Selecting the right patients for the right trials.

Transcription

1 Selecting the right patients for the right trials. Paul Waring Professor of Pathology University of Melbourne June 21, 2011 RCPA Genetics short course

2 Drug development challenges.

3 Current model of drug development is becoming unsustainable Data for for 10 largest pharmaceutical companies 1 in 14 drugs currently entering development is approved. Kola & Landis, Nature Reviews Drug Discovery 2004

4 Designer drugs

5 Tyrosine kinase pathways in cancer R R RAS RAF PTEN PI3-K AKT py K K py STAT SOS py GRB2 MEK MAPK proliferation/ maturation chemotherapy/ radiotherapy resistance DNA Gene transcription Cell cycle progression PP Jun Fos myc Myc survival/anti-apoptosis cyclin D1 Cyclin D1 angiogenesis metastasis

6 Trastuzumab (Herceptin TM )

7 HER2 is amplified in 15-25% of breast cancers. 1.0 Disease-free survival probability Not amplified Amplified > 5 copies Time (months) Slamon et al., Science 235: , 1987

8 Herceptin s Effects Correlate with HER2 Expression Antibody Inhibition (4D5) of Anchorage-Independent Growth HER2 Expression Level SK-BR-3 BT-474 MDA-MB-361 MDA-MB-453 MDA-MB-436 ZR-75-1 MDA-MB-231 MCF Growth Inhibition (%)

9 Her-2 amplified breast cancer

10 Clinical trial enrichment. Negative (70%) - 35 patients t identified d for alternative therapy - 3% potential responders missed - 50 unselected patients -22% benefit from therapy = will benefit from therapy Positive (30%) = will not benefit from therapy - 15 patients t selected - 67% benefit from therapy

11 Herceptin : The Power of Patient Selection Unselected Selected (HER2+) Unselected Selected Target prevalence 25% 100% Expected survival benefit 1.25m (5.7%) 5m (22.7%) Sample size 11,000 1,250 Study duration 349m 52m

12 HercepTest for Her2 screening - the first FDA - approved predictive test. Genentech approached DAKO to co-develop a commercial IHC kit. Validated during phase III by demonstrating equivalence to the clinical trial assay. Joint approval of drug and test in Sept Pathologists became the decision - makers for targeted therapies.

13 Companion Diagnostic Co-Development

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15 Imatinib (Gleevec TM )

16 Gastrointestinal stromal tumours

17 Gleevec TM and GISTs Pre Post (Day 7) Phospho-KIT

18 Signal - seeking clinical trials Hypereosinophilia syndrome Cyr Cryptic PDFRA-FIP1LI rearrangement

19 EGFR inhibitors EGFR is overexpressed in many common carcinomas. Overexpression of EGFR protein is rarely the result of gene amplification (except GBM). Target for EGFR inhibitors- Small molecules (NSCLC): Gefitinib (Iressa) Erlotinib (Tarceva) Monoclonal antibodies (CRC): Cetuximab (Erbitux) Panitumumab (Vetibix)

20 EGFR TKI in lung adenocarcinoma Lynch et al. 2004

21 BR.21: Tarceva monotherapy vs. placebo in chemotherapy-relapsed (2 nd /3 rd line) NSCLC 1.00 Overall survival: TARCEVA (n=488) Placebo (n=243) Survival rate TARCEVA Placebo Median survival (months) 1 year survival rate (%) Hazard Ratio 0.73 (95% CI, )* P< Months 21.5

22 EGFR mutations Exons EGFR Activating mutations exon 19 deletion L858R Overall incidence in population G719X 3.2% Deletion 48.2% P-loop C helix ~10% in Western countries Insertion 3.7% 20 Kinase domain K ~30% in Asian countries L858R 21 A-loop 42.7% Mitsudomi T, et al. Int J Clin Oncol 2006

23 EGFR is a founder mutation in lung adenocarcinoma. Yatabe Y. Cancer Metastasis Rev 2010

24 BR.21: Survival and EGFR Mutations EGFR Wild Type G. EGFR Wild Type EGFR Mutation H. EGFR Mutant Placebo Log-Rank: p=0.13 HR: 0.73 (0.49,1.10) Tarceva Placebo Log-Rank: p=0.45 HR: 0.77 (0.40,1.50) Tarceva Per cen t age Pe r cen t age At Risk Placebo Tarceva Time(Months) 6 9 Tarceva median = 8.6 mo (n=93) Placebo median = 3.5 mo (n=44) At Risk Placebo Tarceva Time(Months) 1 1 Tarceva median = 7.4 mo (n=21) Placebo median = 7.7 mo (n=19) Tsao M-S, NEJM 2005;353:133-44

25 Sample attrition and assay failure BR.21 N % Total patients enrolled % IHC Analysis % FISH Analysis % EGFR Sequence Analysis % Patients with EGFR mutant tumors 45* 6% TRIBUTE: Total number of patients enrolled % Total number of patients participating in % optional tissue collection Patients with samples available for analysis % Patients with samples suitable for sequencing % Patients with EGFR mutant tumors 29 3% * in 40 patients, 24 were not previously described. Eberhard DA, JCO 2005;23:5900-9, Tsao M-S, NEJM 2005;353:133-44

26 EGFR inhibitor prolongs survival in EGFR mutant tumours PFS probability Erlotinib (n=82) Gem/carbo (n=72) HR=0.16 ( ) Log-rank p< Patients at risk Time (months) Erlotinib Gem/carbo

