Clinical Trials in the Era of Personalized Oncology
Michael L.Maitland,MD,PhD1;Richard L.Schilsky,MD2
Abstract
The rapid pace of discoveries in tumor biology,imaging technology,and human genetics hold promi for an era of personalized oncology care.The successful development of a handful of new targeted agents has generated much hope and hype about the delivery of safer and more effective new treatments for cancer.The design and conduct of clinical trials has not yet adjusted to a new era of personalized oncology and so we are more in transition to that
era than in it.With the development of treatments for breast cancer as a model,we review the approaches to clini-
cal trials and the development of novel therapeutics in the prior era of population oncology,the current transitional era,and the future era of personalized oncology.CA Cancer J Clin2011;61:365-381.V C2011American Cancer Society.
Introduction
If it were not for the great variability among individuals,medicine might as well be a science and not an art.
William Osler,1892
Medicine has always been personalized.Cancer specialists have long appreciated that each patient prents with her/his own unique clinical history,prognosis,treatment tolerance,and supportive care needs.Physicians have always focud on what is best for each individual patient.1Advances in both biology and information tech-nology have brought‘‘personalization’’forward as a new buzzword in health care.For the last2decades,labora-tory scientists,clinicians,and epidemiologists have applied technological advances so that we now recognize that just as patients differ in how they are affected by their dias,cancers have unique natural histories with dis-tinctive biology.Tumors once described solely by their organs of origin now compri subts with different biological drivers and clinical outcomes.Artful humanistic skills remain important to personalizing cancer care,
but science-bad tools increasingly guide the design of a patient’s individualized treatment plan.
Advances in cancer care with the potential for widespread impact are made through clinical trials.The stud-
ies provide structure to the lection of patients,control the delivery of standard and test interventions,and pro-vide reliable estimates of the therapeutic benefit of the interventions tested when they are delivered to patients similar to tho enrolled and treated on the study protocol.Acknowledging the limitations of the generalizability
of clinical trial results,they remain the primary means by which advances in science and drug development can
be translated into advances in patient care throughout health systems.
Technological innovations and scientific advances in understanding cancer at the molecular level have acceler-ated the discovery and development of diagnostics and therapeutics.Today,an oncologist can perform some impressive feats that were just exciting new ideas in rearch10years ago.At the start of the day’s clinic,the clinician could cure a woman with human epidermal growth factor receptor2(HER2)gene-amplified breast cancer by adding trastuzumab to standard adjuvant chemotherapy.Just after lunchtime,the same oncologist can review a report of the results of polymera chain reaction tests on DNA in the peripheral blood of an asymp-tomatic patient with chronic myelogenous leukemia(CML)and if necessary,change the patient’s prescription
1Assistant Professor of Medicine,Section of Hematology/Oncology,Associate Director,Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago,Chicago,IL;2Professor of Medicine and Chief,Section of Hematology/Oncology,Deputy Director,Comprehensive Cancer Center, University of Chicago,Chicago,IL.
Corresponding author:Richard L.Schilsky,MD,Section of Hematology/Oncology,Comprehensive Cancer Center,University of Chicago,MC2115,5841S Maryland Ave,Chicago,IL60637;rschilsk@medicine.bsd.uchicago.edu
DISCLOSURES:Dr.Maitland was supported by K23CA124802.
V C2011American Cancer Society,Inc.doi:10.3322/caac.20135.
Available online
VOLUME61_NUMBER6_NOVEMBER/DECEMBER2011365
from imatinib to dasatinib or nilotinib to maintain the patient’s clinical remission.At the end of the day,a patient with KRAS–mutated metastatic colo-rectal cancer can be saved from unnecessary toxicity and cost by discussing whether to proceed with cetuximab or panitumumab treatment.
Scientists and clinicians celebrate the advances. They get excited by the potential for new technolo-gies and insights to lead to more life-changing breakthroughs for patients.However,obrvers out-side of cancer rearch argue that the success are too small and too few.2,3Despite new technologies for drug discovery,novel cancer therapeutics typically fail to complete clinical development.4,5 Although we savor the promi of a new era of per-sonalized oncology,we are more transitioning into that era than truly there.
Progress to personalized oncology requires advances in the design and conduct of clinical trials.The ulti-mate goal for personalized oncology is to maximize the therapeutic index for treating or curing cancer in each patient.In medical oncology specifically,this means lecting the right drug and administering it at the do that produces the maximum efficacy and with the least toxicity every time,for every patient.6During this period of transition from population-bad to per-sonalized oncology,cancer investigators are facing2 concurrent and sometimes competing challenges: 1)conducting clinical trials of new,potentially more effective therapeutic interventions,more quickly than ever before;and2)transforming the clinical trials’infrastructure and designs from tho suited for the era of population oncology to tho necessary in the era of personalized oncology.
