Evolving Paradigms in HER2+ MBC: Strategies for Individualizing Therapy with Available Agents

Transcription

1 Evolving Paradigms in HER2+ MBC: Strategies for Individualizing Therapy with Available Agents Kimberly L. Blackwell MD Professor Department of Medicine and Radiation Oncology Duke University Medical Center Director, Breast Cancer Program Duke Cancer Institute Durham, North Carolina

2 Overview HER2+ Metastatic Breast Cancer Timing Special Patient Populations ER+ Brain Metastasis

3 NCCN: First-line Treatment of HER2+ MBC Preferred regimens Docetaxel + trastuzumab + pertuzumab (category ) Paclitaxel + trastuzumab + pertuzumab Other regimens Chemotherapy + trastuzumab NCCN. Clinical practice guidelines in oncology: breast cancer. v..24.

4 MA.3/EGF899: Design Randomize 24 Wks: Lapatinib + taxane Experimental Arm Until PD: Lapatinib 24 Wks: Trastuzumab + taxane Standard Arm Until PD: Trastuzumab Primary Outcome: PFS Sample size: ~ 6 (536 patients centrally confirmed with HER2+) ClinicalTrials.gov. NCT66725.

5 PFS (%) MA.3/EGF899 : PFS (Intent-to- Treat Analysis) 8 6 Median PFS TTAX/T:.4 mos Median PFS LTAX/L: 8.8 mos HR:.33 (95% CI:.6-.67; P =.) 4 Pts at Risk, n TTAX/T LTAX/L Mos TTAX/T LTAX/L Gelmon KA, et al. ASCO 22. Abstract LBA

6 First-Line Treatment With T-DM vs Trastuzumab + Docetaxel N = 37 MBC patients (never received chemotherapy or HER2-targeted therapy for locally advanced or metastatic HER2-positive breast cancer) R a n d o m i z e : T-DM 3.6 mg/kg IV q3wk Trastuzumab 6 mg/kg IV (8 mg/kg in cycle ) + Docetaxel 75 or mg/m 2 IV q3wk until disease progression or unacceptable toxicity, and then followed for survival Primary objectives were investigator-assessed PFS and safety. Results are based on a clinical data cutoff date of November 5, 2 Hurvitz S et al. European Multidisciplinary Cancer Congress; 2. Abstract 5. 6

7 First-Line Treatment of HER2-Positive MBC With T-DM vs H + T Provides Significant Improvement in PFS Docetaxel + Trastuzumab T-DM Comparison No. Patients 7 67 Efficacy Median PFS (months) ORR n (%) (95% CI) Toxicity 4/69 (58.%) (45.5, 69.2) 43/67 (64.2%) (5.8, 74.8) Grade 3-4 events 89.4% 46.4% Treatment discontinuation due to adverse events 28.8 % 7.2% HR.59 (.36,.97, P =.35) ORR = overall response rate. Hurvitz S et al. 23 7

8 MARIANNE: Trial Design Eligibility Histologically/cytologically confirmed breast adenocarcinoma Locally recurrent or mbc HER2 positivity Candidate for chemotherapy Measurable or nonmeasurable disease per RECIST. Adequate organ function Primary endpoint: PFS * Docetaxel or paclitaxel R Trastuzumab + taxane* T-DM + pertuzumab T-DM + placebo June 22. Ellis PA et al. Proc ASCO 2;Abstract TPS2.

9 Treatment of HER2+ MBC Beyond First Line With Previous Trastuzumab Exposure Continued HER2 blockade Preferred: T-DM Chemotherapy + trastuzumab Trastuzumab + lapatinib Capecitabine + lapatinib Vinorelbine + trastuzumab + everolimus?

