2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

DRUG DEVELOPMENT AND PERSONALIZED ONCOLOGY
Fig 1. Matching tumor type, molecular
aberration, screening platform, and
early clinical trial with targeted agent.
In the first scenario (left to right), a patient
with ovarian cancer (whose tumor
may present PI3K pathway aberrations,
RAS, RAF or BRCA mutations) will
have molecular prescreening with multiple
assays and will be ultimately referred
to a corresponding phase I trial.
On the other hand (right to left), if the
screening is performed according to
the molecular target agent available
at the site (e.g., FGFR inhibitor), screening
will be focused on different tumor
types, such as HR positive breast cancer
and squamous NSCLC.
Abbreviations: HR, hormone receptor;
NSCLC, non-small cell lung cancer; CRC,
colorectal cancer; IHC, immunohistochemistry;
FISH, fluorescence in situ hybridization;
CGH, comparative genomic
hybridization; PCR, polymerase chain
reaction.
identifying mechanisms of drug resistance, describing new
oncologic signaling pathways, or establishing predictors of
a favorable or unfavorable outcome. 24 To date, many assays
still require fresh, frozen samples for technical reasons.
Biomarker analysis can sometimes directly benefit the patient
(for example, in breast cancer relapses presenting a
change in hormonal receptor and HER2 status) and also
future patients with cancer. Mandatory biopsies are acceptable
when investigators appropriately weigh the risks
against the necessity of the correlative question. However,
various hurdles must be faced when protocols mandate
biopsies. Ethical concerns have been raised when the participant’s
enrollment in a clinical trial depends on his or her
consent to undergo a research biopsy. Investigators may feel
forced to find suitable on-trial or off-trial options for patients
whose tumors have been biopsied and undergone molecular
profiling. The risks of the procedure also need to be taken
into consideration. However, according to the experience of
large centers, biopsies in early phase clinical trials are safe,
with less than 1.5% risk of serious complications. 25
Ongoing Innovative Trials
Clinical trial design needs to be adjusted to a new era of
personalized oncology. Novel approaches include histologyindependent
trials (for example, patients with BRCA1/2
mutated tumors, regardless of histology), window-ofopportunity
trials (when standard anticancer therapy is
delayed, and patients receive first a matched MTA allowing
chemotherapy-free intervals) or trials that subclassify a
specific disease into discrete molecular categories (such as
the Investigation of Serial Studies to Predict Your Therapeutic
Response with Imaging and Molecular Analysis [I-
SPY 2] trial in breast cancer and the Biomarker-integrated
Approaches of Targeted Therapy for Lung Cancer Elimination
[BATTLE] trial in NSCLC). 26,27 For these approaches
to be possible, a cooperative environment is necessary, with
experienced academic institutions, regulatory authorities,
and pharmaceutical and diagnostic companies working together
in order to promote data sharing, standardized procedures,
technology exchange, and avoidance of duplicative
efforts. 2 Initiatives, such as Worldwide Innovative Network
(WIN) Consortium, are a great example of this collaboration
toward a common goal. Together, investigators can utilize
structured methods to define when a new agent should cease
further study and when it has demonstrated sufficient
likelihood of potential benefit to proceed to the next phase of
testing.
Preliminary results from personalized medicine programs
suggest that molecular analysis of tumors and the use of
MTAs to counteract the effects of specific aberrations improves
the outcomes of affected patients. In a seminal trial,
Von Hoff and colleagues used molecular profiling (based
on immunohistochemistry, immunofluorescence, and microarray
analysis) to select a targeted agent and were able to
prove that this approach is feasible. In 27% of the patients,
treatment based on molecular analysis resulted in longer
progression-free survival than the prior unmatched therapy.
28 Similar results were seen in an innovative model for
phase I clinical trials performed at the University of Texas
M. D. Anderson Cancer Center. Matching patients with an
MTA in early clinical trials, mainly based on mutation
status of frequently activated genes in cancer (KRAS,
NRAS, BRAF, PIK3CA, EGFR, CKIT) and PTEN protein
expression levels, resulted in longer time to treatment
failure (5.3 vs. 3.2 months) compared with their prior systemic
antitumor therapy. In addition, for patients with one
molecular aberration, the response rate was 29% with
matched targeted therapy versus 8% without matching,
highlighting the potential improved outcomes of heavily
pretreated patients enrolled in genomic-driven phase I trials
of MTAs. 18 Based on these and other observations, our
institute, the Massachusetts General Hospital, the Royal
Marsden Cancer Center, and the Institute Gustave Roussy,
among others, are already building flexible programs
(adapting the putative predictive biomarkers and the clinical
trials available on-site) to serve their phase I trials.
Figure 1 exemplifies different ways of matching tumor type,
molecular aberration, screening platform, and early clinical
trials with MTAs.
Conclusion
Phase I trials in which an MTA can be matched precisely
with a population of patients whose tumors are driven
predominantly by the target of interest are still uncommon.
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