Current and Future Vision of Breast Cancer: Pipeline and NGS Implications

Transcription

1 Current and Future Vision of Breast Cancer: Pipeline and NGS Implications Edith A. Perez, M.D. Vice President, BioOncology USMA Genentech, A Member of the Roche Group Professor of Medicine, Mayo Clinic

2 Our Oncology Medical Leadership Strategy Understand the biology Prioritize & accelerate the pipeline Develop a personalized treatment paradigm Targets, Drugs and Combinations Research Better understand the underlying immune response to tumor cells SCIENCE PHC PIPELINE Clinical Design studies demonstratin g program activity and informing immune system biology Reverse Translation for Biomarker Data / Biological Insights

3 Clinicopathologic and Genomic Factors Relevant to Personalized Rx in Breast Cancer Conglomerate of multiple, molecularly defined syndromes with different natural histories and sensitivities to therapeutics ER, PR, and HER2 represent critical molecular markers that identify the largest subsets High throughput diagnostic techniques to identify novel molecular markers might serve to identify new subsets, new targets

4 Overall Treatment and Research Decisions Partially Based on HR and HER2 Status ER+ HR+: Endocrine Rx Palbo, abemo-ciclib Everolimus Taselisib? All Breast Cancers HER2+ HER2+: Trastuzumab/Pertuz umab T-DM1 Triple - TNBC: Chemotherapy PARPi? CIT? Ipatasertib? Cobimetinib?

5 Genentech/Roche Breast Cancer Pipeline

6 Proposed mechanisms of primary or secondary resistance in the HR+ setting HER2 FGFR amplification Activation of growth factor signalling pathways: PI3K/AKT/mTOR; RAS/MAPK Loss of ERα ER mutations ESR1 mutations Overexpression/amplification of ER coactivators MYC amplification and overexpression Cyclin D1 amplification or expression Impact in early vs. advanced stage disease? Impact of outcome to existing and novel therapies?

7 Taselisib: molecule summary Compound Generic name Other names Molecule type Mechanism of action Ongoing clinical trials Drug Overview RG7604 Taselisib GDC-0032 Small-molecule, mutant-selective PI3Ki Interferes with oncogenic signaling as a selective mutant PI3Kα inhibitor ER-positive, HER2-negative mbc; solid tumors Development phase Phases I, Ib, II, III Molecular Information Binds to the ATP-binding pocket of mutant PI3Kα References: 1. Saura C, et al. SABCS PD

8 Randomize 2:1 Randomize 2:1 Taselisib + fulvestrant: Phase III SANDPIPER study overview Study in locally advanced/metastatic setting Key inclusion criteria Postmenopausal women with ER-positive, HER2-negative locally advanced or mbc Recurrence/progression on or after aromatase inhibitor Consent to provide tumor tissue for PIK3CA mutation testing ECOG PS 1 N = 600 Patients with mutated PIK3CA n = 480 Patients with wildtype PIK3CA n = 120 Taselisib 4 mg PO QD + fulvestrant 500 mg* Placebo PO QD + fulvestrant 500 mg* Taselisib 4 mg PO QD + fulvestrant 500 mg* Placebo PO QD + fulvestrant 500 mg* Treat until PD No crossover permitted *Given IM D1 and D15 of C1 and then D1 of each subsequent 28-d cycle. Primary endpoint PFS in patients with PIK3CA mutation Secondary endpoints OS, ORR, CBR, DOR by RECIST, PROs AEs ClinicalTrials.gov: NCT (last verified 2017).

9 Steps to Optimize Personalized Medicine in TNBC TNBC 1. What are the relevant molecular subsets in TNBC, both in the early or advanced stage? Understand the prevalence, overlap and prognostic value of biomarkers such as TILs, multigene profiles Is there a predictive marker for activity of platinum agents? Is there a validated role for homologous recombination testing, DNA repair alterations as predictors of platinum, PARPi? What subset of patients may derive benefit of various investigational agents? Cobimetinib, Ipatasertib 2. What is the role of immunotherapy in TNBC?

