Sessione 4: La malattia metastatica La malattia HER2-positiva: strategia terapeutica nella pratica clinica e il futuro G. RICCIARDI UOC Oncologia Medica, A.O. Papardo, Messina Dir. Prof. V. Adamo giusyricciardi81@hotmail.it
Outline HER2+ MBC: where are we now? Emerging approaches in triple positive MBC Role of pan-her inhibitors Emerging therapeutic strategies in pts with brain metastases Which new anti-her2 drugs are coming? Is there a role for Immunotherapy? Trastuzumab biosimilars Final Remarks
Milestone of HER2/anti-HER2 Therapies in BC
Survival with HER2+ Metastatic Disease Tolaney S, ASCO 2018
What is the optimal regimen in 1 st line regimen?
Swain SM, et al. NEJM 2015 Pertuzumab-Trastuzumab-Docetaxel the SOC in 1 st line HER2+ MBC...in patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel, as compared with the addition of placebo, significantly increased the median overall survival to 56.5 months, an improvement of 15.7 months over survival in the control group... 56.5 mos 40.8 mos 15.7 mos
Pertuzumab-Trastuzumab-Docetaxel in a real world setting...there is some concern and debate about whether results obtained in clinical trials can be applied tout court to clinical practice. (...) The most relevant differences between our population and patients enrolled in the CLEOPATRA trial was the presence of brain metastases, the prevalence of HR positivity, visceral vs non-visceral pattern of metastasization and the prevalence of (neo)adjuvant pretreatment with HT and trastuzumab. Importantly, as shown by our survival analyses, these differences did not seem to affect efficacy. (...) Notably, mpfs was unexpectedly much greater in the RL setting than in the CLEOPATRA trial (27.8 vs 18.5 months, respectively)... De Placido S, et al. Breast 2018
Pertuzumab: Key Clinical Questions? What is the efficacy of pertuzumab in trastuzumab pretreated real life populations? Can pertuzumab use be delayed until second line setting? Should pertuzumab be given beyond progression? NO, but an important question to test in clinical trial(s)
Baselga J, et al. NEJM 2012 What is the efficacy of pertuzumab in trastuzumab-pretreated real life populations? Baseline characteristics of patients enrolled in the CLEOPATRA trial Only a minor fraction of patients enrolled in the CLEOPATRA trial were previously exposed to Trastuzumab Are the results of the trial reproducible in real practice?
Ricciardi GRR & Adamo V, et al. ASCO 2017 Safety and Efficacy of the combination of Pertuzumab plus Trastuzumab plus Docetaxel for HER2-positive MBC in pretreated patients with Trastuzumab in neo/adjuvant setting: a real-life study Population 35 Median age (range) 50 (20-71) ECOG PS, median (range) 0 (0-1) Menopausal Status, n (%) Pre-menopausal 16 (45.7) Post-menopausal 19 (54.3) Surgery, n (%) Mastectomy 17 (48.6) Quadrantectomy 18 (51.4) Lymphadenectomy n (%) 27 (77.1) Sentinel Node Biopsy n (%) 7 (20) Subtypes, n (%) Luminal B 14 (40) HER2-enriched 21 (60) Metastatis sites (%) Lung 20% Lymph nodes 14.3% Liver 11.4% Median PFS 12 mos TRASTUZUMAB Neoadjuvant, n (%) 12 (34.3) Adjuvant, n (%) 28 (80) Median OS 15.2 mos Median FU 55.6 mos
Pertuzumab: Key Clinical Questions? What is the efficacy of pertuzumab in trastuzumab pretreated real life populations? Can pertuzumab use be delayed until second line setting? Should pertuzumab be given beyond progression? NO, but an important question to test in clinical trial(s)
Is there a role for Pertuzumab- Trastuzumab outside of 1 st line? Limitations: H/X not the SOC in 2 nd line Open label design No statistically-significant improvement in PFS Benefit in OS, but less than observed in the CLEOPATRA trial (HR 0.76 vs. 0.68) Urruticoechea A, et al. ASCO 2018
Pertuzumab: Key Clinical Questions? What is the efficacy of pertuzumab in trastuzumab pretreated real life populations? Can pertuzumab use be delayed until second line setting?e be delayed until second line setting? Should pertuzumab be given beyond progression? NO, but an important question to test in clinical trial(s)
What is the optimal regimen in 2 nd and other lines?
