Updates From San Antonio Breast Cancer Symposium 2017 Rob Coleman University of Sheffield
Presentation Outline New Insights into adjuvant endocrine treatment Duration of treatment Perioperative therapy Options for premenopausal women Fertility preservation Other adjuvant treatments HER-2 targeted treatment Chemotherapy developments Adjuvant bisphosphonates Metastatic breast cancer Refining the use of CDK4/6 inhibitors Novel Anti HER-2 strategies
Duration of Endocrine Treatment Gnant M et al. SABCS 2017
Duration of Endocrine Treatment Gnant M et al. Cancer Res. 2018;78(4 Suppl): Abstract GS3-01
ABCSG 16 ITT Results Gnant M et al. Cancer Res. 2018;78(4 Suppl): Abstract GS3-01
ABCSG 16 Treatment Adherence Gnant M et al. Cancer Res. 2018;78(4 Suppl): Abstract GS3-01
ABCSG 16: Results II Adherent Population Gnant M et al. Cancer Res. 2018;78(4 Suppl): Abstract GS3-01
POETIC Trial Robertson J et al. Cancer Res. 2018;78(4 Suppl): Abstract GS1-03
POETIC: Timing of Endocrine Treatment and Relapse Robertson J et al. Cancer Res. 2018;78(4 Suppl): Abstract GS1-03
POETIC Baseline Ki67 and Recurrence Robertson J et al. Cancer Res. 2018;78(4 Suppl): Abstract GS1-03
POETIC Ki67 Box Plots By Treatment Group Robertson J et al. Cancer Res. 2018;78(4 Suppl): Abstract GS1-03
Impact of 2 week Ki67 on Disease Recurrence Robertson J et al. Cancer Res. 2018;78(4 Suppl): Abstract GS1-03
TEXT and SOFT Designs Enrolled: Nov03-Apr11 Premenopausal HR+ 12 wks after surgery Planned OFS No planned chemo OR planned chemo Premenopausal HR+ 12 wks after surgery No chemo OR Remain premenopausal 8 mos after chemo R A N D O M I Z E R A N D O M I Z E TEXT TAMOXIFEN AND EXEMESTANE TRIAL (N=2672) Tamoxifen+OFS x 5y Exemestane+OFS x 5y SOFT Tamoxifen x 5y Tamoxifen+OFS x 5y Exemestane+OFS x 5y Joint Analysis (N=4690) Tamoxifen+OFS x 5y SUPPRESSION OF OVARIAN FUNCTION TRIAL (N=3066) Exemestane+OFS x 5y Median follow-up 9 years OFS=ovarian function suppression Francis P, et al. Cancer Res. 2018;78(4 Suppl). Abstract GS4-02.
Patient Characteristics No chemo TEXT (N=1053) No chemo SOFT (N=943) Chemo TEXT (N=1607) Prior chemo SOFT (N=1087) Overall (N=4690) Age <40 yr 16% 9% 30% 49% 27% LN + 21% 8% 66% 57% 42% T-size >2cm 19% 15% 53% 47% 36% HER2 + 5% 3% 17% 20% 12% Surgery to random. (median) 1.5 mo 1.8 mo 1.2 mo 8.0 mo 1.6 mo Francis P, et al. Cancer Res. 2018;78(4 Suppl). Abstract GS4-02.
SOFT Adverse Event Profiles Francis P, et al. Cancer Res. 2018;78(4 Suppl). Abstract GS4-02.
SOFT DFS 8 years median follow-up T+OFS significantly improves DFS vs T-alone in the overall population Francis P, et al. Cancer Res. 2018;78(4 Suppl). Abstract GS4-02.
Francis P, et al. Cancer Res. 2018;78(4 Suppl). Abstract GS4-02. SOFT Distant DFS and OS ALL CHEMO PTS
SOFT: DFS Absolute Benefit in Very Young Patients (n=350) Tamoxifen alone vs patients < 35 years 8 year DFS = 8.7% Tamoxifen + OFS vs Exemestane + OFS patients < 35 years 8 year DFS = 13.1% Francis P, et al. Cancer Res. 2018;78(4 Suppl). Abstract GS4-02.
SOFT and TEXT Combined Analysis 4.0% absolute improvement in 8-yr DFS for E+OFS after 9 years median follow-up Fleming G, et al. Cancer Res. 2018;78(4 Suppl). Abstract GS4-03.