10 Randomized Trials of Continuing Anti-HER2 Therapy After Progression on First-Line Anti-HER2 Therapy Cameron et al EGF5 Von Minckwitz et al GBG26/BIG3-5 Phase 3 3 No. of patients Second-line HER2 therapy Lapatinib vs placebo Trastuzumab vs none Concurrent chemotherapy Capecitabine Capecitabine Median PFS Median OS 8.4 vs 4.4 mo HR.49, P<. 75 wk vs 64.7 wk HR.87, P = vs 5.6 mo HR.69, P = vs 2.6 mo HR.94, P =.73 Geyer CE et al. N Engl J Med. 26;355: ; Cameron D et al. The Oncologist. 2;5: ; Von Minckwitz G et al. Eur J Cancer. 2;47:

11 TH3RESA Study Schema HER2-positive (central) advanced BC a (N=6) T-DM 3.6 mg/kg q3w IV (n=4) PD 2 prior HER2-directed therapies for advanced BC Prior treatment with trastuzumab, lapatinib, and a taxane Treatment of physician s choice (TPC) b (n=2) PD T-DM c (optional crossover) Stratification factors: World region, number of prior regimens for advanced BC, d presence of visceral disease Co-primary endpoints: PFS by investigator and OS Key secondary endpoints: ORR by investigator and safety a Advanced BC includes MBC and unresectable locally advanced/recurrent BC. b TPC could have been single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a HER2-directed therapy with a chemotherapy, hormonal therapy, or other HER2-directed therapy. c First patient in: Sep 2. Study amended Sep 22 (following EMILIA 2nd interim OS results) to allow patients in the TPC arm to receive T-DM after documented PD. d Excluding single-agent hormonal therapy. BC, breast cancer; IV, intravenous; ORR, objective response rate; PD, progressive disease; q3w, every 3 weeks.

12 TPC Treatment Category TPC treatment category Combination with HER2-directed agent, % Chemotherapy b + trastuzumab Lapatinib + trastuzumab Hormonal therapy + trastuzumab Chemotherapy b + lapatinib TPC (n=84 a ) T-containing 8.4 Single-agent chemotherapy, b % 6.8 a Includes patients who received study treatment. b The most common chemotherapy agents used were vinorelbine, gemcitabine, eribulin, paclitaxel, and docetaxel.

13 Proportion progression-free PFS by Investigator Assessment..8.6 TPC (n=98) T-DM (n=44) Median (months) No. of events Stratified HR=.528 (95% CI,.422,.66) P< Time (months) 2 4 No. at risk: TPC T-DM Median follow-up: TPC, 6.5 months; T-DM, 7.2 months. Unstratified HR=.52 (P<.).

14 PFS Subgroup Analyses TPC T-DM Baseline characteristic Total n n Event Median (months) n Event Median (months) HR a (95% CI) T-DM Better TPC Better All patients (.42,.65) Age group <65 years (.44,.7) years (.22,.8) 75 years NE.4 (.2,.79) World region United States (.44,.4) Western Europe (.32,.6) Other (.36,.78) Race White (.39,.64) Asian (.35,.4) Other (.23,.4) Baseline ECOG PS (.3,.64) (.47,.85) (.9,.92) a Unstratified HR. NE, not estimable.

15 Proportion surviving First Interim OS Analysis. Observed 2% of targeted events.8.6 No. at risk: TPC 98 T-DM Time (months) TPC (n=98) 5 27 T-DM (n=44) Median (months) 4.9 NE No. of events 44 6 Stratified HR=.552 (95% CI,.369,.826); P=.34 Efficacy stopping boundary HR<.363 or P< patients in the TPC arm received crossover T-DM treatment after documented progression. Unstratified HR=.57 (P=.4).

16 BOLERO-3: Study Design Treatment Groups Follow-up/Survival N = 569 Locally advanced or metastatic HER2 + breast cancer Prior taxane required Resistance to trastuzumab required R : Everolimus (5 mg PO daily) + Vinorelbine (25 mg/m 2 weekly) + Trastuzumab (2 mg/kg weekly*) (n = 284) Placebo (PO daily) + Vinorelbine (25 mg/m 2 weekly) + Trastuzumab (2 mg/kg weekly*) (n = 285) Key Endpoints: Primary: PFS Secondary: OS, ORR, time to deterioration of ECOG PS, safety, DoR, CBR, and QoL Therapy until PD or intolerable toxicity Stratification by prior lapatinib use (yes/no) * Following a 4-mg/kg loading dose on day, cycle ( cycle = every 2 days). AE = adverse event; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; PD = progressive disease; PO = oral; PS = performance status; QoL = quality of life 23 ASCO Annual Meeting. Oral Abstract 55. Presented by: Ruth M. O Regan, MD.