Overview of improvements in OS brought by anti-her2 agents in T-pretreated pts 1 Cameron D, et al. Oncologist 2010; 2 Geyer CE, et al. NEJM 2006; 3 Blackwell KL, et al. JCO 2012; 5 Verma S, et al. NEJM 2012; 6 Krop IE, et al. Lancet Oncol 2014; 7 Wildiers H, et al. SABCS 2015. T-DM1 22,7 TH3RESA [6, 7] CAPE + LAP 15,8 T-DM1 30,9 EMILIA [5] TPC 25,1 EGF 104900 [3] LAP LAP + T 9,5 14,0 Cameron D, 2011 [1, 2] CAPE + LAP 17,25 CAPE 14,88 0 10 20 30
Verma S, et al. NEJM 2012; Die ras V, et al. Lancet Oncol 2017 T-DM1 vs. capecitabine plus lapatinib previously treated HER2-positive MBC: the EMILIA trial...t-dm1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane...
Questions regarding T-DM1 What is the efficacy of T-DM1 in pertuzumab pre-treated real life populations? Should T-DM1 only be used in the second line setting?
Fabi A, et al. Fut Oncol 2017 What is the efficacy of T-DM1 in pertuzumabpretreated real life populations? Overall response rate was 33.3% in patients with prior pertuzumab and 57.1% in the remaining subjects. Disease control rate was 47 and 43%, respectively, and clinical benefit rate was 43.3 and 71.1%, respectively. P + T: mpfs 5.0 months (95% CI: 4.3 5.7); T only: mpfs 11.0 months (95% CI: 7.8 14.2) Median progression-free survival was 5.0 months in patients with prior pertuzumab and 11.0 months in those without (hazard ratio: 2.02; 95% CI: 1.14 3.58; p = 0.01). Patients treated with T-DM1 who previously received pertuzumab have poorer clinical outcomes compared with those receiving a trastuzumab-onlybased regimen in the first-line setting.
Questions regarding T-DM1 What is the efficacy of T-DM1 in pertuzumab pre-treated real life populations? Should T-DM1 only be used in the second line setting?
Perez EA, et al. JCO 2017 & ASCO 2017 Is there a role for T-DM1 in 1 st line HER2-positive MBC? T-H= T-DM1 = T-DM1 + P T-DM1 remains the SoC in 2 nd line Possible option for first line in pts unsuitable for TPH What would be the role of T- DM1 if P (APHINITY trial) will be moved in the adjuvant setting in high risk pts?
What is the role of lapatinib in the pertuzumab/t-dm1 era?