SOFT and TEXT Combined Analysis Breast Cancer-Free Interval Distant Recurrence-Free Interval 4.1% absolute improvement in 8-yr freedom from breast cancer for E+OFS 2.1% absolute improvement in 8-yr freedom from distant recurrence for E+OFS Fleming G, et al. Cancer Res. 2018;78(4 Suppl). Abstract GS4-03.
Ovarian Protection Meta-analysis: Study Characteristics Definition of premature ovarian insufficiency (POI) PROMISE-GIM6 1,2 No resumption of menstrual activity and postmenopausal levels of FSH and E2 POEMS/SWOG Anglo Celtic Group S0230 3 Moffitt-Led Trial 4 GBG-37 ZORO 5 OPTION 6 Amenorrhea for the prior 6 months and postmenopausal levels of FSH No maintenance of menses and no resumption of menses No reappearance of two consecutive menstrual periods within 21 to 35 days Amenorrhea with elevated FSH Timing of POI after chemotherapy 12 months 24 months 24 months 6 months Between 12 and 24 months Sample size 281 257 48 60 227 ER status for eligibility ER-positive and ER-negative ER-negative only ER-positive and ER-negative ER-negative only ER-positive and ER-negative Upper age limit for eligibility 45 years 49 years 44 years 45 years None Type of GnRHa Triptorelin Goserelin Triptorelin Goserelin Goserelin 1. Del Mastro L, et al. JAMA. 2011;306(3):269-276. 2. Lambertini M, et al. JAMA. 2015;314(24):2632-2640. 3. Moore HC, et al. N Engl J Med. 2015;372(10):923-932. 4. Munster P, et al. J Clin Oncol. 2012;30(5):533-538. 5. Gerber B, et al. J Clin Oncol. 2011;29(17):2334-2341. 6. Leonard RCF, et al. Ann Oncol. 2017;28(8):1811-1816. Lambertini M, et al. Cancer Res. 2018;78(4 Suppl): Abstract GS4-01.
Baseline Characteristics GnRHa group n = 436 Number (%) Control group n = 437 Number (%) P value* Age, median (interquartile range), years 38 (34-42) 39 (35-42).258 Age distribution, years 40 41 Estrogen receptor status Positive Negative Missing Type of chemotherapy Anthracycline only-based Anthracycline- and taxane-based Nonanthracycline-based Missing 297 (68.1) 139 (31.9) 177 (40.6) 257 (58.9) 2 (0.5) 194 (44.5) 227 (52.1) 6 (1.4) 9 (2.1) 283 (64.8) 154 (35.2) 173 (39.6) 262 (59.9) 2 (0.5) 198 (45.3) 210 (48.0) 13 (3.0) 16 (3.7) Cumulative cyclophosphamide dose, median (interquartile range), mg/m 2 4000 (3420-5185) 3960 (3082-5400).585.316.782.196 *Calculated by excluding missing data Lambertini M, et al. Cancer Res. 2018;78(4 Suppl): Abstract GS4-01.
Premature-Ovarian Insufficiency Rate 50% OR* 0.38 (95% CI 0.26 0.57) P<.001 14.1% 30.9% Study Meta-analysis approach GnRHa Control Events/pts Events/pts OR (95% CI) 40% PROMISE-GIM6 16/148 40/133 0.29 (0.15, 0.57) 30% POEMS/SWOG S0230 5/66 UCSF-led trial 3/26 15/69 2/21 0.33 (0.10, 1.14) 1.17 (0.14, 9.55) 20% GBG-37 ZORO 6/28 13/29 0.54 (0.14, 2.07) OPTION 21/95 41/107 0.41 (0.20, 0.81) 10% Overall (I =0%,p=0.73) 51/363 111/359 0.37 (0.25, 0.57) 0% GnRHa Group n = 363 Control Group n = 359 *Odds ratio (OR) adjusted for age, estrogen receptor status, type and duration of chemotherapy administered.0982 1 10.2 GnRHa better Control better Lambertini M, et al. Cancer Res. 2018;78(4 Suppl): Abstract GS4-01.
