Slide 1: NSABP FB-10: Phase IB Dose-Escalation Study of T-DM1 with Neratinib
NSABP FB-10: Phase IB Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) with Neratinib in Women with Metastatic HER2- Positive Breast Cancer Jame Abraham,1 Shannon L. Puhalla,2 William M. Sikov,3 Alberto J. Montero,1 Jan H. Beumer,2 Marc E. Buyse,4 Laura M. Adamson,5
Slide 2: Disclosure Information
AACR 2017 Disclosure Information The following authors declare the following potential conflicts of interest: - Jame Abraham: Genentech (Speaker); Pfizer (Speaker) - Shannon L. Puhalla: Abbvie, Pfizer, Lilly, Novartis, Incyte, Covance-Bayer, Eisai (Grant/Research support); Abbvie, Medimmune, Alldex
Slide 3: Trastuzumab Emtansine (T-DM1)
Trastuzumab Emtansine (T-DM1) • T-DM1 is a conjugated antibody. Trastuzumab is armed to deliver the maytansinoid antimicrotubule agent, DM1, to antigen- expressing HER2-positive cells • DM-1, a potent cytotoxic agent, binds to microtubules similar to vinca alkaloids LoRusso PM, et al. Clin Cancer Re
Slide 4: Neratinib: Tyrosine Kinase Inhibitor
Neratinib: Tyrosine Kinase Inhibitor • Neratinib, an oral TKI, irreversibly inhibits pan-ERBB receptor tyrosine kinases • Irreversible binding due to covalent interaction between neratinib and cysteine residue within ATP binding site Mohamed A, et al. Am J Pathol 2013; 183:1096-12 DOI: 10.1016/j.ajp
Slide 5: Clinical Background
Clinical Background • EMILIA, a phase III randomized trial of T-DM1 v capecitabine plus lapatinib (C-L) in MBC pts previously treated in first-line with trastuzumab plus taxane – PFS: T-DM1 v C-L was 9.4 mo v 6.4 mo (p<0.001) – ORR: T-DM1 v C-L was 43.6% v 30.8 % (p=0.001) • T-DM1 after trastuzumab
Slide 6: NSABP FB-10 Overview
NSABP FB-10 Overview Metastatic HER2-Positive Breast Cancer with Prior Trastuzumab and Pertuzumab Treatment Study Entry Treatment Regimen for All Patients T-DM1 3.6 mg/kg i.v. Day 1 every 21 days* Neratinib PO daily beginning on Day 1 of T-DM1 and continuing until disease progression *T-DM1 Dose lev
Slide 7: Primary Aim for Phase Ib
Primary Aim for Phase Ib Aim: To determine the safety and tolerability of T-DM1 and neratinib Endpoint: Recommended phase II dose (RP2D) of T-DM1 and neratinib that can be administered in combination
Slide 8: Secondary Aims
Secondary Aims • Objective response rate (ORR) • Progression-free survival (PFS) • Clinical benefit rate (CR, PR, and SD) • Toxicity • Correlative studies
Slide 9: Key Eligibility
Key Eligibility • Confirmed diagnosis of invasive adenocarcinoma of the breast • Documentation of measurable disease • Breast cancer determined to be HER2-positive • Must have had anti-HER2-based therapy with trastuzumab and pertuzumab as neoadjuvant, adjuvant, or in first-line metastatic disease
Slide 10: Key Ineligibility
Key Ineligibility • Previous therapy with T-DM1 or any HER2 TKI • Persistent > grade 2 diarrhea • Symptomatic brain metastases • Active hepatitis • Conditions significantly affecting GI function
Slide 11: Patient Characteristics
Patient Characteristics Characteristic N=22 Age Mean 48.3 Range 34-67 Performance status 0 16 1 6 ER- or PR-positive Yes 12 No 10 Trastuzumab + pertuzumab Neoadjuvant 13 Adjuvant 3 Metastatic 6 Sites of metastatic disease Brain 7 Visceral 14 Skin / lymph node 13 Bone 9
Slide 12: Dose-Limiting Toxicities (DLTs) by Dose of Neratinib
Dose-Limiting Toxicities (DLTs) by Dose of Neratinib Grade of diarrhea Cohort, mg/d No. of pts No. of DLTs / dehydration of neratinib (No. of pts) 120 6 1 3 (1) 160 4 0 _ 2 (1) / 3 (1) 200 8 3 3 (2) 2 (1) / 3 (1) 240 3 2 3 (1)
Slide 13: Treatment-related Adverse Events (All doses)
Treatment-related Adverse Events ( All doses) N=21 Gr 1 Gr 2 Gr 3 Gr 4 Gr 5 Adverse Event Any Grade #Pts (%) #Pts (%) #Pts (%) #Pts (%) #Pts (%) Diarrhea 85% 3 (14) 11 (52) 4(19%) 0 0 Nausea 66% 4 (19) 7 (33) 3 (14) 0 0 Anorexia 39% 2 (10) 6 (29) 0 0 0 Fatigue 39% 1 (5) 6 (29) 1 (5) 0 0 Vomiting 47%
Slide 14: % Change in Size of Target Lesions
% Change in Size of Target Lesions PD 100% SD 80% CR/PR 60% 40% 20% 0% -20% -40% -60% -80% -100% 5 non-evaluable pts: Withdrew consent: 1; DLTs: 4
Slide 15: Evaluable Patients by Dose-level (RECIST)
Evaluable Patients by Dose-level ( RECIST) 240 mg 16 15 * 14 13 + 12 Progressive 11 200 mg 10 * Stable 9 8 Partial 7 6 ** + 160 mg Complete 5 4 * + On treatment 3 2 1 * 120 mg * Off tx AE/withdraw 0 10 20 30 40 50 60 70 80 Weeks
Slide 16: Neratinib Trough Concentration at Steady-state
FC-7 and FB-10: Neratinib Trough Concentration at Steady-state, Day 1 of Cycle 2 Corrected [neratinib] vs Dose • Trough levels are overlapping at all 50 45 study doses C-Neratinib (ng/mL) 40 35 FC7 • Need more 30 25 FB10 complete PK data 20 15 to correlate 10 toxicity and 5 0 response (peak 0 60 120
Slide 17: Progression in skin, contralateral breast mass, lung, and liver lesions
Progression in skin, contralateral breast mass, lung, and multiple liver lesions Neratinib 120 mg
Slide 18: Before treatment, Neratinib 120 mg, After 2 cycles
Before treatment Neratinib 120 mg After 2 cycles of treatment
Slide 19: Baseline and After Cycles of Treatment, Neratinib 160 mg
Baseline After 1 Cycle of Treatment After 3 Cycles of Treatment Neratinib 160 mg
Slide 20: Conclusions
Conclusions • Diarrhea was the major dose-limiting toxicity in this dose-escalation trial • In patients with prior trastuzumab and pertuzumab, activity was seen across all dose-levels of neratinib – ORR (CR/PR): 9 of 16 (56%) • Additional patients are being accrued at 160 mg/d of neratinib to define
Slide 21: Future Directions
Future Directions • A Phase II trial will be conducted at the RP2D and will evaluate PK more fully to determine if any correlation with response and toxicity • Phase II study will evaluate anti-diarrheal regimen with loperamide and budesonide, which has been shown to decrease occurrence of grade 3 d
Slide 22: Acknowledgements
Acknowledgements • We thank our patients and their family members • Our outstanding clinical trial team • NSABP study team • Puma Biotechnology, Inc.