Keynote lecture 5: Priorities for clinical research in GI cancer
Daniel G. Haller, MDProfessor of Medicine
Abramson Cancer Center and thePerelman School of Medicine at the University of
Pennsylvania
Establishing a Balance of Priorities
• Clinical trials are designed to ultimately benefit patients with cancer, but motivations are varied and frequently contradictory– Patients: want better treatment, but <10%
participate in trials– Investigators: same as above plus career-building– Pharma: same as above plus $$$– Government: same as above plus bureaucracy
Research hurdles faced by investigators
• Regulatory hurdles• Access to new drugs• Funding • Independence• Registration of academic trials• International collaborations• Publication bias
Rational vs. personal(ized) medicine
• Clinicians have been practicing personal, individualized oncology for years, based on– Clinicopathologic factors, frequently qualitative– Demographics– Patient and physician preference
• Rational (personalized) oncology practice identifies unique, quantifiable and validated tumors biology (targets) with interventions that relate to targets, identifiable MOA and proven efficacy in specific subsets of patients
Biomarker Research
Type of marker: Identification Validation
Prognostic Easy, but often flawed
Frequent, but often disappointing
Predictive Hard, needs randomized trial
Very rare, needs large randomized trial
Surrogate Hard, needs meta-analysis or large randomized trial
Very rare, needs large randomized trial
In GI cancer are there predictive biomarkers beyond KRAS in mCRC,MSI in Stage II colon cancer and HER2 in metastatic gastric cancer?
Endpoints in Clinical Trials: the need for innovative and validated endpoints
Endpoint
Event DFS RFS TTR TTF CSS OSLocoregional recurrence
Distant metastases
Second primary, same cancer
Second primary, other cancer
Death from same cancer
Death from other cancer
Non-cancer death
Treatment-related death
Loss to follow- up
= failure = censored observation
Endpoints in Clinical Trials: the need for innovative and validated endpoints
WGIC Barcelona 2012: Friday, June 29th 08:00Session X: Clinical trials for GI oncologists – Trials and endpoints in GI cancer
Chairs: Fortunato Ciardiello, MD, PhD and Alberto Sobrero, MD
Is DFS, RR or survival the best endpoint in colorectal cancer? Marc Buyse, ScDWhich difference should we target? Alberto Sobrero, MDPharmacodynamic endpoints Fortunato Ciardiello, MD, PhD
ARCAD Principles and Goals• ARCAD Clinical Trials Program: International group of
oncologists, statisticians, and trialists, formed with the goal of accelerating the development of new drugs and treatment strategies in gastrointestinal oncology by helping establish guidelines for smaller, faster, and less expensive clinical trials
• Ongoing program of original research and consensus discussions, focused on endpoints, biomarkers, and clinical trials design. Free academic collaboration—members receive no remuneration for attending meetings/participating in consensus discussions
• Sponsorship will be sought to meet general running costs and costs of specific research initiatives ARCAD Database Project is the Main research initiative of the program—a database of large clinical trials in advanced colorectal cancer. Initial goal will be clarifying/standardizing PFS and related end points
ARCAD Publications Update
Toward Efficient Trials in Colorectal Cancer: The ARCAD Clinical Trials Program
Journal of Clinical Oncology, Vol 28, No 4 (February 1), 2010: pp. 527-530
International collaboration
• Pros:– GI cancers taken together constitute a large proportion
of the burden of cancer– Large studies may accrue more rapidly
• Cons:– Tumor biology and host factors may vary from region
to region, introducing heterogeneity of clinical effects and toxicity
– Bureaucracy in establishing and maintaining individual trials and ongoing relationships
U.S. NCI GI Intergroup
• To coordinate the clinical research of the 8 (now 4) adult cooperative groups in the US
• Ideas and protocols are developed with the Groups for randomized phase II/III trials
• Vetted and approved protocol concepts are discussed in each of the organ site Task Forces
• Task Force concept proposals are submitted to the GI Steering Committee for review and approval
U.S. NCI GI Intergroup
• Within a month of submission protocol concepts are externally reviewed and CTEP reviewed, queries raised and one hour of teleconference with investigators dedicated to proposal.