10 Compound Generic name Other names Molecule type Mechanism of action Ongoing clinical trials Cobimetinib: molecule summary Drug Overview RG7421 Cobimetinib GDC-0973 Small molecule Development phase Phases I, II, III Potent and specific allosteric inhibitor of MEK in the MAPK signaling pathway Previously untreated 1L mtnbc, advanced solid tumors with or without mutant KRAS Molecular Information Collaborators Exelixis Binds to MEK References: 1. Long GV, et al. ASCO

11 Randomized Cobimetinib: Randomized Phase II clinical study (COMET) Combination with paclitaxel as first-line treatment for metastatic TNBC Key inclusion criteria Metastatic or unresectable locally recurrent ER /PR /HER2 breast cancer ECOG PS 0-1 N = 112 Open-label safety run-in n = 12 Cobimetinib 60 mg/day PO QD* + paclitaxel 80 mg/m 2 IV daily Randomized, double-blind expansion n = 100 Cobimetinib 60 mg/day PO QD* + paclitaxel 80 mg/m 2 IV Placebo PO QD* + paclitaxel 80 mg/m 2 IV *on D3-D24 of each 28-d treatment cycle. on D1, D8 and D15 of each 28-d cycle according to prescribing information. Study: WO29479 ClinicalTrials.gov: NCT g (last verified 2017). Primary objectives PFS Safety Secondary objectives OS, ORR (by RECIST) PK Note: Cobimetinib is being developed in collaboration with Exelixis.

12 Ipatasertib: Molecule summary Compound Generic name Other names Molecule type Mechanism of action Ongoing clinical trials Drug Overview RG7440 Ipatasertib GDC-0068 Small molecule Development phase Phases Ib, II Collaborators Interferes with oncogenic signaling as an ATP-competitive Akt inhibitor Neoadjuvant TNBC, 1L advanced/metastatic TNBC, 2L castration-resistant prostate cancer, 1L metastatic gastric or gastroesophageal junction adenocarcinoma, solid tumors Array BioPharma Molecular Information Binds to activated Akt References: 1. Isakoff SJ, et al. ESMO PD. 2. Bang Y-J, et al. ASCO TPS

13 Ipatasertib: proposed mechanism of action Ipatasertib is a novel, potent and highly selective, ATP-competitive Akt inhibitor that binds to activated Akt 1,2 Ipatasertib inhibits growth and proliferation in cancer cell lines and xenograft models, including those with loss of PTEN, oncogenic PIK3CA mutations and HER2 amplification 1,2 Growth factor receptors Cell membrane RTK domain PIP 2 PIP 3 PTEN AKT Ipatasertib PI3Kα (p85 and p110 subunits) Cell proliferation, cell survival, etc. References: Based on 1. Lin K. AACR DDT Tabernero J, et al. Ann Oncol 2011;22(suppl 3) [abstract IL33]. Note: Ipatasertib is being developed in collaboration with Array Biopharma.

14 Randomize 1:1 Paclitaxel +/- ipatasertib: Randomized Phase II LOTUS study 1L advanced/metastatic TNBC Key inclusion criteria Locally advanced or metastatic TNBC Tumor sample required Stratify: 1. Prior adjuvant/neoadjuvant treatment (yes vs no) 2. Disease-free interval ( 12 mo vs > 12 mo) 3. Tumor PTEN status N = 120 Paclitaxel 80 mg/m 2 IV* + ipatasertib 400 mg QD Paclitaxel 80 mg/m 2 IV* + placebo 400 mg QD *Given as infusion on D1, D8 and D15 of each 28-d cycle. Given 3 weeks on/1 week off. Primary objective PFS by RECIST Secondary objective OS, confirmed ORR and DOR ClinicalTrials.gov: NCT (last verified 2017). Note: Ipatasertib is being developed in collaboration with Array Biopharma.

15 LOTUS: Study Endpoints Co-Primary: PFS in the ITT population PFS in the PTEN-low subgroup (predefined before analysis as IHC 0 in 50% of tumor cells using the Ventana IHC assay) Secondary: ORR (investigator assessed according to RECIST version 1.1), duration of response, and OS in the ITT population and PTEN-low subgroup PFS, ORR, duration of response, and OS in patient with PI3K/AKT pathway-activated tumors (predefined before analysis as PI3K/AKT/PTENaltered tumors by the FoundationOne NGS assay) Safety and tolerability (NCI CTCAE version 4.0) PROs of treatment related symptoms, patient functioning, and HRQoL were assessed using the EORTC QLQ-C30

