PERIPHERAL NEUROPATHY, THROMBOCYTOPAENIA, AND CENTRAL NERVOUS SYSTEM - PowerPoint PPT Presentation

PERIPHERAL NEUROPATHY, THROMBOCYTOPAENIA, AND CENTRAL NERVOUS SYSTEM RECURRENCE: AN UPDATE OF THE PHASE III KATHERINE TRIAL OF POST- NEOADJUVANT TRASTUZUMAB EMTANSINE (T-DM1) OR TRASTUZUMAB IN PATIENTS WITH RESIDUAL INVASIVE HER2-POSITIVE BREAST CANCER Michael Untch 1 , Charles E. Geyer, Jr. 2 , Chiun-Sheng Huang 3 , Sibylle Loibl 4 , Norman Wolmark 5 , Max S. Mano 6 , Gunter von Minckwitz 7 , Adam Brufsky 8 , Xavier Pivot 9 , Jonathan Polikoff 10 , Andrea Fontana 11 , Bella Kaufman 12 , Juan Carlos Alcedo 13 , Thomas Boulet 14 , Haiying Liu 15 , Chunyan Song 15 , Eleftherios P. Mamounas 16 1 AGO-B and HELIOS Klinikum Berlin Buch, Berlin, Germany; 2 NSABP Foundation and Virginia Commonwealth University Massey Cancer Center, Richmond, VA, USA; 3 National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; 4 GBG, Neu-Isenburg, Germany; Centre for Haematology and Oncology Bethanien, Frankfurt, Germany; 5 NSABP Foundation and The University of Pittsburgh, Pittsburgh, PA, USA; 6 Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil; 7 GBG, Neu-Isenburg, Germany; 8 UPMC, Pittsburgh, PA, USA; 9 Centre Paul Strauss, l'Institut Régional du Cancer, Strasbourg, France; 10 Southern California Kaiser Permanente Medical Group, San Diego, CA, USA; 11 Azienda Ospedaliero Universitaria Pisana, Ospedale Santa Chiara, Pisa, Italy; esmo.org 12 Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; 13 Centro Hemato Oncologico, Panama City, Panama; 14 F. Hoffmann-La Roche, Basel, Switzerland; 15 Genentech, Inc., South San Francisco, CA, USA; 16 NSABP Foundation and Orlando Health University of Florida Health Cancer Center, Orlando, FL, USA Access slides at: https://bit.ly/2NGjKsV

DISCLOSURES Consulting fees from the following companies have been paid to Prof. Untch’s institution: Abbvie, Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Lilly Germany, Lilly International, Merck, MSD Mundipharma, Myriad Genetics, Novartis, Odonate, Pierre Fabre, Pfizer, PUMA Biotechnology, F. Hoffmann-La Roche, Sanofi Aventis, and TEVA Pharmaceuticals Access slides at: https://bit.ly/2NGjKsV

BACKGROUND • Patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant treatment have worse outcomes than those with a complete response 1–5 • The KATHERINE study (NCT01772472) investigated the use of adjuvant T-DM1 versus trastuzumab in patients with HER2-positive early breast cancer and residual invasive disease following neoadjuvant treatment and showed significant IDFS benefit and a positive trend for OS benefit with T-DM1 – T-DM1 is now approved in the US for the adjuvant treatment of residual invasive HER2-positive breast cancer after neoadjuvant taxane- and trastuzumab-based treatment • In KATHERINE, patients in the T-DM1 arm had higher rates of peripheral neuropathy and thrombocytopaenia. There was also a numerically higher incidence of CNS recurrence as first invasive disease-free survival event in the T-DM1 arm 6 • This analysis aimed to gain greater insight into these findings 1. Untch M, et al. J Clin Oncol. 2011;29:3351–7; 2. Cortazar P, et al. Lancet. 2014;384:164–72; 3. de Azambuja E, et al. Lancet Oncol. 2014;15:1137–46; 4. Gianni L, et al. Lancet Oncol. 2014;15:640–7; 5. Schneeweiss A, et al. Eur J Cancer. 2018;89:27–35; 6. von Minckwitz G, et al. N Engl J Med 2019;380:617–28. Access slides at: https://bit.ly/2NGjKsV

KATHERINE STUDY DESIGN • cT1-4/N0-3/M0 at presentation (cT1a-b/N0 excluded) T-DM1 • Centrally confirmed HER2-positive BC 3.6 mg/kg IV Q3W R • Neoadjuvant therapy 14 cycles 1:1 – ≥6 cycles of chemotherapy – ≥9 weeks of taxane and trastuzumab Trastuzumab N=1486 • Residual invasive tumour in breast or 6 mg/kg IV Q3W axillary nodes 14 cycles • Randomization within 12 weeks of surgery Radiation and endocrine therapy per • Patients with grade 1 peripheral neuropathy protocol and local guidelines were eligible Stratification factors: Clinical presentation (inoperable vs operable); hormone receptor status (ER+ or PR+ vs ER− and PR− or unknown); preoperative therapy (trastuzumab vs trastuzumab plus other HER2- targeted therapy); pathological nodal status after neoadjuvant therapy (+ vs − or not done) Access slides at: https://bit.ly/2NGjKsV

