Updates in HER2-Targeted Therapy from SABCS Outline

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1 Updates in HER2-Targeted Therapy from SABCS 2018 Melanie Majure, MD Assistant Professor University of California San Francisco Helen Diller Comprehensive Cancer Center Outline Neoadjuvant Therapy (PEONY; EFS after PCR) Post-Neoadjuvant Therapy (KATHERINE) Extended Adjuvant Therapy (EXTENET) Adjuvant Trastuzumab Duration (PHARE) Cardio-Protection Investigational Agents for HER2+ MBC 1

2 PEONY: NACT with pertuzumab Phase III, randomized, double-blinded 23 centers in mainland china, Taiwan, Thailand, Republic of Korea 2:1 randomization N = 329 patients Patients 52% ER+ 60% premenopausal 73% (pertuzumab) vs 81% (placebo) node negative Shao et al, SABCS 2018 PEONY: PCR rates Shao et al, SABCS

3 PEONY: NACT with pertuzumab Adverse Events: Diarrhea (38.5 vs 16.4%) Mouth ulcers (11 vs 7.3%) Neutropenia (48.2 vs 44.5%) Pyrexia (14.2 vs 10%) Malaise (5.5 vs 1.8%) Respiratory tract infection (15.1 vs 6.4%) Epistaxis (5 vs 0%) Conclusions: Neoadjuvant therapy combining pertuzumab with trastuzumab improved pcr with minimal increase in toxicity other than diarrhea in Asian patients, similar to that seen in NeoSphere Dual antibody therapy is the standard of care as neoadjuvant therapy for HER2+ breast cancer Shao et al, SABCS 2018 Influence of PCR on HER2+ Event Free Survival Difference between pcr vs. residual disease greater for ER- and ER+ consistent with meta-analysis from Cortazar et al, Lancet 2014 Yee et al, SABCS

4 Impact of pcr on Recurrence and Survival Pathological complete response (pcr) after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival, stratified by breast cancer subtypes and adjuvant chemotherapy usage: Patient-level meta-analyses of over 27,000 patients Spring et al, SABCS 2018 Impact of pcr on Recurrence and Survival Study & Year pcr Events / pcr N RD Events / RD N Abrail / / 564 Al-Tweigeri / / 45 Al-Tweigeri / / 54 Andre / / 434 Arun / / 230 Bear / / 812 Chang / / 52 Chen / / 197 Cortazar / 2,131 2,003 / 9,824 de-azambuja / / 274 Dieras / / 174 Eralp / / 90 Esserman / / 134 Fasching / / 408 Frasci / / 28 Gianni / / 323 Gonzales-Angulo / / 386 Groheux / / 51 Guarneri / / 1,072 Guarneri / / 75 Guiu / / 294 Hurley / 8 10 / 40 Hurley / / 99 Im / 31 5 / 22 Jinno / / 62 Kawajiri / / 52 Kim / / 231 Ko / / 137 Krishnan / / 315 Kuerer / / 329 Lee / / 46 Li / / 144 Lin / / 67 Marme / / 127 Masuda / 12 9 / 21 Mayer / / 66 Melichar / / 257 Natoli / / 36 Ring / / 383 Shao / / 36 Takada / / 365 Tanioka / / 134 Villarreal-Garza / / 125 Villarreal-Garza / / 1,173 Wang / / 265 Wu / / 211 Yoo / / 231 Zelnak / 13 3 / 14 Zhang / / 57 Zhang / / 64 Overall 881 / 5,748 5,877 / 20,630 Overall 881/ /20630 Patients who had pcr, compared to those with residual disease (RD), had significantly better EVENT FREE SURVIVAL (HR 0.31, 95% CI: , N = 26,378) Spring et al, SABCS