16 LOTUS: Summary (as of June 2017) In this phase II trial, adding ipatasertib to paclitaxel as 1st-line therapy for TNBC improved PFS in the biomarker-selected and unselected ITT population The effect was more pronounced in predefined analysis of the pt subgroup with PIK3CA/AKT/PTEN-altered tumors (HR 0.44 [90% CI ], median 9.0 vs 4.9 mo with ipatasertib vs placebo, respectively) A substantial proportion of patients with PTEN-low tumors by IHC did not have a genetic alteration, consistent with the literature The most common AEs were gastrointestinal, particularly diarrhea Most cases of diarrhea were grade 1 or 2 (grade 3 in 23%, no grade 4) Diarrhea was manageable and led ipatasertib discontinuation in only 2 patients (3%) Patient-reported global health status/hrqol was generally maintained up to and including cycle 5 Dent R, et al. ASCO 2017

17 Immuno-oncology in Breast Cancer Management: Will it be personalized? Activity in the known subsets of breast cancer o TNBC, HER2+, HR+ Biomarkers o TILs, CD8+ T cells?, T-effector gene signature? o Mutational load quantitation across targeted genes Future o Neoantigen identification o Whole transcriptome sequencing to identify neoantigens and T-specific subsets in a given patient

18 We are Investigating Multiple Targets of the Cancer Immunity Cycle Trafficking 3 NMEs T cell migration T cell infiltration Antigen presentation 1 NME Cancer T cell recognition 2 NMEs Antigen release T cell killing 3 NMEs In-house immunotherapynmes in clinical development 18

19 BC: Heterogeneous Disease With Oncogenic Drivers, Hypotheses about Role of CIT HR+ BC well characterized as endocrine driven with immune desert Drivers of immune resistance unknown and may overlap with AR+ TNBC, HER2+ BC Efforts to advance our understanding HR+ DESERT Activate TNBC+ EXCLUDED Recruit / Infiltrate HER2+ INFLAMED Kill Cancer Cells Opportunity to lead science with knowledge in HER2 resistance and prognosis. Ongoing studies will inform definition of high risk patients, superior combinations, role of CIT Broad development strategy, including CIT and targeted agents. Need to identify relevant subsets to also lead development of next generation SOC Unique developmental challenges remain in each segment: Future development options need to account for differences in SOC and efficacy/ safety hurdles 19

20 Breast Cancer Immune Landscape Gene set analysis for immune cell subsets across indications

21 Atezolizumab: Molecule summary Compound Other names Molecule type Mechanism of action Ongoing clinical trials Drug Overview RG7446 Anti-PDL1, RO Development phase Phases I, II, III Engineered IgG1 monoclonal antibody to eliminate Fc-effector function to avoid killing of activated T cells Binds PD-L1 on tumor cells and tumor infiltrating immune cells to promote antitumor immune responses mnsclc, TNBC, mubc, mrcc, Relapsed/refractory follicular lymphoma and DLBCL, solid tumors Molecular Information Binds to PD-L1 References: 1. Herbst et al. Nature. 2014; 515(7528): Powles et al. Nature. 2014; 515(7528): Bellmunt et al., ESMO McDermott et al., ESMO Lieu et al., ESMO McDermott et al., KCS, L Horn et al, IASLC Lancet Oncol

22 inflammation Immunotherapy Combinations May Help in Maintaining Tumor Inflamed State Hypothetical curve Optimal window for initiating immunotherapy combination Maintenance of inflamed state Treatment (e.g. chemotherapy) Diagnosis Response Immunotherapy CD8 CD8 CD8 CD8 staining images are illustrative

23 IMpassion130: Phase 3 1 st linelmtnbc Trial 1L mtnbc n=900 (1:1 double-blinded) Atezolizumab 840 mg q2wk + Nab-paclitaxel 100 mg/m 2 qwk 3/4 wks Placebo q2wk + Nab-paclitaxel 100 mg/m 2 qwk 3/4 wks Co-primary Endpoints Secondary Endpoints PFS (RECIST 1.1); OS ORR, DOR, HRQoL Key efficacy populations ITT and Dx+ (IC 1/2/3) Stratification factors Liver mets: Y/N Dx+ (IC 1/2/3): Y/N Prior Taxane: Y/N Key eligibility criteria Tissue mandatory; prospective PD-L1 IHC testing 1 ITT population here is all comers ClinicalTrials.gov: NCT

