1 Rosario García Campelo, MD Clinical Trial Endpoint Selection in Oncology: What Can Make a Difference?

1

Rosario García Campelo, MD

Clinical Trial Endpoint Selection in Oncology: What Can Make a Difference?

Clarify expectations…

What do patients - and the world - considerMEANINGFUL CLINICAL BENEFIT?

What do patients and physicians want? To be cured…

To relieve a person of the symptoms of a

disease or condition

To eliminate a disease or condition with medical treatment

Benefit in Oncology

Prolong survival

Improve QoL

The magnitude of survival benefit depends on many factors…

Verheven et al. EJC 2007

Schiller et al. NEJM 2002

STAGE IV GERM-CELL TUMORS

STAGE IV NSCLC

Estimate of 75% survival rate at 10 y

Less than 10% survival rate at 30 months

A drug that cures…

• Effective• Non-toxic• At a manageable financial cost

ANYTHING LESS IS A COMPROMISE.HOW MUCH ARE WE WILLING TO COMPROMISE?

The appearance of progress

COST

VALUE

Defining the value of a new drug

VALUE

COST

Cancer symptoms

Side effects of treatment

QoL

Survival

Moore M J et al. JCO 2007;25:1960-1966

Median survival11.3 vs 10.1 M

P=0.044HR 0.87

Pirker et al. Lancet 2009

Median survival6.2 vs 5.9 M

P=0.038HR 0.82APPROVED

NOT APPROVED

NOT APPROVED

Median PFS10.2 vs 6.6

P<0.001HR 0.58APPROVED

Median PFS6.7 vs 6.1P=0.003HR 0.75

STAGE IV PANCREATIC CANCER STAGE IV NSCLC

STAGE IV NSCLCSTAGE IV NSCLC

How to define clinical benefit?

Reck et al. J Clin Oncol 2009

First task…

• Define patient population to treat– Type of cancer– Subtype of cancer– Adjuvant setting– Metastatic disease– Line of therapy

• Determine current expectations of both, clinicians and patients– What is current OS for each cancer/setting– Determine what would be a clinically meaningful increase in the primary endpoint chosen: OS,

PFS, RR????

Who decides what is important?

• Patients

• Clinicians

• Regulatory agencies

• Industry

What is a clinical trial?

• A clinical trial is a research study conducted in patients, with patients and for patients, to answer specific questions about their treatment, diagnostic or follow-up

• Clinical trials are used to determine whether new biomedical or behavioral interventions are both safe for patients and effective at treating their disease(National Institutes of Health’s (NIH) definition http://grants.nih.gov/grants/glossary.htm#C)

• Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people

Historical clinical trials design

PHASE I: maximum-tolerated dose assessment Find a dose that kills the tumor rather than the patient…

PHASE II: response signalTreat patients but expect no response…

PHASE III: comparison to the standard or added to the standardRandomize and hold your breath

From G. Blackledge

Just to remember…

• Pvalue: – Is a function of the observed sample results (a statistic) that is used

for testing a statistical hypothesis – It gives no indication about the clinical importance of the observed

association

• CLINICAL BENEFIT– Clinically meaningful outcome to be offered to patients in OS and/or

quality of life– Activity is different to benefit…

• ENDPOINT– A measure to clarify potential efficacy or safety– OS, PFS, TTF, TTP, ORR, DCR

The true clinical efficacy measures:Robust, clear…

What makes a good endpoint?

CHARACTERISTIC MEANING

Relevant Clinically important/ useful

Quantifiable Measured on a appropiate scale

Valid Measures the intended effect

Objective Interpreted effect yields consistent measurements

Reliable Same effect yields consistent measuremnts

Sensitive Respond to small changes in effect

Specific Unaffected by extraneous influences

Precise Small variability

Other Tradition, cost, time…

Regulatory Evidence Endpoint Advantages Disadvantages

Surrogate

RR/CRR 1-arm possible, smaller, shorter, attributable to drug

No direct measure of benefit/no comprehensive measure of drug activity/only subset of benefiting patients

DFS Smaller, shorter Not stat. validated as surrogate for OS/not precise, open to bias/many definitions

PFSSmaller, shorter, SD included,

crossover/other Tx not affecting, objective & quantitative

Not stat. validated as surrogate for OS/not precise, open to bias/many definitions/frequent assessment /need to balance

timing x arms

Clinical benefitSymptoms Patient perspective of direct

clinical benefitBlinding hard, missing data, clinically relevant effect, validated

tools lacking

OS Direct measure of benefit, easy, precise

Large studies, crossover/follow-up Tx affects, noncancer deaths

Endpoints – FDA view

Guidelines for endpoint selection

The decision should always be related to:• The patient subpopulation of interest

• The stage of disease (depends on the type of cancer)

