New Avenues for the development and evaluation of therapy: Complex, multi-pronged, not one size fitting all Antoine Yver MD MSC Senior VP & Head Oncology Global Medicines Development AstraZeneca, Gaithersburg MD
Disclosures Full time employee of AstraZeneca
2000 188 Hanahan and Weinberg, Hallmarks of Cancer
2000 188 Hanahan and Weinberg, Hallmarks of Cancer: The Next Generation, Cell, Volume 144, Issue 5, 2011, 646-674
Patient segmentation will evolve from clinical outcome to biomarker defined populations: the case of Ovarian Cancer Today Tomorrow Platinum Resistant/ Refractory No Specific Biomarker gbrca HRD sbrca PDL1+ Platinum Sensitive Other Genomic Instability AADX+ HRD (non-brca)* Non-HRD 5 *Additional HRR genes of interest may include: ATM, RAD51, DSS1, RAD54, RPA1, NBS1, ATR, CHK1, CHK2, FANCD2, FANCA, FANCC, etc
Major near-term shifts will shape the EGFRm space, and drive research priorities 2015 2016 2017 2018 2019 2020 2021 2022 2023 T790M inhibitors segment the 2L population; new resistance patterns emerge Launch of IMT in NSCLC offers the promise of long term benefit First generic TKIs hit the market Definitive role of T790M inhibitors in 1L is clarified Longitudinal, multiplex, blood based testing and monitoring gradually become new standard for disease management and treatment decisions 6
% Survival Combination of targeted therapy and immune checkpoints Targeted therapies: Response rates >70% IO: High duration of response Example of AZD9291 + Targeted therapies + IO Immunotherapy Targeted therapy Time Chemotherapy Potential synergistic effect High RR and median PFS of targeted therapies with extended duration of response of IO 7
EGFRm+ NSCLC: SM-IO combination strategy 1L EGFRm+ 2L EGFRm+ T790M+ T790M- Targeted therapy Iressa AZD9291 AZD9291 Improving response rates and prolonging duration of response Targeted therapy + IO Iressa + MEDI4736 AZD9291 + MEDI4736 TATTON study 8
Iressa + durvalumab (MEDI4736) in EGFRm TKI-naïve NSCLC Providing evidence of good combinability for MEDI4736 Initial clinical data Both drugs tolerated at full dose Two expansion cohorts at full doses: Arm 1 concomitant (n=6 evaluable) Arm 2 four weeks monotherapy Iressa then combination (n=8 evaluable) 9/14 (64%) partial responses AEs of interest: Grade 3 AST/ALT Tumour assessment: Expansion phase Iressa + MEDI4736 combination in 1L EGFR+ NSCLC to be tested in Phase III study 9
AZD9291 + durvalumab (MEDI4736): TATTON study Basket study in EGFRm+ NSCLC after progression on prior EGFRi AZD9291 + MEDI4736 arm Both drugs tolerated at full dose One grade 3 AE at this dose (WBC decrease) One complete response 9/14 (64%) PRs (four confirmed PRs) 6/7 (85%) in T790M+ 3/7 (43%) in T790M- 80% 60% 40% 20% 0% -20% -40% -60% -80% -100% Best percentage change from baseline in target lesion size Unknown T790M positive T790M negative EGFR remains one of the major tumour drivers despite progression on EGFRi Combination with MEDI4736 might increase RR and DoR in 2L EGFR+ NSCLC 10
Durvalumab (MEDI4736, anti-pdl1) + tremelimumab effective in PDL1 negative NSCLC ORR: durva + treme looks effective in PDL1 negative patients and is well tolerated Regimen n AE G3/4* MEDI4736 + treme M10-20 + T1 56 29% M10-20 + T3 34 53% M15 + T10 9 78% Nivo 1 + ipi 3 529 60% Nivo 3 + ipi 1 62 38% Pembro 2 + ipi 1 34 35% 9/27 32/200 9/27 23/84 3/9 23/84 3/9 5/92 5/92 5/13 5/13 * Average numbers for dose across multiple studies 11 ASCO2015