5 Impact of pcr on Recurrence and Survival TNBC HER2+ HR+/HER2- Event Free Survival 5-year EFS pcr vs RD: 90% vs 57% Event Free Survival 5-year EFS pcr vs RD: 86% vs 63% Event Free Survival 5-year EFS pcr vs RD: 97% vs 88% BLUE: pcr group TAN: Residual disease (RD) group Similar results seen with OS Spring et al, SABCS 2018 Adjuvant Chemotherapy after pcr Event Free Survival 5-year EFS in patients with pcr followed by adjuvant chemotherapy: 86%; pcr without additional adjuvant chemotherapy: 88% Adjuvant Hazard Ratio Chemotherapy (pcrand EFS) 95% PI Yes No pcr was associated with significantly improved EFS in both groups, and there was no significant difference in Hazard Ratios between the two groups BLUE: pcr without subsequent adjuvant chemotherapy TAN: pcr with subsequent adjuvant chemotherapy Spring et al, SABCS

6 Conclusion: Impact of pcr on Recurrence and Survival Achieving pcr following NACT is associated with significantly improved EFS and OS, particularly for more aggressive tumors, such as HER2+ breast cancer. Similar outcomes with or without adjuvant chemotherapy in patients who attain pcr after NACT likely reflects tumor biology and suggests adjuvant chemotherapy could potentially be omitted in certain circumstances. Spring et al, SABCS 2018 HER2+ ESBC with Residual Disease 40-60% of patients achieve a PCR BUT 40-60% of patients don t achieve a PCR 6

7 KATHERINE (NSABP B50, GBG 77) Phase III Study of Adjuvant T-DM1 versus trastuzumab in Patients with HER2+ ESBC with Residual Invasive Disease after Neoadjuvant Chemotherapy plus HER2-Targeted Therapy Geyer et al, SABCS 2018; von Minckwitz et al, NEJM 2018 KATHERINE: T-DM1 First antibody drug conjugate approved in a solid tumor; 2 nd line therapy for MBC HER2+ Mechanism of action Targeted delivery of chemotherapy Anti-HER2 activity Trastuzumab linked to small dose of emtansine (DM-1), a microtubule inhibitor 400x more potent than paclitaxel Limited toxicity Rare liver toxicity Thrombocytopenia Mild fatigue 7

8 KATHERINE: Study Schema ct1-4/n0-3/m0 at presentation (ct1a-b/n0 excluded) Centrally confirmed HER2-positive breast cancer Neoadjuvant therapy: Minimum of 6 cycles of chemotherapy Minimum of 9 weeks of taxane Anthracyclines and alkylating agents allowed All chemotherapy prior to surgery Minimum of 9 weeks of trastuzumab Second HER2-targeted agent allowed Residual invasive tumor in breast or axillary nodes Randomization within 12 weeks of surgery R 1:1 N=1486 T-DM1 3.6 mg/kg IV Q3W 14 cycles Trastuzumab 6 mg/kg IV Q3W 14 cycles Radiation and endocrine therapy per protocol and local guidelines Primary endpoint: Invasive Disease Free Survival (70 -> 76.5%), boundary HR <0.732, p<.0124 First interim OS analysis to be done at interim IDFS if boundary crossed Geyer et al, SABCS 2018; von Minckwitz et al, NEJM 2018 KATHERINE: Stratification Factors of ITT Population Clinical stage at presentation, n (%) Trastuzumab (n=743) T-DM1 (n=743) Operable (stages ct1-3n0 1M0) 553 (74.4) 558 (75.1) Inoperable (stage ct4nxm0 or ctxn2 3M0) 190 (25.6) 185 (24.9) Hormone receptor status, n (%) ER and/or PgR positive 540 (72.7) 534 (71.9) ER negative and PgR negative/unknown 203 (27.3) 209 (28.1) Preoperative HER2-targeted therapy, n (%) Trastuzumab alone 596 (80.2) 600 (80.8) Trastuzumab plus additional HER2-targeted agent(s)^ 147 (19.8) - Trastuzumab plus pertuzumab * 139 (18.7) Pathologic nodal status after preoperative therapy, n (%) 143 (19.2) 133 (17.9) Node positive 346 (46.6) 343 (46.2) Node negative/not done 397 (53.4) 400 (53.8) ^Non-pertuzumab HER2-targeted agents included: neratinib, dacomitinib, afatinib, lapatinib. * Not a stratification factor, included for informational purposes. Geyer et al, SABCS 2018; von Minckwitz et al, NEJM