Post-Treatment Pregnancy Rate GnRHa Group: 37/359 (10.3%) vs Control Group: 20/367 (5.5%) Meta-analysis approach IRR* 1.83 (95% CI 1.06-3.15) P =.030 Study GnRHa Events/pts Control Events/pts IRR (95% CI) Age distribution, years 40 41 GnRHa Group n = 37 Number (%) 37 (100) 0 (0.0) Control Group n = 20 Number (%) 20 (100) 0 (0.0) PROMISE-GIM6 8/148 3/133 POEMS/SWOG S0230 22/105 12/113 OPTION 7/106 5/121 Overall (I =0%,p=0.85) 37/359 20/367 2.52 (0.67, 9.50) 1.77 (0.87, 3.57) 1.54 (0.49, 4.85) 1.82 (1.05, 3.14) Estrogen receptor status Positive Negative 6 (16.2) 31 (83.8) 2 (10.0) 18 (90.0).105 1 9.5 Control better GnRHa better IRR, Incidence rate ratio Lambertini M, et al. Cancer Res. 2018;78(4 Suppl): Abstract GS4-01.
Disease Free Survival (%) Disease-Free Survival, % Overall Survival (%) Overall Survival, % Disease-Free Survival/Overall Survival 100 Median follow-up = 5.0 years (IQR, 3.0 6.3 years) All Patients All Patients 100 80 80 60 60 40 HR* 1.01 (95% CI 0.72 1.42) P =.999 40 HR* 0.67 (95% CI 0.42 1.06) P =.083 20 0 Number at risk Control group GnRHa group TREATMENT Patients Events DFS Control group 407 67 80.0 GnRHa group 402 69 79.5 0 1 2 3 4 5 Time Since Random Assignment (years) Time Since Random Assignment, Years 407 352 322 268 232 172 402 356 323 286 240 174 20 0 Number at risk Control group GnRHa group TREATMENT Patients Events OS Control group 408 44 86.3 GnRHa group 404 33 90.2 0 1 2 3 4 5 Time Since Random Assignment (years) Time Since Random Assignment, Years 408 362 342 291 254 188 404 370 350 313 265 199 *Hazard ratio adjusted for age, estrogen receptor status, type and duration of chemotherapy administered and tumor stage IQR, interquartile range Lambertini M, et al. Cancer Res. 2018;78(4 Suppl): Abstract GS4-01.
HER-2 Targeted Treatments in HER-2 NEGATIVE Disease Fehrenbacher L et al. Cancer Res. 2018;78(4 Suppl): Abstract GS1-02
NSABP B47 Trial Results Fehrenbacher L et al. Cancer Res. 2018;78(4 Suppl): Abstract GS1-02
Shorter Duration Adjuvant Trastuzumab SOLD Trial Joensuu H et al Cancer Res. 2018;78(4 Suppl): Abstract GS3-04
SOLD Trial Study Population Joensuu H et al Cancer Res. 2018;78(4 Suppl): Abstract GS3-04
SOLD - Results Joensuu H et al Cancer Res. 2018;78(4 Suppl): Abstract GS3-04
Dose Dense Adjuvant Chemotherapy EBCTCG Meta-analysis: All 24 trials ER ve (n=9209) RR = 0.82 (0.76-0.88) 10y gain 4.7% 2p <0.00001 ER +ve (n=23495) RR = 0.86 (0.81-0.91) 10y gain 3.1% 2p <0.00001 Gray R. et al. Cancer Res. 2018;78(4 Suppl): Abstract GS1-01
Dose Dense Adjuvant Chemotherapy EBCTCG Meta-analysis Gray R. et al. Cancer Res. 2018;78(4 Suppl): Abstract GS1-01
SUCCESS A Study Design 5- FU 500 mg/m 2, Epirubicin 100 mg/m 2, Cyclophosphamide 500 mg/m 2 q3w Docetaxel 100 mg/m 2 q3w Endocrine treatment: Docetaxel 75 mg/m 2, Gemcitabine 1.000 mg/m 2 d1,8 q3w before chemotherapy after chemotherapy after 2 years after 5 years Blood sampling for CTC assessment First randomization: 3 cycles FEC100 followed by 3 cycles docetaxel vs. 3 cycles FEC100 followed by 3 cycles docetaxel plus gemcitabine Tamoxifen 20 mg qid p.o. x 2a (plus Goserelin 3.6 mg depot x 2a in premenopausal pts Anastrozole 1 mg qid p.o. x 3a in postmenopausal pts (Tam in premenopausal pts) Second randomization: 5 years vs. 2 years of zoledronate (4 mg i.v. every 3 months for 2 years, followed by 4 mg i.v. every 6 months for 3 years vs. 4 mg i.v. every 3 months for 2 years) Janni W et al. Cancer Res. 2018;78(4 Suppl): Abstract GS1-06
