ESMO PRECEPTORSHIP PROGRAM – BC ZUERICH, 28 JUNE 2019 Evandro de Azambuja, MD, PhD with the help of Daniel Eiger, Medical Fellow Institut Jules Bordet, Université Libre de Bruxelles (ULB) ESMO Council Member Chair of the Fellowship Committee HER2-Positive Metastatic Breast Cancer
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HER2-Positive Metastatic Breast Cancer · 1- M V Dieci; 186O Tumor-infiltrating lymphocytes (TILs) as an independent prognostic factor for early HER2+ breast cancer patients treated
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ESMO PRECEPTORSHIP PROGRAM – BC ZUERICH, 28 JUNE 2019
Evandro de Azambuja, MD, PhD
with the help of Daniel Eiger, Medical Fellow
Institut Jules Bordet, Université Libre de Bruxelles (ULB)
ESMO Council Member
Chair of the Fellowship Committee
HER2-Positive
Metastatic Breast
Cancer
Disclosure information
◆ Honoraria and advisory board from Roche/GNE
◆ Travel grants from Roche/GNE and GSK/Novartis
◆ Research grant from Roche/GNE (my institution)
◆ Research grant from Astra-Zeneca (my institution)
◆ Research grant from GSK/Novartis (my institution)
◆ Research grant from Servier (my institution)
IntroductionLife expectancy from HER2 + ABC diagnosis according to year analyzed - a consistent shift toward better survival
Roth J et al ESMO 2017 Abstract 263P
The management of ABC is complex and, therefore, involvement of all appropriate
specialties in a multidisciplinary team is crucial
Decisions should always take into account patient preferences, values and needs as
◆ Higher TILs, a surrogate marker of immunological activity against the tumor, are associated with better outcomes in HER2 + EBC treated with trastuzumab (ultimately, an immunotherapy itself)1
◆ Immune evasion may play an important role in trastuzumab resistance2
◆ Pre-clinical studies demonstrated improved trastuzumab therapeutic activity with anti-PD13
1- M V Dieci; 186O Tumor-infiltrating lymphocytes (TILs) as an independent prognostic factor for early HER2+ breast cancer patients treated with adjuvant chemotherapy and trastuzumab in the randomized shortHER trial, Annals of Oncology, Volume 29, Issue suppl_8, 1 October 2018, mdy270.183, https://doi.org/10.1093/annonc/mdy270.1832- Vanessa G. Martinez; ONCOIMMUNOLOGY 2017, VOL. 6, NO. 12, e1362530 (10 pages) https://doi.org/10.1080/2162402X.2017.13625303- Stagg J. Anti–ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti–PD-1 or anti-CD137 mAb therapy. Proceedings of the National Academy of Sciences Apr 2011, 201016569; DOI:10.1073/pnas.1016569108
LA Emens, F Esteva, M Beresford, C Saura, M De Laurentiis, S-B Kim, S-A Im, M Patre, Y Wang, A Mani, H Liu, S de Haas and S LoiDOI: 10.1158/1538-7445.SABCS18-PD3-01 Published February 2019
KATE-2 studyResults – ITT patients
LA Emens, F Esteva, M Beresford, C Saura, M De Laurentiis, S-B Kim, S-A Im, M Patre, Y Wang, A Mani, H Liu, S de Haas and S LoiDOI: 10.1158/1538-7445.SABCS18-PD3-01 Published February 2019
Serious AEs (SAEs): 33% (Atezo) vs. 19% (Placebo)
KATE-2 study
Results – PD-L1 positive patients
LA Emens, F Esteva, M Beresford, C Saura, M De Laurentiis, S-B Kim, S-A Im, M Patre, Y Wang, A Mani, H Liu, S de Haas and S Loi DOI: 10.1158/1538-7445.SABCS18-PD3-01 Published February 2019
New Anti-Body Drug Conjugates
The success of T-DM1 has created a lot of excitement around ADCs
Drug Name Antibody Chemotherapy
SYD- 0985 Trastuzumab Duocarmycin
DS – 8201a Humanized anti-HER2 antibody
Exatecan
MM - 302 Humanized anti-HER2 antibody
Lipossomaldoxorrubicin
XMT - 1522 HT-19 (Humanized anti-HER2 antibody )
Auristatin
1. Barok M. Breast Cancer Res. 2014; 16(2): 209; 2. Dokter W. et al Mol Cancer Ther 2014;13(11):2618–29; 3. Ogitani Y et Al Clin Cancer Res 2016 22 (20) 5097-5108; 4. Espelin CW et al Cancer Res 2016 76(6):1517-27; 5. Bergstrom DA et al AACR Abstract 6716.
Why target PI3K? ◆ Signaling to PI3K-Akt as a result
of HER2-HER3 dimerization is the most important survival pathway downstream of HER2 1
◆ Resistance to anti-HER2 treatment may arise from persistence or reactivation of PI3K signaling, via mutations on its components 2
◆ Preclinical data suggests that trastuzumab resistance is overcome by PI3K pathway inhibitors 3
3
1- Junttila TT. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. May 5; 2009 15(5):429–40.2- Eichhorn PJA. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. Nov 15; 2008 68(22):9221–30. 3- Chakrabarty A. Trastuzumab-Resistant Cells Rely on a HER2-PI3K-FoxO-Survivin Axis and Are Sensitive to PI3K Inhibitors. Cancer Res. Feb 1; 2013 73(3):1190–200.
