Keywords: Clinical trial; immunotherapy; radiotherapy
Trial Design
An important aspect of clinical trials is the choice of
trial design, that is, whether the trial is meant to be
observational or experimental. Observational studies,
that is, cohort studies, case?control studies, and case
series, often involve generating a hypothesis which
leads to further questions to be asked. Experimental
studies, on the other hand, aim to test established hypotheses
and to evaluate the effects of planned interventions
on a particular group of patients.
Experimental trials can be randomized or non-randomized, cross-over, or factorial.
Randomized clinical trials involve comparing two
or more groups of patients with similar characteristics
that are assigned randomly to different treatment
groups or "arms;" the intervention is tested in
one group, and the other group or groups are given
standard treatment. The trial is evaluated in terms of
its primary and secondary objectives, which usually focus on the relative toxicity and effectiveness of the
treatments being tested.[
One example of a randomized trial is PEMBRORT,
in which immunotherapy and radiation were
evaluated in 78 patients with metastatic non-small
cell lung cancer who were treated with pembrolizumab
with or without stereotactic ablative RT.[
A different type of trial design, a cross-over study,
involves comparing patients who receive the same
treatment at different periods during the study. In
other words, the study participants serve as their own
controls. Cross-over studies therefore require fewer
participants than a standard parallel, randomized, and
controlled trial.
An example of a study with a cross-over design
(NCT02710253) is an ongoing Phase II trial in which
salvage RT is used in an attempt to induce systemic
disease regression in patients with metastatic disease
that has advanced during systemic immunotherapy.
Patients in this trial can be "crossed over" to receive RT
in addition to immunotherapy after progression.
Because most clinical trials of RT with immunotherapy
being conducted at this time involve patients
with metastatic disease, the characteristics of the patients
in these trials are inevitably heterogeneous.
Another type of trial designed to account for this heterogeneity
is the basket trial, in which a specific investigational
treatment is given to patients with different
diseases or disease subtypes with the goal of identifying
molecular or other characteristics that can affect response
to treatment. Pembrolizumab was approved in
one such basket trial of patients with metastases from
different types of solid tumors with the shared characteristics
of high microsatellite instability or deficiencies
in mismatch repair.
Choice of Endpoints
In addition to providing statistically meaningful information
to distinguish the effects of one treatment
over another, the primary endpoint in randomized,
Phase II, and Phase III trials should also be clinically
meaningful for patients and society. The traditional
"gold standard" endpoint has been OS, but progression-
free survival (PFS) is also being evaluated as a
clinically meaningful and specific parameter. Other
endpoints used in trials of immunotherapy versus chemotherapy,
or in early trials evaluating the addition
of RT to immunotherapy, are the ORR or the abscopal
response rate (that is, the response rate of disease
at unirradiated sites). The classic system for assessing
response has been the Response Evaluation Criteria in
Solid Tumors, but trials involving immunotherapy increasingly
use a slightly different version, the immunerelated
response criteria.[
Other aspects to be considered in the choice of trial
endpoints are toxicity and cost-effectiveness. First,
differences in toxicity can be clinically meaningful,
but the greater concern may be differences in efficacy.
For example, studies in which one treatment modality
is added to another to treat metastatic disease cannot
be expected to be less toxic than either modality
used alone, but could be more effective in controlling
disease than either modality used alone. The relatively
new endpoint of cost-effectiveness represents an attempt
to incorporate efficacy, safety, and quality of life
into a single quantitative metric.
Another important consideration in designing trials
of RT and immunotherapy for patients with metastatic
disease is the choice of inclusion and exclusion
criteria, that is, characteristics that would include or
exclude patients from a given trial. Reviewing the past
and current literature is crucial for defining appropriate
criteria and endpoints for all clinical trials. Precise
identification of inclusion and exclusion criteria helps to balance the number of patients needed within a
predefined accrual time with maintaining the homogeneity
of the results to the greatest extent possible. Although
accrual rate and study criteria can be amended
over the course of a trial, that necessarily increases the
time and cost of the trial. Indeed, the previous studies
that included patients with a broad spectrum of metastatic
diseases are giving way to more modern trials in
which the inclusion criteria are stricter as reliable data
on whether and how a particular treatment works are
obtained.
Another factor to consider in the choice of trial
endpoints is that patients with metastatic disease often
receive more than one form of immunotherapy over
time, with RT usually used if the disease progresses.
Therefore, endpoints that focus solely on survival may
be inadequate for such trials. More meaningful endpoints
may be the development of resistance to immunotherapy
or the immune-boosting effects of RT on the
development of resistance. Indeed, the slope and tail
of the survival curve for long-term survivors may be
useful for distinguishing the effects of combination immunotherapy
and RT over the longer term (e.g., up to
3 years after the treatment).
