Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Review Experience in Evaluating Predictive Biomarkers – Design and Analysis Considerations Yuan-Li Shen, Dr. P.H. U.S. Food and Drug Administration Center for Drug Evaluation and Research Office of Biostatistics Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Acknowledgement Somesh Chattopadhyay Kun He Rajeshwari Sridhara Qiang (Casey) Xu Sue Jane Wang The views expressed in this talk are those of the author, not of the FDA Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Outline Motivation : HER2, EGFR Types of designs Prospective (Adaptive, enrichment, all-comer) Prospective-Retrospective Phase II – biomarker subgroup selection Issues in designs and analysis - Example of HER-2 for MBC (metastatic breast cancer) - Example of EGFR for NSCLC (non-small cell lung cancer) - Example of K-ras for mCRC (metastatic colorectal cancer) Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Why targeted in Cancer trials Limit drug exposure to those who benefit Avoid drug use in those who will be harmed Optimize drug dosing • Improve efficiency of trial design Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Terminology Targeted : selected; enrichment Untargeted: unselected; all-comers Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Spectrum in study designs incorporating biomarkers Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Spectrum in study designs incorporating biomarkers Targeted e.g. Hormonal therapy in ER/PR positive breast cancer women; e.g. Herceptin for HER2+ metastatic breast cancer; Note: HER2–amplified in 25–30% of all breast cancer patients (Cobleigh et al, 1999) e.g.Gleevec for KIT+ Gastrointestinal Stromal Tumor (GIST); e.g. products underdevelopment: BRAF inhibition in melanoma; ALK inhibition in NSCLC e.g. K-Ras WT for metastatic colorectal cancer (mCRC) e.g. EGFR for non-small cell lung cancer (NSCLC) (???) e.g. EGFR in squamous cell head and neck cancer. Note: EGFR is overexpressed in 80% of squamous cell carcinoma (Kumar, et al,2003) Untargeted Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Design – Issues to be considered Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Design – Issues to be considered Strength of the biological evidence (e.g. relationship between biomarker and treatment; treatment effectiveness) Prevalence of the biomarker Validity and reliability of the testing tool Feasibility of the assessment Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Type of Trial Designs Prospective design --- Enrichment (e.g. Herceptin in HER2 positive for mBC) --- Biomarker stratified (with subgroup hypothesis) --- Planned Adaptation Drop a biomarker subgroup, based on a futility analysis Adaptive signature design Prospective-retrospective (e.g. anti-EGFR mAb in K-ras WT for patients with mCRC) Phase II : Exploratory biomarker subgroup selection (e.g. I-SPY 2) Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Prospective design – Enrichment Randomize New Rx Biomarker + Control Screen Biomarker status Biomarker - Off study Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Issues in Enrichment Design Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Issues in Enrichment Design Requires smaller sample size (relative to all comers design), however….. Can not answer if the biomarker is predictive Testing assay may not correctly identify the subgroup (misclassification) Can not be used for clinical validation of the diagnostic tool Slow accrual if only a small proportion of the biomarker positive subgroup is in the population (low prevalence) Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Example of limitation in assay precision from an enrichment design (Herceptin) DFS results in Herceptin for adjuvant breast cancer trial by HER2 overexpression or amplification Reference: Herceptin package insert Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Prospective design – Biomarker Stratified New Rx Biomarker + Control Screen Biomarker status New Rx Biomarker - Control Randomize Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Analysis Issues in the Biomarker Stratified Design Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Analysis Issues in the Biomarker Stratified Design Potential Analysis Plan: Treatment by biomarker interaction Issues: May not have enough power for interaction and failure to show interaction does not mean no differential subgroup effect Hierarchical testing: Issues: more complicated when interim analyses for efficacy and futility will be performed and more endpoints (e.g. PFS, OS) will be involved. α-splitting: Issues: Overall treatment effect may be driven by one of the Biomarker subgroup; when to perform the event driven analysis Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Adaptation for selecting biomarker subgroup Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Adaptation for selecting biomarker subgroup Planned adaptation: -- Futility analysis -- Combining Phase II and III data -- Adaptive signature design : Stage 1 data will be used to define a biomarker “sensitive” subgroup and the rule will be applied to stage 2 to select a biomarker sensitive subgroup; Analysis will be performed to evaluate treatment effect in overall population and biomarker subgroup selected at stage 2 Unplanned adaptation based on independent information – include subgroup hypothesis e.g. HER2+ in Lapatinib+Letrozole trial (studied in all comers; change analysis population to HER2+; not stratified by HER2 status); Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Prospective - Retrospective • Working Definition : In completed or post-interim-analysis trial where genomic samples were collected prior to treatment initiation, whether or not full ascertainment, the genomic hypothesis is ‘prospectively specified’ prior to diagnostic assay testing. However, the clinical outcome data without genomic information have already been (partially) collected, unblinded, and analyzed. The genomic data analysis might be arguably ‘prospectively performed, which is a retrospective analysis. * Wang et al (2006 TPJ) ; Wang, et. al. (2010, Clinical Trials) Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Prospective-retrospective – Criteria for Consideration • A pragmatic approach may be considered if Adequate, well-conducted and well-controlled trial Large sample size if no stratification by biomarker status for randomization (??) Biomarker ascertainment in a large portion of randomized subjects Assay – acceptable analytical performance Acceptable statistical analysis plan O’Neill, Dec. 2008 ODAC Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Retrospective Analysis Issues Retrospective analysis is for hypothesis generating and should not be used to salvage a failed trial Issues:  type I error, if the primary endpoint from the ITT population is not significant; possible selection bias; imbalance between treatment arms. Convenience sample – Issues Studies with smaller the sample size, more likely to have imbalance of baseline characteristics Imbalance in biomarker distribution and baseline characteristics leads to biased treatment effect Results confounded – depending on ratio of biomarker + vs. – and distribution of the baseline characteristics To confirm the results requires replication

