Nera%nib plus capecitabine versus lapa%nib plus capecitabine in pa%ents with HER2-posi%ve metasta%c breast cancer previously treated with ≥2 HER2-directed regimens: Findings from the mul%na%onal, randomized, phase 3 NALA trial Cris%na Saura, Mafalda Oliveira, Yin-Hsun Feng, Ming-Shen Dai, Sara A Hurvitz, Sung-Bae Kim, Beverly Moy, SuzeBe Delaloge, William Gradishar, Norikazu Masuda, Marketa Palacova, Maureen E Trudeau, Johanna MaBson, Yoon Sim Yap, Richard Bryce, Bin Yao, Judith Bebchuk, Kiana Keyvanjah, Adam Brufsky, NALA Inves%gators Vall d’Hebron University Hospital, Vall d’Hebron Ins6tute of Oncology (VHIO), Barcelona, Spain; Chi Mei Medical Centre, Tainan, Taiwan; Tri-Service General Hospital, Taipei, Taiwan; UCLA Hematology/Oncology Clinical Research Unit, Santa Monica, CA; University of Ulsan College of Medicine, Seoul, Republic of Korea; MassachuseNs General Hospital Cancer Center, Boston, MA; Ins6tut Gustave Roussy, Villejuif, France; Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; NHO Osaka Na6onal Hospital, Osaka, Japan; Masaryk Memorial Cancer Ins6tute, Brno, Czech Republic; Sunnybrook Health Sciences Centre, Toronto, ON; Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland; Na6onal Cancer Centre Singapore, Singapore, Singapore; Puma Biotechnology Inc, Los Angeles, CA; Magee-Womens Hospital of UPMC, PiNsburgh, PA 1 Adam Brufsky
Disclosure informa%on – Adam Brufsky Consul%ng or Advisory Role Eisai, Myriad Pharmaceu%cals, Merck, Bioarray Therapeu%cs, Puma Biotechnology, Genomic Health, NanoString Technologies, BioTheranos%cs, Lilly, Bayer, Novar%s, Celgene, Agendia, Genentech/Roche, Pfizer Adam Brufsky
Nera%nib: An irreversible pan-HER TKI EGFR:EGFR HER2:EGFR HER2:HER3 HER2:HER2 HER2:HER4 Aberrant HER activation by: • Gene amplification • Receptor overexpression • Somatic mutations HER receptor dimerization Kinase activation Neratinib • Nera%nib: pan-HER (HER1, 2, and 4) TKI RAS PI3K • Breadth of targets for nera%nib in HER Downstream signal family of receptors (HER1, 2, and 4 for transduction RAF AKT PI3K pathway MAPK pathway nera%nib; HER1 and 2 for lapa%nib) MEK mTOR • Nera%nib binds irreversibly to HER1, 2, ERK and 4; lapa%nib binds reversibly Tumor growth, survival, Nucleus and spread • Cell cycle control and proliferation • Cell survival and decreased apoptosis • Cellular migration and metastasis • Angiogenesis TKI, tyrosine kinase inhibitor Rabindran et al. Cancer Res 2004 3 Nera%nib US PI 2018 Adam Brufsky
Clinical experience with nera%nib Extended adjuvant: Approved by FDA and EMA based on reduced risk of recurrence of iDFS event • with nera%nib vs placebo in ExteNET 1 Neoadjuvant: Higher pCR rates with chemotherapy + nera%nib vs chemotherapy + trastuzumab in • pa%ents with HER2+ breast cancer in I-SPY2 2 Metasta%c HER2+ disease: • – Study 2206: Promising efficacy with nera%nib + capecitabine in trastuzumab-pretreated pa%ents (recommended doses: nera%nib 240 mg/d + capecitabine 1500 mg/m 2 ) 3 – NSABP FB-10: Evidence of efficacy with nera%nib + T-DM1 in pa%ents previously treated with trastuzumab + pertuzumab 4 – NEfERT-T: Delayed CNS progression with nera%nib + paclitaxel in pa%ents with HER2+ brain metastases 5 – TBCRC 022: Nera%nib + capecitabine ac%ve against refractory brain metastases in pa%ents with HER2+ brain metastases 6 1. Mar%n et al. Lancet Oncol 2017; 2. Park et al. N Engl J Med 2016; 3. Saura et al. J Clin Oncol 2014 4 4. Abraham et al. J Clin Oncol 2018; 5. Awada et al. JAMA Oncol 2016; 6. Freedman et al. J Clin Oncol 2019 Adam Brufsky
NALA study design Nera%nib 240 mg/d + PD Capecitabine 1500 mg/m 2 14/21 d Inclusion criteria Loperamide (cycle 1) a Metasta%c breast cancer (MBC) • R Centrally confirmed HER2+ disease • Follow-up No endocrine therapy permi\ed (1:1) (survival) ≥2 lines of HER2-directed therapy for MBC • Asymptoma%c and stable brain • Lapa%nib 1250 mg/d + n=621 metastases permiBed PD Capecitabine 2000 mg/m 2 14/21 d Stra%fica%on variables Endpoints Number of prior HER2 therapies for MBC Co-primary: PFS (centrally confirmed) and OS • • Disease loca%on Secondary: PFS (local), ORR, DoR, CBR, interven%on for • • CNS metastases, safety, health outcomes HR status • Geographic loca%on • Loperamide 4 mg with first dose of nera%nib, followed by 2 mg every 4 h for first 3 d, then loperamide 2 mg every 6–8 h un%l end of Cycle 1. Therea`er as needed 5 Adam Brufsky
NALA Sta%s%cal methods Co-primary endpoints of PFS and OS • Conducted under an FDA Special Protocol Assessment • Study posi%ve if either co-primary endpoint met: – p<0.01 for PFS (419 target events required for 85% power) – p<0.04 for OS (378 target events required for 85% power) Planned analyses • Stra%fied log-rank test; Kaplan–Meier curves for PFS and OS • Stra%fied Cox propor%onal hazards model for hazard ra%os – Prespecified restricted means analysis, if propor%onal hazards assump%on did not hold 1 • Gray’s test of cumula%ve incidence for CNS endpoints 6 1. Uno et al. J Clin Oncol 2014 Adam Brufsky
NALA Baseline characteris%cs Nera%nib + Capecitabine Lapa%nib + Capecitabine (n=307) (n=314) Age <65 years, n (%) 244 (79) 248 (79) Geographic region, n (%) Europe 121 (39) 123 (39) North America 59 (19) 65 (21) Rest of world 127 (41) 126 (40) HR+ (ER+ and/or PR+), n (%) 181 (59) 186 (59) Disease loca%on at enrollment, n (%) Non-visceral only 60 (20) 61 (19) Visceral 247 (80) 253 (81) De novo metasta%c disease, n (%) 139 (45) 136 (43) No. of prior HER2 targeted therapies for MBC, n (%) 2 215 (70) 215 (68) ≥3 92 (30) 99 (32) Prior HER2 therapies for MBC, n (%) Trastuzumab only 124 (40) 113 (36) Trastuzumab + pertuzumab 24 (8) 23 (7) Trastuzumab + T-DM1 58 (19) 64 (20) Trastuzumab + pertuzumab + T-DM1 101 (33) 114 (36) 7 Adam Brufsky
