Post-ASCO 24 th June 2017, Dolce La Hulpe, Belgium ASCO 2017 BREAST CANCER HIGHLIGHTS Martine J. Piccart-Gebhart, MD, PhD Jules Bordet Institute, Brussels, Belgium Université Libre de Bruxelles Breast International Group (BIG aisbl), Chair
ASCO 2017 Breast Cancer (BC) Highlights The three breaking news Molecular profiling / biomarkers [Locoregional therapy : see text] Plan of the talk Locoregional relapse: chemotherapy (CT)? Randomized trials of CT regimens for high risk BC (luminal B / TNBC / HER2+) TNBC HER2+ BC Luminal BC [Brain metastases : see text] Key messages for clinical practice
ASCO 2017 Breast Cancer Highlights The 3 breaking news The end of large adjuvant trials for HER2+ BC The promising results of anti-pd(l)1 incorporation into neoadjuvant CT regimens, even in luminal BC! The positive results of OLYMPIAD (olaparib or CT of physician s choice in BRCA mutation carriers with advanced disease)
S U R G E R Y Central confirmation of HER2 status (N = 4805) Randomisation and treatment within 8 weeks of surgery APHINITY: Trial Design R Chemotherapy* + trastuzumab + pertuzumab Chemotherapy* + trastuzumab + placebo Anti-HER2 therapy for a total of 1 year (52 weeks) (concurrent with start of taxane) Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy F O L L O W - U P 10 Y E A R S *A number of standard anthracycline-taxane-sequences or a non-anthracycline (TCH) regimen were allowed
APHINITY: Statistical Assumptions EXPECTED 3-year IDFS rate* Placebo vs. Pertuzumab HR=0.75 89.2% vs. 91.8% (Δ=2.6%) Placebo arm IDFS rate was based on BCIRG 006 data 1, assuming a 35% / 65% node-negative / node-positive split 379 events and 4800 patients required for 80% power and alpha of 5% * IDFS as per FDA definition with exclusion of second primary non BC 1 Slamon D, NEJM 2011
APHINITY: Intent-to-Treat Primary Endpoint Analysis Invasive Disease-free Survival 63% N+ 36% HR Number neededto treat: 112 78% A-based CT ASCO 2017, LBA 500
APHINITY: Cardiac Endpoints N (%) Pertuzumab n=2364 Treatment difference (95% CI) Placebo n=2405 Primary cardiac endpoint 17 (0.7) 0.4 (0.0, 0.8) 8 (0.3) Heart failure NYHA III/IV + LVEF drop* Cardiac death** 15 (0.6) 2 (0.08) 6 (0.2) 2 (0.08) Recovered according to LVEF 7 4 Secondary cardiac endpoint Asymptomatic or mildly symptomatic LVEF drop* 64 (2.7) -0.1 (-1.0, 0.9) 67 (2.8) *LVEF drop = ejection fraction drop 10% from baseline AND to below 50%; **Identified by the Cardiac Advisory Board for the trial according to a prospective definition
APHINITY: Common Grade 3 Adverse Events Pertuzumab n=2364 Placebo n=2405 Neutropenia 385 (16.3%) 377 (15.7%) Febrile Neutropenia 287 (12.1%) 266 (11.1%) Anaemia 163 ( 6.9%) 113 ( 4.7%) Diarrhoea 232 (9.8%) 90 ( 3.7%) - with chemotherapy and targeted therapy 232 ( 9.8%) 90 ( 3.7%) - with targeted therapy (post-chemotherapy) 12 ( 0.5%) 4 ( 0.2%) - with AC->T (N=1834; 1894) 137 ( 7.5%) 59 ( 3.1%) - with TCH (N= 528; 510) 95 (18.0%) 31 ( 6.1%)
N = 180 N = 69 I-SPY 2 TRIAL Schema: HER2- Signatures Presented By Rita Nanda at 2017 ASCO Annual Meeting (abst 506)
I-SPY 2 Results Reporting Presented By Rita Nanda at 2017 ASCO Annual Meeting (abst 506)
