Gracie Lieberman, Genentech 2006 FDA/Industry Workshop   Biomarkers and Surrogate Endpoints in Drug Development Technical and Regulatory Considerations   Gracie Lieberman, Genentech 2006 FDA/Industry Workshop

Content Changing landscape Efficacy surrogate endpoints used for approval – case studies Herceptin Iressa Surrogate endpoints in proof of concept trials Selecting sub-population Selecting dose Role of mechanism-based biomarkers PET studies in cancer

Changing landscape In the past 15-20 years: Impact on clinical trials Better molecular understanding of diseases Earlier, more precise diagnosis New targeted, improved therapies Impact on clinical trials Assessment of improvements in clinically meaningful endpoints require enrolling many patients and then following them for a long time.  Emerging need Develop strategies for reducing the time and cost of drug development.  Use of surrogate endpoints either in proof-of-concept or label-enabling trials. Defined in clinical practice and used by clinicians to monitor and treat patients New mechanism-driven biomarkers

Endpoint considerations Study defined endpoints supporting product labeling Demonstrate clinically meaningful benefit Relevant to a specific indication and study population Reliable and reproducible Study defined endpoints supporting early decisions Correlated with clinically meaningful outcomes Sensitive to small sample sizes Pharmacodynamic markers Surrogate endpoints

Case Studies Herceptin – PFS as an endpoint Iressa – Risks of accelerated approval

Herceptin in MBC Herceptin a is recombinant DNA-derived humanized monoclonal antibody that targets HER2, the protein product of c-erbB-2. In September 1998 Herceptin was approved for: First line treatment in combination with paclitaxel in MBC patients whose tumors overexpress HER2. The primary endpoint used was not overall survival (OS) but progression free survival (PFS).

PFS as a primary endpoint How to assure objectivity and minimize bias Randomized, placebo control study Weekly placebo infusions for months Impact on enrollment Strict schedule of efficacy assessment Independent review of radiographic images Process for collecting images Assessment of skin lesions required distribution of cameras to sites Strictly define rules for missing data Independent review of images not available

PFS as a primary endpoint The challenge continues 21% enrolled in the first year Protocol amendment to remove placebo Impact on primary endpoint (PFS) Invoke real time independent review of radiographic images Primary endpoint had to be confirmed by the review committee Patients and investigators compliance Turn-around review time was critical Offer cross-over to control patients

PFS as a primary endpoint Conclusions In September 1998 Herceptin was approved based PFS Survival as a secondary endpoint was statistically significant 65% of control patients crosses-over to receive Herceptin Two years later the survival benefit continued to be present Sub-group analysis impacted by crossover

Case Studies Herceptin – PFS as an endpoint Iressa – Risks of accelerated approval

Iressa in NSCLC Iressa a quinazoline-based small molecule, an EGFR TK inhibitor In phase I objective responses observed in NSCLC Two phase II monotherapy trials Response rate (RR) as primary endpoint Two dose groups May 2003 - Accelerate approval for 3rd line monotherapy use based on RR

Accelerated approval - risks Need to conduct large, confirmatory trials What if negative? Despite meaningful responses in recurrent NSCLC patients, Phase III trials failed to show any significant clinical benefit Approval was revoked in June 2005 The medicine should be used only in cancer patients who have already taken the medicine and whose doctor believes it is helping them. New patients should not be given Iressa because in a large study Iressa did not make people live longer. What went wrong? Patient selection ? Dose/schedule ?

Can this be avoided? Demonstrating clinical benefit with molecular-targeted agents is more complex than with conventional cytotoxic agents Selection of sub-population: who is most likely to benefit Identification of optimal biological dose Answers before phase III – is this achievable Proof-of-concept trials Is PFS a sufficient endpoint

Sub-population selection Complex process Tissue samples required Blood/serum feasible Tumor samples are challenging Missing data Archival samples not always relevant Randomized, controlled studies required Stratification by biomarker for sub-population selection At randomization or during analysis Not possible to distinguish between a prognostic and predictive biomarker without a proper control

Biomarker based population selection PFS with no control arm Time (days) Proportion progression-free 0.2 0.4 0.6 0.8 1.0 100 200 300 400 Median PFS pHER2 positive n=8 20.9 weeks pHER2 negative n=20 5.8 weeks pHER2 unknown n=27 9.1 weeks All subjects n=55 6.6 weeks All patients treated with pertuzumab pHER2+ tumors trend toward longer PFS Treatment effect or natural course of disease? Gordon et al. J Clin Oncol. 2005;23:16S (abstract 5051). Gordon et al. J Clin Oncol. In press.

Dose/schedule selection Complex process May be indication specific May be regimen specific Typical trial Randomized 3 arms Control/lower dose/higher dose 30-40 subjects per arm PFS as primary endpoint How is dose selected Better efficacy compared to control - winner

Time to event endpoints Optimal vs. sub-optimal dose Probability that the observed HR  0.75 True HR Number of events 40 60 80 100 200 0.67 0.64 0.70 0.72 0.80 0.42 0.40 0.39 0.37 0.33 0.90 0.28 0.24 0.21 0.18 0.02 We need to do better

Mechanism-based biomarkers Demonstrating clinical benefit with molecular-targeted agents is more complex than with conventional cytotoxic agents Escalating clinical trials costs and large numbers of patients required for currently used clinical endpoints mandate becoming more efficient in determining how well new agents can address unmet medical needs. That efficiency can be achieved by validating correlations between specific biological mechanisms of disease and clinical outcomes. Easier said than done!

Mechanism-based biomarkers Technological advances provide great opportunity for the development of biomarkers Molecular and cellular techniques Tissue samples Tumor/blood/surrogate Imaging technologies Current pre-clinical models still have limit ability to predict clinical effects Biomarkers need to be co-developed with the novel agent In early phases – no clinical data This will benefit second generation of the new agents or new indications Systematic way of analyzing and interpreting data

Mechanism-based biomarkers PET imaging Use of surrogate endpoints in cancer prevention

PET studies Speed development Tissue samples are not required Provide information about the activity of molecular pathways Determine if new agents are hitting the target Measure treatment effect Tissue samples are not required

FDG PET in NSCLC Wolfgang Weber et al. J Clin Oncol. 2003;21:2651

FDG PET in Lymphoma L. Kostakoglu, J Nuc Med 43:1018 2002

Challenges How to define metabolic response Change in standard uptake values (SUV) that based on re-tests can be reliably detected Arbitrary cut-off Optimized thresholds correlated with outcomes Based on analysis What adjustments made for minimum p-values Not applicable to other treatments or indications Use of core labs in multi-center trials Not ready as a surrogate efficacy outcome for combination trials Not all lesions are PET avid

Cancer Prevention Preventing heart diseases Lowering cholesterol / blood pressure Surrogate biomarker endpoints for cancer prevention trials Establishment of long term safety and efficacy for preventive drugs is critical Process for accelerated approval based on biomarkers will be needed Colorectal adenomas Current development of mechanism-driven biomarkers is critical for future cancer prevention trials.

Questions? Thank you!