Phase I study of alpelisib (BYL-719) and T-DM1 in HER2 + ABC after trastuzumab and taxane therapy
• Phase 1 dose de-escalation
• Alpelisib orally daily plus T-DM1 3.6mg/kgMethods
• MTD and toxicity of alpelisib combined with T-DM1
• ORR according to PIK3CA mut status (mut 40%, WT 22%)
• mPFS 7.6 months
CDK 4/6 and anti-HER2 Resistance
Corona SP et al Crit Rev in Oncol/Hematol 2017 112: 208-2014; Goel S et al Cancer Cell 2016 29 (3):255-269
Palbociclib Phase 2 designPATRICIA
N = 225
N = 138
R
Ciruelos E, Villagrasa P, Paré L, Oliveira M, Pernas S, Cortés J, Soberino J, Adamo B, Vazquez S, Martínez N, Perelló A, Bermejo B, Martínez E, Garau I, Melé M, Morales S, Galván P, Pascual T, Canes J, Nuciforo P, Gonzalez X, Prat A. SOLTI-1303 PATRICIA phase II trial (STAGE 1) --Palbociclib and trastuzumab in postmenopausal patients with HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-03
Arm A
Arm B1
Arm B2
PATRICIA stage 1 results
N = 225
N = 138
Ciruelos E, Villagrasa P, Paré L, Oliveira M, Pernas S, Cortés J, Soberino J, Adamo B, Vazquez S, Martínez N, Perelló A, Bermejo B, Martínez E, Garau I, Melé M, Morales S, Galván P, Pascual T, Canes J, Nuciforo P, Gonzalez X, Prat A. SOLTI-1303 PATRICIA phase II trial (STAGE 1) -- Palbociclib and trastuzumab in postmenopausal patients with HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-03
Investigational treatment optionsNew TKIs: a niche for patients with CNS involvement?
Drug/target Trial name Phase Population Regimen Sample Size
Pyrotinib NCT02973737 Phase 3 Failed up to 2 lines, including taxane/trastuzumab
Pyrotinib + Cape vs Placebo + Cape
279
Neratinib NCT01808573 Phase 3 Failed at least 2 lines of anti-HER2 therapy
Neratinib + Cape vs Lapatinib + cape
621
Tucatinib NCT02614794 Phase 2 Failed at least 2 lines of anti-HER2 therapy (including T and L)
Cape+T+Tucatinibvs Cape+T+placebo
480
Poziotinib NCT02418689 Phase 2 Failed at least 2 lines of anti-HER2 therapy (including T, L, P, T-DM1)
Poziotinib 104
Poziotinib NCT02544997 Phase 2 HER2+ (or EGFR/AR+) failed at least two lines of therapy including useof Anthra and taxane
Poziotinib 30
Poziotinib NCT02659514 Phase 2 Failed at least 2 lines of anti-HER2 therapy (including T and T-DM1)
Poziotinib 70
PHENIX Study Design<br /> Pyrotinib combined with capecitabine in women with HER2+ metastatic breast caNcer prevIously treated with trastuzumab and taXanes: a randomized
phase 3 study<br />
Presented By Zefei Jiang at 2019 ASCO Annual Meeting
• No pts previously pre-treated with T-DM1 or Pertuzumab
Slide 9
Presented By Zefei Jiang at 2019 ASCO Annual Meeting
• AE profile consistent with the class of TKIs: G3 diarrhea and hand-foot syndrome of 30.8% and 15.7% in experimental arm vs 12.8% and 5.3% in placebo arm, respectively
Slide 11
Presented By Zefei Jiang at 2019 ASCO Annual Meeting
Slide 14
Presented By Zefei Jiang at 2019 ASCO Annual Meeting
NALA study design
Presented By Cristina Saura at 2019 ASCO Annual Meeting
• Only ≈ 34% pre-treated with trastuzumab/pertuzumab and afterwards T-DM1
Centrally confirmed PFS (co-primary endpoint)
Presented By Cristina Saura at 2019 ASCO Annual Meeting
PFS: Forest plot
Presented By Cristina Saura at 2019 ASCO Annual Meeting
• No OS benefit (HR 0.88; p = 0.2086)
Time to intervention for CNS metastases
Presented By Cristina Saura at 2019 ASCO Annual Meeting
Most frequent grade 3/4 adverse events
Presented By Cristina Saura at 2019 ASCO Annual Meeting
Margetuximab: Fc-engineered to Activate Immune Responses
Presented By Hope Rugo at 2019 ASCO Annual Meeting
Study CP-MGAH22-04 (SOPHIA) Design1,2
Presented By Hope Rugo at 2019 ASCO Annual Meeting
ITT Population: Prior Cancer Therapy
Presented By Hope Rugo at 2019 ASCO Annual Meeting
PFS Analysis in ITT Population
Presented By Hope Rugo at 2019 ASCO Annual Meeting
PFS Subgroup Analyses
Presented By Hope Rugo at 2019 ASCO Annual Meeting
AEs Regardless of Causality<br /><br />
Presented By Hope Rugo at 2019 ASCO Annual Meeting
Conclusions (I)◆ We walked a long path during the last 15 years.
◆ There is a better understanding of the optimal sequencing in metastatic disease:
◆ So far, more data is needed to safely eliminate ChT in 1° line, although frail patients may benefit from this strategy.