9 KATHERINE: Invasive Disease Free Survival Invasive Disease-Free Survival Rate (%) No. at Risk Trastuzumab T-DM Trastuzumab T-DM Time (months) year IDFS 77.0% 88.3% Trastuzumab T-DM1 (n=743) (n=743) IDFS Events, no. (%)165 (22.2) 91 (12.2) Unstratified HR=0.50 (95% CI, ) P< Geyer et al, SABCS 2018; von Minckwitz et al, NEJM KATHERINE: Secondary Endpoints First IDFS Events Trastuzumab T-DM1 Patients (%) Total patients with IDFS event^ CNS* (4.3) CNS* (5.9) Distant recurrence 4.6 Locoregional recurrence Contralateral breast cancer Death without prior event ^Patients who experience additional IDFS event(s) within 61 days of their first IDFS event are reported in the category according to the following hierarchy: [1] Distant recurrence; [2] Locoregional recurrence; [3] Contralateral breast cancer; [4] Death without prior event. *CNS metastases as component of distant recurrence (isolated or with other sites). Trastuzumab T-DM1 Geyer et al, SABCS 2018; von Minckwitz et al, NEJM

10 KATHERINE: IDFS Subgroup Analysis Trastuzumab (n=743) T-DM1 (n=743) Group Total N 3-Year IDFS 3-Year IDFS Hazard Ratio 95% CI T-DM1 Better Trastuzumab Better All Clinical stage at presentation Operable Inoperable Hormone receptor status Negative (ER negative and PgR negative/unknown) Positive (ER and/or PgR positive) ( ) ( ) ( ) ( ) ( ) Preoperative HER2-directed therapy Trastuzumab alone Trastuzumab plus additional HER2-directed agent(s) ( ) ( ) Pathological nodal status after preoperative therapy Node positive Node negative/not done Age group (years) < ( ) ( ) ( ) ( ) ( ) Race^ White Asian American Indian or Alaska Native Black or African American ( ) ( ) ( ) ( ) ^149 were of multiple races or unknown race Geyer et al, SABCS 2018; von Minckwitz et al, NEJM 2018 KATHERINE: Distant Recurrence Free Interval 100 Distant Recurrence-Free Rate (%) Trastuzumab T-DM1 Trastuzumab T-DM1 (n=743) (n=743) DRFI Events, no. (%) 121 (16.3) 78 (10.5) Unstratified HR=0.60 (95% CI, ) 3-year event-free rate 83.0% 89.7% 0 No. at Risk Trastuzumab T-DM Time (months) Geyer et al, SABCS 2018; von Minckwitz et al, NEJM

11 KATHERINE: Overall Survival Survival (%) No. at Risk Trastuzumab T-DM Trastuzumab T-DM Trastuzumab T-DM1 (n=743) (n=743) Events, no. (%) 56 (7.5) 42 (5.7) Unstratified HR=0.70 (95% CI, ) P= Boundary for statistical significance HR 0.43 or P< Time (months) Geyer et al, SABCS 2018; von Minckwitz et al, NEJM 2018 KATHERINE: Adverse Events Trastuzumab grade 1 Trastuzumab grade 2 Trastuzumab grade 3 T-DM1 grade 1 T-DM1 grade 2 T-DM1 grade 3 Patients (%) Fatigue Nausea Platelet count decreased AST increased Headache Arthralgia Radiation skin injury ALT increased Epistaxis Sensory neuropathy^ Constipation Myalgia ^74.6% (103/138) events in T-DM1 arm reported as resolved by data cutoff Geyer et al, SABCS 2018; von Minckwitz et al, NEJM

