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

esmo.org

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 Untch1, Charles E. Geyer, Jr.2, Chiun-Sheng Huang3, Sibylle Loibl4, Norman Wolmark5, Max S. Mano6, Gunter von Minckwitz7, Adam Brufsky8, Xavier Pivot9, Jonathan Polikoff10, Andrea Fontana11, Bella Kaufman12, Juan Carlos Alcedo13, Thomas Boulet14, Haiying Liu15, Chunyan Song15, Eleftherios P. Mamounas16

1AGO-B and HELIOS Klinikum Berlin Buch, Berlin, Germany; 2NSABP Foundation and Virginia Commonwealth University Massey Cancer

Center, Richmond, VA, USA; 3National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan;

4GBG, Neu-Isenburg, Germany; Centre for Haematology and Oncology Bethanien, Frankfurt, Germany; 5NSABP Foundation and The

University of Pittsburgh, Pittsburgh, PA, USA; 6Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil; 7GBG, Neu-Isenburg, Germany; 8UPMC, Pittsburgh, PA, USA; 9Centre Paul Strauss, l'Institut Régional du Cancer, Strasbourg, France; 10Southern California Kaiser Permanente Medical Group, San Diego, CA, USA; 11Azienda Ospedaliero Universitaria Pisana, Ospedale Santa Chiara, Pisa, Italy;

12Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; 13Centro Hemato Oncologico, Panama City, Panama; 14F. Hoffmann-La Roche,

Basel, Switzerland; 15Genentech, Inc., South San Francisco, CA, USA; 16NSABP 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 response1–5

• 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 arm6

• 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

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)

T-DM1 3.6 mg/kg IV Q3W 14 cycles Trastuzumab 6 mg/kg IV Q3W 14 cycles

Radiation and endocrine therapy per protocol and local guidelines R 1:1

N=1486

• cT1-4/N0-3/M0 at presentation

(cT1a-b/N0 excluded)

• Centrally confirmed HER2-positive BC
• Neoadjuvant therapy

– ≥6 cycles of chemotherapy – ≥9 weeks of taxane and trastuzumab

• Residual invasive tumour in breast or

axillary nodes

• Randomization within 12 weeks of surgery
• Patients with grade 1 peripheral neuropathy

were eligible

Access slides at: https://bit.ly/2NGjKsV

PRIMARY ENDPOINT: INVASIVE DISEASE-FREE SURVIVAL

100 80 60 40 20

743 743

• No. at Risk

Trastuzumab T-DM1 676 707 635 681 594 658 555 633 501 561 342 409 220 255 119 142 38 44 4 4

6 12 18 24 30 Time, mo Invasive Disease-Free Survival Rate, % 36 42 48 54 60 Trastuzumab T-DM1 3-year IDFS 77.0% 88.3% Trastuzumab T-DM1 (n=743) (n=743) IDFS Events, no. (%) 165 (22.2) 91 (12.2) P<0.0001 Unstratified HR=0.50 (95% CI, 0.39–0.64) von Minckwitz G, et al. N Engl J Med. 2019;380:617-28.

Access slides at: https://bit.ly/2NGjKsV Median follow-up time: ~40 months

On-Study Peripheral Neuropathya (safety population) BL Neuropathy No BL Neuropathy T-DM1 H T-DM1 H All Grades, % 36.3 17.5 31.1 16.8 Grade 1 18.5 12.3 23.1 14.3 Grade 2 14.3 5.2 7.0 2.3 Grade 3 3.6 0.0 1.0 0.2 Grade 4 0.0 0.0 0.0 0.0 Median Duration, d 352 337 243 232 Resolutionb Rate, % 66.0 63.6 81.2 82.5

• BL neuropathy was well balanced between

treatment arms: T-DM1 22.7%; H 21.4%

• Incidence of peripheral neuropathy was higher

with T-DM1, regardless of BL neuropathy

• Resolution rate was similar in both arms,

regardless of BL neuropathy

• Irrespective of study treatment, BL neuropathy

was associated with:

– Longer median peripheral neuropathy duration – Lower rates of peripheral neuropathy resolution

EFFECT OF BASELINE PERIPHERAL NEUROPATHY ON TREATMENT-INDUCED PERIPHERAL NEUROPATHY

BL, baseline; d, days; H, trastuzumab.

aIncidence refers to peripheral neuropathy; duration and resolution applies

to peripheral sensory neuropathy; bReported by investigator as “resolved.”