Pembrolizumab graduated in all HER2- signatures:<br />Both HR+/HER2- and TN Presented By Rita Nanda at 2017 ASCO Annual Meeting (abst 506)
Adverse Events of Special Interest <br />(including immune-related toxicities) Presented By Rita Nanda at 2017 ASCO Annual Meeting (abst 506)
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Definition ESMO-MCBS substantial improvements Curative setting A & B or non-curative setting 5 & 4 Curative A B C Non-curative 5 4 3 2 1 Olaparib PFS HR 0.58 (0.43 0.80) should be < 0.65 + longer time to deterioration of quality of life Pertuzumab [DFS HR > 0.8]
Molecular profiling ASCO 2017 Breast Cancer Highlights is not ready for prime time but is there to stay! Reliable Informative about disease biology (ex. ESR1 mutations ) Broadens access to clinical trials New potential biomarkers of response to therapy FGFR amplification (FISH 2.0) and endocrine resistance (abst 1013) CtDNA drop on day 15 of fulvestrant + palbociclib predicts large benefit (PFS 11m) (abst 1016)
ASCO 2017 Breast Cancer Highlights Molecular profiling (plasma/tumor) in MBC N of patients CtDNA N= 318 N= 39/71 with PD on AI Primary tumor/relapse pairing N= 61 pairs Testing Foundation med. (62 genes) ESR1 digital PCR Targeted gene sequencing Results Positivity = 90% Recapitulates known mutations Positivity for mutations = 50% most = polyclonal Shift in clinical subtype means drastic changes at genomic level abstract 1016 1015 1017
ASCO 2017 Breast Cancer Highlights Potential new biomarkers of (lack of) response to treatment in MBC N of patients FGFR amplification 95 HR+ MBC ctdna early dynamic change N= 445 patients from PALOMA-3 N 60 patients with baseline / D15 samples Testing FISH Digital pcr (pik3ca / ESR1) Results Positive in 25% (younger patients, PgR ) Linked to shorter TTP under endocrine therapy Baseline: pikca mutation ctdna = 22% ESR1 mutation ctdna = 26% D15: suppression of ctdna more frequent in palbociclib arm and associated with prolonged PFS (± 11m) abstract 1013 1018
ASCO 2017 Breast Cancer Highlights Isolated locoregional relapse: chemotherapy YES or NO (CALOR Trial) (abst 513) N= 162 patients Completely resected isolated LR relapse (+ RT if + margins) 104 ER+ 58 ER Endocrine treatment R R CTX CTX CTX CTX 10y follow-up DFS H.R. 1.07 DFS H.R. 0.29 (0.13-0.66) results
ASCO 2017 Breast Cancer Highlights Randomized trials of (neo)adjuvant CT in high risk BC Can we omit anthracyclines?
Can we omit anthracyclines in high risk patients? (selected by genomic profiling : oncotype-dx/mammaprint) Plan B trial (abst 504) N = 2116 Mindact trial (abst 516) N = 1301 (mostly N-) C L G H ABC trials (ASCO 2016) N = 3970 1-3 N+ RS > 11 C H G L C H G H 1-3 N+ N- 4 N+ N RS > 11 4 N+ R R R Doc Cyclo x6 EC x4 Doc x4 Doc-Capecit A/T regimen Doc Cyclo x6 TAC x6 or AC x4 Pwk 5y results 5y results 4y results D.F.S. H.R. 0.99 (0.77-1.29) D.F.S. H.R. 0.83 (0.60-1.15) id.f.s. H.R. 1.23 (1.01-1.50)
ASCO 2017 Breast Cancer Highlights Randomized trials of (neo)adjuvant CT in high risk BC Does platinum have a special merit or is it just another alkylating agent?