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Trial Designs- Phase II dose/biomarker screening I-SPY (2) : (Investigation of Serial Studies to Predict Your therapeutic response with imaging and molecular analysis 2) – a process targeting the rapid, focused clinical development of paired oncological therapies and biomarkers. Framework : Adaptive phase II clinical trial design in the neoadjuvant setting for women with high risk, locally advanced breast cancer Rationale: -- identify a biomarker subgroup which is more likely to respond to a chemotherapy -- test, analytically validate and qualify biomarkers -- employ an adaptive trial design to enable efficient learning -- utilize organizational management principles and bioinformatics to eliminate current inefficiencies in clinical trial Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 I-SPY 2 Biomarkers: ER (+,-), PR(+,-), HER2 (IHC/FISH, gene expression, protein microarray), MammaPrint score (higher MP2, other MP1) Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 I-SPY 2 : Standard therapy: weekly paclitaxel(+trastuzumab for HER2 positive) doxorubicin+cyclophosphamide (AC) Drugs: 5 new chemotherapies are tested simultaneously (each will be tested in a min. of 20 and a max. of 120 patients) Biomarkers: 14 out of 256 possible biomarker combinations are of interest Endpoint: pathologic complete response Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

I-SPY 2 : Issues More for hypothesis generating Difficulties in interpreting the results – comparative analysis not interpretable Not clear about the robustness of Baysian adaptation Products with toxicity, clinical trial hold issues, differential toxicity and benefit risk can not be identified

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Prospective - Retrospective K-ras in EGFR inhibitor for mCRC Background The efficacy of EGFR inhibitors is restricted to patients with wild-type (WT) K-ras status (Amado, JCO 2008, Van Cutsem ASCO 2008 and others) June 2008, NIH/NCI issued an action letter to exclude enrollment to mutant K-ras subgroup Dec. 16, 2008 Oncologic Advisory Committee was held to discuss the considerations based on retrospective analyses for a biomarker subgroup Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Retrospective analysis results (Dec. 2008 ODAC) Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Retrospective analysis results (Dec. 2008 ODAC) Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Retrospective analysis results (Dec. 2008 ODAC) Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Retrospective analysis results (Dec. 2008 ODAC) Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Issues in retrospective analysis (Dec. 2008 ODAC) If no statistical significance in the primary efficacy endpoint, all other analyses are exploratory (i.e. can not be used to salvage a failed trial) : e.g. EPIC, OPUS and PACCE Convenience sample, e.g. EPIC Interim results may not be robust and reproducible No documented evidence that the treatment groups with ascertained biomarker status are comparable in baseline characteristics