24 Phase 1b Atezo + HER2 Directed Therapy (GO29381) PART 1: mbc Safety cohorts HER2+ MBC n=12 n=6 n=6 Trastuzumab Pertuzumab Atezo T-DM1 (3.6 mg/kg) Atezo n=14 Treat until disease progression and/or loss of clinical benefit T-DM1 (3.6 mg/kg) Atezo Primary endpoint: Safety of combination therapy DLTs evaluated over 2 cycles Treat until disease progression and/or loss of clinical benefit PART 2: NEOADJUVANT Window cohorts 21-day cycles x 2 (6 weeks) STANDARD-OF-CARE THERAPY FOR HER2+ HER2+ Early BC n=40 n=20 n=20 Tissue collection Trastuzumab Pertuzumab Atezo T-DM1 Atezo Tissue collection Docetaxel Carboplatin Trastuzumab Pertuzumab S U R G E R Y Tissue collection Adjuvant Trastuzumab Goal: Pre- and Post-treatment biomarker collection/analysis ClinicalTrials.gov: NCT ClinicalTrials.gov: NCT

25 Phase II: T-DM1 +/- Atezolizumab in 2 nd line HER2+ mbc (KATE2) HER2+ (central) MBC or LABC (N=200) Prior taxane and trastuzumab Progression on metastatic tx or within 6 months of adjuvant tx Measurable disease 1 2 T-DM1 3.6mg/kg Q3W + Placebo T-DM1 3.6mg/kg Q3W + Atezolizumab 1200 mg Q3W Stratification Factors: world region, liver mets, PD-L1 IC 0 vs 1/2/3 Primary endpoint: PFS by INV per RECIST 1.1 Secondary efficacy endpoints: PFS by biomarker (PD-L1+/-), ORR, DOR, OS, PFS irrecist ClinicalTrials.gov: NCT

26 imcore Immunotherapy Centers of Research Excellence 26 sites globally

27 CITC vs. imcore high level CITC CIT strategy across Roche/GNE Review sponsored and supported scientific research that requires CITC funding CIT IISs CIT Sponsored studies (Morpheus) JEWEL program imcore

28 Utilize resources and leverage expertise across the network Academic Institutions Preclinical and Clinical Data Sharing and Platforms Translational Science Pooled BioSpecimens NETWORK Roche and Genentech Scientists Preclinical and Clinical Access to Innovative Technology Access to Broad CIT Portfolio

29 Biomarker discovery and development at Genentech/Roche 2 Understand disease biology 3 Develop new technologies Biomarker prevalence Prognostic significance Subsets of unmet need Pipeline opportunities Dx hypotheses Disease Technology Multiplex assays Real-time Dx Monitoring 1 Identify biomarkers Pharmacodynamic Predictive Response surrogate Resistance (innate/acquired) Therapeutics 125 people ~70 technical staff (25 PhD scientists) ~30 operations experts ~25 diagnostics/device experts 4 Define diagnostic endpoints Companion Dx endpoints Response surrogates 29

30 Comprehensive technical capabilities for biomarker analyses Comprehensive tumor analysis: Continuous Monitoring over time: DNA-Mutation & CNVs Ex: EGFR, BRAF mrna-expression Cell signatures, targets Protein-Expression PDL1, other CI targets 2 Cell free Tumor DNA Ex: EGFR, BRAF Imaging Ex: ImmunoPet DNA Sequencing RNA Sequencing Multiplex IHC Blood DNA Sequencing Imaging Immune cell types and signatures Mutation burden & neo-epitope prediction Discovery and impact to practice 30

31 Essential components to realize the impact of molecularly-guided therapy Genomic profiling identifies genomic alterations and features (e.g. tumor mutational burden) Clinically relevant genomic alterations Detect genomic alterations Sequencing can detects genomic alterations in tumor tissue FMI service and Some features alterations are potentially clinically relevant based on available evidence Linking of alterations and therapies Specific genomic alterations in certain tumor types can predict response to certain therapies Driving future improvements in oncology HCP experience Patient report provides scientific rationale for potential additional treatment options Support HCP with choice of therapeutic approach FMI report provides both prognostic and predictive value allowing for more Does informed genomic profiling decisions support treatment decision making? Prospective clinical studies and Real world data Patient outcome Ensure access to therapy Requires: Drug availability or clinical trial access Outcome increases information on potential alternative care ) HCP: healthcare professional Tracking of patient outcome Collect outcome of therapeutic plans chosen based on genomic profiling testing Does genomic profiling improve patient outcome? 31

32 Summary: New Paradigm in Breast Cancer Increase patient screening and participation into clinical trials Global collaboration will speed accrual of patients with rare genomic alterations Options for innovation: biomarkers, adaptive designs, data sharing Provide highly effective agents faster to our patients with cancer development and access