ASCO 2017 Breast Cancer Highlights GeparOcto: Platinum weekly or high dose cyclophosphamide? (abst 518) N= 961 o+ TNBC 43% HER2+ 40% N+ 46% G3 66% R E E E P P P C C C S u r 150 mg/sqm 225 mg/sqm 2000 mg/sqm L D P L D P L D P L D P L D P L D P L D P L D P L D P L D P L D P L D P g e r y 20 mg/sqm 80 mg/sq If TNBC Cb weekly If HER2+ Identical pcr rates 48% High toxicity / discontinuation rates: 16% and 34% Severe toxicities (pneumonitis / pneumonia 2 toxic ) E= Epirubicin P= paclitaxel C= cyclophosphamide LD= liposomal doxorubicin Cb= carboplatin trastuz pertuz
ASCO 2017 Breast Cancer Highlights Triple Negative Breast Cancer
ASCO 2017 Breast Cancer Highlights: TNBC The Brightness trial (abst 520) pcr AC x 4 53% 634 women with TNBC Veliparib 50 mg PO BiD T2-T4 No-2 T1 N1-2 R AC x 4 57% Placebo Carbo AUC 6 mg/ml/min Placebo Carbo Veliparib 50 mg PO BiD Placebo Veliparib Paclitaxel 80 mg/ml/min P L A C E B O Placebo AC x 4 31%
ASCO 2017 Breast Cancer Highlights HER2+ B.C.
ASCO 2017 Breast Cancer Highlights HER2+ BC: advanced disease N = 1095 > 6 m from adj T 44% de novo met. N = 355 PD after CT + Trastuzumab (75%) A) Update on MARIANNE (abst 1003) R R TDM1 + Pertuzumab TDM1 Docetaxel + Trastuzumab B) The Alternative study : an effective chemo-sparing option (abst 1004) A.I. + Trastuzumab + Pertuzumab A.I. + Trastuzumab A.I. + Lapatinib At median follow-up of 55 m Median OS = 52 m, identical in 3 arms Crossover to TDM1: 18% Crossover to Pertuzumab 10% Better toxicity profile in TDM1 arms PFS 11 m 5.7 m 8.3 m PFS HR 0.62 (0.45-0.83) p 0.006 Triplet superior but more toxic (rash/diarrhea)
Number of patients APT trial (abst 511) N = 406 (mostly N o HR + ) ASCO 2017 Breast Cancer Highlights HER2+ BC: early disease A) Update on already presented trials NEOALTTO (abst 502) ALTTO (abst 502) N = 455 N = 8381 Regimen(s) Weekly P x12 + Trastuzumab x1y Weekly P + Trastuzumab or Lapatinib or Trastuzumab + Lapatinib then FEC x3 anti HER 2 for 1 year A T or T Cb with Trastuzumab, Lapatinib, Trastuzumab Lapatinib, Trastuzumab + Lapatinib Seq. CTX/anti HER 2 = 55% Medical follow-up 6.5 years 6.5 years 6.9 years (705 events) Results 7y DFS = 93.3% ER+ 94.6% ER 90.7% 7y 7y RFI RFI = 97.5% = 97.5% 4 distant relapses 5 locoregional relapses pcr do better than non pcr (significantly for all and for HR ) But 7y EFS for pcr = 77%! 85% T + L 6y DFS 84% T L (no p value!) 82% T For HR : HR 0.80 T + L
ASCO 2017 Breast Cancer Highlights HER2+ BC: early disease B) New trials Neoadjuvant trial TRAIN 2 Adjuvant trial SHORT-HER
ASCO 2017 Breast Cancer Highlights HER 2 + BC : the TRAIN 2 neoadjuvant trial Do anthracyclines still provide benefit in the presence of dual HER2 blockade? Stage II/III HER2+BC N=438 R C A R B O F E C P P F E C P P F E C P P P P P P P P P P P P P P P P P P P P P P P P P P S U R G E R Y pcr 67% pcr 68% F (500 mg/sqm) E (90 mg/sqm) C (500 mg/sqm) Carbo AUC 6 mg/ml/min q3 weeks P = 80 mg/sqm day 1+8 No difference! High degree of neurotoxicity! (gr 2 30%) BOOG, abst 507, ASCO 2017
[N=2500 needed] N=1250 recruited N = 54% ER+ = 68% Postmenop. = 63% ASCO 2017 Breast Cancer Highlights HER 2 + BC The SHORT-HER adjuvant trial (abst 501) R T D D D E C E C E C E C F E C F E C F E C D D D D 5y DFS HR 1.15 (0.91 1.46) Docetaxel (100 mg/sqm) FE (60) C E (90) C Trastuzumab Non inferiority margin set at 1.29 Non inferiority can not be claimed Reduced risk of LVEF drops in the short arm T 1 y 85.4% vs 87.5% 5y DFS rates Conte, abst 501
ASCO 2017 Breast Cancer Highlights LUMINAL B.C.
