LCA Breast Pathway 4 th Clinical Forum Systemic Treatments of Breast Cancer 3 rd December 2013

Transcription

1 LCA Breast Pathway 4 th Clinical Forum Systemic Treatments of Breast Cancer 3 rd December 2013

2 Welcome and LCA Breast Pathway Update Dr Will Teh, Chair - LCA Breast Pathway Group

3 Thank you for coming today Presentations will be on the website

4 LCA Breast 4 th Breast Pathway Clinical Forum Updates Treatment Summaries, Holistic Needs Assessment Self managed pathways Quality Framework (core MDT attendance, network audits) Transforming Cancer For London: Reducing Variation (screening, 23 hour stay, access to reconstruction, self managed pathways, management of metastatic disease Breach allocation 6 month pilot (Oct 2013) Breast metrics

5 Chairs Introduction Dr Mark Harries, Guy s and St Thomas' NHS Foundation Trust, LCA Breast Pathway Chemotherapy Lead Dr Susan Cleator, Imperial College Healthcare NHS Trust

6 Extended Adjuvant Endocrine Therapy Dr Susan Cleator Imperial College Healthcare NHS Trust

7 Suzy Cleator: Consultant Clinical Oncologist, Imperial College Healthcare NHS Trust

8 Adjuvant Tamoxifen Five years of adjuvant tamoxifen decreases annual odds of breast cancer recurrence by 39% annual odds of death by 31%, Regardless of patient age, menopausal status axillary lymph node status or the use of chemotherapy. These effects are maintained for a further ten years after an initial 5 years of treatment is completed Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365(9472):1687e717.

9 AI versus tamoxifen

10 Clear Rationale Clear Rationale Late relapses Dormant disease

11 For ER positive cancers -relapses do not appear to level off ongoing hazard rate for recurrence in ER+ BC does not decline over time >50% all recurrences and >66% of deaths in patients occur >5 years from diagnosis The cumulative recurrence rates in node neg patients are 5%-10% at 10 years 14% at 15 years Kennecke HF, Olivotto IA, Speers C, Norris B, Chia SK, Bryce C, et al. Late risk of relapse and mortality among postmenopausal women with estrogen responsive early breast cancer after 5 years of tamoxifen. Ann Oncol 2007;18(1):45e51.

12 Evidence of tumour persistent viable Dormant Disease tumour cells dormancy

13 Lines of clinical evidence Three large studies to support extended endocrine MA.17 attom ATLAS

14 Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended Mitch adjuvant Dowsett therapy in early breast cancer: NCIC CTG MA Postmenopausal women: on completion of 5 yrs of tamoxifen: 5 yrs letrozole vs 5 years placebo Trial unblinded after a median follow-up of 30m J Ingle et al. Annals of Oncology 19(5), 2007

15 JCO, Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. Jin H et al NCIC CTG MA.17: adjusting for cross-over 2/3 of the patients switched to letrozole on unblinding Two methods to correct for this: Inverse probability of censoring weighted (IPCW) Cox proportional hazard model SCC approach readers should be aware there are strong assumptions behind these analyses

16 distant disease free survival Extended endocrine therapy after a gap Younger and higher risk women switched from PAC-LET JCO, 2008 Apr 20;26(12): doi: /JCO Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. Goss P et al Adjusted hazard ratio between PLAC-LET and PLAC-PLAC: 0.39; 95% CI, 0.20 to 0.74; P.004

17 ATLAS (Adjuvant Tamoxifen, Longer Against Shorter): toxicity 6846 women with ER pos breast cancer 617 recurrences vs 711 in controls, p= deaths vs 722 deaths p=0 01 At 10 yrs since entry, breast cancer mortality- 12% v 15%

18 ATLAS (Adjuvant Tamoxifen, Longer Against Shorter) RRs were as follows: pulmonary embolus 1 87 (95% CI , p=0 01 stroke 1 06 ( ) ischaemic heart disease 0 76 ( , p=0 02) endometrial cancer 1 74 ( , p=0 0002) cumulative risk of endometrial cancer during years 5 14 was 3 1% (mortality 0 4%) vs 1 6% (mortality 0 2%) for controls (absolute mortality increase 0 2%) Davies C et al, Lancet 2013; 381:

19 attom (Adjuvant Tamoxifen-To Offer More) 6,953 women enrolled in the trial (pre- and postmenopausal) unknown ER status in 60% - 15% of patients likely had ER-negative disease and did not benefit from tamoxifen Further 5 years of tamoxifen vs placebo: 15% reduction in the risk of recurrence (relative risk [RR] 0.85, 95% CI [0.76, 0.95]; p = 0.003) 25% reduction in the risk of breast cancer mortality starting at year 10 (RR 0.75, 95% CI [0.63, 0.90]; p = 0.007)

20 Pooled analysis Pooled analysis Pooled analysis of the 17,477 patients enrolled in attom and ATLAS showed 9% reduction in the risk of death after patients received 10 versus 5 years of tamoxifen for the entire follow-up period (RR 0.91, 95% CI [0.84, 0.97]; p = 0.008)

21 Comparison of HR reduction in breast cancer mortality Antracyclines versus CMF (MA5): HR for 10 yr overall survival 0.85 Antracyclines versus Taxanes (EBCTCG 2012)

22 risk: benefit Patient selection

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24 Patient selection Offer to all except very low risk Exclude those who have tolerated oestrogen deprivation poorly Is it worth re-starting after a gap of 5 years? Do we offer fertility preservation to a 35 year old diagnosed with a strongly ER pos cancer not requiring chemotherapy What do you recommend if: Completed 5 years of AI Completed 5 years of tam/ AI switch How safe is 10 years of an AI?