Lapatinib remains a therapeutic option for pts with HER2-positive MBC despite being previously treated with multiple anti-her2 therapies. 50% of pts obtained clinical benefit for over 6 mos with no significant toxicity Lapatinib shows a partial lack of cross-resistance with pertuzumab and T-DM1 thus further emphasizing the benefit of using beyond the 2 nd line setting 1. Of the 34 pts identified as the target cohort with prior pertuzumab and/or T-DM1 exposure, 29 were available for outcome analysis 2. In the comparison cohort (n= 536) who had received lapatinib without prior pertuzumab and/or T-DM1 exposure, 445 pts were available for outcome analysis Ba ez-vallecillo L, et al. SABCS 2016
Current advanced HER2-positive breast cancer treatment guidelines Pondé N, et al. Cancer Treat Rev 2018
Outline HER2+ MBC: where are we now? Emerging approaches in triple positive MBC Role of pan-her inhibitors Emerging therapeutic strategies in pts with brain metastases Which new anti-her2 drugs are coming? Is there a role for Immunotherapy? Trastuzumab biosimilars Final Remarks
Cross-talk between different signal transduction is the best studies cause of resistance pten cbl 25 Johnston S R Clin Cancer Res 2010;16:1979-1987
Kaufman B, et al. JCO 2009, Johnston S, et al. JCO 2009; Burstein HJ, et al. JCO 2014 Single Agent HER2 Targeted Therapy Adds Modestly To Endocrine Therapy TAnDEM EGF30008 CALGB 40302 mpfs: 4.8 vs. 2.4 mos mpfs: 8.2 vs. 3.0 mos mpfs: 5.9 vs. 3.3 mos Anastrazole vs. Anastrazole + Trastuzumab Letrozole vs. Letrozole + Lapatinib Fulvestrant vs. Fulvestrant + Lapatinib
1 st line Trastuzumab + AI ± Pertuzumab: the PERTAIN study Rimawi M, et al. JCO 2018
PERTAIN efficacy results P + T significantly improved PFS compared with trastuzumab alone in all population Among patients who did not receive induction chemotherapy: mpfs was 21.72 mo in the pertuzumab+ trastuzumab arm and 12.45 mo in the trastuzumab arm Rimawi M, JCO 2018
ALTERNATIVE: efficacy results Study Ph. Design Population n. Arm(s) Objectives DETECT V/CHEVENDO III Randomized, open-label 1 st -3 rd line therapy HER2+/ER+ MBC 270 CHT + T + P vs. ET + T + P AEs (primary); Quality-adjusted survival, ORR, OS, PFS (secondary) Dual HER2 blockade with LAP + TRAS + AI showed superior PFS benefit versus TRAS + AI in pts with HER2-positive/HR-positive MBC.This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this pts population Johnston SR, et al. JCO 2018
CDK4/6 inhibitors in HER2+ BC
Adapted from Branda o M, et al. Exp Rev Anticancer Ther 2018 Ongoing clinical trials with anti-her2 agents + ET+ CDK4/6 inhibitors Study Ph. Design Population n. Arm(s) Objectives PATINA II Randomized, open-label HER2+/ER+ MBC, prior anti-her2 + CHT induction therapy 496 Palbociclib + T + P + ET vs. T + P + ET PFS (primary); OS, 3-yr/5-yr OS, ORR, DOR, CBR, PROs (secondary) PATRICIA II Randomized, open-label HER2+ MBC, 2-4 prior anti-her2 therapy lines 138 ER-: T + Palbociclib ER+: T + Palbociclib ± Letrozole PFS (primary); CBR, ORR, safety (secondary) MonarcHER II Randomized, open-label HER2+/ER+ MBC, postmenopausal, 2 prior anti-her2 therapies 225 Abemaciclib + T + Fulvestrant vs. Abemaciclib + T vs. T + SoC CHT PFS (primary); OS, ORR, DOR, CBR (secondary) Legend: CHT, chemotherapy; T, Trastuzumab; P, Pertuzumab; ET, endocrine therapy.
Outline HER2+ MBC: where are we now? Emerging approaches in triple positive MBC Role of pan-her inhibitors Emerging therapeutic strategies in pts with brain metastases Which new anti-her2 drugs are coming? Is there a role for Immunotherapy? Trastuzumab biosimilars Final Remarks
