Royal Melbourne Hospital Early Drug Development and Companion ...

Royal Melbourne Hospital Early Drug Development and Companion ...

Precision Medicine RMH Phase I clinic and Molecular Profiling Program Ben Tran Medical Oncologist Peter MacCallum Cancer Centre Walter and Eliza Hall Institute Trials Supporting precision medicine through clinician directed, tailored molecular profiling Michael Lam, Ben Tran, Jeanne Tie, Sophie Beck, Sumitra Ananda, James R. Whittle, Ravikiran Vedururu, Stephen B. Fox, Andrew Fellowes, Lara Rachel Lipton, Peter Gibbs, Mark Rosenthal, Jayesh Desai Personalized Cancer Medicine Matched therapies In cancer, Precision Medicine involves the use of

molecular information regarding each patients cancer in making patient care decisions. It is based on the premise that 1. 2. 3. 4. 5. Genetic aberrations exist in human cancers A subset of these aberrations are drivers of oncogenesis and tumour biology These genetic aberrations can be detected Tolerable medicines that can effectively modulate these targets exist Matching treatment to molecular target provides benefit ? 3 Molecular Profiling Program Identifiable Molecular Aberrations

Targets Precision Medicine Molecularly Matched Treatments Bullets Molecularly Targeted Agents Early Phase Clinical Trials Program Molecular Profiling Programs Who do you test? Everyone All metastatic patients Phase I patients What do you test for? Exomes Comprehensive panel Targeted panel

Which specimen do you test? Metastatic versus Primary Fresh versus Archival Need to have identified an actionable and druggable target when patient needs one Only need to identify targets for which there are molecularly matched treatments available Need to acknowledge potential clonal evolution and tumour heterogeneity International Molecular Profiling Programs IMPACT: Princess Margaret MOSCATO: Gustave Roussy Khalifa :MD Anderson

IMPACT: Princess Margaret (Toronto, Canada) IMPACT: Princess Margaret (Toronto, Canada) IMPACT: Princess Margaret (Toronto, Canada) IMPACT: Princess Margaret (Toronto, Canada) MOSCATO: Gustave Roussy (Paris, France) MOSCATO: Gustave Roussy (Paris, France) MOSCATO: Gustave Roussy (Paris, France) MOSCATO: Gustave Roussy (Paris, France) Khalifa Institute: MD Anderson (Houston, USA) Khalifa Institute: MD Anderson (Houston, USA) Khalifa Institute: MD Anderson (Houston, USA)

Overview of Molecular Profiling Programs Linked to large early drug development programs Ensures access to molecularly targeted therapies Profiling of large cohorts (except for MOSCATO) Lots of patients tested Not all patients will be candidates for early phase studies Relatively low yield Relatively high cost Hypothesis A clinician directed, tailored approach to molecular profiling will identify sufficient numbers of patients for molecularly matched treatments and support precision medicine without the high costs Objectives

1. Examine the feasibility of a clinician-directed, tailored approach to molecular profiling Endpoints: Proportion of patients receiving molecularly matched treatments Number of actionable targets identified 2. Examine the benefits of molecularly matched treatments Endpoints: PFS for matched versus unmatched treatments Background: RMH Phase I Clinic Referred

Referred back back to to clinician clinician Private Private Practice Practice Referral Referral Triaged Triaged RMH RMH Public Public Hospitals Hospitals RMH

RMH Phase Phase II Clinic Clinic Unsuitable Unsuitable for for Early Early Phase Phase Trials Trials (+ (+ telemedicine telemedicine and and outreach outreach clinics) clinics)

Candidate Candidate for for Early Early Phase Phase Trials Trials +/+/- Known Known Actionable Actionable Target Target Clinician Clinician Directed Directed Tailored Tailored Molecular Molecular Profiling Profiling

Enrolment Enrolment onto onto Early Early Phase Phase Trials* Trials* Dynamic Dynamic waiting waiting list list Molecularly Molecularly Matched Matched UnMatched UnMatched *Patients referred to trials across CTA Network

Background: RMH Early Drug Development Program Most trials require a companion diagnostic 10 9 8 7 6 No marker Companion Diagnostic 5 4 3 2 1 0 2015 2014

2013 2012 2011 Background: RMH Molecular Profiling Program Constantly Evolving Rationalised to reflect clinical trials Does not encompass individual tumour stream programs Melanoma, NSCLC, CRC, GBM Somatic Mutations Truseq Cancer Amplicon Panel (47 genes) Customised Somatic Panel (19 genes) Individual Genes (IDH1) Gene Amplification FISH (FGFR1, FGFR2, FGFR3, cMET)