• The characteristics of the treatment (toxicity, efficacy)

• The aims of trial (superiority/noninferiority/safety)

• The other treatments already available to that group of patients

• Ethics

• Practical feasibility (costs, logistics…)

OS as the gold standard for demonstrating clinical benefit

ACCURATE

OBJECTIVE

CLINICALLY SIGNIFICANT

EASILY MEASUREDUNAMBIGUOUS

READILY COMPARED

ACROSS DISEASES

NOT PRONE TO INVESTIGATOR OR ASSESSMENT BIAS

Cheema PK, Curr Oncol 2013

Advanced NSCLC:Why overall survival?

• Most relevant to patient

• Most objective endpoint– Clear and accurate endpoint– Usually easy to get this information

• Relevant for other reasons– It is easier to decide upon a treatment when its impact on survival

is known– Reimbursement issues– Assessment in earlier disease stages– Impact on drug development in general

A trial that looks for OS…

• Takes too long• Requires large sample sizes• Is complex• Influenced by post-trial therapy• Is more expensive

• But… the cost of a trial is a small fraction of the costs to society for not having a reliable answer to a question, since today’s treatments can be extremely expensive

• Just to remember: – RCT only require large sample sizes when one is looking for small treatment effects– Larger trials can stop early with formal internal monitoring if the treatment effect is

surprisingly large

Korn E. J Clin Oncol 2012

• OS is a feasible endpoint, though the OS benefit may be clouded by subsequent therapies

• Clinical trials should aim to improve OS by >25%

Main consensus ASCO: “OS endpoint is important”

ASCO stresses the use of the OS endpoint.Agents not expected to provide such OS gain would no

longer be needed in clinical practice.

http://www.asco.org/practice-research/clinically-meaningful-outcomes

Ellis et al. J Clin Oncol 2014

Let´s talk about surrogate markers…

…a measurement used in trials as an early and adequate substitute for OS, like ORR or PFS

Introduction to surrogate endpoint

• Why do we use a surrogate endpoint?– Can be measured earlier– Convenient or less invasive– Can be measured more frequently– Can accelerate the approval process

• Advantages:– May reduce the size of clinical trials– May shorten the duration of clinical trials– May reduce the cost of clinical trials

Let´s talk about surrogate markers…

…a measurement used in chemo trials as an adequate substitute for OS, like ORR or PFS

…An endpoint that is a surrogate for OS would be helpful in addressing the limitations of OS but must first be validated by

satisfying statistical criteria

…A growing belief in the oncology community that delaying progression in metastatic disease is a worthy goal,

even if OS is not improved

Use of PFS in the contemporary era

1975-19841985-1994

1995-20042005-2009

0

50

100

150

200

47 107 167137

0

2

1135

No. PUBLISHED RCT PFS AS PRIMARY ENDPOINT

Booth C. J Clin Oncol 2012

Can PFS be considered a strong and robust surrogate marker?

• Is a treatment that improves PFS really an advance for patients even if OS is not improved?

• How does PFS relate to patient benefit?

• Or is it only lowering the bar to declare efficacy and accelerate drug approval?

Buyse M. Stat Methods Med Res 2008Booth C. J Clin Oncol 2012

Saad, Katz. Ann Oncol 2009; Burzykowski et al. JCO 2008Shi et al. Int J Clin Oncol 2009

PFS as an endpoint has potential advantages

• Progression events occur early and more frequently than death events

• Less influenced by competing causes of death

• PFS is not influenced by post-progression therapy

• Faster time to drug approval

• Faster receipt by patients of novel therapies

• Less cost to manufacturer or sponsor

But also many disadvantages…

ASSESSMENT BIASThe investigator may declare a control-arm case a progression to get a patient on an active therapy ASAP

EVOLUTION-TIME BIASA suspected progression may be formally evaluated at a later time when patients are in one arm rather than the other arm

THE EXACT TIME OF PROGRESSION IS UNKNOWNIt requires frequent radiologic assessment, which introduces imprecision

ATTRITION BIASMore patients may withdraw from one arm than from the other arm

Study Control arm Ethnicity Rx evaluation Independent review PFS

LUX-lung 3(n=345)

Afatinib vsCis/pem

Asian (71%) Caucasian 6w Yes 13.6 vs 6.9

11.1 vs 6.9

LUX-LUNG 6(n=364)

