New Drug Development in HER2+ Breast Cancer

Transcription

1 New Drug Development in HER2+ Breast Cancer Philippe Aftimos, M.D. Senior Research Physician Clinical Pharmacology Unit Institut Jules Bordet

2 Background Amplification of HER2 occurs in approximately 20% of breast cancers This alteration was associated with shortened survival Anti-HER2 therapies changed the prognosis of patients with HER2+ breast cancer The CNS remains a sanctuary for the disease

3 The Trastuzumab (Herceptin ) Story 1979: HER2 oncogene discovery 1984: HER2 protein discovery 1987: HER2 and breast cancer linked 1989: Synthesis of trastuzumab 1998: FDA approval 2006: FDA approval adjuvant setting 19 ans 27 ans

4 ER+/ HER2+ MBC Endocrine + anti-her2 therapy Johnston S et al. JCO 2009 Kaufman B et al. JCO 2009

5 Chemotherapy + trastuzumab

6 HER2+ MBC Chemotherapy + trastuzumab What to combine with trastuzumab? Paclitaxel Docetaxel Platinum combo Vinorelbine Capecitabine Gemcitabine Monotherapy

7 Eribulin + Trastuzumab phase II trial first-line: Disease control rate = 96.2% Wilks S et al. Clinical Breast Cancer 2014

8 Trastuzumab Beyond Progression: GBG 26/ BIG phase 3 trial MBC HER2-positive Progression under trastuzumab-based first-line therapy (TFI < 6 wks) with taxane (n=156) or monotherapy or non-taxane (n=42) Capecitabine 2500 mg/m 2 bid d1-14 q21d + continuation of Trastuzumab 6 mg/kg q3w (n=78) Capecitabine 2500 mg/m 2 bid d1-14 q21d (n=78)

9 Trastuzumab Beyond Progression: GBG 26/ BIG phase 3 trial PFS: 8.2 vs 5.6 months OS: 25.5 vs 20.4 months Response rate: 48% vs 27% von Minckwitz G et al. JCO 2009

10 Pan-HER tyrosine kinase inhibitors

11 Small molecule TKIs But also neratinib and afatinib Vandana Abramson, and Carlos L. Arteaga Clin Cancer Res 2011;17: by American Association for Cancer Research

12 Lapatinib + Capecitabine Geyer C et al. NEJM 2006

13 Class-Specific Toxicities Geyer C et al. NEJM 2006

14 Neratinib phase II Trial Burstein H et al. J Clin Oncol 2010.

15 Neratinib in the adjuvant setting: 1 year of Neratinib vs Placebo after 1 year of Trastuzumab Grade 3 diarrhea in 40% of patients. Chan A et al. ASCO Annual Meeting 2015.

16 NALA trial in the Metastatic Setting ClinicalTrials.gov Identifier: NCT

17 Double HER2 Blockade

18 Lapatinib + Trastuzumab vs Lapatinib Blackwell K et al. JCO 2012

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20 Higher pcr rate Baselga J et al. Lancet 2012.

21 ALTTO: Double Blockade in the Adjuvant Setting Piccart-Gebhart M et al. J Clin Oncol 2015.

22 No improvement in disease-free survival: 1 year of trastuzumab remains the standard of care. Piccart-Gebhart M et al. J Clin Oncol 2015.

23 Dual HER2 blockade with trastuzumab and pertuzumab in HER2-amplified breast cancer Hector Boix-Perales et al. The Oncologist 2014;19: by AlphaMed Press

24 CLEOPATRA: Double HER2 blockade in the 1 st line setting Patients with HER2-positive first-line MBC central confirmation (N=808) 1:1 n=406 n=402 Placebo + trastuzumab Docetaxel 6 cycles recommended Pertuzumab + trastuzumab Docetaxel 6 cycles recommended PD PD Primary endpoint: Independently assessed PFS Secondary endpoints included Overall survival; PFS by investigator assessment; Safety Baselga et al. N Engl J Med 2012;366:109-19

25 CLEOPATRA: Impressive Efficacy and Survival 56.5 mo vs 40.8 mo Baselga J et al. NEJM Swain S et al. NEJM 2015.

26 Baselga J et al. NEJM Swain S et al. NEJM 2015.

27 Novel Antibodies

28 Margetuximab: MGAH22 (macrogenics) Chimeric anti-her2 monoclonal antibody Specificity and affinity similar to trastuzumab Fc domain engineered for increased binding to both alleles of human CD16A Margetuximab may have utility in patients with low HER2 expressing tumors or carrying the CD16A low-binding allele. Nordstrom J et al. Breast Cancer Research 2011