Microsatellite Instability Protein Expression IHC (MMR, PTEN) Background: RMH Phase I Clinic Database Prospective data collection Records basic clinical and pathological information Facilitates molecular profiling and tracking of actionable targets in individual patients Maintains an active waiting list for early phase trials Enables production of complex ad hoc reports Audits clinic performance and metrics Records which trials patients are enrolled onto and their outcomes Methods Interrogated Database Identified all new patients seen in Phase I clinic over two years September 2013 September 2015 Recorded clinicopathological data, molecular profiling data,

clinical trial data Results: Phase I Clinic 374 new patients seen between Sep 2013 and Sep 2015 VCCC Sites: 75 patients (20%) Rural and Interstate: 45 patients (12%) Private practice: 117 patients (31%) Multiple tumour streams represented Large proportion Colorectal, Gynae-Onc, Uro-Onc, UGI ECOG 0-1: 84% Median prior treatments: 2 (65% >2) ACUP Colorectal UGI Neuro Gynae Lung GU

Breast Endocrine Head & Neck Sarcoma Skin Other Results: Molecular Testing 234 patients had molecular testing ordered 26 Not phase I trial candidates 69 Known actionable target 45 Unlikely to benefit from molecular testing 140 120 100 80 60

40 20 0 SOMP Truseq QUAD FGFR1 FISH FGFR2 FISH FGFR3 FISH PTEN IHC KIT IHC

Results: Targets Identified 35 30 25 186 186Targets Targetsidentified identifiedinin112 112(48%) (48%)patients patients 92 92Actionable Actionabletargets targetsinin89 89(38%) (38%) patients

patients 20 15 10 5 0 m Am Fm loss Nm Rm Km 2m ITm 2m 3m Sm mp 1m mp Lm Rm I H S A 3C RA N E GF AL BB K FR FR RA 3a FR 1a VH KD MS R T K IK B TE

E P N FR FG FR ER FG FG P P FG FG Results: Actionable Targets Already Known 50 69 69Actionable Actionabletargets targetsinin67 67(17%) (17%) patients patients

45 40 35 30 25 20 15 10 5 0 KRASm BRAFm NRASm PIK3CAm MSI H EGFRm KITm FGFR1amp

Results: Clinical Trial Enrolment 94 (25%) patients enrolled onto clinical trials 39 patients received a molecularly matched treatment on trial *1 patient received a molecularly matched treatment off-label 19 patients had actionable targets through testing 10 patients had previously identified actionable targets BRAFm BYL/BGJ EVICT BGB283 TAS120 IPINIVO LGX818 CLOP628 KITm 6 2 KRASm

17 1 2 NRASm PIK3CAm 2 FGFR1amp 1 FGFR3amp 2 1 MSI H 2

1 1 Results: PFS Matched versus Unmatched 55 53 51 49 47 45 43 41 39 Matched Treatments Matched Treatments 9 of 39 (23%) 6mo PFS 14 of 39 (36%) 4mo PFS

37 35 39 35 33 33 31 31 29 29 27

27 25 25 23 23 21 21 19 19 17 17

15 15 13 13 11 11 9 9 7 7

5 5 3 Light blue indicates still on study 1 0.0 2.0 4.0 6.0 8.0 10.0

12.0 14.0 16.0 Unmatched Treatments Unmatched Treatments 5 of 55 (9%) 6mo PFS 11 of 55 (20%) 4mo PFS 37 3 Light green indicates still on study 1 0.0 2.0

4.0 6.0 8.0 10.0 12.0 14.0 16.0 374 Results: RMH Phase I Clinic RMH RMH Phase Phase II

Clinic Clinic Unsuitable Unsuitable for for Early Early Phase Phase Trials Trials 26 7% (Friday (Friday morning) morning) Candidate Candidate for for

Early Early Phase Phase Trials Trials 67 18% 45 12% 39 10% Known Known Actionable Actionable Target Target Not Not likely likely to to benefit

benefit from from testing testing 94 25% 234 63% Clinician Clinician Directed Directed Tailored Tailored Molecular Molecular Profiling Profiling Molecularly Molecularly Matched Matched

Enrolment Enrolment onto onto Early Early Phase Phase Trials Trials 55 15% UnMatched UnMatched Comparison to other programs Program Patients IMPACT MOSCATO

MDA Patients with Actionable targets 678 176 295 127 2,000 789 RMH (all) RMH (test) 374 234 159 92

Patients Matched Matched receiving treatments treatments Matched % tested % actionable treatments 23 3% 13% 65 22% 51% 83 4% 11% 39

19 10% 8% 24% 20% Back of envelope cost-effectiveness calculation Key data from RMH Molecular Profiling Program 234 tests ~$500 per test 39 patients enrolled onto a matched trial Matched treatment provides 41% improvement in PFS (1.7mo benefit) PBS listing requires cost effectiveness to be at least $50,000 per QALY

Key Calculations 234 tests at ~$500 each = $117,000 39 patients with 1.7mo benefit = 5.5 years gained $117,000 for 5.5 years gained = $21,000 per life year gained Conclusions Clinician-directed, tailored approach to the use of molecular profiling is feasible Identifies ~10% of patients for molecularly matched treatments Early phase clinical trials provides patients with access to molecularly targeted agents Molecularly matched treatments appear to provide greater benefit than unmatched treatments A personalized approached to molecular profiling facilitates precision medicine in a cost-effective manner Questions?

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