pan-her inhibitors in HER2-positive MBC STUDY Phase Drug(s) Population ORR PFS OS LUX-Breast-1 [1] III Afatinib + VNB vs. VNB + H HER2+ MBC, prior trastuzumab 46.1% vs. 47.0% 5.5 mos vs. 5.6 mos 19.6 mos vs. 28.6 mos LUX-Breast-3 [2] II Afatinib vs. Afatinib + VNB vs. TPC HER2+ BC with progressive BMs prior Trastzumab and/or Lapatinib 0%* vs. 8%* vs. 14%* 2.74 mos vs. 2.83 mos vs. 4.23 mos 13.27 mos vs. 8.58 mps vs. 11.98 mos Martin M, 2013 [3] II Neratinib vs. Lap-Cape HER2+ MBC, prior trastuzumab 29% vs. 41% 4.5 mos vs. 6.8 mos 19.7 mos vs. 23.6 mos Saura C, 2014 [4] I/II Neratinib + Cape HER2+ MBC, prior trastuzumab and lapatinib 64% (no prior lapatinib) 57% (prior lapatinib) 9.27 mos (no prior lapatinib) 8.26 mos (prior lapatinib) N.R. TBCRC 022 [5] II Neratinib HER2+, BMs 8%* 1.9 mos N.R. NEfERT-T [6] II Neratinib-Tax vs. H-Tax HER2+, 1 st line 74.8% vs. 77.6% 12.9 mos vs. 12.9 mos N.R * Intracranial ORR 1 Harbeck N, et al. Lancet Oncol 2016; 2 Cortes J, et al. Lancet Oncol 2015; 3 Martin M, et al. Eur J Cancer 2013; 4 Saura C, et al. JCO 2014; 5 Freedman RA, et al. JCO 2016; 6 Awada A, et al. JAMA Oncol 2016
Outline HER2+ MBC: where are we now? Emerging approaches in triple positive MBC Role of pan-her inhibitors Emerging therapeutic strategies in pts with brain metastases Which new anti-her2 drugs are coming? Is there a role for Immunotherapy? Trastuzumab biosimilars Final Remarks
Brain Metastases from Breast Cancer CNS tropism Limited systemic options In the RegisHER study 37% of pts with HER2+ BC had brain mts detected over the study 7% of diagnosis 30% over course of their disease Worse outcome with presence of brain mts median survival 26.3 months with vs 44.6 months without Sperduto PW, et al. J Neurooncol. 2013; Brufsky AM, et al. Clin Cancer Res 2011
Morikawa A, et al. Clin Breast Cancer 2018 HER2-positive Breast Cancer With Brain Metastases in the era of HER2-targeted therapy...significantly better survival from BM was noted for patients with higher performance status, fewer BM lesions, continued use of HER2- targeted therapy after BM diagnosis, and better controlled extracranial metastatic disease. Systemic Treatment anti-her2 play an important role especially in HER2+ patients: Median OS from BMs onset can now exceed 2 years.
Completed prospective clinical trials of TKIs in HER2+ BC with established brain metastases Study Phase n EGF105084 [1] II 237 50 previous CHT/anti-HER2 Previous WBRT yes/yes 100% Arm(s) Lapatinib Lapatinib + Capecitabine CNS ORR TTP/PFS (mos) LANDSCAPE [2] II 45 yes/no 0% Lapatinib + Capecitabine 66% 5.5 EMILIA [3] III 95* yes/yes 60% 51% T-DM1 Lapatinib + Capecitabine 6% 20% N.R. 2.4 3.6 5.6 5.7 OS (mos) 6.4 N.R. 91% at 6 mos 26.8 12.9 Shawky et al. [4] II 21 yes/yes 76% Lapatinib + Capecitabine 33% 5.5 11.0 TBCRC [5] II 37 yes/yes 65% Neratinib + Capecitabine 49% 5.5 13.5 LUX-Breast 3 [6] II 121 yes/yes 65% 74% 60% Afatinib Afatinib + Vinorelbine TPC 0% 8% 14% 2.6 2.7 4.1 13 8 12 *Subset analysis Adapted from Duchnowska R, et al. Cancer Treat Rev 2018 [1] Lin NU, et al. Clin Cancer Res 2009; [2] Bachelot T, et al. Lancet Oncol 2013; [3 ]Krop IE, et al. Ann Oncol 2015; [4] Shawsky H, et al. J Egypt Natl Cancer Inst 2014; [5] Freedman RA, et al. JCO 2016; [6] Cortes J, et al. Lancet Oncol 2015.
Murthy R, et al. Lancet Oncol 2018; Borges VF, et al. JAMA Oncol 2018...The triplet combination of tucatinib, capecitabine, and trastuzumab demonstrated preliminary activity in pretreated HER2-positive pts with MBC, including patients previously treated with pertuzumab, T-DM1 and lapatinib. The mpfs in pts with brain metastases of 6.7 months was encouraging when compared with other systemic therapies used in a similar patient population......the combination of tucatinib and T-DM1 demonstrated preliminary activity in pretreated pts with ERBB2/HER2- positive MBC as reflected by a mpfs of 8.2months (95%CI, 4.8-10.3 months). The mpfs among pts with brain metastases was 6.7 months (95% CI, 4.1-10.2 months), which is encouraging compared with other systemic therapies used to treat a similar pts population...