29 Margetuximab HER-2 Binding Nordstrom J et al. Breast Cancer Research 2011

30 Margetuximab ADCC Nordstrom J et al. Breast Cancer Research 2011

31 Margetuximab phase I trial (solid tumors expressing HER2) Patients with refractory carcinomas that overexpress HER2 for whom no standard therapy was available were enrolled Regimen A: 3W/4 Regimen B: Q3W Fifty-two patients received M (34 patients received 0.1 to 6.0 mg/kg in Regimen A and 18 patients received 10 to 18 mg/kg in Regimen B) The MTD was not reached Burris H et al. ASCO 2015

32 Margetuximab phase I trial (solid tumors expressing HER2) Toxicity: Mostly Grade 1 and 2 Infusion-related reactions Constitutional symptoms such as pyrexia, nausea, anemia, diarrhea, and fatigue Activity: PR were observed in 8 patients and SD in 21 patients Tumor reductions were observed in 11 of 19 patients with BC, including 4 patients with confirmed PR, 3 of whom had received prior trastuzumab and lapatinib Median PFS for patients with BC was 169 days Burris H et al. ASCO 2015

33 Margetuximab: current development SOPHIA trial (NCT ) Phase III HER2 positive MBC 2 prior lines of anti-her2 therapy Chemo Margetuximab in HER-2 2+, FISH negative MBC (NCT ) Phase II Recruitment to end soon (tentative on clinicaltrials.gov) Macrogenics and Merck collaboration Announced in October 2015 Pembrolizumab + margetuximab in HER2+ gastric cancer

34 Antibody-Drug Conjugates

35 T-DM1: Trastuzumab-based antibody-drug conjugate Trastuzumab-specific MOA Antibody-dependent cellular cytotoxicity (ADCC) Inhibition of HER2 signaling Inhibition of HER2 shedding HER2 T-DM1 Emtansine release Inhibition of microtubule polymerization Lysosome P P P Internalization Nucleus Adapted from LoRusso PM, et al. Clin Cancer Res 2011.

36 TDM4450g: T-DM1 compared with trastuzumab + docetaxel in the first-line treatment of HER2+ MBC HER2-positive, recurrent LABC or MBC (N=137) 1:1 Trastuzumab + Docetaxel T-DM1 PD PD Crossover to T-DM1 (optional) Randomized, Phase II, international, open-label study Stratification factors: World region, prior adjuvant trastuzumab therapy, disease-free interval Primary endpoints: PFS by investigator assessment, and safety Data analyses were based on clinical data cut-off Nov 15, 2010 prior to T-DM1 crossover Key secondary endpoints: OS, ORR, DOR, CBR, and quality of life Hurvitz S et al. JCO LABC = locally advanced breast cancer; PD = progressive disease; PFS = progression-free survival;os = overall survival; ORR = objective response rate; DOR = duration of response; CBR = clinical benefit rate

37 Proportion progression-free TDM4450g: T-DM1 improved PFS compared with trastuzumab + docetaxel T-DM1 (n=67) Trastuzumab + docetaxel (n=70) Median PFS (months) HR (95% CI) p value (0.364, 0.968) Time (months) Hurvitz S et al. JCO HR = hazard ratio; CI = confidence intervals

38 Hurwitz S et al. JCO 2013 TDM4450g: T-DM1 Safety Profile

39 EMILIA Phase III study: T-DM1 vs lapatinib + capecitabine in patients previously treated with trastuzumab and taxane HER2+ (central) LABC or MBC (N=980) Prior taxane and trastuzumab Progression on metastatic treatment or within 6 months of adjuvant therapy 1:1 T-DM1 PD Lapatinib + Capecitabine PD Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Primary end points: PFS by independent review, OS, and safety Key secondary end points: PFS by investigator, ORR, DOR, time to symptom progression Verma S et al. NEJM 2012

40 Proportion progression-free Independently assessed PFS benefit for T-DM Median (months) No. of events Cap + Lap T-DM Stratified HR=0.650 (95% CI, 0.55, 0.77) P< Time (months) No. at risk by independent review: Cap + Lap T-DM Unstratified HR=0.66 (P<0.0001). Verma S et al. NEJM 2012