25 Molecular Profiles Sgroi et al, Lancet Oncology, 2013.

26 Practical Issues Patient information Patient recall GP funding of medication

27 Subcutaneous Herceptin Dr Mark Harries Guy s and St Thomas' NHS Foundation Trust LCA Breast Pathway Chemotherapy Lead

28 Herceptin SC Herceptin SC A subcutaneous formulation of Herceptin has been developed for patients with HER2-positive breast cancer Administered as a fixed dose formulation containing 600mg Herceptin plus recombinant human hyaluronidase (rhuph20) in a 5 ml liquid solution 1,2 Delivery technology Herceptin SC utilises rhuph20 as an excipient rhuph20 transiently hydrolyses hyaluronan, a component of the SC matrix rhuph20 results in decreased viscosity and improved delivery of SC administered drugs to the systemic circulation Product supply Herceptin SC is being developed for delivery via two methods: Vial for SC injection via hand-held syringe Single-use injection device (SID) 1.Wynne C, et al J Clin Pharmacol : 2. Jackisch C, et al. Oral presentation EBCC 2012 #1BA

29 Development of a SC formulation of Herceptin Subcutaneous Herceptin is combined with recombinant human hyaluronidase Subcutaneous administration of large volumes is restricted by the structure and physiology of the subcutaneous layer Contains a matrix of hyaluronan fibres and collagen fibres, which limits subcutaneous administration to < 2ml Hyaluronan is broken down by the naturally occurring enzyme, hyaluronidase, on a daily basis Recombinant human hyaluronidase (rhuph20) causes temporary and local degradation of hyaluronan Results in a temporary increase in the local subcutaneous dispersion area, enabling large volumes of fluids to be administered. After SC administration, skin returns to normal Frost GI. Expert Opin Drug Deliv 2007;4(4):

30 Herceptin SC: Overview of clinical studies Study Study type N Status Details SC manual injection extension application CP1 Clinical pharmacology 115 Completed Identified concentration of rhuph20 required for comfortable and safe injection of volumes greater than 2 ml 1 CP2 BP Dose finding/confirmation study (Phase Ib) 66 Completed and reported 1 Dose finding study, evaluated the safety of Herceptin SC, establishing a platform for the Phase III study programme HannaH (BO22227) 2,3 International, randomised, multicentre Phase III study 596 Results presented at EBCC and published in Lancet Oncology 8 August Pivotal registrational study to compare SC manual injection and standard IV in the (neo)adjuvant setting PK, efficacy, safety, tolerability and immunogenicity PrefHer (MO22982) 4 Randomised, twocohort global preference study 400 First cohort: enrolment complete Second cohort: enrolling Compares patient preference for IV or SC administration of Herceptin Includes Time & Motion sub-study 5 SafeHer (MO28048) PK, pharmacokinetic Global safety study 2500 Enrolling from April 2012 Evaluates safety of Herceptin SC in the adjuvant setting Includes Time & Motion sub-study 1. Wynne C, et al. 2012; 2. Jackisch C, et al. 2012; 3. Ismael G, et al. 2012; 4. Pivot X, et al De Cock et al. 2012

31 CP2 : BP22023: Phase I dose finding/dose confirmation of Herceptin SC Open-label, 2-part, phase I/Ib dose-finding and dose confirmation study Conducted at 2 centres in New Zealand and 1 in Australia Patient population 24 healthy male volunteers and 42 female patients with HER2-positive breast cancer Primary objective To select the dose of Herceptin SC that results in comparable exposure to Herceptin IV at 6 mg/kg in healthy male volunteers and in patients with HER2-positive EBC Evaluated by analyzing the area under the serum concentration time curve (AUC) Secondary objective To assess the safety and tolerability of IV and SC Herceptin in healthy male volunteers and patients with HER2-positive EBC EBC, early breast cancer Wynne C, et al. 2012

32 Mean Herceptin concentration ( g/ml) BP22023: Exposure to Herceptin comparable for 8 mg/kg SC vs. 6 mg/kg IV in patients with HER2-positive EBC mg/kg IV 8 mg/kg SC *C trough of 20 g/ml depicts PK target established from preclinical xenograft models Nominal time (h) C trough * Adapted from Wynne C, et al. 2012

33 HannaH (BO22227) Phase III study SC versus IV administration of (neo)adjuvant Herceptin (trastuzumab) in patients with HER2-positive, clinical stage I III breast cancer (HannaH* study): phase 3, open-label, multicentre, randomised *Hannah: enhanced Neoadjuvant Herceptin