Phase II study of Tucatinib vs. Placebo in Combination with Capecitabine & Trastuzumab in HER2+ MBC
Outline HER2+ MBC: where are we now? Emerging approaches in triple positive MBC Role of pan-her inhibitors Emerging therapeutic strategies in pts with brain metastases Which new anti-her2 drugs are coming? Is there a role for Immunotherapy? Trastuzumab biosimilars Final Remarks
New combination strategies in HER2-positive MBC Pondé N, et al. Cancer Treat Rev 2018
Antibody-drug conjugates Tolaney S. ASCO 2018
Saura C, et al. ASCO 2018 SYD985: preliminary data from HER2-positive MBC expansion cohort of the phase 1 study FDA granted Fast Track Designation
Novel Anti-HER2 Antibodies: Margetuximab
Novel Anti-HER2 Antibodies: Other
Outline HER2+ MBC: where are we now? Emerging approaches in triple positive MBC Role of pan-her inhibitors Emerging therapeutic strategies in pts with brain metastases Which new anti-her2 drugs are coming? Is there a role for Immunotherapy? Trastuzumab biosimilars Final Remarks
The prevalence of somatic mutations across human cancer types Lower median rate of somatic mutations detected compared to most immune sensitive cancers Alexandrov LB, et al. Nature 2013
Rationale for immunotherapy in HER2- positive breast cancer HER2+ Breast Cancer are higly infiltrated with T cells Quantity is prognostic and TIL biomarker is robust surrogate Trastuzumab has know immune MOA Trastuzumab elicits antitumor immunity producing antibody-dependent cellular cytotoxicity (ADCC) Solinas C, et al. ESMO Open. 2017; Denkert C, et al. Lancet Oncol 2017; Stagg J, et al. Proc Natl Acad Sci U S A. 2011
Pembrolizumab + Trastuzumab in HER2- positive MBC: the phase I/II PANACEA study Loi S, et al. SABCS 2017
Higher stromal TILs (stils) associated with better response and disease control Loi S, et al. SABCS 2017 stils 5% as potential predictive marker
Outline HER2+ MBC: where are we now? Emerging approaches in triple positive MBC Role of pan-her inhibitors Emerging therapeutic strategies in pts with brain metastases Which new anti-her2 drugs are coming? Is there a role for Immunotherapy? Trastuzumab biosimilars Final Remarks
HERITAGE: EFFICACY RESULTS Rugo HS, et al. ASCO 2018
Outline HER2+ MBC: where are we now? Emerging approaches in triple positive MBC Role of pan-her inhibitors Emerging therapeutic strategies in pts with brain metastases Which new anti-her2 drugs are coming? Is there a role for Immunotherapy? Trastuzumab biosimilars Final Remarks
Final Remarks Pertuzumab and T-DM1 led to improved outcomes with favorable toxicity in 1 st and 2 nd line HER2+ MBC, respectively, and are the preferred regimens in these settings; However, some important clinical questions (Pertuzumab in T-pretreated pts? Pertuzumab outside 1 st line? T-DM1 in pertzumab-pretreated pts?) are still open. Endocrine therapy + dual-blockade HER2 therapy is associated with significant improvement in PFS and can be considered for selected triple positive pts; In 3 rd and later lines of therapy (or where pertuzumab/tdm1 are not available), the addition of a HER2-directed agent improves outcomes compared to chemotherapy alone and thus should be continued whenever possible; Several different agents are under development in HER2-positive MBC, trying to overcome mechanisms of resistance to currently approved anti-her2 agents; For HER2-disease, Immunotherapy development still lagging behind due to effective anti-her2 therapies. The use of T biosimilars may reduce cancer care costs, with similar outcomes and safety profile to originator T.
Grazie!