12 KATHERINE: Treatment Exposure Trastuzumab (n=720) T-DM1 (n=740) Cycles of trastuzumab/t-dm1 completed, n (%) 7 cycles 664 (92.2) 637 (86.1) 14 cycles 583 (81.0) 528 (71.4) Patients with a dose reduction, n (%) No dose reduction N/A 634 (85.7) One dose level reduction (3.0 mg/kg) N/A 77 (10.4) Two dose level reductions (2.4 mg/kg) N/A 29 (3.9) Completed 14 cycles of any study treatment^ 583 (81.0) 593 (80.1) 2% (trastuzumab) vs 18% (T-DM1) discontinued therapy due to adverse events Geyer et al, SABCS 2018; von Minckwitz et al, NEJM 2018 KATHERINE: Summary and Conclusions T-DM1 demonstrated a statistically significant and clinically meaningful improvement in IDFS compared with trastuzumab Unstratified HR=0.50; 95% CI ; P< year IDFS increased from 77.0% to 88.3% (difference=11.3%) The IDFS benefit was consistent across all key subgroups including HR status, extent of residual invasive disease, and single or dual HER2-targeted neoadjuvant therapy The safety data were consistent with known toxicities of T-DM1, with expected increases in manageable AEs associated with T-DM1 compared to trastuzumab Additional follow-up will be necessary to evaluate the effect of T-DM1 on OS THE NEW STANDARD OF CARE 12

13 How Much trastuzumab is Enough? Standard of care for HER2+ ESBC is 1 year of trastuzumab 1 year was not scientifically determined HERA demonstrated that 2 years was not better than 1 year Multiple studies have compared various durations under 1 year with the standard PHARE: 6 vs 12 mo. of adjuvant trastuzumab (final results) Protocol Herceptin Adjuvant Reduction Exposure Non-Inferiority in Disease Free Survival (margin 1.15 or a <2% absolute difference) n = 3384 Inclusion Criteria: normal cardiac function and receiving trastuzumab 2012 report: 6 months NOT NON-inferior; suggested difference based on HR status and chemotherapy regimen Pivot et al, SABCS

14 PHARE: 6 vs 12 mo. of adjuvant trastuzumab (final results) DFS on ITT HR (95% CI) P value P value (non inf.) adjusted HR (1) 1.10 ( ) unadjusted HR 1.09 ( ) adjusted HR (2) 1.09 ( ) : Adjusted for stratification factors - Estrogen receptor status (+ vs -) and chemotherapy (concomitant vs sequential) 2: Adjusted for Estrogen-receptor status (+ vs -), chemotherapy (concomitant vs sequential), Age ( < 50 vs 50), Tumor size ( < 2 vs 2 cm), progesterone-receptor status (+ vs -), nodal status (+ vs -). Pivot et al, SABCS 2018 META-ANALYSIS of Shorter Duration trastuzumab Trial N Trastuzumab duration Noninferiority DFS HR Observed DFS HR Persephone m vs 12m < ( ) Short-HER w vs 12m < ( ) PHARE m vs 12m < ( ) SOLD w vs 12m < ( ) HORG 481 6m vs 12m < ( ) Total 1.21 ( ) Node ( ) Node ( ) ER ( ) ER ( ) Cardiac events longer duration OR = 2.48 ( ) Earl et al, ASCO 2018; Conte et al, Ann Oncol 2018; Pivot et al, Lancet Oncol 2013; Joensuu et al, JAMA Oncol 2018; Mavroudis et al, Ann Oncol 2015; Niraula & Gyawali, BCRT 2018; Carey

15 ExteNET: Sequential neratinib after 1 year trastuzumab HER2+ s/p chemo and 1y trastuzumab (N = 2480) R Neratinib Placebo Subsets HR idfs Node-negative 0.83 (ns) 1-3+ nodes 0.75 (ns) 4+ nodes 0.67 * ER * ER (ns) 2.5% increase in invasive disease free survival at 5 years 4.5% in HR+, esp LN++ FDA approval 2017 Diarrhea prophylaxis key: 40% gr3+ without it Martin et al, Lancet Oncol 2017; Goldhirsch et al, Lancet 2013; Carey, SABCS 2018 ExteNET: Exploratory Sub-Group Analysis (HR+/HER2+) Invasive DFS in patients with HR+ tumors without pcr after NACT and <1 year from last dose of trastuzumab to randomization (n=295) 4.6% at 2 years 7.4% at 5 years Gnant et al. SABCS 2018 P