34 Surgery 18 cycles/ 1 year Follow-up: 24 mo HannaH Phase III study SC Herceptin HER2- positive EBC (N=596) R 1:1 Clinical stage Ic to IIIc including IBC Central HER2 testing IV Herceptin Neoadjuvant pcr Adjuvant Docetaxel FEC Herceptin IV Herceptin SC 75 mg/m 2 500/75/500mg/m 2 6 mg/kg q3w 600 mg/5 ml q3w (8 mg/kg loading dose) (fixed dose) Goal: Show non-inferiority of SC vs. IV based on co-primary endpoints Co-Primary Objective: PK: observed Herceptin C trough pre-dose Cycle 8 (pre-surgery) Efficacy: pathological complete response (pcr) in the breast IBC, inflammatory breast cancer. FEC, 5-fluorouracil, epirubicin and cyclophosphamide Secondary endpoints include: tpcr, ORR, TTR, EFS, OS PK profile Safety and tolerability Immunogenicity Adapted from Ismael et al., Lancet Oncol 2012

35 Baseline characteristics were well balanced(i) Herceptin IV n=263 Herceptin SC n=260 Age in years Median Min-Max n Weight in kg Median Min-Max n Region / Area Asia Pacific 54 (20.5%) 59 (22.7%) Eastern European 105 (39.9%) 94 (36.2%) South Africa 11 (4.2%) 13 (5.0%) South America 42 (16.0%) 46 (17.7%) Western EU incl. Canada 51 (19.4%) 48 (18.5%) n LVEF (%) at baseline Median Min-Max n Jackisch C et al Oral presentation at EBCC 2012 #1BA

36 Baseline characteristics were well balanced (II) Herceptin IV n=263 Herceptin SC n=260 Breast cancer type* Inflammatory 15 (5.7%) 19 (7.3%) Locally advanced 99 (37.6%) 105 (40.4%) Operable 149 (56.7%) 136 (52.3%) n Oestrogen receptor status* Negative 132 (50.2%) 125 (48.1%) Positive 130 (49.4%) 135 (51.9%) Unknown 1 (0.4%) n Breast cancer subtype Ductal 240 (91.3%) 240 (92.3%) Lobular 17 (6.5%) 12 (4.6%) Other 6 (2.3%) 8 (3.1%) n Histological grade Well differentiated 6 (2.3%) 12 (4.6%) Moderately differentiated 136 (51.7%) 142 (54.6%) Poorly differentiated 120 (45.6%) 106 (40.8%) Anaplastic 1 (0.4%) n *Stratification factors Jackisch C et al Oral presentation at EBCC 2012 #1BA

37 PK Results: Co-primary PK endpoint met with comparable exposure between IV and SC Primary endpoint Observed C trough pre-dose Cycle 8 Herceptin IV n = 235 Herceptin SC n = 234 Geometric mean (µg/ml) Geometric mean ratio (90% CI) Secondary endpoints 1.33 (1.24; 1.44) Non-inferiority of SC vs IV demonstrated as lower bound of 90% CI > pre-specified non-inferiority margin of 0.8 Patients >20 µg/ml pre-dose Cycle (98.7%) 227 (97.0%) AUC at Cycle 7 Geometric mean (µg/ml*day) Geometric mean ratio (90% CI) 1.07 (1.01; 1.12) Pharmacokinetic per protocol population. 20 µg/ml is the therapeutic target threshold Jackisch C et al., EBCC 2012

38 Efficacy Results: Co-primary pcr endpoint met Primary endpoint Herceptin IV n=263 No. (%) Herceptin SC n=260 No. (%) pcr in the breast 107 (40.7%) 118 (45.4%) Difference in pcr rates (95% CI) 4.7% (-4.0%; 13.4%) Secondary endpoints Non-inferiority of SC vs IV demonstrated as lower bound of 95% CI > pre-specified non-inferiority margin -12.5% pcr in breast and axilla (tpcr) 90 (34.2%) 102 (39.2%) Difference in tpcr (95% CI) 5.0% (-3.5%; 13.5%) Overall response rate 231 (88.8%) 225 (87.2%) Median time to response 6 weeks 6 weeks Efficacy per protocol population. Pathological tumor response was assessed locally. Difference in pcr/tpcr calculated as SC-IV. pcr defined as absence of invasive neoplastic cells in the breast. Residual ductal carcinoma in situ (DCIS) is acceptable for pcr Jackisch C et al., EBCC 2012

39 Results: Safety and Tolerability n (%) Herceptin IV n = 298 Herceptin SC n = 297 Total patients with at least one AE 280 (94) 289 (97) Severe (grade 3) AE 155 (52) 154 (52) Serious AEs (SAEs)* 37 (12) 62 (21) Deaths due to AEs 1 (< 1) 3 (1) Imbalance in SAE reports was not explained by underlying patient baseline or treatment characteristics. No difference in NCI-CTC Grade 3 events but 18.1% (SC) vs 7.7% (IV) were classed as Serious AE s. Similarly with Grade 2 events, 1.5% (SC) vs 0.5% (IV) classed as Serious AE s 2. The largest difference was seen in the infections and infestations category. Cardiac safety Asymptomatic LVEF decrease* 6 (2.0) 7 (2.4) Symptomatic CHF, NYHA class II 0 2 (0.7) Cardiac AEs Grade 3 3 (1.0) 5 (1.7) Safety population * LVEF decrease of 10 points from baseline to below 50% 1.Jackisch C et al., EBCC 2012; 2. Ismael et al., Lancet Oncol 2012