Afatinib vs Cis/Gem Asian 6w Yes 11 vs 5.6

EURTAC(n=174)

Erlotinib vsCT Caucasian 6w Yes 10.4 vs 5.4

OPTIMAL(N=165)

Erlotinib vsCarb/Gem Asian 6w No 13.1 vs 4.6

WJTOG(n=172)

Gefitinib vsCis/Doc Asian 8w No 9.6 vs 6.3

NEJ002(n=230)

Gefitinib vsCarb/pacl Asian 8w Yes 10.8 vs 5.4

IPASS(n=261)

Gefitinib vsCarb/pacl Asian 6w No 8.4 vs 6.7

SIGNAL(n=42)

Gefitinib vsCis/Gem Asian 9w Yes 9.5 vs 6.3

Afatinib Erlotinib Gefitinib

Phase III trials comparing TKI vs conventional CT in EGFR mutation–positive NSCLC

What is the true defitinion of meaningful clinical benefit?

BASAL 8 weeks Erlotinib

What is the true defitinion of PFS?EGFR MUT PATIENT: Slow progression to erlotinib, excellent symptoms control

After 1 year…

February 2012 July 2012 October

2012

ALL THESE MAY CONFOUND THE INTERPRETATION OF TRUE PFS

EFFECT

What we know of PFS as a tool..And this is evidence…

• Published literature on advanced breast, prostate, and NSCLC have not supported the surrogacy of PFS for OS

• Colorectal cancer and ovarian cancers seem to be the only tumor types for which data supporting the surrogacy of PFS for OS have been demonstrated…and this is not completely true

Booth C. J Clin Oncol 2012

Surrogacy of PFS in advanced NSCLC?

• IPD-based analysis

• 5 RCT DOC vs VNB

• PFS - OS: some correlation (τ=0.59; 95% CI 0.58 to 0.61)

• Great magnitude of PFS benefit (at least HR <0.5) needed to predict any significant OS effect (HR <1.0)

• Most trials have usually failed to show such PFS

• PFS is unlikely to be an acceptable endpoint

Laporte S et al. BMJ Open 2013

However…

• Although I do believe it is time to significantly raise the bar…superstars in oncology are the exception, but progress in oncology is incremental

• I do believe we know much more about cancer than some years ago: – Tumors can now be defined by molecular drivers

• New challenges posed by the new classes of agents

• New trial designs and validated endpoints are needed to test them

What is the true definition of clinical benefit?

Shaw A, et al. N Engl J Med 2013;368:2385–2389

1980 19902010

Times have changed...

EMPIRICAL ONCOLOGY

MOLECULAR ONCOLOGY

New challenges for new therapies

• INMUNOTHERAPY– Pseudo progression effect: Go vs no-go decision– Survival benefit in the absence of significant responses, or very significant PFS

• PERSONALIZED THERAPIES– Intra-patient heterogeneity– How to deal with

• Brain mets• Single site progression• Benefit beyond progression

• WILL WE BE ABLE TO DEFINE THE BEST SEQUENCING?

If the design of trials is evolving, should trial endpoints evolve in parallel?

New trends of drug development

Phase I Phase II Phase III

Phase I -II Phase III

Novel clinical trial designs

• PHASE I: – Limited number of doses, drug combinations, and selected

populations of patients

• PHASE II: – Randomized designs

• PHASE III: – Smaller and smarter

• Adaptative designs (adaptative enrichment or adaptative estratification design)

• Basket designs: multiple diseases for a given marker• Umbrella designs: multiple markers for a given disease

KEYNOTE-001 phase Ib trial(NSCLC cohorts): Study design

Garon et al. ESMO 2014 (abstract LBA-43)

irRC: immune-related response criteria.*An initial cohort of 38 patients was also enrolled; ‡First 11 patients were randomized to 2mg/kg q3w and 10mg/kg q3w, and the remaining 34 patients were randomized to 10mg/kg q2w and 10mg/kg q3w; §Additional non-randomized cohort not included in the previously treated population of 217.