Access slides at: https://bit.ly/2NGjKsV

On-Study Peripheral Neuropathy (safety population) Docetaxel Paclitaxel T-DM1 (n=402) H (n=411) T-DM1 (n=351) H (n=319) All Grades, % 32.1 17.8 31.9 16.6 Grade 1 22.1 14.1 21.7 13.8 Grade 2 8.0 3.6 9.4 2.5 Grade 3 2.0 0.0 0.9 0.3 Grade 4 0.0 0.0 0.0 0.0

• The type of neoadjuvant taxane was similar

between treatment arms:

– Docetaxel: T-DM1 54%; H 57% – Paclitaxel: T-DM1 47%; H 44% – Nab-paclitaxel: T-DM1 0.8%; H 0%

• BL neuropathy incidence was the same

between treatment arms in patients with prior docetaxel (T-DM1 23%; H 23%) but was numerically higher in the T-DM1 arm in those with prior paclitaxel (T-DM1 23%; H 18%)

• The incidence of peripheral neuropathy was

similar within each treatment arm, irrespective

• f the type of neoadjuvant taxane received

EFFECT OF PRIOR TAXANE TYPE ON INCIDENCE OF PERIPHERAL NEUROPATHY

BL, baseline; H, trastuzumab.

Access slides at: https://bit.ly/2NGjKsV

Thrombocytopaenia (safety population) Prior platinum No prior platinum T-DM1 H T-DM1 H All Grades, % 36.2 3.3 26.7 2.1 Grade 1 15.6 3.3 13.9 1.6 Grade 2 7.1 0.0 9.0 0.2 Grade 3 8.5 0.0 2.5 0.2 Grade 4 5.0 0.0 1.3 0.2 Median Duration of Grade 3–4, d 33 — 29 110a Resolution Rate of Grade 3–4, % 95 — 96 100a

• Overall, 20% of patients received prior

carboplatin or cisplatin (T-DM1 arm 19%, H arm 21%)

• Prior platinum was associated with a

higher incidence of thrombocytopaenia in the T-DM1 arm

• The median duration and resolution rate of

grade 3–4 thrombocytopaenia were similar irrespective of prior platinum therapy

EFFECT OF PRIOR PLATINUM THERAPY ON T-DM1–ASSOCIATED THROMBOCYTOPAENIA

d, days; H, trastuzumab.

aBased on two events.

Access slides at: https://bit.ly/2NGjKsV

Site of First Invasive Disease Event Event, n (%) T-DM1 (n=743) H (n=743) Any Invasive-Disease Event 91 (12.2) 165 (22.2) Category of Invasive Event Distant Recurrence 78 (10.5) 118 (15.9) CNS 44 (5.9) 32 (4.3) Non-CNS 34 (4.6) 86 (11.6) Locoregional Recurrence 8 (1.1) 34 (4.6) Contralateral Breast Cancer 3 (0.4) 10 (1.3) Death without Previous Event 2 (0.3) 3 (0.4)

• In the primary KATHERINE

results, there was a numerically higher rate of CNS recurrence as first site of recurrence in the T-DM1 arm1

• To better understand these

data and the potential impact

• n overall survival, additional

analyses were performed

CNS RECURRENCE: BACKGROUND

H, trastuzumab.

• 1. von Minckwitz G, et al. N Engl J Med. 2019;380:617–28.

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.