NALA Centrally confirmed PFS (co-primary endpoint) 1.0 Hazard ra%o (95% CI) Log-rank p-value 0.9 Nera%nib + Capecitabine 0.8 0.76 (0.63–0.93) 0.0059 Lapa%nib + Capecitabine 0.7 PFS probability 0.6 47% 0.5 0.4 38% 29% 0.3 16% 0.2 15% 0.1 7% 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time since randomiza%on (months) No. at risk: 9 7 2 N+C 307 183 113 69 54 35 20 13 3 2 2 183 39 9 3 2 1 L+C 314 82 24 8 2 2 8 Adam Brufsky
NALA Prespecified restricted means analysis – PFS 1.0 Mean PFS (months) p-value 0.9 Nera%nib + Capecitabine 8.8 0.8 0.0003 Lapa%nib + Capecitabine 6.6 0.7 PFS probability 0.6 Restric%on: 24 months 0.5 0.4 0.3 2.2 months 0.2 0.1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time since randomiza%on (months) No. at risk: 9 7 2 N+C 307 183 113 69 54 35 20 13 3 2 2 183 39 9 3 2 1 L+C 314 82 24 8 2 2 9 Adam Brufsky
NALA PFS: Forest plot Hazard ra%o Events Interac%on test Hazard ra%o p-value (95% CI) (95% CI) Subgroup N N+C vs L+C Overall 621 210 vs 223 0.76 (0.63–0.93) Age group 0.463 0.74 (0.60–0.91) <65 years 492 169 vs 181 0.83 (0.53–1.28) ≥65 years 129 41 vs 42 Race 0.86 (0.67–1.11) 0.166 White 355 125 vs 117 Asian, black, or other 266 0.63 (0.47–0.85) 85 vs 106 Geographic region 0.051 0.81 (0.53–1.25) North America 124 41 vs 46 0.99 (0.72–1.35) Europe 244 83 vs 78 0.55 (0.41–0.75) Rest of world 253 86 vs 99 Disease loca%on 0.007 0.85 (0.69–1.04) Visceral 500 181 vs 185 0.44 (0.26–0.73) Non-visceral only 121 29 vs 38 HR status <0.001 0.42 (0.31–0.57) HR– 254 82 vs 108 1.08 (0.84–1.40) HR+ 367 128 vs 115 No. of prior HER2 regimens 0.614 0.76 (0.60–0.96) 2 430 148 vs 151 0.71 (0.50–1.00) ≥3 191 62 vs 72 0.25 1 4 Nera%nib + Capecitabine beBer Lapa%nib + Capecitabine beBer 10 Adam Brufsky
NALA OS (co-primary endpoint) 1.0 Mean OS Hazard ra%o (months) (95% CI) Log-rank p-value 0.9 Nera%nib + Capecitabine 24.0 0.8 0.88 (0.72–1.07) 0.2086 Lapa%nib + Capecitabine 22.2 0.7 OS probability 0.6 0.5 Restric%on: 48 months 0.4 0.3 0.2 1.7 months 0.1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 Time since randomiza%on (months) No. at risk: 82 64 47 34 28 18 15 294 244 182 112 13 4 1 N+C 307 275 220 142 6 2 47 22 84 67 36 27 17 12 1 L+C 314 303 273 240 208 170 132 107 8 4 3 11 Adam Brufsky
NALA OS: Forest plot Events Hazard ra%o Interac%on test Hazard ra%o N+C vs L+C (95% CI) p-value Subgroup N (95% CI) Overall 192 vs 218 621 0.88 (0.72–1.07) Age group 492 149 vs 171 0.86 (0.69–1.08) 0.941 <65 years 129 43 vs 47 0.86 (0.57–1.30) ≥65 years Race 355 113 vs 122 0.88 (0.68–1.13) 0.939 White 266 79 vs 96 0.85 (0.63–1.14) Asian, black, or other Geographic region 124 46 vs 51 1.06 (0.71–1.58) 0.313 North America 244 70 vs 85 0.82 (0.60–1.13) Europe 253 76 vs 82 0.83 (0.60–1.13) Rest of world Disease loca%on 500 165 vs 180 0.94 (0.76–1.16) 0.067 Visceral 121 27 vs 38 0.60 (0.36–0.98) Non-visceral only HR status 254 87 vs 101 0.76 (0.57–1.01) 0.252 HR– 367 105 vs 117 0.94 (0.72–1.22) HR+ No. of prior HER2 regimens 430 139 vs 149 0.95 (0.75–1.19) 0.146 2 191 53 vs 69 0.71 (0.50–1.02) ≥3 0.3 1 3.5 Nera%nib + Capecitabine beBer Lapa%nib + Capecitabine beBer 12 Adam Brufsky
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