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Poster session 06

1670P - Circulating tumor DNA (ctDNA) dynamics of response and resistance in BRAF V600E mutant (mt) metastatic colorectal (mCRC) and other cancers: Data from EVICT (erlotinib and vemurafenib in combination trial)

Date

10 Sep 2022

Session

Poster session 06

Topics

Translational Research;  Targeted Therapy;  Molecular Oncology

Tumour Site

Colon and Rectal Cancer

Presenters

Lavinia Tan

Citation

Annals of Oncology (2022) 33 (suppl_7): S758-S771. 10.1016/annonc/annonc1078

Authors

L. Tan1, B. Tran1, J. Tie1, E. Link2, S.Q. Wong3, S. Chandrashekar3, J. Guinto3, B. Markman4, S. Ananda1, N.C. Tebbutt5, M. Michael1, B.J. Solomon1, G. McArthur6, P. Gibbs7, S. Dawson1, J. Desai1

Author affiliations

  • 1 Medical Oncology, Peter MacCallum Cancer Centre, 3000 - Melbourne/AU
  • 2 Centre For Biostatistics And Clinical Trials, Peter MacCallum Cancer Centre, 3000 - Melbourne/AU
  • 3 Cancer Research, Peter MacCallum Cancer Centre, 3000 - Melbourne/AU
  • 4 Medical Oncology, Monash Health - Monash Cancer Centre, 3165 - Bentleigh East/AU
  • 5 Medical Oncology, Olivia Newton John Cancer Wellness and Research Centre, 3084 - Heidelberg/AU
  • 6 Victorian Comprehensive Cancer Center, Peter MacCallum Cancer Centre, 3000 - Melbourne/AU
  • 7 Medical Oncology, WEHI - Walter and Eliza Hall Institute of Medical Research, 3052 - Parkville/AU
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Abstract 1670P

Background

In the phase Ib/II EVICT trial, the combination of vemurafenib and erlotinib demonstrated promising efficacy with response rates of 32% (10/31; 16% -5/31 confirmed) in patients (pts) with BRAF V600E mt mCRC and 43% (3/7) in pts with other cancers. The overall clinical benefit rate (partial response + stable disease) was 71% (27/38). Here we report the utility of ctDNA as a biomarker to predict outcomes and understand mechanisms of treatment resistance.

Methods

Serial plasma samples were available from 25 pts. Paired baseline and progression samples were analyzed by targeted sequencing (AVENIO ctDNA expanded assay, Roche diagnostics). Droplet digital PCR was used to serially monitor mutations of interest.

Results

BRAF V600E mt ctDNA was detected at baseline in 21/25 pts (84%). Other frequently altered genes included TP53 (60%), EGFR (52%), and MET (40%), with mutational burden higher in pts who did not derive clinical benefit (P=0.04). MET amplification was associated with inferior overall survival (OS) (median OS 4.9 vs 8.8 months; HR 2.2; [95% CI 0.84-6.0]; P=0.04). Decline in ctDNA levels (copies/mL) between baseline to week 2 was greater in pts who derived clinical benefit (P<0.001). Reduction in ctDNA variant allele fraction at 2 weeks predicted longer progression free survival (PFS) (median PFS 1.8 vs 6.4 months; HR 3.6, 95% CI 1.30-9.76, P<0.001) and OS (median OS 5.6 vs 9.9 months; HR 2.9, 95% CI 1.01-8.36, P<0.01). Of the 18 pts with plasma available at progression, 9/18 (50%) showed emergence of >1 KRAS or NRAS mutation. Polyclonal KRAS mutations were observed in 6/9 pts (67%). Other frequently acquired MAPK pathway alterations included MAP2K1 mutations (22%) and MET amplification (17%).

Conclusions

In pts with BRAF V600E mt cancers treated with vemurafenib and erlotinib, baseline ctDNA profile and an early decline in ctDNA were predictive of clinical outcomes. ctDNA analyses provided a mechanistic understanding of intrinsic and acquired resistance, revealing frequent evidence of convergent evolution and MAPK pathway reactivation as the dominant mechanism of therapeutic escape.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Peter MacCallum Cancer Centre.

Funding

The Victorian Cancer Agency, Clinical Trials Grants; and Roche.

Disclosure

All authors have declared no conflicts of interest.

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