27 Mechanisms of acquired resistance - dodging the magic bullets. Disease Gene Drug Resistance mechanism Alternate drug NSCLC EGFR Tarceva Iressa T790M / D761Y Met Ampl XL647 / HK1272 Met SMI CML ABL Gleevec T351I +20 others - Dasatinib* GIST KIT Gleevec V654A Sutent* +14 others PDGFR D842V HES PDGFR Gleevec T674I PKC412 EGFR T790M Pao W et al. PLoS Medicine 2005

28 Iressa & Tarceva Ph II s Positive EGFR TKI Roller-Coaster Tarceva BR21 Positive Mutation is it Mutation does not predict survival in BR21. FISH is it Commercial concerns over patient selection Adjuvant study in FISH + PhIII IPASS positive Ph IV SATURN IHC negative Ph III INTACT I/II, TALENT, TRIBUTE Negative Iressa ISEL Negative

29 Targeted therapies The right trial The right target The right patients (biomarkers) The right drug The right disease subset (indication)

30 Break-apart FISH assay 2p23 region 3 5 t(2;5) ALK gene breakpoint region ~250 kb ~300 kb EML4-ALK frequency: ~4-10% Primary lung adenocarcinoma Soda et al., Nature 448: , 2007

31 Tumor Responses to PF for Evaluable NSCLC ALK Patients Tumor Size Change and Treatment Duration (weeks) Overall RR 59% (17/29) % of best change from baseline Green - PR Blue - SD Black - PD Two patients had clinical progression and discontinued without radiographic confirmation.

32 Vemurafenib inhibits BRAF V600E Kinase RAS RTK 40-60% of melanomas ATP ATP RAF BRAF V600E MEK VEMURAFENIB (PLX4032, RO ) ERK Cellular Proliferation

33 PLX4032

34 BRIM-3 Progression-free survival Progression-free survival (%) Median 1.6 mos Dacarbazine (N=274) Vemurafenib (N=275) Median 5.3 mos Hazard Ratio 0.26 (95% CI; ) Log-rank P< No. of patients in follow up Months

35 BRIM -3 Overall survival Overall survival (%) Dacarbazine (N=336) Est 6 mo survival 64% Hazard ratio 0.37 (95% CI; ) Log-rank P< Vemurafenib (N=336) Est 6 mo survival 84% Months

36 Cetuximab (Erbitux TM ).

37 75% expression 10% amplified Ligand 0% mutant EGFR Cetuximab PI3K K K Grb-2 SOS RAS PTEN AKT RAF MEK mtor STAT3/5 MAPK Survival Proliferation

38 Ligand EGFR Cetuximab PI3K K K Grb-2 SOS RAS 35% mutant PTEN AKT RAF MEK mtor STAT3/5 MAPK Survival Proliferation

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40 Ligand EGFR Cetuximab 15-25% mutant PI3K K K Grb-2 SOS RAS 35% mutant 40% loss PTEN AKT RAF MEK 10% mutant mtor STAT3/5 MAPK Survival Proliferation

41 Mutations in PTCH and SMO are found in hereditary & sporadic basal cell carcinomas Inactive receptor Ligand-dependent activation Loss of PTCH mutations Activating SMO mutations PTCH/Gli1 IGF Cyclin D1 Other targets Tumour growth

42 A naturally occurring inhibitor of SMO showed that the Hedgehog pathway was drugable. Shepherds in Idaho in 1950s identified cyclopic lambs. Pregnant ewes feeding on corn lily plants. The teratogen, cyclopamine, targets SMO. GDC-0449

43 Phase 1 trial GDC-0449 in metastatic BCC Partial response with multiple daily doses (150 mg) of GDC-0449 Baseline After 8 weeks After 16 weeks 8/9 patients treated so far have had benefit.

44 BRCA1&2 - deficient tumors are defective in homologous recombination

45 PARP repairs DNA single strand breaks

46 Guha M. Nature Biotechnology 2011: 29: Synthetic lethality

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48 Trade name Target Type Company TGA approved use. ( *pending) Trastuzumab (Herceptin ) HER2 McAb Genentech / Roche Met and adjuvant HER2+ breast cancer Metastatic HER2+ gastric cancer* Cetuximab (Erbitux ) Panitumumab (Vectibix ) EGFR McAb Imclone / BMS / Merck EGFR + KRAS wt Metastatic CRC H & N SCC EGFR TK SMI Amgen EGFR + KRAS wt Metastatic CRC Gefitinib (Iresssa ) Erlotinib (Tarceva ) EGFR TK SMI AstraZeneca 1L EGFR mut metastatic NSCLC* EGFR TK SMI Genentech / OSI / Roche 2L NSCLC 1L EGFR mut metastatic NSCLC* Crizotinib ALK SMI Pfizer EML4-ALK+ NSCLC* Imatinib (Gleevec ) Dasatinib (Sprycel ) Sunitinib (Sutent ) ABL KIT PDGFR TK SMI Novartis CML Adult Ph+ ALL GIST DFSP Hypereosinophilia syndrome PDGFR rearranged MDS/MPD Systemic mastocytosis ABL TK SMI BMS Gleevec resistant CML Gleevec resistant Adult Ph+ ALL KIT VEGFR TK SMI Pfizer Gleevec resistant GIST Met renal cell cancer Vemerafenib BRAF TK SMI Plexikon / Roche BRAF V600E + metastatic melanoma* Olaparib PARP SMI AstraZeneca BRCA1 & 2 mut Breast cancer* BRCA1 & 2 mut Ovarian cancer*

49 Pharmaceutical oncology pipeline Project Initiation Research Clinical Candidate Selection Early Development IND Filing Phase III Decision Phase I Phase II Phase III Success rate is now 1 in 5