Bone Recurrences By Zoledronate Treatment Arm Bone recurrences as first distant recurrence* 5 years of zoledronate: 25 events 2 years of zoledronate: 28 events * with or without concurrent other recurrence Janni W et al. Cancer Res. 2018;78(4 Suppl): Abstract GS1-06
SUCCESS - Results Janni W et al. Cancer Res. 2018;78(4 Suppl): Abstract GS1-06
SUCCESS: Presence of CTCs After 5 Years Presence of CTCs five years after adjuvant chemotherapy assessed in 714 patients 5 years of zoledronate (n = 410) 43 (10.5%) CTC positive 2 years of zoledronate (n = 304) 22 (7.2%) CTC positive Chi-square test, p = 0.135 Janni W et al. Cancer Res. 2018;78(4 Suppl): Abstract GS1-06
Selective CDK 4/6 Inhibitors IC 50 Palbociclib Ribociclib Abemaciclib CDK4 9 11 nm 10 nm 2 nm CDK6 15 nm 39 nm 5 nm CDK2 >10 µm >50 µm >500 nm CDK9 ND ND 57 nm Kinase selectivity tree : Bigger circles = more inhibition Chen P, et al. Mol Cancer Ther 2016;15:2273 81. Asghar U, et al. Nat Rev Drug Discov 2015;14:130 46;
Development of CDK 4/6 inhibitors in HR+/HER2 MBC: 1 st line and subsequent lines PALOMA-1 PALOMA-2 MONALEESA-2 MONARCH 3 1L ER+, HER2 mbc Palbociclib + AI (letrozole) 1L ER+, HER2 mbc Palbociclib + AI (letrozole) 1L ER+, HER2 ABC Ribociclib + letrozole 1L ER+, HER2 mbc Abemaciclib + NSAI 2014 Data read-out dates 2015 2016 2017 PALOMA-3 MONARCH 1 MONARCH 2 MONALEESA-7 Recurrent HR+, HER2 mbc Palbociclib + fulvestrant Palbociclib: NCT00721409, NCT01740427, NCT01942135 Abemaciclib: NCT02102490, NCT02107703, NCT02246621 Ribociclib: NCT01958021, NCT02278120 Recurrent ER+, HER2 mbc Abemaciclib ET resistant ER+, HER2 mbc Abemaciclib + fulvestrant 1L ER+ HER2 pre/perimenopausal ABC Ribociclib + goserelin + tamoxifen / NSAI
PFS Benefit in 1 st Line AI + CDK 4/6 inhibitor Phase III Trials PALOMA-2 MONALEESA-2 MONARCH-3 mpfs (months) Palbociclib letrozole: 24.8 Placebo letrozole: 14.5 Finn R, et al. NEJM. 2016;375:1925 1936 Hortobagyi G, et al. NEJM 2016; 375:1738-1748 Goetz MP, et al. J Clin Oncol 2017;35:3638-46
MONALEESA 7: Results Tripathy D et al. Cancer Res. 2018;78(4 Suppl): Abstract GS2-05
Prognostic Analyses Individual Study Data, MONARCH 2 and MONARCH 3 Starting Variables MONARCH 2 MONARCH 3 ET Resistance (Primary vs Secondary) Number of Prior ETs (1 vs 2) ET for Metastatic Disease (Yes vs No) Treatment-Free Interval after ET (<36 vs 36 mo) Time from Diagnosis to Recurrence ( 10 vs >10 yrs) De Novo Metastatic Disease (Yes vs No) Variables identified as prognostic (p<.05) by univariate analysis of PFS, based on a univariate Cox model stratified by treatment arm Treatment-free Interval after ET (<36 vs 36 mo) Goetz et al, Cancer Res. 2018;78(4 Suppl). Abstract GS6-02
Treatment-free Interval (TFI) MONARCH 3 NSAI +/- abemaciclib abemaciclib arm placebo arm ORR abemaciclib arm: 43.3% placebo arm: 22.7% ORR abemaciclib arm: 56.9% placebo arm: 46.7% Note: Study protocol required a TFI of at least 12 months for those patients who had received adjuvant ET. The 36-month cutoff was arbitrarily selected to be as short as possible while providing an adequate sample size. Goetz et al, Cancer Res. 2018;78(4 Suppl). Abstract GS6-02