MEDI4736 + treme show efficacy regardless of PD-L1 status Treme doses beyond 1 mg/kg do not increase efficacy 12 M10-20 Q4/2W T1 mg/kg M10-20 Q4/2W T3 mg/kg M15 Q4W T10 mg/kg All cohorts All evaluable subjects 1 (n) 27 24 9 63 2 ORR[2] - n (%) 9 (33%) 6 (25%) 2 (22%) 17 (27%) 95% CI (17% - 54%) (10% - 47%) ( 3% - 60%) (17% - 40%) PD-L1 positive (n) 9 5 4 18 ORR[2] - n (%) 3 (33%) 2 (40%) 1 (25%) 6 (33%) 95% CI (7% - 70%) (5% - 85%) (1% - 81%) (13% - 59%) PD-L1 negative (n) 13 14 4 33 2 ORR[2] - n (%) 5 (38%) 3 (21%) 1 (25%) 9 (27%) 95% CI (14% - 68%) (5% - 51%) (1% - 81%) (13% - 46%) PD-L1 unknown (n) 5 5 1 12 2 ORR[2] - n (%) 1 (20%) 1 (20%) 0 (0%) 2 (17%) 95% CI (1% - 72%) (1% - 72%) (0% - 98%) (2% - 48%) Dose selected for Phase III studies 1 Includes confirmed and unconfirmed complete response (CR) or partial response (PR). In patients with measurable disease at baseline, 1 follow-up scan + those that discontinued due to PD or death without any follow-up scan. All subjects were dosed sixteen weeks prior to the cut-off date. 2 Includes three subjects (two PD-L1 negative and one PD-L1 unknown) treated at M3 Q4W + T1 mg/kg
Responses with MEDI4736 + treme: Rapid and durable Similar activity across PD-L1 positive and negative subsets PD-L1 positive PD-L1 negative 13 M=MEDI4736; PD-L1=programmed death-ligand 1; Q#W=every # weeks; SD=stable disease; T=tremelimumab
T u m o r V o lu m e (m m 3 ) T u m o r V o lu m e (m m 3 ) T u m o r V o lu m e (m m 3 ) The promise of combinations PD-L1 + OX40 and CTLA-4 + OX40 Brakes off T-cell activation T + Gas on T-cell activation T PD-L1 OX40 PD-L1 Pre-clinical 1 data with PD-L1 OX40 PD-L1 + OX40 2 0 0 0 2 0 0 0 2 0 0 0 1 5 0 0 1 5 0 0 1 5 0 0 1 0 0 0 CR=0/10 1 0 0 0 CR=1/10 1 0 0 0 CR=5/10 5 0 0 5 0 0 5 0 0 0 0 1 0 2 0 3 0 4 0 5 0 T im e (D a y s ) 0 0 1 0 2 0 3 0 4 0 5 0 T im e (D a y s ) 0 0 1 0 2 0 3 0 4 0 5 0 T im e (D a y s ) CTLA-4 Pre-clinical 1 data with CTLA-4 OX40 CTLA-4 + OX40 CR=2/14 CR=3/14 CR=10/14 14 1 Mouse model used in experiments CR = complete response McGlinchey et al. Poster AACR 2014
Change from baseline (%) BRAFi + MEKi + MEDI4736 Unprecedented ORR (69%) and DCR (100%) Potential for well-tolerated, durable benefit in BRAFm melanoma Screening Tumour size change from baseline: Cohort A Cohort A (M+D+T) N- / n = 24 / 25 Cohort A BRAF mutation positive 12 month treatment period MEDI4736 3 or 10 mg/kg Q2W dabrafenib 150 mg BID trametinib 2 mg QD until PD Follow-up Cohort B BRAF wild type 12 month treatment period MEDI4736 10 mg/kg Q2W trametinib 2 mg QD until PD Follow-up Data cut-off: 30 April 2015 Time (weeks) Cohort C BRAF wild type 6 week trametinib 2 mg QD 12 month treatment period MEDI4736 10 mg/kg Q2W Follow-up Clinical activity, n (%) Cohort A (n=26) M + D + T Cohort B (n=19) M + T Cohort C (n=18) T M (sequential) ORR 18 (69) 4 (21) 2 (13) DCR 26 (100) 15 (79) 12 (80) DoR, wks (range) (7.7+, 50.6+) (7.9+, 24.7+) (7.0+, 8.0+) 15
Lynparza + durvalumab (MEDI4736) DNA damage prone to immune response Rationale T-cell infiltrates in BC BRCA-mutant breast and ovarian cancers associated with a CXCR3+ T-cell lymphocytic infiltrate: Immune response associated with DNA damage 1,2 High CXCL10, IDO, IFN gene expression Sporadic BRCA-pathway deficient Combination trials to start by Q3 2015 DDR deficient ovarian cancer (BRCA, ATM etc.) DDR deficient SCLC, TNBC, bladder, gastric, NSCLC, H&N, cervical and pancreatic cancer Add tremelimumab if doublet combination well tolerated High CXCL10, IDO, IFN gene expression 16 1 Lakhani et al Breast Cancer Res. 1999;1(1):31-5; 2 Fujiwara et al Am J Surg Pathol. 2012;36(8):1170-7; Images courtesy of Almac diagnostics
Additional small molecule + MEDI4736 combinations Significant opportunities across multiple tumour types Mechanism IDO BTK/ITK STAT3 CXCR2 FGFR PI3Kb/d PI3Kd Indication Solid tumours CLL/DLBCL and solid tumours Solid tumours Solid tumours Bladder cancer Bladder cancer Haematological tumours 17
New Avenues for the development and evaluation of therapy: Complex, multi-pronged, not one size fitting all
So, let us embrace a culture that addresses problems deemed impossible to solve Stefan W. Hell, Nobel Prize for Chemistry 2014