Prospective Designed, with subgroup hypothesis Study BO18192 (SATURN) Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Prospective Designed, with subgroup hypothesis Study BO18192 (SATURN) Multicenter, International, Randomized, Double-blind, Placebo-controlled, Phase III – maintenance therapy after platinum-based doublet chemotherapy in patients with advanced or recurrent or metastatic NSCLC Patients who had CR, PR or SD were randomized to receive Tarceva or placebo using adaptive randomization method (Pocock and Simon, 1975) based on the following stratification factors : EGFR protein expression, stage of disease, ECOG performance status, chemotherapy regimen, smoking status and region. Tarceva (Erlotinib) : EGFR tyrosine kinase inhibitor (TKI) Co-primary hypothesis : PFS in all randomized patients PFS in EGFR IHC positive subset Alpha – allocation : 0.03 for PFS in all randomized patients; 0.02 for PFS in EGFR IHC positive subset Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Study BO18192 (SATURN) Design (continue…)

Study BO18192 (SATURN): Biomarker Characteristics Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Study BO18192 (SATURN): Biomarker Characteristics Note: Protocol implemented a hierarchy of biomarker ascertainment Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Study BO18192 (SATURN): Issues of the EGFR IHC status Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Study BO18192 (SATURN): Issues of the EGFR IHC status ~16% unevaluable EGFR IHC status EGFR (IHC) test was not reliable Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 SATURN : Statistical Issues in biomarker subgroup analysis More than 16% had missing or indeterminate EGFR IHC status which may create problems in interpreting the biomarker subgroup results; (2) The test used for EGFR IHC status is not approved by FDA for NSCLC. (3) Whether EGFR IHC testing is more likely to accurately assess EGFR status for NSCLC is uncertain – Other EGFR status (mutation, FISH) had close to 50% patients with missing or indeterminate status, so the analyses based on the other biomarker testing are considered only exploratory. Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Prospective designed, unplanned adaptation Study EGF 3008: Randomized, double-blind, placebo-controlled, parallel-group, multi-center, study to evaluate the efficacy and tolerability of the combined treatment of lapatinib and letrozole versus the treatment of placebo and letrozole in 1286 post-menopausal women with hormone receptor positive (ER positive and/or PgR positive) advanced or metastatic breast cancer and had not received prior therapy for advanced or metastatic disease. Stratified by site of disease and prior adjuvant endocrine therapy Adaptation -- Sample size increased from 760 to 1280 -- Change primary population (from ITT to HER2+) (after 760 patients were randomized) -- Hierarchical testing 10 : PFS in HER2+ 20 : PFS in ITT

Study EGF 3008 design 10 objective : PFS in HER2+ 20 objective : PFS in ITT

Study EGF 3008: Patient populations Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Study EGF 3008: Patient populations HER2 : FISH + or IHC : 3+ Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Study EGF 3008 : Kaplan-Meier Estimate of Investigator-Evaluated PFS Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Review Experience in Evaluating Predictive Biomarkers April 15, 2017 Study EGF 3008 : Statistical Issues (1) The primary efficacy population was changed from ITT to HER2-positive after 760 patients were randomized, and sample size was increased to 1286 to have adequate HER2-positive patients; (2) Study was not stratified at randomization by HER2 status; (3) Demonstration of OS benefit has generally been the standard for consideration of regular approval in first-line setting of breast cancer. Currently, the OS benefit of Lapatinib has not been demonstrated. Note: Lapatinib was approved under accelerated approval. Yuan-Li Shen, Dr. P.H. FDA/CDER/OTS/OB/DBV

Summary The prospective designed trial is preferred. -- if there is no clear biological evidence of the biomarker subgroup and diagnostic tool can reliably identify the biomarker subgroup, biomarker stratified design may be preferred. If the retrospective analysis would be performed, high biomarker ascertainment rate should be required. It can not be used to salvage a failed study. Robustness of the results should be demonstrated and an additional study that can replicate the results is required as the supporting information.

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