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Retratamiento con anti-EGFR: ¿debe ser guiado por la biopsia liquida?
Dr. Rafael López LópezOncología Médica Traslacional
Hospital Clínico Universitario e Instituto de Investigación SanitariaSantiago de Compostela
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Disclosures
Advisory role: Roche, AstraZeneca, Merck, MSD, Bayer, BMS, Novartis, Janssen, Lilly, Pfizer, Leo
Speaker’s fee: Roche, Novartis, Pharmamar
Research support: Roche, Merck
Co-founder and shareholder: Nasasbiotech, S.L., Mtrap Inc
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Retratamiento con anti-EGFR: ¿debe ser guiado por la biopsia liquida?
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….Sí…claro
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Anti-EGFR rechallenge strategy
Goldberg et al., ESMO Open 2018. doi:10.1136/ esmoopen-2018-000353
RECHALLENGE: Reintroduction, after an intervening treatment, of the same therapy to which tumour has already proved to be resistant
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How to resolve these problem?
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Continously monitoring de cancer cells
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From the practical point of view
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1 2-5
1-3 2-7
2-7
2-3
2-5
3-15 1-5
1-7
1 5 (3-15) 1-7
1
14-48 days
7-14 days
1.500€-30.000€ (one)
300€-3.000€(one)
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Clonal evolution of CRC
Siravenga et al., Nature Rev 2017
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From the scientific point of view
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Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients
Emergence of RAS mutations at progression to anti-EGFR treatmentBaseline
PD
Vidal et al., Annals of Oncology, 2017
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10:48Van Emburgh. Nat Comm 2016
Emergence of mutations of resistance in mCRC patients with anti-EGFR
Dienstmann et al., Ann Oncol , 2016
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Resistance to anti-EGFR mAbs
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Retreatment with anti-EGFR based therapies in metastatic colorectal cancer:
impact of intervening time interval and prior anti-EGFR response
Liu et al. BMC Cancer 2015;15:713; Goldberg et al., ESMO Open 2018.
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INCLUSION CRITERIAHistologically confirmed diagnosis of metastatic colorectal cancer;Documented WT RAS exons 2, 3 and 4 (KRas and NRas) and WT BRAF V600E;Complete or partial response to frontline chemotherapy including anti-EGFR mAb.Imaging documented progression while on therapy or maintenance regimen including anti-EGFR mAb;RAS-extended mutational load with > 3% fractional abundance, measured on plasma ctDNA at BML (maximum within 2 weeks of last anti EGFR administration);Planned 2nd line chemotherapy of any type with the exclusion of further anti EGFRs (regorafenib is allowed).
Rechallenge With Panitumumab Driven by RAS
Dynamic of Resistance (CHRONOS)
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Khan et al., Cancer Discov, 2018
The PROSPECT-C trial
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Longitudinal Liquid Biopsy and Mathematical Modeling of Clonal Evolution Forecast Time to Treatment Failure in the
PROSPECT-C Phase II Colorectal Cancer Clinical Trial
Khan et al., Cancer Discov, 2018
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Cremolini C et al. JAMA Oncol. doi:10.1001/jamaoncol.2018.5080
The CRICKET trial (a proof-of-concept study)
A, Hazard ratio, 0.44 (95%CI, 0.18-0.98; P = .03). B, Hazard ratio, 0.58 (95% CI, 0.22-1.52; P = .24).
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Take Home Message
• Rechallenge with anti-EGFR provides clinical benefit in molecularlyselected mCRC patients beyond second line.
• ctDNA analyses to determine RAS and other genes status will be a key element to guide rechallenge in CRC patients
• Ongoing clinical trials will solidify the concept of anti-EGFR rechallenge as a routine strategy to optimise the therapy
• Additional biomarkers of response to anti-EGFR agents will ensuredefinition of the optimal patient populations for these strategies
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Future
RL Foro debate oncología 2019
Heitzer et al Nat Rew Genetics 2018 doi.org/10.1038/s41576-018-0071-5