Pembrolizumab in treatment-naïve patients with PD-L1+ NSCLC

(n=45)

Pembrolizumab in previously treated patients with PD-L1+ or PD-L1-

NSCLC

2mg/kg q3w

10mg/kg q2w

10mg/kg q3w

10mg/kg q2w; PD-L1+(n=58)

10mg/kg q3w; PD-L1+(n=86)

10mg/kg q2w; PD-L1-(n=40)

10mg/kg q3w; PD-L1+(n=33)

2mg/kg q3w§

(n=45)

≥2L

≥3L

1:1‡

3:2

• Measurable disease• ECOG PS 0–1• Known PD-L1 status (PD-L1+ defined as ≥1%

expression)• EGFR mutations or ALK gene rearrangements

permitted in previously treated patients (with PD on relevant EGFR TKI) but not for treatment-naïve patients

• Disease progression on most recent prior systemic therapy

• No systemic steroid therapy, active autoimmune disease or active brain metastases

(n=345*)(n=307 for expansion cohorts)

R

Currently only investigator-assessed ORR by irRC is

available for this cohort

R

Primary endpoints• DLTs• AEs• ORR

Secondary endpoints• Pharmacokinetics • PFS

2 • OS • DoR

1 • Biomarker expression

PCD4989g: Phase I study design

NCT01375842Soria, et al. ESMO 2014 (abstract 1322P); Hodi, et al. ECC 2013RP2D = recommended phase II dose

Dose escalation Expansion Incurable/metastatic solid tumours

Tumour specimen available

ECOG PS 0–1(n=1,242)

(safety evaluation, response assessment)

MPDL3280A10, 15 and 20mg/kg iv q3w

RCCMelanomaNSCLC Other tumour typesUBC

Mandatory serial tumour

biopsiesTNBC

PD(safety evaluation)

MPDL3280A0.01–20mg/kg iv q3w

Secondary endpoints• Pharmacokinetics• ATAs• Best ORR• Objective response• DoR• PFS• Potential biomarkers

Primary endpoints• Safety• Tolerability• MTD and DLTs• RP2D

3 Exploratory objectives• Assess tumour cell

PD-L1 expression (IHC), evaluate baseline tumour cell transcript expression of immune and checkpoint markers (PCR)

21

Ariel Lopez-Chavez et al. JCO 2015;33:1000-1007

Basket trials

KEY STRENGTHS OF THE BASKET TRIAL DESIGN

The ability to identify a favorable response to targeted therapy with a small number of patients

The ability to validate a clinical target

KEY CONDITIONS FOR BASKET TRIALS SUCCESS

The tumor must depend on the target pathway

The targeted therapy must reliably inhibit the target

Development of reliable endpoints to allow an early recognition of clinical benefit

Wilson et al. Lancet Oncol 2015

MOLECULAR ONCOLOGY…NEW TRIALS ENDPOINTS

TREATMENTS

Signal transduction inhibitors

Gene expression modulators

Angiogenesis inhibitor

Immunotherapies

ENDPOINTS

Effect on molecular target

Circulating tumor cells

Circulating tumor DNA

Functional imaging

Buyse, M. et al. Nat. Rev. Clin. Oncol 2010

Necessary changes to drug development

• Development and agreement on quality standards for biomarkers and routines for quality assessment

• Harmonisation of biomarker validation

• Collaboration between drug developers and regulatory agencies

• Agreement on best practices for co-development of diagnostics and drugs

• Educating citizens and health professionals on the need to collect biomarkers

Kheif et al. Clin Cancer Res 2013

How PD-L1 is being assessed?“ME TOO DRUGS…WITH MY OWN BIOMARKER TEST”

HARMONISATION OF BIOMARKER VALIDATION!!!

PATIENT REPORTED OUTCOMES (PRO)Are PRO measures underappreciated and underused in oncology?

• PRO address more than just symptoms

• Direct measures of patient benefit, they can be considered independent endpoints

• This approach is especially useful in trials of drugs for patients with incurable cancers, in which one of the main goals is to improve palliation of symptoms

• Only 1/3 of phase 3 breast cancer trials registeries with US NIH have collected or are presently collecting PRO

Wilson et al. Lancet Oncol 2015

In summary

• A difference is only a difference if it makes a difference…

• Overall survival remains the most relevant endpoint for phase lll trials in patients with advanced NSCLC– Easy to assess, accurate, and reliable

• It is time to change the traditional design of clinical trials

• It is time to advance endpoints to parallel changes in trial design and therapeutic intervention

• Consistency and validation in outcome of the various endpoints is also important– RR– PFS– QoL – PRO– Biomarkers

McNamara Fallacy, 1960

1. Measure whatever can be easily measured…This is correct2. Disregard that which cannot be measured easily…This is

artificial and leads to errors3. Presume that which cannot be measured easily is not

important…This is blindness4. Presume that which cannot be measured easily does not

exist…This is suicide

Basier MH. BMJ 2009