To illustrate how advances in laboratory and clini-cal science have propelled us into the current trans
i-tional period and how clinical trials must evolve to lead us into the era of personalized oncology,this arti-cle will focus on systemic therapy options for the treatment of invasive breast cancer in the adjuvant and advanced dia ttings(Table1).Among solid tumors,breast cancer treatment arguably has made some of the greatest advances during the previous3 decades.During that period,breast cancer was approached as a homogeneous dia,except for the recognition of hormone responsive or unresponsive tumors identified by expression of the estrogen recep-tor.The goal was to reduce suffering and death from this dia.The strategy entailed public health approaches such as raising awareness,developing screening and early detection methods to reduce the risk of death from breast cancer,and studying surgical and adjuvant therapy methods to improve cure rates while reducing morbidity.Treatments were developed first by testing for safety and signs of efficacy in cohorts of patients with advanced dia with the intent to then test promising drugs in patients with earlier stages of dia to increa cure rates.The focus of this strategy was to improve outcomes for the entire population of women at risk of or tho who developed breast cancer and so we refer to this period as the era of population oncology.
TABLE1.Oncology Care and Clinical Trials in the Eras of Population Oncology,Transition,and Personalized Oncology POPULATION ONCOLOGY TRANSITION PERSONALIZED ONCOLOGY
Screening Population-wide risk reduction Population-wide approaches modified
for at-risk subpopulations Individualized risk estimation and programs adapted to individual risk
Diagnosis Organ-of-origin-/histology-bad Organ of origin,histology,and
www neworiental orgsome molecular markers
Primarily molecular marker-bad
Staging Anatomic extent of dia Anatomic extent with some
molecular risk profiling
Primarily molecular risk-bad
Treatment determination Typically organ-of-origin-
and stage-bad
Organ-of-origin-and stage-bad with some
implementation of molecular markers
Primarily molecular marker-bad
Asssment intervals Bad on clinical evaluation/
examination findings Bad on routine interval imaging Early,frequent rial asssments by
imaging,circulating tumor cells,and other
approvalmarker asssments
Early pha clinical trials Oriented to maximum
查韦斯遗体tolerated do
Oriented to‘‘optimum biologic do’’Determine range of tolerable and active dos
Mid-pha clinical trials Histology and prior treatment-
bad eligibility;typically
rectussingle-arm,noncomparator trials
Histology and prior treatment-bad
eligibility;some marker-bad screening;
some randomized controlled trials
Some trials,histology,and prior treatment-bad
奥林匹克颂歌
eligibility with rapid,rial asssments;many
with eligibility restricted to tumor marker subts
366CA:A Cancer Journal for Clinicians
The landmark studies of trastuzumab,for patients with a specific subtype of breast cancer,signaled the beginning of the current transitional period in cancer clinical trials.We provide a framework for under-standing how clinical trial designs and operations need to adapt in order for us to deliver more scien-tifically bad personalized cancer care and describe some promising innovations that will likely usher us into the era of personalized oncology.
Clinical Trials in the Era of Population Oncology
Perspective on Clinical Trials and Progress
in Breast Cancer Care
The experiences of our grandmothers with breast can-cer illustrate the critical importance of clinical trials to progress in cancer care.The nior author has already described the disappointment and agony his grand-mother experienced after being diagnod with breast cancer in1965.1She underwent radical mastectomy and chest wall radiation associated with vere skin toxicity,developed chronic lymphedema,and devel-oped a cond primary tumor in the contralateral breast.This resulted in another radical mastectomy and more radiation and within a few more years,pro-gressive metastas,debility,ineffective systemic hor-monal therapy,and death preceded by much suffering. Twenty-five years later,the junior author’s grand-mother(E.L.)had stage II breast cancer identified on screening mammography(grading determined bad on the American Joint Committee on Cancer,3rd edi-tion).She underwent lumpectomy with clean margins, and rected axillary lymph nodes revealed no evidence of metastas.She received adjuvant radiation therapy bad on the results of the National Surgical Adjuvant Breast and Bowel Project(NSABP)trial B-06.7,
8 Near the completion of the planned25fractions of radiation,she developed uncomfortable skin toxicity. Her radiation oncologist encouraged her to complete the25-fraction cour and additional fractions focud on the tumor site as a‘‘boost,’’an emerging standard of care bad on yet-to-be published clinical trials. Without evidence of a survival benefit for the boost approach and weary from the treatment,she elected to complete25fractions and not to proceed with further radiation therapy.Twenty years later,she remains free from tumor recurrence and shortly after being inter-viewed for this article,she attended a jazz concert.