• Votes: Approve, Reject, Pending response/revision• Decisions of GISC NOT made on NCI budget
constraints ; GISC and ultimate CTEP decisions based on science
• Current approval ~50%
U.S. NCI GI Intergroup
• Issues:– Rejections after long incubation times in cooperative
groups and Task Forces• Most common cause of rejection
– Statistics and endpoints not optimal– Accrual goals overly optimistic– For cytotoxic biologic combinations, insufficient data
available to move forward to randomized phase II/III trials– No integrated biologic correlative studies
• ? Possibility of GISC concept pre-review
U.S. NCI IntergroupClinical Trials Planning Meetings
• Goal of CTPMs: to design clinical trials in GI cancer that can be successfully performed in the US Cooperative Group system
• CTPMs– Hepatocellular– NET– Pancreas– Colorectal
NCI IntergroupColorectal Clinical Trials Planning Meeting
(2011): Conclusions• Advances in understanding molecular characterization of tumors and
germline variations requires a national infrastructure to provide real-time clinical testing of patient specimens for treatment assignment.
• Integral marker studies are a high priority.• Existing tissue banks should be exploited for predictive classifier
discovery; treatment-classifier-response relationships defined in banked tissue are necessary to design prospective validation studies.
• Banking of patient tumors and germline DNA for future research is an imperative.
• High-priority therapeutic targets include signaling kinases, stem cells, DNA damage response, host response.
NCI IntergroupColorectal Clinical Trials Planning Meeting
(2011): ConclusionsEarly Stage Adjuvant Therapy• There is not currently a new agent of sufficient promise to warrant
testing in a phase III adjuvant study.• A triple drug combination regimen, FOLFOXIRI should be tested
against standard FOLFOX as adjuvant therapy in high-risk stage III colon cancers.
• Neoadjuvant approaches in early stage colon cancer should be considered to establish a model for evaluation of agents potentially active in the adjuvant setting.
• Discovery efforts should continue to focus on identification of populations at particularly high risk of recurrence, as a setting for testing new agents in early stage disease.
NCI IntergroupColorectal Clinical Trials Planning Meeting
(2011): ConclusionsResectable liver-confined metastatic diseasePreoperative treatment with a new agent will permit in vivo pharmacodynamic assessment of treatment effect.“Adjuvant” treatment after potentially curative resection will allow testing of new approaches in this high-risk setting using resected stage IV disease as a model for micrometastatic disease.Oligometatatic disease with extrahepatic componentA common clinical setting is liver metastasis with intraabdominal extrahepatic disease. A study is suggested to test the combination of surgical (resection/ablation) plus systemic approach in the setting where minimal residual disease can be accomplished with surgical treatment.
NCI IntergroupColorectal Clinical Trials Planning Meeting
(2011): ConclusionsUnresectable metastatic disease• Tumors with BRAF mutations have a poor prognosis. A first-line randomized
phase II study involving new agents, with or without conventional cytotoxics is suggested in this population.
• Patients often have a period of stable disease after initial treatment response. This “window” after response is an opportunity to test targeted approaches in molecularly-defined patient groups. A randomized phase II study of combinations of signaling inhibitors is suggested.
• Irinotecan is commonly administered as a component of second-line treatment. A phase II trial of irinotecan plus novel agent(s) with treatment assignment based on tumor molecular characterization is suggested.
• “Last-line”, salvage settings present a patient population of high clinical need with opportunities for drug development.
NCI IntergroupColorectal Clinical Trials Planning Meeting
(2011): ConclusionsRectal Cancer• Current treatment algorithms typically involve trimodality therapy in a “one-size
fits all” approach. Future trials should tailor treatment to patient risk of local and distant recurrence.
• For upper rectal cancer, studies should explore the selective use of radiotherapy.• For lower rectal cancer or upper rectal cancer at high risk for local recurrence,
studies should explore novel agents in addition to a backbone of neoadjuvant fluoropyrimidine plus radiation.
• Explore the role of 5 x 5 radiation therapy in high risk rectal cancer.• Examine/identify appropriate early end-points/prognostic markers for
neoadjuvant clinical trials that can subsequently be integrated into future trials. These endpoints and classifiers will correlate with local recurrence and overall, and include pathological assessment, imaging biomarkers, and molecular classifiers.
Less is more in adjuvant therapy, does everyone need radiation?
• For patients at lowest risk of locoregional failure– Pancreas (RTOG): Head of pancreas, R0.