ASCO 2017 Breast Cancer Highlights Luminal BC: advanced disease The MONARCH-2 Trial (abst 1000)
ASCO 2017 Breast Cancer (BC) Highlights Luminal BC: CDK4-6 inhibitors for advanced disease MONALEESA-2 PALOMA-1 TREND trial Quality of life (abst. 1020) O.S. (abst. 1001) Palbociclib alone or with ET at PD on ET (abst. 1002) Number of patients N=668 N=165 (median follow-up = 65m) N=115 Type of trial Phase III Randomized phase 2 2 stage non-comparative Treatment arms Letrozole + ribociclib Letrozole + placebo Letrozole + palbociclib Letrozole PD on ET same ET + palbociclib Palbociclib alone Results Similar time to quality of life deterioration Med OS 36m vs 33m (pns) Similar clinical benefit rates of 55-60%
ASCO 2017 Breast Cancer Highlights Luminal BC: early disease The SOLE Trial (abst 503)
SOLE: Study of Letrozole Extension<br />After 4 to 6 years of Prior Adjuvant Endocrine Therapy<br />Postmenopausal, HR-positive, Node-positive Presented By Marco Colleoni at 2017 ASCO Annual Meeting
Statistical Considerations Presented By Marco Colleoni at 2017 ASCO Annual Meeting
Characteristics Presented By Marco Colleoni at 2017 ASCO Annual Meeting
Primary Endpoint: Disease-Free Survival Presented By Marco Colleoni at 2017 ASCO Annual Meeting
SOLE: Conclusions Presented By Marco Colleoni at 2017 ASCO Annual Meeting
ASCO 2017 Breast Cancer (BC) Highlights Luminal BC: early disease The Korean NEST neoadjuvant trial (abst. 516) N= 174 premonopausal HER2 ER+ (Allred 5) Node+ R AC x 4 T x 4 24 weeks 24 weeks Zoladex + Tamoxifen S u r g e r y RR pcr Breast pcr Nodes Switch to 84% 3% 14% 13% 71% 1% 5% 7% But very similar results if Ki67 20%!
ASCO 2017 Breast Cancer (BC) Highlights Luminal BC: early disease The FATA-GIM3 trial (Italy) with a 3x2 factorial design (abst. 515) N= 3697 Anastrozole Upfront AI x 5y 89.8% 5y DFS Median age : 64y Node 64% HER2+ 9% Adj CTX 38% R Exemestane R 5y DFS HR 0.89 (95% CI 0.73-1.08 pns) Letrozole Tam x 2y AI x 3y 88.5% 5y DFS No difference Very small difference (pns)
ASCO 2017 Breast Cancer Highlights Take home messages for clinical pratice
ASCO 2017 Breast Cancer (BC) Highlights Messages for clinical practice Early disease Locoregional relapse Advanced disease TNBC HER2 BC Luminal BC BRCA Mutation Carbo pcr in well designed Brightness trial but long-term outcome still unknown Consider dual HER2 blockade (P+T) if N+ / ER Intermittent AI in y 5 to 10? Hope for anti-pd(l)1 + chemo as neoadjuvant therapy If ER and complete excision chemo to be considered (CALOR trial) Dual HER2 blockade (T+P) + AI = effective chemo sparing option Abemaciclib: new option in ET resistant patients, in combination with fulvestrant (MONARCH-2) Olaparib likely to be a new standard of care (ESMO clinical benefit scale: 4)
ESMO Magnitude of Clinical Benefit Scale! SURVEY! Deadline 30 th June 2017
ASCO 2017 Breast Cancer (BC) Highlights Messages for clinical practice Small volume disease and HR+ Early HER2+ BC Large volume disease and/or HR Tolaney regimen Consider dual HER2 blockade Cost considerations (US) (trastuzumab + pertuzumab) Trastuzumab Trastuzumab + Pertuzumab Trastuzumab + Lapatinib Trastuzumab x 9 weeks 55.900 $ 150.500 $ 98.712 $ 9.670 $ N+ / ER+ : how to position sequential trastuzumab neratinib?
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Demographics Presented By Rita Nanda at 2017 ASCO Annual Meeting (abst 506)