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meeting the eligibility criteria are entered the trial, regardless of the PGx marker status, but prospectively
specified subgroup analysis of the treatment effect within biomarker-defined subgroups can be included to
explore the predictive potential of the biomarker; this design is recommended when preliminary evidence
on the biomarker is low, and when its prevalence in the population is high. Another key feature of phase 2
trials is the possibility to randomize patients. Since most phase 1 trials are single-arm trials with no control
arm, prognostic and predictive values of PGx findings can’t be discerned in this setting; in the context of
phase 2 trials, instead, there’s a growing trend in designing randomized phase 2 trials (in a 2008 review of
[38]
targeted agents phase 2 trials, as many as 30% of the trials where randomized ). Randomization enhances
the potential for biomarker discovery and the ability to discern the potential predictive value of previously
[39]
discovered PGx findings, reducing the risk for bias existent in comparisons with historical controls . PGx
biomarker inclusion in the trial design, together with randomization of patients, represent powerful tools in
the discovery and exploration of predictive PGx biomarkers, which can inform the design of confirmatory
phase 3 trials in a more tailored and efficacious way.

Challenges in Pharmacogenomics implementation
The implementation of PGx in cancer drug development, although undoubtedly promising, still needs to
address a certain number of issues. First of all, obtaining enough tissue for genomic tests can be challenging.
The identification of PGx biomarkers of safety and activity should ideally involve multiple biopsies, at drug
initiation, during treatment and at disease progression. Although the first usually provides benefits to the
patients, the two last are mainly meant to inform the researchers, exposing the patient to invasive techniques
from which they derive no direct benefit, addressing a sensitive ethical question. This well-known issue has
emerged more than ever in precision medicine trials, where the identification of mechanisms of resistance
[40]
is crucial for the optimization of treatments . In this setting, the promising alternative of liquid biopsy
could provide the needed information with a simple and non-invasive blood draw. Landmark examples are
[41]
the detection of T790M mutation in NSCLC treated with anti-EGFR , the early detection of emergence
[42]
of KRAS mutations in colorectal cancer and the detection of mutations reverting sensitivity to PARP-
[43]
inhibitors in prostate cancer . Liquid biopsy could solve another emerging issue related to precision
medicine: it could catch the intrinsic intratumoral heterogeneity of cancer, providing an integrated picture of
the mutational scenario of the neoplasia which could prioritize druggable alterations and guide therapeutic
[44]
decisions .
An important controversy is related to the meaning of mutational findings in tumors, most of which are
expected to be passenger mutations, as opposed to fewer driver mutations promoting cancer growth and
[45]
spread . Frequency-based and function-based approaches are being applied to individuate driver mutations,
and have recently lead to the publishing by ESMO of a scale of actionability of molecular targets (ESCAT
scale) based on the strength of the evidence supporting them, which will serve as a base to interpret PGx
[46]
findings and improve clinical trials, as well as clinical practice. The scale is meant in a plastic way, and
enables mutations to be upgraded or downgraded in response to newly available data.

Time remains a concern: adding PGx profiling in the inclusion/exclusion criteria of trials harbors the risk of
delaying the initiation of experimental drugs, leaving patients off-treatment for a longer time. Such issue is
especially relevant when a centralized confirmation of the biomarker status is required: mutation detection
or gene expression assays might require up to 10 business days from the shipping of the sample to the
report results, and assays that require macro-dissection of FFPE slides may take even longer time. Although
sequencing time is expected to fall with the evolution of NGS techniques, logistics remain the rate-limiting
step of the equation, meaning that solving the issue will require innovative organizational improvements.

Finally, ethics remain an important issue; especially in the context of enriched trials: by treating only
the population of biomarker-positive patients, no data is collected regarding the biomarker-negative