Nera%nib plus capecitabine versus lapa%nib plus capecitabine in - - PowerPoint PPT Presentation

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

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Adam Brufsky

Disclosure informa%on – Adam Brufsky

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

• Nera%nib: pan-HER (HER1, 2, and 4) TKI
• Breadth of targets for nera%nib in HER

family of receptors (HER1, 2, and 4 for nera%nib; HER1 and 2 for lapa%nib)

• Nera%nib binds irreversibly to HER1, 2,

and 4; lapa%nib binds reversibly

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Rabindran et al. Cancer Res 2004 Nera%nib US PI 2018 Aberrant HER activation by:

• Gene amplification
• Receptor overexpression
• Somatic mutations

HER2:EGFR HER2:HER3 HER2:HER2 HER2:HER4 EGFR:EGFR

MAPK pathway PI3K pathway HER receptor dimerization Kinase activation Downstream signal transduction Tumor growth, survival, and spread

Neratinib

RAS RAF MEK ERK PI3K AKT mTOR

• Cell cycle control and proliferation
• Cell survival and decreased apoptosis
• Cellular migration and metastasis
• Angiogenesis

Nucleus

Adam Brufsky

Nera%nib: An irreversible pan-HER TKI

TKI, tyrosine kinase inhibitor

• Extended adjuvant: Approved by FDA and EMA based on reduced risk of recurrence of iDFS event

with nera%nib vs placebo in ExteNET1

• Neoadjuvant: Higher pCR rates with chemotherapy + nera%nib vs chemotherapy + trastuzumab in

pa%ents with HER2+ breast cancer in I-SPY22

• 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/m2)3 – NSABP FB-10: Evidence of efficacy with nera%nib + T-DM1 in pa%ents previously treated with trastuzumab + pertuzumab4 – NEfERT-T: Delayed CNS progression with nera%nib + paclitaxel in pa%ents with HER2+ brain metastases5 – TBCRC 022: Nera%nib + capecitabine ac%ve against refractory brain metastases in pa%ents with HER2+ brain metastases6

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Adam Brufsky

• 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. Abraham et al. J Clin Oncol 2018; 5. Awada et al. JAMA Oncol 2016; 6. Freedman et al. J Clin Oncol 2019

Clinical experience with nera%nib

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Stra%fica%on variables

• Number of prior HER2 therapies for MBC
• Disease loca%on
• HR status
• Geographic loca%on

Inclusion criteria

• Metasta%c breast cancer (MBC)
• Centrally confirmed HER2+ disease
• ≥2 lines of HER2-directed therapy for MBC
• Asymptoma%c and stable brain

metastases permiBed Nera%nib 240 mg/d + Capecitabine 1500 mg/m2 14/21 d Loperamide (cycle 1)a Lapa%nib 1250 mg/d + Capecitabine 2000 mg/m2 14/21 d R (1:1) Follow-up (survival) PD PD Endpoints

• Co-primary: PFS (centrally confirmed) and OS
• Secondary: PFS (local), ORR, DoR, CBR, interven%on for

CNS metastases, safety, health outcomes No endocrine therapy permi\ed

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

n=621

NALA study design

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 hold1

• Gray’s test of cumula%ve incidence for CNS endpoints

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NALA

Sta%s%cal methods

• 1. Uno et al. J Clin Oncol 2014

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Nera%nib + Capecitabine (n=307) Lapa%nib + Capecitabine (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)

NALA

Baseline characteris%cs

307 183 113 69 54 35 20 13 9 7 3 2 2 314 183 82 39 24 9 8 3 2 2 2 2 1 N+C L+C

Adam Brufsky

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 3 6 9 12 15 18 21 24 27 30 33 36

Time since randomiza%on (months) PFS probability

• No. at risk:

Nera%nib + Capecitabine Lapa%nib + Capecitabine

8 15% 29% 38% 47% 7% 16%

Hazard ra%o (95% CI) Log-rank p-value 0.76 (0.63–0.93) 0.0059

NALA

Centrally confirmed PFS (co-primary endpoint)

307 183 113 69 54 35 20 13 9 7 3 2 2 314 183 82 39 24 9 8 3 2 2 2 2 1 N+C L+C

Adam Brufsky

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 3 6 9 12 15 18 21 24 27 30 33 36

• No. at risk:

Nera%nib + Capecitabine Lapa%nib + Capecitabine

9

2.2 months

Mean PFS (months) p-value 8.8 0.0003 6.6

Restric%on: 24 months

NALA

Prespecified restricted means analysis – PFS

Time since randomiza%on (months) PFS probability

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Subgroup

Overall

Age group <65 years ≥65 years Race White Asian, black, or other Geographic region North America Europe Rest of world Disease loca%on Visceral Non-visceral only HR status HR– HR+

• No. of prior HER2 regimens

2 ≥3

N

621

492 129 355 266 124 244 253 500 121 254 367 430 191 210 vs 223 169 vs 181 41 vs 42 125 vs 117 85 vs 106 41 vs 46 83 vs 78 86 vs 99 181 vs 185 29 vs 38 82 vs 108 128 vs 115 148 vs 151 62 vs 72

Hazard ra%o (95% CI)

0.76 (0.63–0.93) 0.74 (0.60–0.91) 0.83 (0.53–1.28) 0.86 (0.67–1.11) 0.63 (0.47–0.85) 0.81 (0.53–1.25) 0.99 (0.72–1.35) 0.55 (0.41–0.75) 0.85 (0.69–1.04) 0.44 (0.26–0.73) 0.42 (0.31–0.57) 1.08 (0.84–1.40) 0.76 (0.60–0.96) 0.71 (0.50–1.00)

Hazard ra%o (95% CI)

Nera%nib + Capecitabine beBer Lapa%nib + Capecitabine beBer

0.25 1 4

Interac%on test p-value

0.463 0.166 0.051 0.007 <0.001 0.614

Events N+C vs L+C

NALA

PFS: Forest plot

11 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57

Time since randomiza%on (months) OS probability

307 294 275 244 220 182 142 112 82 13 6 2 1 314 303 273 240 208 170 132 107 84 12 8 3 1 N+C L+C

• No. at risk:

64 67 47 47 18 22 15 17 4 4 34 36 28 27

Mean OS (months) Hazard ra%o (95% CI) Log-rank p-value 24.0 0.88 (0.72–1.07) 0.2086 22.2

Restric%on: 48 months

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NALA

OS (co-primary endpoint)

1.7 months

Nera%nib + Capecitabine Lapa%nib + Capecitabine

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N

621 492 129 355 266 124 244 253 500 121 254 367 430 191 192 vs 218 149 vs 171 43 vs 47 113 vs 122 79 vs 96 46 vs 51 70 vs 85 76 vs 82 165 vs 180 27 vs 38 87 vs 101 105 vs 117 139 vs 149 53 vs 69

Hazard ra%o (95% CI)

0.88 (0.72–1.07) 0.86 (0.69–1.08) 0.86 (0.57–1.30) 0.88 (0.68–1.13) 0.85 (0.63–1.14) 1.06 (0.71–1.58) 0.82 (0.60–1.13) 0.83 (0.60–1.13) 0.94 (0.76–1.16) 0.60 (0.36–0.98) 0.76 (0.57–1.01) 0.94 (0.72–1.22) 0.95 (0.75–1.19) 0.71 (0.50–1.02)

Hazard ra%o (95% CI) Interac%on test p-value

0.941 0.939 0.313 0.067 0.252 0.146

Events N+C vs L+C

Nera%nib + Capecitabine beBer Lapa%nib + Capecitabine beBer

0.3 1 3.5

Subgroup

Overall

Age group <65 years ≥65 years Race White Asian, black, or other Geographic region North America Europe Rest of world Disease loca%on Visceral Non-visceral only HR status HR– HR+

• No. of prior HER2 regimens

2 ≥3

Adam Brufsky

NALA

OS: Forest plot

Time to interven%on for CNS metastases

13 100 90 80 70 60 50 40 30 20 10 6 12 18 24 30 36 42 48 54 60

Cumula%ve incidence (%) Time since randomiza%on (months) Nera%nib + Capecitabine Lapa%nib + Capecitabine

Overall cumula%ve incidence (Gray’s test): 22.8% vs 29.2%; p=0.043

Interven%on Nera%nib + Capecitabine (n=55/307) Lapa%nib + Capecitabine (n=75/314) Radia%on therapy 11% 15% Surgery/procedure 2% 3% An%cancer medica%on 1% 1%

Adam Brufsky

NALA

Response rate and dura%on of response

14 84 64 39 29 22 15 11 8 3 3 2 2 72 54 24 12 8 3 1

Time since randomiza%on (months) Probability of con%nuing response

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 3 6 9 12 15 18 21 24 27 30 33

Nera%nib + Capecitabine Lapa%nib + Capecitabine

N+C L+C

• No. at risk:

Nera%nib + Capecitabine (n=256) Lapa%nib + Capecitabine (n=270) p-value Objec%ve response rate 33% 27% 0.1201 Clinical benefit rate 45% 36% 0.0328 Median dura%on of response 8.5 months 5.6 months Hazard ra%o (95% CI) 0.50 (0.33–0.74) 0.0004

Adam Brufsky

NALA

Nera%nib + Capecitabine (n=303) Lapa%nib + Capecitabine (n=311) Lapa%nib/Nera%nib Median dura%on of treatment, months 5.7 4.4 Dose reduc%on, n (%) 73 (24) 61 (20) Dose hold, n (%) 145 (48) 134 (43) Capecitabine Median dura%on of treatment, months 5.5 4.8 Dose reduc%on, n (%) 117 (39) 152 (49) Dose hold, n (%) 178 (59) 184 (59)

Treatment exposure

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NALA

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Nera%nib + Capecitabine (n=303) Lapa%nib + Capecitabine (n=311) All grade Grade 3/4 All grade Grade 3/4 Treatment-emergent AE, % 100 61 99 60 Diarrhea 83 24* 66 13* Hand-foot syndrome 46 10 56 11 Hypokalemia 12 5 14 6 Nausea 53 4 42 3 Vomi%ng 46 4 31 2 Fa%gue 34 3 31 3 Neutropenia 7 3 5 2 Asthenia 12 3 12 2 Decreased appe%te 35 3 22 2 Dehydra%on 6 2 6 2 Treatment discon%nua%on due to treatment-emergent AEs: N+C: 10.9%; L+C: 14.5%

Adam Brufsky

NALA

Most frequent grade 3/4 adverse events

*No Grade 4 diarrhea

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Nera%nib + Capecitabine (n=303) Lapa%nib + Capecitabine (n=311) Maximum toxicity, n (%) Grade 1 91 (30) 111 (36) Grade 2 87 (29) 56 (18) Grade 3 74 (24) 39 (13) Time to first onset of diarrhea, days Grade 2 or 3 9 18 Grade 3 11 38 Median cumula%ve dura%on per pa%ent, days Grade 2 or 3 7 9 Grade 3 4 4

Treatment discon%nua%on due to diarrhea: N+C: 2.6% L+C: 2.3%

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NALA

Incidence and dura%on of diarrhea

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EORTC QLQ-C30 summary score Mean score over %me EORTC QLQ-C30 Global health status Mean score over %me

100 90 80 70 60 50 40 30 20 10 Baseline C3D1 C5D1 C7D1 C9D1 C11D1 275 265 210 181 147 70 281 270 215 178 132 32

Study cycle Mean score ± SE

C13D1 C15D1 C17D1 C19D1 112 90 99 64 80 44 55 27 100 90 80 70 60 50 40 30 20 10 Baseline C3D1 C5D1 C7D1 C9D1 C11D1 277 267 212 182 150 71 283 273 219 179 133 32 N+C L+C

• No. of pa%ents:

Study cycle Mean score ± SE

C13D1 C15D1 C17D1 C19D1 115 93 99 64 81 44 55 27

Nera%nib + Capecitabine Lapa%nib + Capecitabine Nera%nib + Capecitabine Lapa%nib + Capecitabine

N+C L+C

• No. of pa%ents:

Adam Brufsky

NALA

Pa%ent reported outcomes

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• NALA met its primary objec%ve: N+C superior to L+C in ≥3L HER2+ MBC

– Significant PFS benefit favoring N+C: HR=0.76; p=0.0059 – Numerical improvement in OS favoring N+C: HR=0.88; p=0.2086

• Fewer pa%ents required interven%on for symptoma%c CNS metastases with N+C

(p=0.043), sugges%ve of a delay in CNS progression

– Consistent with results from previous nera%nib studies1,2

• Dura%on of response significantly improved with N+C: HR=0.50; p=0.0004
• No new safety signals seen. Discon%nua%ons due to diarrhea 2.3% with N+C and a

median cumula%ve dura%on of grade 3 diarrhea of 4 days

• Trial results suggest N+C is an effec%ve op%on for trea%ng progressive HER2+ MBC
• 1. Awada et al. JAMA Oncol 2016; 2. Mar%n et al. Lancet Oncol 2017

NALA

Conclusions

The authors would like to thank pa%ents and their families, and the inves%gators and site staff for par%cipa%ng in this trial We also thank the Independent Data Monitoring CommiBee and the Steering CommiBee

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Adam Brufsky

Thank you