16 ExteNET: Distant Disease Free Survival (HR+/HER2+) Distant DFS in patients with HR+ tumors and <1 year from last dose of trastuzumab to randomization (n=1334) 3.2% at 2 years 4.7% at 5 years Gnant et al, SABCS 2018, P CONTROL: PPx. against neratinib associated diarrhea Data Cutoff: 19-Oct-2018 Am 0-2 Am 3 Am 4 Am 5 Am 6/6.1 Treatment Loperamide L + Budesonide L+ Colestipol PRN Loperamide + colestipol Dose Escalation Total Enrolled Pts on Treatment Pts past cycle All grade diarrhea 109 (79.6%) 55 (85.9%) 111 (81.6%) 98 (94.2%) 17 (68.0%) Grade 3 diarrhea (%) 42 (30.7%) 18 (28.1%) 27 (19.9%) 32 (30.8%) 2 (8.0%) Total Discontinuation 61 (44.5%) 12 (18.7%) 39 (28.7%) 26 (25%) 6 (11.5%) D/C from diarrhea 28 (20.4%) 7 (10.9%) 5 (3.7%) 5 (4.8%) 1 (4.0%) Duration of diarrhea and discontinuation rates significantly lower with prophylaxis 33 16

17 Escalation vs De-escalation in HER2+ ESBC Cossetti R J et al. JCO 2015 Escalation vs De-escalation in HER2+ ESBC Smaller ER+ and LN- ADJUVANT Larger ER+/-; LN+/- NEO-ADJUVANT any ER/PR and node status paclitaxel + trastuzumab * For patients who find it difficult to complete 1 year of trastuzumab, less than 1 year is effective therapy in most patients. * Based on the KATHERINE trial, patients with HER2+ ESBC should generally receive NACT, except for those with very small cancers, to personalize therapy, & increase chance good outcomes Chemotherapy + trastuzumab +pertuzumab in LN+; ER- Consider neratinib in ER+, high risk PCR Complete a year of targeted therapy trastuzumab/pertuzumab Chemotherapy + Trastuzumab (+ Pertuzumab in >T2 or LN+) SURGERY No PCR 14 cycles of TDM-1 Rugo HS,

18 Community Trial of Cardioprotective Agents A randomized community-based trial of an ACE inhibitor, lisinopril, or a beta blocker, carvedilol, for prevention of cardiotoxicity in pts with early stage HER2+ BC receiving adjuvant trastuzumab Double-Blind, Placebo Controlled, Multicenter (127 ctrs) Primary endpoint: cardiotoxicity during year of adjuvant trastuzumab and following year Decrease in LVEF 10% ( 5% if baseline LVEF <50%) Inclusion criteria: SBP >90, HR 60, LVEF 50% N = 468 patients (required 184 treated with anthracycline) HER2+ s/p chemo, receiving trastuzumab (N = 468) (Stratified by anthracycline use) R Placebo Lisinopril 10 mg qd Carvedilol 10 mg qd (For 52 weeks) Munster et al, SABCS 2018 Cardiotoxicity Free Survival Baseline characteristics balanced, except anthracycline use skewed towards younger (48 vs 53 yrs) and lower SBP (120 vs 130) 240 patients completed treatment phase Cardiotoxicity all patients: placebo 32%, carvedilol 29% lisinopril 30% Cardiotoxicity anthracyclines: placebo 47% carvedilol 31% lisinopril 37% Cardiotoxicity-free survival was longer in both carvedilol or lisinopril than placebo Carvedilol: HR 0.49, 95% CI 0.27, 0.89, p=0.009 Lisinopril: HR 0.53, 95% CI 0.30, 0.94, p=

19 CDK 4/6 Inhibitors and HER2+ MBC Finn, Slamon, et al. Breast Cancer Res 2009;11(5):R77 San Antonio Breast Cancer Symposium, December 4-8, 2018 PATRICIA (Stage I): palbociclib/trastuzumab +/- AI Safety/ Efficacy N=15 PAM50 N=14 N=15 N=26 N=15 For Stage I to be successful, at least 6 patients of 15 had to be progressionfree at 6 months (PFS6R of 40%) in each cohort. Ciruelos et al, SABCS