Access slides at: https://bit.ly/2NGjKsV

CNS Recurrence T-DM1 (n=743) H (n=743) Patients with CNS Recurrence, n (%) 45 (6.1) 40 (5.4) As First IDFS Eventa 44 (5.9) 32 (4.3) After First IDFS Eventb 1 (0.1) 8 (1.1) Patients with CNS as Only Eventc 36 (4.8) 21 (2.8) Median Time to CNS Recurrence, mo 17.5 11.9

• The numerically higher rate of CNS recurrence as a first

IDFS event in the T-DM1 arm may be explained by competing risk,1,2 as seen in adjuvant trastuzumab trials3

– Competing risk: The substantial reduction in the incidence of non-CNS recurrences as a first event observed with T-DM1 leads to an increased likelihood of a CNS recurrence as a first event and as the only recurrence

• This is supported by

– Similar cumulative incidence of CNS recurrence in both arms – Longer time (Δ5.6 m) to CNS recurrence in the T-DM1 arm – Higher incidence of CNS recurrence as the only recurrence in the T-DM1 arm

HIGHER CNS RECURRENCE AS FIRST IDFS EVENT IS LIKELY DUE TO COMPETING RISK; T-DM1 WAS NOT ASSOCIATED WITH AN INCREASED OVERALL RISK OF CNS RECURRENCE

• 1. Wolkewitz M, et al. BMJ. 2014; 349:g5060; 2. Gooley TA, et al. Stat Med.

1999;18:695–706; 3. Pestalozzi BC, et al. Lancet Oncol. 2013;14:244–8. Note: CNS recurrence withina or afterb 61 days of first IDFS event, or any timec.

Access slides at: https://bit.ly/2NGjKsV

H, trastuzumab.

OS after CNS Recurrence at Any Time T-DM1 (n=45) H (n=40) Patients with OS Event, n (%) 26 (57.8) 21 (52.5) Patients without OS Event, n (%) 19 (42.2) 19 (47.5) Median Survival (95% CI), mo 12.5 (8.6–26.6) 14.3 (7.6–29.8) Unstratified HR (95% CI) 1.07 (0.60–1.91) 3-Year Event-Free Rate, % (95% CI) 24.2 (5.05–43.3) 25.4 (6.81–44.0)

OVERALL SURVIVAL IS SIMILAR BETWEEN TREATMENT ARMS AFTER CNS RECURRENCE

• There was no evidence that the numerically higher rate of CNS recurrence as a first

event in the T-DM1 arm had a detrimental impact on overall survival

• Between the two treatment arms, there was:

– Similar time from CNS recurrence at any time to death – Similar death rates among patients with CNS recurrence at any time point

Access slides at: https://bit.ly/2NGjKsV

H, trastuzumab.

OVERALL SURVIVAL AFTER CNS RECURRENCE AT ANY TIME

Unstratified HR (95% CI)=1.07 (0.60–1.91)

Trastuzumab (n=40) T-DM1 (n=45) 0.0 0.2 0.4 0.6 0.8 1.0 Proportion Event-Free 6 12 18 24 30 36 42 48 54 60

40 45 24 30 14 19 9 11 7 5 4 3 3 2 1 1 Trastuzumab T-DM1

• No. of patients at risk

Time (mo)

Access slides at: https://bit.ly/2NGjKsV

SUMMARY AND CONCLUSIONS

• In KATHERINE, regardless of treatment arm, baseline neuropathy was associated with a

longer duration and a lower resolution rate of treatment-associated peripheral neuropathy

• The type of neoadjuvant taxane received did not influence the incidence of peripheral

neuropathy in either treatment arm

• Prior platinum therapy was associated with an increased incidence of thrombocytopaenia

in the T-DM1 arm, but it did not affect the duration or resolution of grade 3–4 thrombocytopaenia

• The numerically higher incidence of CNS recurrence as the first IDFS event in the T-DM1

vs the trastuzumab arm is likely due to competing risk. T-DM1 was not associated with an increased overall risk of CNS recurrence

• There was a longer time to CNS recurrence in the T-DM1 arm vs the trastuzumab arm;
• verall survival was similar in the T-DM1 and trastuzumab arms after CNS recurrence
• Therapies that prevent CNS recurrence as first IDFS event remain an unmet need in

HER2-positive breast cancer

Access slides at: https://bit.ly/2NGjKsV

ACKNOWLEDGEMENTS

• The patients and their families
• The KATHERINE investigators and clinical study sites
• This trial was sponsored by F. Hoffmann-La Roche Ltd
• Medical writing assistance for this presentation was provided by Twist Medical and

funded by F. Hoffmann-La Roche, Ltd

Access slides at: https://bit.ly/2NGjKsV