40 HannaH: Impact of body weight and C trough levels on pcr rate pcr Treatment group effects with Herceptin SC Body weight* and Herceptin C trough levels pre-dose at Cycle 8 did not impact pcr rate with Herceptin SC Weight: Odds ratio 0.99 (95% CI 0.98; 1.01), P=0.28 C trough : Odds ratio 1.00 (95% CI 1.00; 1.01), P=0.45 *Multiple logistic regression: Efficacy per protocol population Multiple logistic regression: Pharmacokinetic per protocol population pcr, pathological complete response Jackisch C et al Oral presentation at EBCC 2012 #1BA

41 HannaH met both its co-primary endpoints Non-inferior efficacy(pcr) with Herceptin SC vs IV consistent across patient subgroups. Patient body weight and serum Herceptin C trough (pre-surgery Cycle 8) did not influence the pcr rate achieved with Herceptin SC. Conclusion Non-inferior PK (C trough pre-dose cycle 8) with Herceptin SC vs IV Herceptin trough levels are higher in SC, but exposure (AUC) is comparable between IV and SC PK profile supports fixed dose of 600 mg for Herceptin SC with no loading dose Median time to response 6 weeks for both routes for administration suggesting not using loading dose does not affect efficacy. Rates of severe AEs were balanced, rates of serious AE reporting were not. Not reproduced by the distribution of severe 3-5 AEs, suggesting patient management differed across the arms of this open-label trial, with a more conservative approach taken in the SC arm. 1. Jackisch C et al Oral presentation at EBCC 2012 #1BA 2.Melicher et al., ESMO 2012, 254D, poster presentation

42 Current UK Studies UK Studies PrefHer 1,3 (MO22982) Randomised, twocohort global preference study 400 (UK n=42) First and 2 nd cohort: enrolment complete. Study also provides Time and motion data (First presentation at St Gallens, March 2013 Comparing patient preference for IV or SC administration of Herceptin. Secondary endpoints to include Healthcare professional preference. SafeHer 2 (MO28048) Global safety study 2500 (UK n=280) Enrolment commenced June Currently in recruitment Evaluates safety of Herceptin SC in the adjuvant setting via both methods of SC administration. 1. Pivot X, et al. EBCC 2012 # Gligorov J, et al Pivot X et al 2013

43 PrefHer: Patient preference crossover study Randomised, multicentre crossover study of patient preference and HCP satisfaction with SC administration of Herceptin in patients with HER2-positive EBC SID cohort 1 SID every 3 weeks x 4 Intravenous every 3 weeks x 4 HER2- positive EBC (N=200) R 1:1 Herceptin Remaining Herceptin cycles to complete 18 cycles in total SC manual injection cohort 2 Intravenous every 3 weeks x 4 SC manual injection every 3 weeks x 4 SID every 3 weeks x 4 Intravenous every 3 weeks x 4 Includes optional Time & Motion sub-study HER2- positive EBC (N=200) R 1:1 Herceptin Remaining Herceptin SC cycles to complete 18 cycles in total Intravenous every 3 weeks x 4 SC manual injection every 3 weeks x 4 Pivot X, et al. 2012

44 PrefHer: Endpoints Primary objective Patient preference for route of Herceptin administration (SC vs. IV) using patient interviews Primary endpoint analysis: When the last patient has completed the first 8 cycles of study treatment and their 2 nd patient interview Secondary objectives HCP satisfaction with the SC formulation of Herceptin HCP perceived time savings with the SC Herceptin Safety and efficacy Immunogenicity Exploratory Factors that influence patient preference for the subcutaneous formulation of Herceptin Time & Motion sub-study conducted at selected sites Pivot X, et al. 2012

45 Study Endpoints All things considered, which method of administration did you prefer? Primary endpoint considered to be met if 65% patients preferred SC Herceptin Pivot et al., poster presentation at St Gallen 2013 #207

46 Baseline characteristics ITT population Cohort 1 Pivot et al., poster presentation at St Gallen 2013 #207

47 Results Cohort 1 Overall, 91.5% of patients preferred Herceptin SC (95% CI 87.2% to 94.7%; p < ) Strength of preference IV % (n=16) Very Fairly Not very SC % (n=216) 1.Pivot et al., poster presentation at St Gallen 2013 #207

48 Primary reasons for patients preference Pivot et al., poster presentation at St Gallen 2013 #207

49 Responses to PINT questions related to pain and discomfort A higher proportion of patients reported less pain, bruising, irritation and anxiety with subcutaneous administration of Herceptin than with intravenous administration Fallowfield et al. poster presentation at ECC 2013 #P719

50 Responses to PINT questions related to pain and discomfort A higher proportion of patients reported less pain, bruising, irritation and anxiety with subcutaneous administration of Herceptin than with intravenous administration Fallowfield et al. poster presentation at ECC 2013 #P719

51 Adverse Event Profile Adverse event profile during the cross-over period (safety population) No congestive heart failure was reported during this period SAEs were reported in 2.5% of patients, none were considered to be related to Herceptin Pivot et al., poster presentation at St Gallen 2013 #207