PRIMARY ENDPOINT: INVASIVE DISEASE-FREE SURVIVAL 100 Invasive Disease-Free Survival Rate, % 80 Trastuzumab 60 T-DM1 Trastuzumab T-DM1 (n=743) (n=743) 40 IDFS Events, no. (%) 165 (22.2) 91 (12.2) Unstratified HR=0.50 (95% CI, 0.39–0.64) 20 P <0.0001 3-year IDFS 77.0% 88.3% Median follow-up time: ~40 months 0 0 6 12 18 24 30 36 42 48 54 60 Time, mo No. at Risk Trastuzumab 743 676 635 594 555 501 342 220 119 38 4 T-DM1 743 707 681 658 633 561 409 255 142 44 4 von Minckwitz G, et al. N Engl J Med. 2019;380:617-28. Access slides at: https://bit.ly/2NGjKsV

EFFECT OF BASELINE PERIPHERAL NEUROPATHY ON TREATMENT-INDUCED PERIPHERAL NEUROPATHY On-Study BL No BL Peripheral Neuropathy Neuropathy • BL neuropathy was well balanced between Neuropathy a T-DM1 H T-DM1 H treatment arms: T-DM1 22.7%; H 21.4% (safety population) All Grades, % 36.3 17.5 31.1 16.8 • Incidence of peripheral neuropathy was higher with T-DM1, regardless of BL neuropathy Grade 1 18.5 12.3 23.1 14.3 • Resolution rate was similar in both arms, Grade 2 14.3 5.2 7.0 2.3 regardless of BL neuropathy Grade 3 3.6 0.0 1.0 0.2 • Irrespective of study treatment, BL neuropathy Grade 4 0.0 0.0 0.0 0.0 was associated with: 352 337 243 232 Median Duration, d – Longer median peripheral neuropathy duration Resolution b Rate, % 66.0 63.6 81.2 82.5 – Lower rates of peripheral neuropathy resolution a Incidence refers to peripheral neuropathy; duration and resolution applies to peripheral sensory neuropathy; b Reported by investigator as “resolved.” BL, baseline; d, days; H, trastuzumab. Access slides at: https://bit.ly/2NGjKsV

EFFECT OF PRIOR TAXANE TYPE ON INCIDENCE OF PERIPHERAL NEUROPATHY • The type of neoadjuvant taxane was similar On-Study Docetaxel Paclitaxel between treatment arms: Peripheral Neuropathy – Docetaxel: T-DM1 54%; H 57% T-DM1 H T-DM1 H (safety (n=402) (n=411) (n=351) (n=319) – Paclitaxel: T-DM1 47%; H 44% population) – Nab-paclitaxel: T-DM1 0.8%; H 0% All Grades, % 32.1 17.8 31.9 16.6 • BL neuropathy incidence was the same Grade 1 22.1 14.1 21.7 13.8 between treatment arms in patients with prior Grade 2 8.0 3.6 9.4 2.5 docetaxel (T-DM1 23%; H 23%) but was Grade 3 2.0 0.0 0.9 0.3 numerically higher in the T-DM1 arm in those Grade 4 0.0 0.0 0.0 0.0 with prior paclitaxel (T-DM1 23%; H 18%) • The incidence of peripheral neuropathy was similar within each treatment arm, irrespective of the type of neoadjuvant taxane received BL, baseline; H, trastuzumab. Access slides at: https://bit.ly/2NGjKsV

EFFECT OF PRIOR PLATINUM THERAPY ON T-DM1–ASSOCIATED THROMBOCYTOPAENIA • Overall, 20% of patients received prior Prior platinum No prior platinum Thrombocytopaenia carboplatin or cisplatin (safety population) T-DM1 H T-DM1 H (T-DM1 arm 19%, H arm 21%) All Grades, % 36.2 3.3 26.7 2.1 • Prior platinum was associated with a Grade 1 15.6 3.3 13.9 1.6 higher incidence of thrombocytopaenia in 7.1 0.0 9.0 0.2 Grade 2 the T-DM1 arm Grade 3 8.5 0.0 2.5 0.2 Grade 4 5.0 0.0 1.3 0.2 • The median duration and resolution rate of grade 3–4 thrombocytopaenia were similar Median Duration of 33 — 29 110 a Grade 3–4, d irrespective of prior platinum therapy Resolution Rate of 95 — 96 100 a Grade 3–4, % a Based on two events. d, days; H, trastuzumab. Access slides at: https://bit.ly/2NGjKsV

CNS RECURRENCE: BACKGROUND • In the primary KATHERINE Site of First Invasive Disease Event results, there was a Event, n (%) T-DM1 (n=743) H (n=743) numerically higher rate of Any Invasive-Disease Event 91 (12.2) 165 (22.2) CNS recurrence as first site of Category of Invasive Event recurrence in the T-DM1 arm 1 Distant Recurrence 78 (10.5) 118 (15.9) CNS 44 (5.9) 32 (4.3) • To better understand these data and the potential impact Non-CNS 34 (4.6) 86 (11.6) on overall survival, additional Locoregional Recurrence 8 (1.1) 34 (4.6) analyses were performed Contralateral Breast Cancer 3 (0.4) 10 (1.3) Death without Previous Event 2 (0.3) 3 (0.4) Patients with additional IDFS event(s) within 61 days of their first event were reported in the category according to the following hierarchy: (1) distant recurrence; (2) locoregional recurrence; (3) contralateral breast cancer; (4) death without prior event. 1. von Minckwitz G, et al. N Engl J Med. 2019;380:617–28. H, trastuzumab. Access slides at: https://bit.ly/2NGjKsV