectal Cancer Patients

Stefano Mariani  1 , Marco Puzzoni  1 , Riccardo Giampieri  2 , Pina Ziranu  1 , Valeria Pusceddu  1 , Clelia Donisi  1 , Mara Persano  1 , Giovanna Pinna  1 , Erika Cimbro  1 , Alissa Parrino  1 , Dario Spanu  1 , Andrea Pretta  1 , Eleonora Lai  1 , Nicole Liscia  1 , Alessio Lupi  2 , Enrica Giglio  2 , Grazia Palomba  3 , Milena Casula  3 , Marina Pisano  3 , Giuseppe Palmieri  3 , Mario Scartozzi  1
Affiliations

Liquid Biopsy-Driven Cetuximab Rechallenge Strategy in Molecularly Selected Metastatic Colorectal Cancer Patients

Stefano Mariani et al. Front Oncol. .

Abstract

Background: Rechallenge with EGFR inhibitors represents a promising strategy for patients with RAS wild type (WT) colorectal cancer (CRC) but definitive selection criteria are lacking. Recently, the RAS WT status on circulating tumor DNA (ct-DNA) emerged as a potential watershed for this strategy. Our study explored the liquid biopsy-driven cetuximab rechallenge in a RAS and BRAF WT selected population.

Methods: CRC patients with RAS and BRAF WT both on tumor tissue and on ct-DNA at baseline receiving rechallenge with cetuximab were eligible for our analysis. Ct-DNA was analyzed for RAS-BRAF mutations with pyro-sequencing and nucleotide sequencing assays. Real-time PCR and droplet digital PCR were performed to confirm the RAS-BRAF mutational status.

Results: A total of 26 patients were included in our analysis. In the global population, RR was 25.0%, median overall survival (mOS) was 5.0 months, and median progression-free survival (mPFS) was 3.5 months. Previous response to anti-EGFR was associated with improved mPFS (5.0 vs. 2.0 months, HR: 0.26, p = 0.048); anti-EGFR free interval > 14 months and anti-EGFR free interval > 16 months were associated with improved mPFS (respectively 7.0 vs. 3.0 months, HR: 0.27, p = 0.013 and not reached vs. 3.0 months, HR: 0.20, p = 0.002) and with improved mOS (respectively 13.0 vs. 5.0 months, HR: 0.27, p = 0.013 and 13.0 vs. 5.0 months, HR: 0.20, p = 0.002). Previous lines >2 were correlated with improved mPFS (4.0 vs. 1.0 month, HR: 0.05, p = 0.041) and with improved mOS (7.0 vs. 1.0 month, HR: 0.045, p = 0.034). In a multiple logistic regression model, only the anti-EGFR free interval was confirmed to be a significant predictor for mOS and mPFS.

Conclusions: Liquid biopsy-driven cetuximab rechallenge was confirmed to be effective. The clinical outcome was consistent with available results from phase II studies. In addition to the molecular selection through the analysis of ct-DNA for RAS, the long anti-EGFR free interval is confirmed as a prospective selection criterion for this therapeutic option.

Keywords: RAS; cetuximab; colorectal (colon) cancer; epidermal growth factor receptor (EGFR); liquid biopsy; rechallenge.

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Conflict of interest statement

Author GiuP reports advisory role for BMS, MSD, Roche, Pierre-Fabre, Novartis, and Incyte. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
ROC curve of anti-EGFR free-time predictive of prognosis with rechallenge treatment (AUC 0.81, p < 0.001).
Figure 2
Figure 2
ROC curve of anti-EGFR free-time predictive of response with rechallenge treatment (AUC 0.852; p < 0.001).
Figure 3
Figure 3
CT scan of a patient treated with rechallenge strategy after >2 prior lines of treatment and an anti-EGFR free interval > 16 months.
See this image and copyright information in PMC

References

    1. Puzzoni M, Ziranu P, Demurtas L, Lai E, Mariani S, Liscia N, et al. Why Precision Medicine Should Be Applied Across the Continuum of Care for Metastatic Colorectal Cancer Patients. Future Oncol (2020) 16(2):4337–9. doi: 10.2217/fon-2019-0624 - DOI - PubMed
    1. Diaz LA, Jr, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, et al. The Molecular Evolution of Acquired Resistance to Targeted EGFR Blockade in Colorectal Cancers. Nature (2012) 486(7404):537–40. doi: 10.1038/nature11219 - DOI - PMC - PubMed
    1. Arena S, Bellosillo B, Siravegna G, Martinez A, Canadas I, Lazzari L, et al. Emergence of Multiple EGFR Extracellular Mutations During Cetuximab Treatment in Colorectal Cancer. Clin Cancer Res (2015) 21(9):2157–66. doi: 10.1158/1078-0432.CCR-14-2821 - DOI - PubMed
    1. Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G, et al. Clonal Evolution and Resistance to EGFR Blockade in the Blood of Colorectal Cancer Patients. Nat Med (2015) 21(7):795–801. doi: 10.1038/nm0715-827b - DOI - PMC - PubMed
    1. Parseghian CM, Loree JM, Morris VK, Liu X, Clifton KK, Napolitano S, et al. Anti-EGFR-Resistant Clones Decay Exponentially After Progression: Implications for Anti-EGFR Re-Challenge. Ann Oncol (2019) 30(2):243–9. doi: 10.1093/annonc/mdy509 - DOI - PMC - PubMed