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53 SafeHer: Study design Global safety study of Herceptin SC for 1 year (administered using a syringe, needle and manual injection or an SID) in patients with HER2-positive early breast cancer Cohort A: Hand-held syringe (n = 1800) Patients with HER2- positive early breast cancer N = 2500 Investigator choice of: Cohort Chemo regimen Cohort B: SID (n = 700) with supervised self-administration option Follow-up period Primary objectives Safety and tolerability Secondary objectives Disease-free survival; overall survival Self-administration: patient satisfaction (SID cohort) Exploratory analysis Immunogenicity Gligorov J, et al. 2012

54 Conclusions S/C herceptin is preferred by patients and would seem to have non-inferior clinical and pharmacokinetic properties Less time for patient Less time in day unit Less pharmacy time

55 Who would it be for? All patients? All new patients? All patients not receiving iv therapy on same day? All patients with venous access issues? Not for patients receiving pertuzumab?

56 Implications for Patients Delivery closer to home Less time for pt and carers

57 Cost implications for Commissioners Drug cost about the same Delivery tariff less not paying trusts No/reduced pharmacy costs Commissioners 10 th Dec

58 Cost implications for Trusts No fee for day unit attendance after cycle 1 No fee chargeable by pharmacies Could free up space on day unit only helpful if under pressure Could free up nursing time other work more patients to be treated less staff

59 IV to SC Trastuzumab Switch from IV to SC for the licensed indications. Area Team Cancer Pharmacists worked with LC/LCA Pharmacy leads to estimate the impact of this change for 15 Trusts currently administering IV Trastuzumab for Breast Cancer Data modelled on work done in North of England. Data requested from Trusts: Annual Trastuzumab spend Patient numbers (for Adj & metastatic) Average patient weight Delivery Tariffs (SB12Z & SB13Z) Does the Trust currently vial share or buy in bags ready made?

60 Impact of change Using local or Northern data the following could be calculated (from 11 of 15 Trusts) for a full year effect: Total drug savings 1,188,362 Reduction in Trust Tariff income 100,334 Reduction in pharmacy income (as will not aseptically prepare the SC formulation) 125,993 ( not all Trusts invoice this to commissioners) Pharmacy capacity released 3.48WTE Nursing capacity released 4.47WTE

61 Issues raised Unable to assess impact of Clinical trials on predictions (new opening and others stopping) Nursing & pharmacy capacity (inc Chairs on Day units) likely to be used for the known increase in activity on day units. Assumption had been that all pts get 18 cycles (met and adj), from the figures it is clear that this is not the case. May reduce the numbers of port insertions Trusts to risk assess the change (GSTT doc available) Trusts will need to follow their own governance processes for implementation (D&T, proforma/add to Erx systems) LC/LCA to amend Breast guidelines LCA protocol/pil

62 Personalised Systemic Treatment and NICE Guidance Dr Andreas Makris Mount Vernon Cancer Centre

63 What is personalised medicine? PM is a medical model that proposes the customisation of healthcare with medical decisions/practices/products being tailored to the individual patient PM was in practice long before the term was used In breast cancer Endocrine therapy for ER+ Herceptin for HER2+

64 Adjuvant chemotherapy in early breast cancer Used routinely in women with intermediate/high risk disease to treat micrometastases and increase cure rates Most women do not benefit Either because they are already cured by their Sx/RT/ET Or they relapse despite it Currently there are no biomarkers to reliably predict benefit to chemotherapy The decision whether to offer chemotherapy is made on parameters that reflect prognosis and not responsiveness to chemotherapy Tumour size, nodal status

65 2000 NIH Consensus Conference on adjuvant therapy for breast cancer Adjuvant polychemotherapy should be recommended to most women with primary breast cancers larger than 1 cm in diameter, regardless of nodal, menopausal, or hormone receptor status

66 How are gene expression profiling assays individualising treatment decisions? over the last 3 decades we have lived through the golden age of overtreatment this new technology may allow us to define breast cancer risk and its treatment better this technology is impacting on treatment decisions today how will it be utilised in the future

67 Nottingham Prognostic Index NPI = grade + nodal status x size (cm) grade = 1,2 3; nodal status = 1 (0), 2 (1-3), 3 ( 4) Categorised into risk groups according to score ( ) ( ) ( 3.4) ( ) ( ) ( ) ( ) Historical data from patients treated Blamey et al Eu J Cancer :1548

68 NPI strengths & weaknesses Strengths Easy to calculate Uses UK patient data Well validated Weaknesses Takes no account of ER/HER2 Assumes all parameters are independent No prediction of treatment benefit Unclear how well translates to individuals

69 Survival Benefits of Chemotherapy are proportional (reduction in risk) Chemotherapy benefit independent of:- nodal status age ER status endocrine therapy (EBCTCG Lancet 2012; 379:432) Unlike endocrine treatment and HER2-based therapy, there are NO reliable markers of chemo-sensitivity EBCTCG, Lancet 1998; 352:930

70 Predicting the benefit of adjuvant therapy

71 Predicting the benefit of adjuvant therapy predict.nhs Wishart et al., BJC

72 Breast Cancer-Specific Survival (%) Benefit of Anthracycline Chemotherapy Chemotherapy 15.9% 21.0% No Chemotherapy 29.3% 35.8% Chemotherapy ineffective 6.5% alive at 10 years due to chemotherapy women 82% node+ve Chemotherapy not needed Time (years) Modified from EBCCTG 2012, The Lancet 379:

73 Is there a better way? Genomic tests Extended immunohistochemistry Micro-RNA? Pathological classification Prognosis Prediction of chemotherapy benefit

74 The intrinsic classification of breast cancer 4 main biological subtypes of breast cancer with differing prognosis Perou, Nature 2000; 406:747 Sorlie, PNAS 2001; 98:10869 Sorlie, PNAS 2003; 100:8418

75 Oncotype DX 21-Gene Recurrence Score (RS) Assay 16 Cancer and 5 Reference Genes From 3 Studies PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 INVASION Stromelysin 3 Cathepsin L2 HER2 GRB7 HER2 ESTROGEN ER PR Bcl2 SCUBE2 GSTM1 CD68 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC BAG1 RS = x HER2 Group Score x ER Group Score x Proliferation Group Score x Invasion Group Score x CD x GSTM x BAG1 Category RS (0-100) Low risk RS <18 Int risk RS High risk RS 31

76 Oncotype DX: RS as Continuous Predictor in tamoxifen treated patients Data from NSABP B14: Paik NEJM 2004, 351:2817

77 NSABP B-20 Oncotype DX subpopulation Proportion without Distant Recurrence N ve, ER+ve 651/2299 patients 45% < 50 R Tam + Chemo Tam Tam + MF Tam + CMF Tam 4.4% absolute benefit from tam + chemo at 10 years N Events P = Years Chemotherapy arms combined in this analysis Patient characteristics & outcome consistent with full B-20 population Paik S, et al. J Clin Oncol. 2006;24:

78 Proportion without distant recurrence High Recurrence Score Result Correlates with Greater Benefit from Chemotherapy (NSABP B-20) PATIENTS WITH HIGH RS 28% absolute benefit from tamoxifen + chemotherapy 0.5 N Events All patients RS < 18 Tamoxifen + chemotherapy Tamoxifen Tamoxifen + chemotherapy Tamoxifen P = 0.02 P = % absolute benefit from tamoxifen + chemotherapy 0.2 RS Tamoxifen + chemotherapy Tamoxifen P = RS 31 Tamoxifen + chemotherapy Tamoxifen P < Years RS, Recurrence Score result Paik S, et al. J Clin Oncol. 2006;24:

79 Average Rate of Distant Recurrence at 10 Years % Decrease in Distant Recurrence at 10 Years (mean SE) High Recurrence Score Result Correlates with Greater Benefit from Chemotherapy (NSABP B-20) Node Negative, ER-Positive Breast Cancer Chemotherapy Benefit Recurrence Score vs Distant Recurrence at 10 Years Tam vs Tam + CMF/MF Absolute Benefit of Chemotherapy (CMF/MF) at 10 Years by Recurrence Score Group 50% 45% 40% 35% 30% Rate: Tam 95% Cl: Tam Rate: Tam + CMF/MF 95% Cl: Tam + CMF/MF Tam 50% 40% 30% 25% 20% 20% 15% 10% Tam + CMF/MF 10% 5% 0% 0% Breast Cancer Recurrence Score -10% Recurrence Score < 18 (n = 353) Recurrence Score (n = 134) Recurrence Score 31 (n = 164)

80 The Oncotype DX Report in node negative, ER+ Breast Cancer The Oncotype DX report provides information on: Node-negative prognosis Node-negative predicted chemotherapy benefit Quantitative data on ER/PR/HER2 What is the impact on treatment decisions?

81 Meta-analysis of European data: adjuvant chemotherapy (n=527 N0, ER+, EBC patients) About a third of patients had a recommendation change Pre-Recurrence Score Recommendation Oncotype DX Assay Ordered Treatment Recommendation with Recurrence Score Result 54.6% HT 18.4% CHT 81.6% HT 45.4% CHT 48.1% HT 51.9% CHT Overall, 31.9% of patients (95% CI: 27.9%-35.9%) had a recommendation change. The proportion of patients recommended chemotherapy decreased from 45.4% pre- Oncotype DX assay to 33.6% post-oncotype DX assay (p<0.0001). Albanell et al. ESMO Abstract 252PD.

82 Could Oncotype apply to node-positive disease? SWOG-8814 Adequate surgery Postmenopausal ER+ve and/or PgR +ve N+ R tam CAF-tam CAF tam Main study Endocrine therapy continued to 5 years 1588 patients in parent trial; 1477 included in analysis; median age 61; 58% N1-3 10yr DFS: tam = 48%, CAFT = 53%, CAF-T = 60% 10yr OS: tam = 60%, CAFT = 62%, CAF-T = 68% Translational study 367 blocks from tam & CAF-T arms (=40%); demographics similar to ITT population

83 Disease-free survival Disease-free survival Disease-free survival SWOG-8814: DFS by Recurrence Score- Prediction of Benefit from CAF chemotherapy Low (RS <18) Intermediate (RS 18-30) High (RS 31) CAF-Tam Stratified log-rank p = 0.97 at 10 years Tamoxifen (n=55, 15 events) CAF-T Tam only (n=91, 26 events) Years since registration Tam only Stratified log-rank p = 0.48 at 10 years Tamoxifen CAF-T CAF-Tam (n=46, 22 events) (n=57, 20 events) Years since registration Tam only Stratified log-rank p = at 10 years Tamoxifen (n=47, 26 events) CAF-T CAF-Tam (n=71, 28 events) Years since registration after Albain Lancet Oncol 11:

84 5-Year probability of an event SWOG 8814: Chemotherapy benefit greatest with higher RS values, regardless of number of positive nodes 5-YEAR PROBABILITY OF DEATH OR DISEASE RECURRENCE Tamoxifen, 4 nodes (n = 54) CAF T, 4 nodes (n = 86) Tamoxifen, 1-3 nodes (n = 94) CAF T, 1-3 nodes (n = 133) 0.6 Chemotherapy benefit ( 4 nodes) Chemotherapy benefit (1-3 nodes) Recurrence Score after Albain Lancet Oncol 11:

85 NICE approval of oncotype dx (DG10, September 2013) Oncotype DX is recommended to help make decisions about chemotherapy after surgery in some people with oestrogen receptor positive (ER+), lymph node negative (LN ) and human epidermal growth factor receptor 2 negative (HER2 ) early breast cancer Guidance applies to intermediate risk patients (NPI >3.4) MammaPrint, IHC4 and Mammostrat should only be used in research

86 NICE approval of oncotype dx (DG10, September 2013) The manufacturer provides Oncotype DX to NHS organisations according to the confidential arrangement agreed with NICE NICE recommended that Genomic Health collect additional data showing that Oncotype DX impacts clinical decision making in England.in a multicentre audit

87 Multiparameter assays (1) Test Technology Material Parameters Location Oncotype DX* RT-PCR FFPE 21 genes /RNA Central (USA) MammaPrint* array Fresh 70 genes /RNA Central (NL) BluePrint array Fresh 80 genes /RNA Central (USA) PAM50 RT-PCR FFPE 55 genes /RNA Central (USA) BCI RT-PCR FFPE 7 genes /RNA Central (USA) Randox BCA array FFPE 23 genes /RNA Regional? Mammostrat* IHC FFPE 7 proteins Regional? IHC4* IHC FFPE 4 proteins Local? (QA) NPI plus IHC FFPE 10 proteins?

88 Multiparameter assays (2) Test Validation population Output Marketed in UK? Cost Oncotype DX* ER+ (N0) risk score + yes 2580 MammaPrint* ER+/- (N0/N1) risk score + yes 2675 (+) BluePrint unrestricted subtype yes 0 (with MammaPrint) PAM50 unrestricted subtype + no $3200 BCI ER+ (N0) risk score + yes $3200 Randox BCA unrestricted subtype N/A? Mammostrat* ER+ (N0) risk score + in process? IHC4* ER+, post menopause risk score academic est. NPI plus unrestricted?risk score N/A c. 500?

89 Development of IHC4 ER, PR, HER2, Ki67 Can be used in paraffin-embedded tissue Likely to be much cheaper than other multiparameter assays Initial validation in ATAC trial Not commercially available 8

90 Optimal Personalised Treatment of early breast cancer using Multi-parameter Analysis

91 OPTIMA Objectives 1. To establish a method of selecting patients with hormone sensitive primary breast cancer who are likely to benefit or not benefit from post-operative chemotherapy. 2. To establish the cost-effectiveness of alternative test-guided treatment strategies compared to standard practise

92 OPTIMA Design Adequate surgery Age 40 ER +ve, HER2 ve N+/ N0 & T>30mm Central confirmation of ER & HER2 Exclusion: advanced stage = 10 N+/ IM+ R 1 1 Test Patients receiving chemotherapy blind to randomisation chemo. chemo. endocrine endocrine endocrine Endocrine therapy continued to 5+ yrs Radiotherapy given according to local practise Sample size to demonstrate non-inferiority (-3%) = 1860 per arm i.e., doing the test and choosing patients according to the result does not lead to an inferior outcome, compared with chemotherapy for all Measurement of a panel of assays on all patient samples Oncotype DX, PAM50, IHC4, Mammostrat, Randox BCA

93 Conclusion Many women treated with chemotherapy are unlikely to benefit Waste of resources Unnecessary toxicity Delay in effective treatments (RT and ET) New technologies may identify women with insensitive disease Currently Oncotype Dx is the most developed assay It is cost-effective if used appropriately OPTIMA trial needs your support

94

95 Coffee Break

96 Modernising Chemotherapy Delivery and Service Redesign Dr Marina Parton The Royal Marsden NHS Foundation Trust LCA Chemotherapy Closer to Home Co-Chair

97 The London Cancer Alliance West and South Draft five year strategy for cancer: Chemotherapy NHS England document (London region) Focus on Increasing survival Enhancing patient experience National chemotherapy clinical reference group (CRG) is developing a 5 yr national strategy for chemotherapy London Model of Care 4 recommendations relating to chemotherapy

98 The London Cancer Alliance West and South London Model of Care AOS development to all those with an A+E Minimize IP SACT. Satellites services should be set up with link to a central unit to provide Rc closer to home where appropriate Community setting should be considered by providing networks to provide high quality care closer to home LCNDG- now superseded by national CDF

