Technology Hurdles: Drug Developer Perspective Robert Mass, MD Senior Director Genentech, Inc. June 8, 2009
Diagnostic challenges Genentech has been committed to personalized drug development in oncology since Herceptin In spite of this commitment, our efforts to improve the lives of individual patients have been challenged by: The differential pace of therapeutic drug development/innovation when compared to diagnostic innovation Example: Herceptin and HER2 testing The technical challenges of pre-clinical to clinical diagnostic transition Example: Pertuzumab and HER2 pathway activation The regulatory environment governing the linkage of diagnostic testing and targeted therapy More about that tomorrow Page 2
The Herceptin program had a viable biomarker from day 1 1.0 Amplification Level : > 10 5-10 2-5 1 1 Disease-free survival probability 0.8 0.6 0.4 0.2 Not amplified (n = 52) Amplified (n = 11) > 5 copies 12.5 kb - 4.4 kb - p185 - Southern Northern Western 0.0 0 12 24 36 48 60 72 84 Time (months) Frozen IHC 27% 63% % Women 10% Slamon et al., Science 235:177-182, 1987 Slamon et al., Science 244: 707-712, 1989
The Herceptin program had a viable biomarker from day 1 HER2 Expression Level SK-BR-3 BT-474 MDA-MB-361 MDA-MB-453 MDA-MB-436 ZR-75-1 MDA-MB-231 MCF7 33 25 16.7 16.7 3.3 3.3 1.2 1.2 Cell line HER2/cell* IHC score FISH Score MDA-231 21,600 0 1.1 MDA-175 92,400 1+ 1.3 MDA-361 ~500.000 2+ ~4 SK-BR BR-3 2,390,000 3+ ~8 * Scatchard analysis 0 20 40 60 80 100 Growth Inhibition (%) Antibody Inhibiton (4D5) of Anchorage-Independent Growth Is Related to HER2 Expression Level HER2 IHC score is directly correlated to HER2 density and amplification
And The Rest is History Probability of Survival 1.0 0.8 0.6 0.4 0.2 0.0 Risk ratio = 0.80 95% Cl = 0.64, 1.00 Herceptin + Chemo (n = 235) Chemo Alone (n = 234) 0 10 20 30 40 50 Months
But not so Fast...FISH is here! Orange: Green: HER-2/ 2/neu Chromosome 17 centromere < 2.0 Not Amplified (FISH-) 2.0 Amplified (FISH+)
FISH score distribution in the pivotal Herceptin study 27.9% of study patients were not HER2 amplified 70 60 Number of Cases 50 40 30 20 10 0 1 2 4 6 8 10 12 14 16 18 FISH Ratios 20
Outcome by FISH score in the pivotal Herceptin study FISH+ FISH - Probability of Survival 1.0 0.8 0.6 0.4 0.2 0.0 Herceptin + Chemo (n = 164) Risk ratio = 0.69 95% Cl = 0.53, 0.91 Chemo Alone (n = 161) 1.0 0.8 0.6 0.4 0.2 0.0 Herceptin + Chemo (n = 62) Risk ratio = 1.07 95% Cl = 0.70, 1.63 Chemo Alone (n = 64) 0 10 20 30 40 50 Months 0 10 20 30 40 50 Months Mass R. et al., Clinical Breast Cancer 6:240-46, 2005
What did this entail? Minimizing loss of informative samples Sufficiently validating novel technology Enabled 96% of patients to be included in outcomes analysis Bridging concordance with our FDA approved diagnostic HercepTest vs PathVysion Replicating results 799 samples were analyzed in 2 independent laboratories Time Project initiated in April 1999, FDA approval April 2002 Page 9
Where we are now (but what about CISH, qrt-pcr, or the next real [or perceived] innovation?) Page 10
Pertuzumab What do you do when you don t have a viable biomarker from the start?
Trastuzumab vs Pertuzumab Both anti-her2 antibodies, but distinct epitopes & MOA s Trastuzumab Herceptin Pertuzumab
The start of a pertuzumab biomarker 293/HERX LXFE 211 LXFA 289 LXFA 297 LXFE 397 LXFA 526 LXFL 529 LXFA 629 LXFA 1041 LXFL 1072 LXFE 211 LXFA 289 LXFA 297 LXFE 397 LXFA 526 LXFL 529 LXFA 629 LXFA 1041 LXFL 1072 HER1 A HER1/2 HER2 B HER 2/3 HER3 rhumab 2C4 responsive rhumab 2C4 responsive Not associated with HER receptors Associated with HER heterodimers Data: B. Bossenmaier & H. Koll
How do we detect HER2 heterodimers in clinical samples? (harder than you think) HER2 activation pher2 Directly detect HER dimers Immunoprecipitation and blotting Heterodimer ELISA Development of heterodimer-specific antibody reagents FRET (fluorescence resonance energy transfer) Proximity assays Surrogate markers for receptor activation Gene expression profile Proteomic profile Downstream regulated gene activity
The nearly impossible clinical experiment 1.0 Proportion progression-free 0.8 0.6 0.4 0.2 Median TTP 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 0 0 100 200 300 400 Time to disease progression (days) Every patient underwent laparoscopic biopsy for study entry Gordon et al. J Clin Oncol. 2005;23:16S (abstract 5051). Gordon et al. J Clin Oncol. In press.
Our next trip to the plate Ovarian cancer Platinum-resistant Gemcitabine + Placebo Gemcitabine + Pertuzumab N= 130 1 o EP = PFS Control Pertuzumab 2.6 2.9
The ensuing diagnostic interrogation..
This is an example of detecting HER2 dimerization via downstream regulated gene activity 3.5 3 CTRL HRG Pert + HRG Pert 2.5 6h stimulation Fold CTRL 2 1.5 1 0.5 0 6 out of 8 OvCa cell lines down-regulate HER3 mrna expression after HRG stimulation
Our current trip to the plate in ovarian cancer 1 o EP = PFS Looking for a big treatment effect in a small, selected population
But what about HER2 amplification? HER2+ MBC Progressed on Herceptin Herceptin + Pertuzumab 2 R or 1 R + 12 SD or 13 SD in 1 st 24 patients? YES NO Stage 2 (n=66) Stop trial Complete response a 5 (7.6) Partial response a 11 (16.7) Stable disease for 8 cycles (~6 months) n (%) 17 (25.8) Objective response rate 16 (24.2) Clinical benefit rate b 33 (50.0) Gelmon et al. J Clin Oncol 2008;26(15S): Abstract 1026
But what about HER2 amplification? CLEOPATRA HER2+ MBC (n=800) Docetaxel + trastuzumab + placebo Docetaxel + trastuzumab + pertuzumab An international Phase III randomized, double-blind, placebo-controlled study (approximately 250 sites worldwide) Enrollment stratified by: Prior treatment for breast cancer Geographic region of enrollment Endpoints: PFS and OS Quality of life Biomarker analysis
Conclusions In retrospect, Herceptin was the exception, not the rule This is a lot harder than we thought! A major technologic hurdle remains the availability of appropriately processed tissue for exploratory biomarker assessments FFPE material is a bad platform.most of the time Page 22
Our Touchstone: The Diagnostic Iceberg Page 23