Yet another factor in the choice of trial endpoints
is the complexity of the effects of high-dose RT on the
immune system at both the systemic and tumor-microenvironment
levels.[
This complexity underscores the importance of
choosing translational-science endpoints that consider
the choice of sample type, the time at which to collect
them, and the methods to evaluate them. For example,
flow cytometry phenotyping of blood and biopsy samples
can reveal a wealth of detail regarding the status
of both the innate and adaptive immune systems. Flow
cytometry findings can be complemented with those of
multiplex immunofluorescence staining of tissue samples
to reveal spatial aspects of how specific immune-cell
populations are distributed within the tumor microenvironment.
Translational endpoints from clinical trials
can also provide information on the T-cell immune repertoire,
which could be useful for future research on the
design of prophylactic or curative vaccines.
Tumor-specific epitopes are known to differ among
patients due to gene mutations, variations in antigen
processing, and the diversity of the human leukocyte
antigen (HLA) haplotypes. Detailed analyses of tumor
biopsy specimens, obtained repeatedly over time, can
help to determine the immunogenicity of these peptides,
and tracking changes in epitopes may help to
overcome acquired resistance to therapy. An alternative
approach would be to evaluate circulating tumor cells
obtained from whole-blood samples to identify tumor
mRNA or epitopes. However, longitudinal analyses
such as these pose significant challenges with regard
to patient participation, cost, and resource availability.
Because interactions between HLA-peptide complexes
and T cell receptors also affect the immunogenicity
of tumor epitopes, other evaluations should include
the diversity and clonality of the T-cell receptor
repertoire and the transformation of T cells after RT
and immunotherapy. The presence of highly diverse
receptor repertoires among tumor-infiltrating T cells
has been linked with better responses to primary and
metastatic disease.[
The persistent exposure of T cells to antigens and inflammatory
signals leads to a slow loss of effector function
known as "T cell exhaustion",[
Other issues to be considered in designing clinical
trials that combine RT with immunotherapy are the
timing and sequence of the two modalities for multisite
oligometastatic tumors and the length of the interval
between them. Another consideration is whether
the combined therapy contributes to health-care value.
Although adding RT to immunotherapy has been
found to improve response rates in some situations,
the ultimate aim is to maintain improved results and
cost-effectiveness in the long-term relative to standardof-
care treatments. The financial cost of adding RT to
immunotherapy presumably would be lower than the
cost of switching to a different type of immunotherapy
to address acquired resistance.
The choice of endpoints is also crucial and endpoints
are different in Phase I, Phase II, and Phase III trials.
Phase I trials are designed to evaluate the safety of a
proposed therapy intended to be an effective treatment
without increased risk of unacceptable and potentially
life-threatening toxic effects. Phase II trials mainly
evaluate the effectiveness of an experimental treatment
option compared with standard treatment. Phase II trials
also assess toxicity to confirm that the incidence of dose-limiting toxicity is not higher than that associated
with the standard treatment. Because Phase II trials often
involve small numbers of patients, and the selection
process may include some patient- or disease-related
factors but not others, the conventional endpoint
of overall survival (OS) cannot be assessed reliably and
is thus inappropriate for Phase II trials. Therefore, OS
is more often used as an endpoint in Phase III trials,
which are typically more comprehensive and involve
larger numbers of patients and longer-follow-up time.
However, Phase II trials can be a less expensive and
faster way to provide information on whether a proposed
treatment is worth pursuing in a more comprehensive
(and more expensive) Phase III trial.
Peer-review: Externally peer-reviewed.
Conflict of Interest: JWW reports research support from GlaxoSmithKline, Bristol Meyers Squibb, Merck, Nanobiotix, RefleXion, Alkermes, Artidis, Mavu Pharma, Takeda, Varian, Checkmate Pharmaceuticals, HotSpot Therapeutics, Inc., Gilead and Kiromic. JWW serves/served on the scientific advisory board for Legion Healthcare Partners, RefleXion Medical, MolecularMatch, Merck, AstraZeneca, Aileron Therapeutics, OncoResponse, Checkmate Pharmaceuticals, Mavu Pharma, Alpine Immune Sciences, Ventana Medical Systems, Nanobiotix, China Medical Tribune, GI Innovation, Genentech and Nanorobotix. JWW serves as consultant for Lifescience Dynamics Limited. JWW has/had Speaking Engagements for Ventana Medical Systems, US Oncology, Alkermes, Boehringer Ingelheim, Accuray and RSS. JWW holds/held stock or ownership in Alpine Immune Sciences, Checkmate Pharmaceuticals, Healios, Mavu Pharma, Legion Healthcare Partners, MolecularMatch, Nanorobotix, OncoResponse, and RefleXion. JWW has accepted honoraria in the form of travel costs from Nanobiotix, RefleXion, Varian, Shandong University, The Korea Society of Radiology, Aileron Therapeutics and Ventana. JWW has the following patents; MP470 (amuvatinib), MRX34 regulation of PDL1, XRT technique to overcome immune resistance. MD Anderson Cancer Center has a trademark for RadScopalTM. The rest of the authors disclosed no competing interests.
Financial Support: None declared.