99 The London Cancer Alliance West and South Chemotherapy closer to home; rationale Patient Desirable- surveys from o/s London models- choice of location and convenience Safe, high standard oncological treatment as per centre: Governance arrangements in place Improving the patient experience/outcomes (improve accessibility) Oncological care Releasing capacity Data/IT requirements, adequately staffed (medical and nursing) and workforce changes Research implications Financial Improves capacity Overhead costs/set up arrangements VAT savings/patients numbers

100 The London Cancer Alliance West and South National models DGH- satellite Unit linked to Cancer Centre DGH-independent of Cancer Centre Community hospital GP practice/healthcentre Mobile chemotherapy vehicle (NMP led) Homecare- via centre nurses or Homecare company nurses

101 The London Cancer Alliance West and South Existing LCA Models In Centre and DGH satellites All A+Es have AOS No community based or Homecare models for NHS patients outside pilots

102 RM Chelsea RM Sutton The London Cancer Alliance West and South Chemotherapy services in WL Hospitals STGeorges STGeorges Croydon Epsom St Helier Kingston Royal Marsden Hospital Queen Mary, Roehampton (minor injuries, rehab, OPD services cancer -STG or KHT/RM) Tolworth (rehab/elderly) Springfield (mental health) St John Therapy centre (community therapy,mental health, GP) Nelson (mental health)

103 The London Cancer Alliance West and South Chemotherapy Services in SEL complete Partial No service

104 The London Cancer Alliance West and South Chemotherapy service in NWL (MVH) NWLH ICHT (CXH, HH, SMH) HHT EH CWH WMUH RBH HH CXH SMH

105 The London Cancer Alliance West and South Initial survey of current status Various models across our alliance, mostly working well to meet local needs Pilot in one area has to be adapted to the configuration of another area Centres mostly at capacity Some DGH sites limit their activity due to historical oncological pathways or absence of a local clinician. DGHs sometimes at capacity already- Variable use of local phlebotomy services Variable electronic prescribing

106 The London Cancer Alliance West and South SEL patient experience survey Choice of location desirable Phlebotomy choices favoured Often Non-medical support led out of centre Medical support if needed by telephone or AOS in hours/clear out of hours plan Not homecare

107 The London Cancer Alliance West and South Models suitable for the LCA Expanding existing resources Increasing DGH delivery as multiple sites throughout LCA, some with existing chemotherapy units Developing onto new sites with some clinical activity eg community hospitals, healthcentres Probably not Mobile vehicles/homecare

108 The London Cancer Alliance West and South Definition of Chemotherapy services Any cancer related drug treatment that can be given closer to home including: Oral chemotherapy agents Monoclonal antibodies (MABs) Chemotherapy Supportive treatments /Additional services

109 The London Cancer Alliance West and South Proposed Pilots Oral chemotherapy and home delivery SC clinic (?NMP led, in a outpatient setting ) Expansion of iv delivery in existing units (eg increasing the number of schedules given, different tumour types with centre review of patients) New locations in the community

110 The London Cancer Alliance West and South Oral Chemotherapy A few models already in place Centre review of patients followed by home delivery of drug by 3rd party Reduces waiting time of patients VAT saving Good feedback so far Sharing the model and the experience (GSST) Capecitibine, lapatinib, vinorelbine

111 The London Cancer Alliance West and South SC/ IM oncology care Breast Adjuvant trastuzumab (after chemotherapy) or maintenance trastuzumab in MBC Denosumab for all MBC requiring bone therapy on endocrine agents or off chemotherapy A sig proportion of patients on chemo units Can be given after first dose in OPD setting by NMP To return to chemo unit administration if iv chemo?pertuzumab patients Goserelin and fulvestrant

112 The London Cancer Alliance West and South IV therapy Expanding existing delivery at a DGH satellite Offering more schedules on site (why not?) Extending the tumour types offered New location eg community hospital/gp practice Financial model has to be developed as complicated! Tariff for procedure v costs of site and administration/oncological management and supervision

113 The London Cancer Alliance West and South Generic points Extension of existing hours of treatment of satellites? Splitting the oncological supervision and direction to give chemotherapy from the delivery of therapy? Removing the barrier that only some schedules are ok to deliver in a satellite (why?) Devolving supportive care out of chemo units eg blood transfusions

114 The London Cancer Alliance West and South Your input CCTH questionnaire Expressions of interest in pilots

115 Panel Discussion

116 The London Cancer Alliance West and South Discussion points Should patients be recalled to be offer extended adjuvant therapy? How far back should we go? GP letter? Patient info sheet Open Access Team? Do we see all patients? Do we continue to follow-up? Do we offer to pts who have had an AI in first 5 yrs?

117 The London Cancer Alliance West and South Discussion points Dosing for obese patients with sub-cutaneous Herceptin All patients? Pertuzumab? Anyone where not appropriate? Docetaxel and herceptin together first cycle?

118 The London Cancer Alliance West and South Discussion points How do we implement Oncotype in LCA? Strictly NICE? Who requests the test? Who gets the result? Chemotherapy closer to home Implications trials

119 Summary and Close Chairs Dr Mark Harries Dr Susan Cleator

120 Thank you for coming today Presentations will be available on the website shortly.