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The right target for the right patient: a genomic-oriented approach in Basket trials and
Umbrella trials
One important application of PGx in cancer drug development regards molecularly targeted therapy, an
approach deriving from the idea that targeting a driver molecular alteration found in cancer tissue might
control cancer proliferation. This principle provided great improvements in cancer treatment, leading to a
[23]
new paradigm of drug choice, molecular-alteration-centered rather than histology-oriented .
New trial designs (the so called Master Protocols) have been developed in order to validate this approach;
this term includes three different trial types: Umbrella trials, which study various targeted agents in the
context of a single disease (e.g., NCI-MATCH trial); Basket trials, which study a single targeted therapy
in the context of multiple diseases or disease subtypes (e.g., Braf V600 trial); Platform trials, which study
multiple targeted therapies in the context of a single disease in a perpetual manner, allowing to add or
remove therapies from the platform on the basis of a decision algorithm with an adaptive statistical design
[24]
(e.g., I-SPY2) . Such trials might accelerate the approval of targeted drugs, by hitting “the right target”
in “the right patient” regardless of the histological type of tumor. By now, contradicting results have been
obtained from molecularly driven trials, with the disappointing results retrieved from the Phase 2 SHIVA
[25]
trial in contrast to the positive signals deriving from the NCI MATCH trial [26,27] together with the success
[28]
of the Phase 2 basket trial of larotrectinib in TRK-fusion positive patients and the demonstration of the
[29]
activity of pembrolizumab in mismatch-repair deficient tumors , which lead to their agnostic approval for
any solid tumor type. Many answers are awaited from the results of the aforementioned Master Protocols,
which might lead to the approval of more drugs with the same agnostic paradigm, avoiding the canonical
phase 1 to phase 3 drug development, particularly in the genomic- oriented approach targeting rare genomic
alterations, requiring huge efforts to be tested in randomized phase 3 histology- oriented trials.

The role of Pharmacogenomics in early developmental phases
The adoption of PGx principles in cancer drug development can be beneficial in every phase of drug
development, from compound discovery to post-marketing surveillance [Figure 3]. Although most of the
PGx discoveries to date have emerged from phase 3 or post-marketing studies, evidence of a critical role of
[30]
PGx in early-phase trials are arising . The late implementation of PGx can in fact lead to discard potential
useful drugs, or to the approval for unselected patients of drugs which are beneficial only in a subset of
them: one clear example is the approval of cetuximab in 2004 for the treatment of unselected colorectal
cancer patients, and the following discovery in 2006 of no-benefit, possibly detrimental, from the therapy in
[31]
KRAS mutated patients .

The traditional limitations of early-phase setting (small samples, short trial duration, variable doses)
are being addressed by the emergence of new trial designs, which benefit of the implementation of PGx
biomarkers in different manners. Not every early phase of Clinical Trials benefits in the same way of PGx
implementation, and the role of PGx varies according to the target of the phase. For instance:

Traditional Phase 1 trials in the past aimed at exploring the safety of compounds, and finding the maximum
tolerated dose for phase 2 development (recommended phase 2 dose, RP2D), by a progressive escalation of
[32]
the administered doses trough what is known as the 3 + 3 design . Until 2006, the vast majority of phase
[33]
1 trials would apply this classic design . Nonetheless, it necessarily exposes a part of the patients to sub-
therapeutic doses of the study drugs, thus posing ethical concerns. This consideration, together with the
increase of targeted therapies and immunotherapies being investigated in clinical trials, provided the basis
for the development of new early phase trial Designs. In the current era of targeted and immune therapies,
the assumption that higher, more toxic doses of study drugs result in higher antitumor activity have been
brought into question, leading to the new concept of “optimal biologic dose”. During the development of
pembrolizumab, for example, despite toxicity studies reached doses up to 10 mg/kg without the observation