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FIGURE 2.5 Schema for the BATTLE
study. (Reprinted from Kim et al. [126] .)
Umbrella protocol
Core needle biopsy
Biomarker profile
EGFR mutation/
copy number
KRAS/BRAF mutation
• VEGF/VEGFR-2
expression
• RXRs/Cyclin D1
expression and
CCND1 copy number
Equal followed by
adaptive
randomization
Erlotinib +
bexarotene
Erlotinib
Vandetanib
Sorafenib
within each treatment arm. Using the biomarker-DCR results, future randomization probabili-
ties were adjusted using a Bayesian model, such that if a patient presented with a particu-
lar biomarker signature, he or she had a >25% chance of being randomized to a treatment on
which prior patients with the same biomarker signature had positive results.
Results from the BATTLE study revealed interesting biomarker-treatment relationships
that had previously not been extensively explored. For example, a better eight week DCR was
observed for patients with EGFR amplification receiving erlotinib plus bexarotene; a worse
eight week DCR was observed for patients with EGFR mutations receiving sorafenib; and,
compared to other treatments tested, sorafenib had a higher DCR (64% versus 33%) in EGFR-
wild-type patients and a nonstatistically significant trend toward better DCR (61% versus
32%) in KRAS-mutant patients. Another key finding was a promising relationship between
KRAS or BRAF mutation-positive patients and sorafenib therapy. Biomarker-positive patients
had a 79% eight week DCR compared to a 14% eight week DCR with erlotinib [126-128] . The
adaptive randomization design likely enhanced the ability to make this observation by pref-
erentially randomizing KRAS or BRAF mutation-positive patients to the sorafenib arm. The
success of the BATTLE trial in demonstrating the feasibility of the novel design and poten-
tial to reveal informative biomarker associations has already inspired similar designs, such
as the BATTLE-2 trial, which will further refine the approach taken in the BATTLE study by
pre-specifying a limited set of markers in the first half of the study population (200 patients)
to conduct prospective testing of biomarkers / signatures. The most predictive markers and
signatures will then be used to guide patient assignments to the most favorable matched
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