• Gemcitabine ± erlotinib, if relapse free at 13 weeks, ± radiation
– Gastric (Dutch)• CT vs. CT/XRT
– Rectal (Alliance): High T3, N0-1• Neoadjuvant CT » if no PD, CT ± XRT
Less is More : Part IIIntermittent Rx and Maintenance
• Premise: in mCRC, continuous therapy may result in excessive toxicity, patient/physician burnout, excess cost
• Treatment “holidays” may ameliorate this clinical conundrum
• Induction-maintenance therapy
Treatment-Free Intervals• Rationale
– Decrease intensity of therapy– Reduce toxicity– Prevent discontinuation of therapy– Preserve ability to administer later therapy– Maximize time on treatment – Increase QOL
• Recognize drug toxicities – Proactively determine therapeutic strategy– Assess acute and cumulative toxicity– Develop strategies to avoid or minimize toxicity
Treatment-Free Intervals• Types of treatment breaks
– Treatment break with maintenance regimen• OPTIMOX-1
• CONcePT
– Complete chemotherapy-free intervals (CFI) • OPTIMOX-2
• When to interrupt/restart therapy– After pre-planned number of cycles– When toxicity reaches a certain grade– When tumor progresses– Planned reintroduction
• Stop 1 drug (e.g. oxaliplatin) or all?• Optimal maintenance: biologics, cytotoxics or both
Raising the Bar: Can we surpass PFS/OS benefits of 1-2 months?
• ASCO 2012– DREAM: biologic maintenance in mCRC– TML: bevacizumab in 2nd line beyond progression– VELOUR: aflibercept (VEGF-TRAP) in 2nd line, w/wo
bevacizumab in 1st line– CORRECT: regorafenib in last-line therapy
OPTIMOX3 – DREAM protocol
mFOLFOX7 + bevacizumaba
XELOX2 +bevacizumabb
FOLFIRI +bevacizumabc
aOxaliplatin 100 mg/m² d1 (6 cycles), 5-FU 2.4 g/m² d1–2, FA 400 mg/m² d1, bev 5 mg/kg d1, q2w, 6–12 cyclesbOxaliplatin 100 mg/m² d1 (6 cycles), capecitabine 1.25–1.5 g/m² bid d1–d8, bev 5 mg/kg d1 q2w, 6–12 cyclesc Irinotecan 180 mg/m² d1, 5-FU 2.4 mg/m² d1–2, FA 400 mg/m² d1, bev 5 mg/kg d1, q2w, 12 cycles
Bevacizumab (7.5 mg/kg q3w)
+ erlotinib (150 mg/d)
until PD
RANDOMI
SAT
ION
NoPD
n=222
n=2244 Jan 2007 – 13 Oct 2011
INDUCTION (N=700) MAINTENANCE (N=446)
Bevacizumab (7.5 mg/kg q3w)
until PD
REGISTRATION
Summary
Randomized patients
Bevacizumab(N=224)
Bevacizumab + erlotinib(N=222)
HR[95% CI] p-value
Maintenance PFS(from randomisation)
4.57 [4.11–5.52]
5.75 [4.50–6.20]
0.73[0.59--0.91] 0.0050
PFS(from registration)
9.23 [8.54–10.05]
10.22 [9.63–11.10]
0.73[0.59--0.91] 0.0045
Overall survival (all patients): 25.44 months [95% CI 22.96–28.19]
CAIRO3CKTO 2006-17
MTD chemotherapy6 cycles ofOxaliplatin +Capecitabine +Bevacizumb
SDPRCR
PD
observation
LD capecitabine +bevacizumab
not eligible
RANDOMIZE
PROGRESSION
MTDchemotherapy+ bevacizumab
PFS1 PFS2
PROGRESSION
VEGF = vascular endothelial growth factor.
Continuation of Bevacizumab Beyond Progression: Pros
• Decreased intratumoral interstitial pressure leads to higher concentrations of chemotherapeutic agents
• Normalization of vasculature and better oxygenation
• Cytotoxic effects of all chemotherapeutics, regardless of “line of therapy” enhanced
• In experimental models, rapid regrowth of blood vessels after withdrawal of VEGF-inhibitors
FGF = fibroblast growth factor; PDGF = platelet-derived growth factor; GIP = gastrointestinal perforations; RPLS = reversible posterior leukoencephalopathy syndrome.