E.L.was cured of her dia with less morbidity than the previous standard of care,modified radical mastectomy.Her suitability for this treatment approach(her age,stage of dia,and abnce of comorbidities),guidance on the execution of the surgery(achieving an adequate margin for breast-conrving surgery),the do and schedule of her radiation treatment(50gray in25fractions),and prognostic expectations for her freedom from local recurrence(90%over8years)were bad on multiple clinical trials culminating in NSABP B-06and sub-quent analys of data collected in that trial.Her individualized treatment plan included a decision
not to proceed with the tumor site‘‘boost’’or to receive adjuvant hormonal therapy.The decisions were not scientifically bad,but rather were bad
on E.L.’s unwillingness to experience the short-term toxicities of additional therapy and her intuition that
her dia was likely cured.
Paclitaxel for Breast Cancer,Archetype Drug
of the Population Oncology Era
At the time fronted her breast cancer,pacli-taxel was under active development as a novel agent
for the systemic treatment of advanced breast cancer. Thefirst major publication,characteristic of clinical trials of that period,reported a single-arm study of
25patients with metastatic breast cancer that pro-gresd despite previous systemic therapy.9No agents were known to be effective on dia at this advanced state;therefore,a comparator arm was not necessary.Having even a small fraction of patients with objective evidence of tumor shrinkage(the respon rate)would be sufficient evidence of drug effect to warrant further study.Standardized meth-
ods of asssing and reporting toxicities and treat-ment respons were ud.In this study,3patients developed complete respons and another11 showed objective evidence of tumor shrinkage.Two other similarly designed clinical trials were con-ducted at other institutions with minor differences
in the range of dos tested,the supportive care delivered,and the number of prior therapies allowed
for eligible patients.10,11Both studies ud the same
24-hour drug infusion,and respon rates of30%to 57%were obrved.A subquent pha3trial of
gre词汇量
3-hour infusions of paclitaxel randomized patients with advanced breast cancer to receive135mg/m2or 175mg/m2.12Again,with no known standard of
VOLUME61_NUMBER6_NOVEMBER/DECEMBER2011367
care for such patients,there was no standard com-parator or placebo control arm.The overall objective respon rate of26%in the multicenter tting with evidence of do respon effect was sufficient to jus-tify the approval of paclitaxel by the US Food and Drug Administration(FDA)for the tr
eatment of metastatic dia after previous systemic therapy. As the authors of that study concluded,‘‘The full impact of this novel agent in the treatment of breast cancer is being evaluated in large trials that u com-bination chemotherapy and involve earlier stages of dia.’’12
In the era of population oncology,this approach to the development of a novel anticancer agent was reasonable and efficient.Testing for safe dosing and evidence of anticancer activity was conducted in cohorts of willing patients for whom there was no established standard of care.The patient population was defined by the organ of origin,the extent of dis-ea,and the previous treatment history(Fig.1). Thefindings from studies in this population were extrapolated to similar populations of patients in community oncology practice.Concurrently,phar-macokinetics and pharmacodynamics data from the trials informed the further development of the
drug in populations of patients
with other dias and in com-
bination regimens administered
to breast cancer patients with韩语能力考试
curable,less extensive dia.
朝露
With additional clinical trials,
paclitaxel became a standard
agent in the treatment of meta-
static breast cancer.Paclitaxel
antyalso became a component of
effective adjuvant therapy regi-
mens designed to cure early
stage breast cancer.13,14Repre-
ntative of clinical trials in the
era of population oncology,
the studies enrolled almost
6200patients to demonstrate a
small but statistically significant
reduction in the risk of dia
recurrence as no methods were
available to identify tho
patients likely to benefit.A
more recent article from the
current transitional era suggests that the benefit of adding paclitaxel as a component of adjuvant chemotherapy is enjoyed only by a subt of patients who can be characterized by the specific tumor marker HER-2,described in the next ction.15
Clinical Trials and Diagnostics Development in the Transitional Era Trastuzumab,Archetype Drug of t
he Transitional Era
During the1990s,as paclitaxel was developed for other indications and dia ttings,the testing of a novel breast cancer treatment,trastuzumab,her-alded the beginning of the current transitional era. This monoclonal antibody binds to HER-2,a sur-face receptor aberrantly expresd in25%to30%of patients with breast cancer.HER-2expression was associated with a poor prognosis,and laboratory studies demonstrated that HER-2expression played a direct role in aggressive tumor growth.A monoclo-nal antibody that binds this protein stopped the growth of tumor cells expressing HER-2in vitro and demonstrated evidence of synergistic effects
FIGURE1.Clinical Trial in the Era of Population Oncology. 368CA:A Cancer Journal for Clinicians
when combined with chemotherapy.In the initial pha116and pha2monotherapy trials,17the drug could be safely administered to achieve rum con-centrations in patients that inhibited growth of HER-2overexpressing tumors in animal models. Few patients experienced acute toxicities other than infusion reactions.
