Phase II Study of Cetuximab Rechallenge in Patients with RAS Wild-Type metastatic Colorectal Cancer: E-Rechallenge Trial
H. Osawa1, E. Shinozaki2, M. Nakamura3, Y. Ohhara4, Y. Shindo5, M. Shiozawa6, H. Uetake7, H. Matsumoto8, N. Ureshino9, H. Satake10, T. Kobayashi11, T. Suto12, S. Kitano13, Y. Ohashi14, K. Uemura15, K. Yamaguchi2
Comprehensive Support Project 1Dept of Oncology and Hematology, Edogawa Hospital, 2Gastrointestinal Oncology, Cancer Institute Hospital of JFCR, 3Aizawa Comprehensive Cancer Center, Aizawa Hospital, Dept of Gastroenterology, Sapporo Medical Center, 5Gastroenterological Surgery, Nakadori General Hospital,
6Gastrointestinal Surgery, Kanagawa Cancer Center, 7Specialized Surgeries, Tokyo Medical and Dental University, 8Dept of Surgery, Cancer and Infectious Diseases Center, Tokyo Metropolitan Komagome Hospital, 9Medical Oncology, Saga-Ken Medical Center Koseikan, 10Dept of Medical Oncology,
For Oncological Research

481P

Kobe City Medical Center General Hospital, 11Dept of Medical Oncology, Kyorin University Faculty of Medicine, 12Dept of gastroenterological surgery, Yamagata Prefectural Central Hospital, 13Graduate School of Engineering, Osaka University, 14Integrated Science and Engineering for Sustainable
Society, Chuo University, 15Division of Biostatistics and Bioinformatics, Interfacluty Initiative in Information Studies, The University of Tokyo   
Several previous reports indicated that cetuximab (Cmab) rechallenge may beefficacious in patients for whom Cmab was previously effective. On the other
hand, some reports did not support this. Considering the plasticity ofsensitive clone, we assumed that an anti-EGFR antibody-free interval (aEFI)and efficacy may be correlated. This current study investigates the efficacy
and safety of Cmab rechallenge as a salvage chemotherapy.

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multicenter phase II study
main eligibility criteria
mCRC patients who have become refractory to fluoropyrimidines, L-OHP, CPT11, Cmab and bevacizumab, and in whom previous treatment with Cmab was
effective
 in any earlier line (achieving CR, PR, or SD that persisted for ≥6 months)
 RAS wild-type measurable disease aEFI ≥16 weeks between the last dose of Cmab during previous treatment
and the start of Cmab rechallenge
Protocol treatment: combination of weekly Cmab with biweekly CPT-11.
Primary endpoint: response rate (RR)
Secondary endpoints: progression free survival (PFS), overall survival (OS),association between the aEFI and efficacy, and safety
Statistical considerations: Using a single-stage binominal design, 45 patientswere required; a RR of ≥ 20% was considered promising, and a RR of ≤ 5%
unacceptable (one-sided α = 2.5%, β = 10%).

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 Between Dec 2014 and Oct 2017, 33 patients were enrolled. The registration of this trial was halted in Oct 2017 due to insufficient accrual.
 The primary endpoint; the rates of PR/SD/PD (95%CI) were PR 15.2% (5.1-31.9%)/SD 39.4% (22.9-57.9%)/ PD 42.4% (25.5-60.8%).
 Secondary endpoints; median PFS and OS (95%CI) were 88 days (62-113days) and 262 days (195-307days).
 There were no statistical significant difference of RR, PFS and OS stratified by median aEFI (311days).
 New safety information were not identified.
 Twenty four patients were enrolled the additional liquid biopsy research which was conducted optionally.
Table1. Patients Characteristics (n=33)
Table2. Response Rate
Table3. Response Rate divided by median aEFI
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Clinical trial identification UMIN 000016439.
Legal entity responsible for the study
Comprehensive Support Project for Oncological Research.
Partially sponsored by Merck Serono.

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Table4. Mutation status of liquid biopsy at baseline (n=24)
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Figure1. Representative Case of Response
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rechallenge

The blue circle indicates the metastasis in segment 1 of the liver. Shrinkage
was seen after rechallenge of CPT-11 + cetuximab.

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Figure2. Survival Curves

Liquid biopsy research
Additional research of ctDNA was conducted optionally.
Blood samples at baseline collected in STRECK BCT® tubes
DNA was extracted from plasma using the QIAamp Circulating Nucleic Acid Kit(Qiagen)
We performed ddPCR assays on a QX200 digital PCR system (BioRad
laboratories) . The PCR data were quantified as copies/μL using QuantaSoft™
software (BioRad laboratories).
A mutation was considered positive with more than 0.1% fractional
abundance of KRAS c12/c13/A59/Q61, BRAF (V600E) and EGFR S492R mutant
droplets. The uniplex ddPCR method had been optimized beforehand bycomparative analysis of a dilution series of synthetic copies of each indicatedmutant oligonucleotide.
LBx® Probe of KRAS G12/G13 Screen (Riken Genesis)
LBx® Probe KRAS A59/Q61Screen (Riken Genesis)
LBx® Probe BRAF V600 Screen (Riken Genesis)
Additionally, we used ddPCR™ probe EGFR S492R as the detection probe for
EGFR S492R(c.1474A>C) and S492R (c.1476C>A) (BioRad laboratories).

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Results of Liquid biopsy research(Table 4 and 5, Figure 4)a)Figure3. Survival Curves divided by median aEFI
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Figure4. Results from ctDNA analysis(n=24)
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By narrowing down all wild type of this liquid biopsy, the response rate wasincreased from 12.5% to 25%.

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Cmab rechallenge showed some activity in the salvage setting, in patientsfor whom Cmab was previously effective.
KRAS and BRAF screening by liquid biopsy may contribute to identify thepatients with benefit from Cmab rechallenge.