Continuation of Bevacizumab Beyond Progression: Cons
• Potential alternative pathways to activate angiogenesis apart from VEGF
• Bevacizumab is not nontoxic (ATE, HTN, RPLS, etc.)• Treatment alternatives exist most of the time• Cost
Bevacizumab beyond progression (BBP)BRiTE* study design
• BRiTE*– total n=1,953 – 1,445 patients with first PD – 932 deaths (21 January
2007 cut-off) – median follow-up
19.6 months
• Primary endpoint: survival beyond first progression
• Secondary endpoints: safety, OS
Grothey, et al. JCO 2008
PD = disease progression*Non-randomised, observational
cohort study
Bevacizumab post-PD
(n=642)
No post-PD treatment
(n=253)
No bevacizumab post-PD(n=531)
Physician decision (no randomization)
Unresectable mCRC treated with first-line chemotherapy + bevacizumab (n=1,953)
First progression(n=1,445)
BRiTE Registry: Bevacizumab Regimens: Investigation Treatment Effects Grothey et al, ASCO, 2007
BEV + standard first-line CT
(either oxaliplatin oririnotecan-based)
(n=820)
Randomise 1:1
Standard second-line CT (oxaliplatin or irinotecan-based) until PD
BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin
or irinotecan-based) until PD
PD
ML18147 study design (phase III)
CT switch:Oxaliplatin → IrinotecanIrinotecan → Oxaliplatin
Study conducted in 220 centres in Europe and Saudi Arabia
Primary endpoint • Overall survival (OS) from randomisationSecondary endpoints included
•Progression-free survival (PFS)•Best overall response rate•Safety
Stratification factors • First-line CT (oxaliplatin-based, irinotecan-based)• First-line PFS (≤9 months, >9 months)• Time from last BEV dose (≤42 days, >42 days)• ECOG PS at baseline (0/1, 2)
OS: ITT populationO
S es
timat
e
Time (months)
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36 42 48
No. at riskCT 410 293 162 51 24 7 3 2 0BEV + CT 409 328 188 64 29 13 4 1 0
CT (n=410)BEV + CT (n=409)
9.8 mo 11.2 mo
Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)p=0.0062 (log-rank test)
Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)p=0.0211 (log-rank test)
aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)
Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)
VELOUR Study Design
Primary endpoint: overall survival
Sample size: HR=0.8, 90% power, 2-sided type I error 0.05
Final analysis of OS: analyzed at 863rd death event using a 2-sided nominal significance level of 0.0466 (α spending function)
Metastatic Colorectal Cancer
RANDOMIZE
Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks
Placebo IV, day 1+ FOLFIRIq2 weeks
1:1 Disease Progression Death
600
600Stratification factors:• ECOG PS (0 vs 1 vs 2)• Prior bevacizumab (Y/N)
VELOUR Study
• Overall results– Adding aflibercept to FOLFIRI in mCRC patients previously treated with an oxaliplatin-
based regimen resulted in significant OS and PFS benefits
Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024.
OS PFS
CORRECT: Patients with metastatic colorectal cancer treated with regorafenib or placebo after
failure of standard therapy
• Multicenter, randomized, double-blind, placebo-controlled, phase III– Stratification: prior anti-VEGF therapy, time from diagnosis of metastatic disease, geographical region
• Global trial: 16 countries, 114 centers• Recruitment: May 2010 to March 2011
2:1
Evaluation with CT scan of abdomen and chest every 8 weeks
Overall survival (primary endpoint)Primary endpoint met prespecified stopping criteria at interim analysis
(1-sided p<0.009279 at approximately 74% of events required for final analysis)
Eligibility: survival ≥ 90 days
Medical Publishing Misadventures:Authorship
An author must meet all three of the following criteria:1) Contribute to the study in one of three ways:
a) Conception and Design b) Acquisition of Data c) Analysis and Interpretation of Data
2) Draft or revise the article for important intellectual content.
3) Approve the final version.
Medical Publishing Misadventures:
• Conflict of Interest:– A conflict of interest exists if you have financial or personal
relationships or academic affiliations that may bias your judgment and influence your work.
– Disclose all relationships that are potential conflicts.– If you are unsure whether a conflict exists, it is better to include
the relationship.
Medical Publishing Misadventures:Author Misconduct
Author misconduct may include, but is not limited to:• Fabrication or falsification of data• Plagiarism (including self-plagiary)• Redundant publication of content
• Electronic journals allow for reader access to the literature, thereby eliminating need for republication in separate journals.
• Duplicate submission• NY Times April 16, 2102: marked rise of retractions for fraud, fabrication,
scientific mistakes. the rate of retractions in 17 journals from 2001 to 2010 and compared it with the journals’ “impact factor,” a score based on how often their papers are cited by scientists. The higher a journal’s impact factor, the two editors found, the higher its retraction rate.