20 San Antonio Breast Cancer Symposium, December 4-8, 2018 PATRICIA (Stage I): palbociclib/trastuzumab +/- AI PFS for each arm PFS-6 months % Number of patients Cohort A 33.3 % 5 /15 Cohort B % 6 / 15 Cohort B % 8 / 15 Toxicity: 60% dose reduction in this heavily pre-treated population For part 1 to be successful, at least 6 patients of 15 had to be progression-free at 6 months (PFS6R of 40%) Ciruelos et al, SABCS 2018 San Antonio Breast Cancer Symposium, December 4-8, 2018 PATRICIA (Stage I): palbociclib/trastuzumab +/- AI Clinical Benefit Rate at 6 months (CBR6) according to PAM50 intrinsic subtype All patients n=40 HR-positive n=26 HR-negative n=14 non CBR6 CBR6 Luminals 3 (27.2%) 8 (72.7%) Non-luminals 20 (69.0%) 9 (31.0%) P-value= PFS according to PAM50 subtypes within all patients PAM50 subtype distribution (sample origin: 22 primary tumors and 18 metastases) Ciruelos et al, SABCS

21 2 Phase II trial Adaptive design PATRICIA (Stage I): palbociclib/trastuzumab +/- AI A phase II Adaptive design of palbociclib in combination with trastuzumab and endocrine therapy versus treatment of physician s choice for pretreated Luminal/ER+ HER2+ MBC N= 232 (516) HER2+ ER+ Luminal PAM50 in primary or metastatic disease 1-4 prior therapies (including Trastuzumab and TDM-1) Primary or metasta-c biopsy: PAM50 and DNA/RNA seq Blood samples: Baseline, C2D1, PD PIs: Eva Ciruelos, Aleix Prat 1:1 StraPfied by: - Number of previous regimens: 1-2 vs Visceral disease: yes vs no Palbociclib 125 mg QD 3W + Trastuzumab * + Endocrine therapy** Trastuzumab* + Physician s treatment choice (capecitabine, gemcitabine, vinorelbine, eribulin or nab-paclitaxel) or TDM-1 1ary Endpoint: PFS * Loading dose: Trastuzumab: 8mg/kg followed 6 mg/kg IV or trastuzumab 600 mg SC administrapon or Trastuzumab biosimilar. ** Endocrine therapy oppons are either an Aromatase Inhibitor, Fulvestrant or Tamoxifen. *** OpPonal crossover PD*** Palbociclib 125 mg QD 3W + trastuzumab*+ Endocrine therapy** KEY SECONDARY OBJECTIVES: DoR, TTP, OS, HRQOL, Safety, CDK 4/6 Inhibitors and HER2+ MBC Front-line: PATINA (NCT ) Induction treatment R Palbociclib + Anti-HER2 PATINA Therapy Trial + Endocrine Therapy Anti-HER2 Therapy + Endocrine Therapy Later-line: MONARCHer (NCT ) Abemaciclib + Trastuzumab R PATINA Abema Trial + Tras + Fulvestrant Trastuzumab + Chemotherapy Multiple additional ongoing trials T-DM1 with palbociclib (standard schedule, d5-18) T-DM1 with palbociclib/letrozole Neoadjuvant palbociclib/letrozole/trastuzumab Ribociclib/trastuzumab/fulvestrant Ribociclib/T-DM1 Neratinib/everolimus plus palbociclib or trametinib Based on mutation status (EGFR, HER2, HER3/4, KRAS) 21

22 AVIATOR: Addition of 4-1BB Agonist to trastuzumab/anti-pd-l1 N=40 Vinorelbine +trastuzumab+ avelumab Advanced HER2+ cancer No prior immunotherapy PD-L1 unselected Vinorelbine +trastuzumab N=20 Vinorelbine +trastuzumab+ avelumab + Utomilumab Tumor Tissue Trastuzumab + avelumab + Utomilumab Utomilumab = 4-1BB/CD137 agonist Tumor tissue Fresh or 1y old N=40 Vinorelbine 25mg/m 2 D1,D8,D15 Trastuzumab D1, D15 Tumor Avelumab D1, D15 10mg/kg IV Tissue Utomilumab D1 100mg IV 28d cycle THANK YOU 22