Thefindings spurred enthusiasm for the3-point concept of‘‘targeted therapy’’:1)develop a drug to interfere with the function of a molecule readily identified in cancer cells but not healthy tissues;
clg
2)know that this target plays a critical role in the abnormal growth and/or invasiveness of the tumor; and3)expect that the relative specificity of the drug for the target molecule and the target molecule for tumor cells rather than normal cells would achieve dramatic improvements in the therapeutic index over standard cancer chemotherapy.Establishing this new paradigm for cancer drug development,patients were lected for the pha2trials bad on criteria to enhance the likelihood of successful clinical devel-opment.First,patients typically experienced recent failure of previous systemic therapy(patients with evidence of active dia progression rather than indolent dia).Second,patients with metastas that could be convincingly assd by rial computed tomography(CT)imaging were preferen-tially enrolled(although bone metastas are common in breast cancer,their respon to therapy is difficult to measure reproducibly).Third,to be enrolled,patients had to have evidence of HER-2 overexpression in the tumor that was detected with an immunohistochemical reagent that bound the same epitope of HER-2as trastuzumab itlf.With this lective approach,single-arm pha2trials demonstrated objective respon rates higher than expected for a typical patient population with advanced breast cancer,even considering the more aggressive natural history of HER-2–expressing breast cancer.
The successful completion of randomized pha3 trials of trastuzumab validated the targeted antica
ncer therapy para-digm.In combination with chemotherapy in the treatment of metastatic dia18and sub-quently in the adjuvant therapy tting,19,20the addi-tion of trastuzumab to standard treatment improved the median survival in patients who had HER-2–overexpressing breast cancer.Recall that,by the original immunohistochemical(IHC)assay criteria,25%to30%of all patients with breast cancer have HER-2–overexpressing tumors(Fig.2).If the trials had been performed in all patients with advanced breast cancer,with and without HER-2overexpres-sion,they would likely have had negative results.For example,in the study of patients with metastatic dis-ea and2þor3þstaining of the tumor for HER-2 expression,the respon rate was50%and the1-year mortality rate was22%for the trastuzumab-treated arm and32%and33%,respectively,for the control arm(Fig.2).By extrapolation,21without lection bad on HER-2expression,the respon rate would have been37%and the1-year mortality rate would have been30%.The difference between the treatment and control arms with this number of patients would
not have been statistically significant.In this ca;the prelection of only tho patients with HER-2–over-expressing tumors enabled detection of the therapeutic benefit.Without focusing the clinical trial on the cor-rect subt of the breast cancer patient population,an effective therapy might well have been discarded. Developing Therapeutics for Biomarker-
Defined Subpopulations Consistently
One of the most striking elements of the successful development of trastuzumab was that it converted a biomarker for negative prognosis(HER-2)into a bio-marker that was predictive of benefit from the drug.
A fundamental challenge for the transitional era has been the concurrent development of anticancer thera-peutics and biomarkers.The question remains for all agents developed with the‘‘targeted therapy’’concept:
can the subpopulation most likely to benefit from therapy be readily and reliably identified?
For trastuzumab,the target disrupted by the drug truly drives progression of dia and/or resistance to other therapies.For many other promising agents in development in the early part of the transitional era,
this has not been the ca.Many cancer therapeutics programs were bad on specific targets that appeared
to be important in cultured tumor cells,animal mod-els,and/or human dia.In some cas,this evi
dence may not have been as strong as for HER-2.
An exemplary ca is the development of marimastat,
an inhibitor of veral matrix metalloproteinas, enzymes thought to be important in tumor invasion and metastasis.However,confirmation of the impor-tance of the target during early clinical development was lacking.Despite the limited evidence,marimastat
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