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Clinical Trial Endpoint Selection in Oncology: What Can Make a Difference? Rosario García Campelo, MD 1 Clarify expectations… What do patients - and the world - consider MEANINGFUL 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… Estimate of 75% survival rate at 10 y STAGE IV GERM-CELL TUMORS Verheven et al. EJC 2007 Less than 10% survival rate at 30 months Schiller et al. NEJM 2002 STAGE IV NSCLC 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 Defining the value of a new drug VALUE COST How to define clinical benefit? STAGE IV PANCREATIC CANCER STAGE IV NSCLC Median survival 11.3 vs 10.1 M P=0.044 HR 0.87 Median survival 6.2 vs 5.9 M P=0.038 HR 0.82 Pirker et al. Lancet 2009 Moore M J et al. JCO 2007;25:1960-1966 STAGE IV NSCLC STAGE IV NSCLC Median PFS 6.7 vs 6.1 P=0.003 HR 0.75 Reck et al. J Clin Oncol 2009 Median PFS 10.2 vs 6.6 P<0.001 HR 0.58 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 signal Treat patients but expect no response… PHASE III: comparison to the standard or added to the standard Randomize 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… Endpoints – FDA view Regulatory Evidence Surrogate Endpoint Advantages Disadvantages 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 PFS Smaller, 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 Symptoms Patient perspective of direct clinical benefit Blinding 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 Clinical benefit 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 NOT PRONE TO INVESTIGATOR OR ASSESSMENT BIAS OBJECTIVE READILY COMPARED ACROSS DISEASES UNAMBIGUOUS CLINICALLY SIGNIFICANT EASILY MEASURED 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 Main consensus ASCO: “OS endpoint is important” • OS is a feasible endpoint, though the OS benefit may be clouded by subsequent therapies • Clinical trials should aim to improve OS by >25% 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 200 11 150 100 50 35 2 0 47 107 167 137 0 1975-1984 1985-1994 No. PUBLISHED RCT 1995-2004 2005-2009 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 2008 Booth C. J Clin Oncol 2012 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 Saad, Katz. Ann Oncol 2009; Burzykowski et al. JCO 2008 Shi et al. Int J Clin Oncol 2009 But also many disadvantages… ASSESSMENT BIAS The investigator may declare a control-arm case a progression to get a patient on an active therapy ASAP EVOLUTION-TIME BIAS A 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 UNKNOWN It requires frequent radiologic assessment, which introduces imprecision ATTRITION BIAS More patients may withdraw from one arm than from the other arm Phase III trials comparing TKI vs conventional CT in EGFR mutation–positive NSCLC Study Control arm Ethnicity Rx evaluation Independent review PFS LUX-lung 3 (n=345) Afatinib vs Cis/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 vs CT Caucasian 6w Yes 10.4 vs 5.4 OPTIMAL (N=165) Erlotinib vs Carb/Gem Asian 6w No 13.1 vs 4.6 WJTOG (n=172) Gefitinib vs Cis/Doc Asian 8w No 9.6 vs 6.3 NEJ002 (n=230) Gefitinib vs Carb/pacl Asian 8w Yes 10.8 vs 5.4 IPASS (n=261) Gefitinib vs Carb/pacl Asian 6w No 8.4 vs 6.7 SIGNAL (n=42) Gefitinib vs Cis/Gem Asian 9w Yes 9.5 vs 6.3 Afatinib Erlotinib Gefitinib What is the true defitinion of meaningful clinical benefit? What is the true defitinion of PFS? EGFR MUT PATIENT: Slow progression to erlotinib, excellent symptoms control 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 Times have changed... EMPIRICAL ONCOLOGY 1980 1990 MOLECULAR ONCOLOGY 2010 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 I -II Phase III 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 2mg/kg q3w • 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 Pembrolizumab in treatment-naïve patients with PD-L1+ NSCLC (n=45) R 10mg/kg q3w 1:1‡ 10mg/kg q2w Currently only investigator-assessed ORR by irRC is available for this cohort 2mg/kg q3w§ (n=45) • 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) 10mg/kg q2w; PD-L1+ (n=58) ≥2L Pembrolizumab in previously treated patients with PD-L1+ or PD-L1NSCLC ≥3L R 3:2 10mg/kg q3w; PD-L1+ (n=86) 10mg/kg q2w; PD-L1(n=40) 10mg/kg q3w; PD-L1+ (n=33) Primary endpoints • DLTs • Biomarker expression • AEs • ORR Secondary endpoints • Pharmacokinetics • PFS • OS • DoR 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. Garon et al. ESMO 2014 (abstract LBA-43) PCD4989g: Phase I study design Incurable/metastatic solid tumours Tumour specimen available ECOG PS 0–1 Dose escalation Expansion (safety evaluation) MPDL3280A 0.01–20mg/kg iv q3w (safety evaluation, response assessment) MPDL3280A 10, 15 and 20mg/kg iv q3w PD (n=1,242) NSCLC Melanoma Primary endpoints • Safety • Tolerability • MTD and DLTs • RP2D RP2D = recommended phase II dose RCC Mandatory serial tumour biopsies UBC Secondary endpoints • Pharmacokinetics • ATAs • Best ORR • Objective response • DoR • PFS • Potential biomarkers TNBC Other tumour types Exploratory objectives • Assess tumour cell PD-L1 expression (IHC), evaluate baseline tumour cell transcript expression of immune and checkpoint markers (PCR) NCT01375842 Soria, et al. ESMO 2014 (abstract 1322P); Hodi, et al. ECC 2013 Basket trials Ariel Lopez-Chavez et al. JCO 2015;33:1000-1007 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 ENDPOINTS Signal transduction inhibitors Effect on molecular target Gene expression modulators Circulating tumor cells Angiogenesis inhibitor Circulating tumor DNA Immunotherapies 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 correct 2. Disregard that which cannot be measured easily…This is artificial and leads to errors 3. Presume that which cannot be measured easily is not important…This is blindness 4. Presume that which cannot be measured easily does not exist…This is suicide Basier MH. BMJ 2009