Optimal Sequencing of Endocrine Therapy in ER+ MBC 1 st line approach 2 nd line approach Delay Start of Chemotherapy OS A. Conventional endocrine mono-therapy AI alone 8 14 months Exemestane 3 4 months AI + everolimus 7 9 months Fulvestrant + CDK4/6 i 11 16 months A B B. Combination Endocrine Strategy AI + CDK4/6 i 24 months? 2 nd Line post CDK 4/6 inhibitors: still endocrine responsive and to what therapy? 0 5 10 15 20 25 30 35 Cumulative Median Progression-Free Survival (PFS) in months Overall Survival (OS)
New Anti Her2 Antibody Drug Conjugates (ADCs): SYD985 Mechanism of Action Available Results a Ongoing Trials TULIP trial: SYD985.002 R 2:1 SYD985 Treatment physician s choice (TPC) a Primary endpoint: PFS (centrally assessed) Secondary endpoints: OS, ORR, investigator assessed PFS, QoL, and safety Fully synthetic duocarmycin analogue Phase I, part 2: 90% patients 4 lines of therapy Toxicity: Conjunctivitis, keratitis TPC: a Lapatinib + capecitabine Trastuzumab + capecitabine Trastuzumab + vinorelbine Trastuzumab + eribulin ORR, overall response rate January 2018: FDA fast-track designation a Aftimos P, et al. Cancer Res. 2017;77(4 Suppl): Abstract P6 12 02.
New Anti-HER2 TKIs: Tucatinib Mechanism of Action Available Results a Outstanding Ongoing Trials HER2CLIMB trial Orally bioavailable, potent HER2- selective TKI HER2 IC50 8 nm > EGFR IC50 > 10,000 nm: Decreased potential for EGFR-related toxicities Phase Ib of tucatinib + capecitabine + trastuzumab in HER2+ MBC, including patients with BM Progression after trastuzumab, taxane, and T-DM1. Pertuzumab or lapatinib permitted. Three to six previous lines Type of response Arm (N) All SD PR CR Tucatinib + Capecitabine N = 7 7 (100) 2 (29) 5 (71) 0 Tucatinib + Trastuzumab N = 18 Tucatinib + Trastuzumab + Capecitabine N = 27 15 (100) 24 (100) 8 (53) 6 (40) 1 (7) 10 (42) 13 (54) 1 (4) Primary endpoint: PFS assessed by central review Key secondary endpoints: PFS in patients with BM, OS BM, brain metastases; MBC, metastatic breast cancer; TKI, tyrosine kinase inhibitor Median PFS for triplet: 7.8 months (95% CI 4.1-12.4) a Hamilton E, et al. Cancer Res. 2017;77(13 Suppl): Abstract P4-21-01.
Combined Anti-HER 2 Treatment + Immune Checkpoint Blockade: PANACEA Study Centrally confirmed HER2+ ECOG 0-1 PD-L1+ Phase Ib Pembrolizumab 2 mg/kg and 10 mg/kg IV + trastuzumab q3w Tumor biopsy sample <1 yr Measurable disease RECIST 1.1 No limit of prior systemic treatment Documented PD on trastuzumab or TDM-1 PD-L1- Phase II Pembrolizumab 200 mg IV + trastuzumab q3w Phase II Pembrolizumab 200 mg IV + trastuzumab q3w Protocol specified followup. Treatment until progression, toxicity, patient withdrawal, investigator decision, or maximum 2 years primary endpoint met Loi S, et al. Cancer Res. 2017;77(13 Suppl): Abstract GS2-06.
Conclusions Extended adjuvant endocrine treatment has a modest effect on disease recurrence (2 years extended AI may be sufficient) Ki67 changes after 2 weeks pre-operative treatment predict DFS Ovarian suppression and an AI should be considered in high risk young premenopausal women Ovarian suppression reduces chemotherapy induced premature ovarian failure One year of adjuvant trastzumab remains standard for vast majority of patients Dose dense 2 weekly chemotherapy appears superior to 3 weekly CDK4/6 inhibitors changing treatment of ER+ MBC.? Needed for all Novel HER2 targeted approaches showing promise in MBC