41 Proportion surviving Significant Overall survival benefit for T-DM % 85.2% Median (months) No. of events Cap + Lap T-DM Stratified HR=0.682 (95% CI, 0.55, 0.85); P= Efficacy stopping boundary P= or HR= % 51.8% Time (months) No. at risk: Cap + Lap T-DM Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012). Verma S et al. NEJM 2012

42 EMILIA Safety Profile Verma S et al. NEJM 2012

43 TH3RESA (T-DM1 versus TPC) phase III trial in heavily pretreated patients HER2-positive (central) advanced BC a (N=600) 2 T-DM1 3.6 mg/kg q3w IV (n=400) PD 2 prior HER2-directed therapies for advanced BC Prior treatment with trastuzumab, lapatinib, and a taxane 1 Treatment of physician s choice (TPC) b (n=200) PD T-DM1 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 Wildiers H. ECC 2013

44 Proportion progression-free PFS benefit by Investigator Assessment TPC (n=198) T-DM1 (n=404) Median (months) No. of events Stratified HR=0.528 (95% CI, 0.422, 0.661) P< Time (months) No. at risk: TPC T-DM Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months. Unstratified HR=0.521 (P<0.0001). Wildiers H. ECC 2013

45 Proportion surviving First Interim OS Analysis: trend towards OS benefit 1.0 Observed 21% of targeted events No. at risk: TPC 198 T-DM Time (months) TPC (n=198) T-DM1 (n=404) Median (months) 14.9 NE No. of events Stratified HR=0.552 (95% CI, 0.369, 0.826); P= Efficacy stopping boundary HR<0.363 or P< patients in the TPC arm received crossover T-DM1 treatment after documented progression. Unstratified HR=0.57 (P=0.004). Wildiers H. ECC 2013

46 SYD985: a novel ADC with a cleavable linker-duocarmycin payload Miranda M.C. van der Lee et al. Mol Cancer Ther 2015;14: by American Association for Cancer Research

47 In vitro profile of SYD985 vs T-DM1 in cell lines with different HER2 expression Miranda M.C. van der Lee et al. Mol Cancer Ther 2015;14: by American Association for Cancer Research

48 mtor inhibitors and trastuzumab

49 Trastuzumab and mtor inhibitors Inhibition of the HER2 PI3K FOXO-survivin axis by trastuzumab and PI3K inhibitors. Brent N. Rexer, and Carlos L. Arteaga Cancer Res 2013;73: by American Association for Cancer Research

50 Phase I proof of concept trial: Objective responses after resistance to taxanes and trastuzumab Study design. q28 days, every 28 days. Fabrice Andre et al. JCO 2010;28: by American Society of Clinical Oncology

51 BOLERO-1 phase III trial in the 1 st line setting: Reversal of trastuzumab resistance? Hurwitz S et al. Lancet Oncol 2015.

52 BOLERO-3 phase III trial Andre F et al. Lancet Oncol 2014

53 BOLERO-3: Longer PFS with the addition of everolimus Andre F et al. Lancet Oncol 2014

54 BOLERO-3 Safety Profile Andre F et al. Lancet Oncol 2014

55 Immunotherapy and anti-her2 combos

56 Preclinical: anti-her2 + anti-pd1 Stagg J et al. PNAS 2011.

57 PANACEA trial

58 HER-TDB: bispecific antibody that targets HER2 and activates T cell Junttila T et al. Cancer research 2014

59 Brain Metastases

60 Favor Lapatinib + Capecitabine for Brain Metastases? Landscape: yes Phase II, 45 patients Patients with newly diagnosed brain metastases 29 patients (66%) with PR 37 patients (84%) had tumor shrinkage Median time to radiotherapy : 8.3 months 22 patients (49%) with grade 3 or 4 AEs Cerebel: no Phase III, 540 patients Cap + Lap vs Cap + Tras Primary endpoint: CNS as first site of relapse No difference Secondary endpoints: Bachelot T et al. Lancet Oncol 2013 Pivot X et al. JCO 2015

61 Neratinib and Brain Metastases Freedman R et al. J Clin Oncol 2016.

62 Abemaciclib (CDK4/6 inhibitor) ClinicalTrials.gov Identifier: NCT

63 HER2-directed Metabolic Imaging

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65 Gebhart G et al. Annals Of Oncology 2015.

66 Today is World Cancer Day #EnsembleContreLeCancer #WeCanICan