17 Probability (%) BOLERO-3: Primary Endpoint Progression-Free Survival by Local Assessment Hazard ratio =.78; 95% CI [.65,.95] Log-rank P value: Median PFS Everolimus: 7. months Placebo: 5.78 months 4 2 Censoring times Everolimus (n/n = 96/284) Placebo (n/n = 29/285) No. of Patients Still at Risk Everolimus Placebo Time (weeks) CI = confidence interval. 23 ASCO Annual Meeting. Oral Abstract 55. Presented by: Ruth M. O Regan, MD

18 BOLERO-3: Most Common Adverse Events (Hematologic) Everolimus Arm (N = 28) Placebo Arm (N = 282) AE, % All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Neutropenia Anemia < Leukopenia Febrile neutropenia Thrombocytopenia < 23 ASCO Annual Meeting. Oral Abstract 55. Presented by: Ruth M.

19 Special Populations

20 Randomized Trials of Endocrine Therapy ± Anti- HER2 Therapy as First-Line Therapy in HER2 Positive Metastatic Disease Kaufman et al Johnston et al Endocrine therapy Anastrozole Letrozole Anti-HER2 therapy Trastuzumab open label Lapatinib (5 mg PO qd) vs placebo Phase 3 3 No. of patients Crossover 7% None Progression assessment Median PFS Median OS Reconciled between treating physician and independent review 4.8 vs 2.4 mo HR.63, P = vs 23.9 mo P =.325 Based on treating physician 8.2 vs 3. mo HR.74, P = vs 33.3 mo P =.88 Kaufman B et al. J Clin Oncol. 29;27: Johnston S et al. J Clin Oncol. 29;27:

21 The Clinical Problem of Her2+ Breast Cancer Brain Metastases (BCBM) Devastating, feared consequence of advanced breast cancer Incidence of ~3% among women with HER2+ metastatic disease Current SOC: radiotherapy (WBRT vs. focused radiation), systemic therapy Post-XRT: Lapatinib/capecitabine, ORR 8 38%; PFS months XRT-naïve: Lapatinib/capecitabine, ORR 67%; PFS 5.5 mos Bendell 23; Lin 29; Lin 2; Boccardo 28; Sutherland 2; Metro 2; Bachelot 2.

22 EMILIA Patients with CNS Brain Metastasis at Enrollment Krop, ASCO, 23

23 Cohorts 3a and 3b Progressive CNS Disease No prior lapatinib (cohort 3a) n=35 Consent and Screening (n = 6) Baseline brain MRI ( measurable lesion) CT Chest/Abdomen/Pelvis, CTCs Prior lapatinib (cohort 3b) n=25 Neratinib (24 mg orally once daily) and capecitabine 75 mg/m2 BID for 4 days followed by 7 days rest Follow-up every 3 weeks Brain MRI & body CT re-staging at week 6 CR, PR, SD Continue therapy PD (CTCs) If CNS PD Off study If non CNS PD extension with trastuzumab offered

24 Evidence for Everolimus BBB penetration Preclinical Evidence: Athymic mouse brain everolimus concentrations above the IC5 values for PTEN-/- glioblastoma cells ~ 24 hours following administration of everolimus 5 mg/kg orally Clinical Evidence: Clinical study of everolimus to treat 28 patients with SEGA (subependymal giant cell astrocytomas) tumors in patients with TSC (tuberous sclerosis) illustrates 78% of patients achieved 3% reduction in tumor burden at 6 months further supporting BBB penetration (Note: MW = daltons) Novartis, data on file. Franz et al. ASCO 2.

25 LCCC 25 Phase II Study Schema N = 35 Two-stage design Current Accrual, n = 8/28 Open at UNC, UVA, MD Anderson-Orlando, UAB U of Chicago; PI: CK Anders

26 Conclusions Evidence supports continue HER2 based therapy after progression T-DM has activity in the first, second and third line setting. In endocrine sensitive tumors, endocrine therapy + HER2 targeted therapy is an option After Pertuzumab and T-DM strategies, small molecule inhibitors of HER2 should be considered, especially in patients with brain metastasis.

27 Thanks!