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Mini Oral session

1O - Neratinib + capecitabine vs lapatinib + capecitabine in HER2+ metastatic breast cancer previously treated with ≥2 HER2-directed regimens: Exploratory biomarker analyses from phase III NALA trial

Date

23 May 2020

Session

Mini Oral session

Presenters

Cristina Saura Manich

Citation

Annals of Oncology (2020) 31 (suppl_2): S15-S41. 10.1016/annonc/annonc117

Authors

C. Saura Manich1, A. Vivancos2, J. Matito3, H. Wildiers4, A.M. Brufsky5, A.M. Antunes De Melo e Oliveira6, S. Waters7, S.A. Hurvitz8, B. Moy9, S. Kim10, W.J. Gradishar11, G.S. Queiroz12, E. Cronemberger13, J. Bebchuk14, K. Keyvanjah15, A.S. Lalani16, L.D. Eli17, S. Delaloge18

Author affiliations

  • 1 Solti Breast Cancer Research Group, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, 08035 - Barcelona/ES
  • 2 Medical Oncology, Vall d’Hebron Institute of Oncology, Barcelona/ES
  • 3 Medical Oncology, Vall d'Hebron University Hospital, Barcelona/ES
  • 4 Medical Oncology, University Hospitals Leuven, Leuven/BE
  • 5 Hematology / Oncology, Magee-Womens Hospital of UPMC, Pittsburgh/US
  • 6 Medical Oncology, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona/ES
  • 7 Medical Oncology, Velindre Cancer Centre, Cardiff/GB
  • 8 Hematology / Oncology Clinical Research Unit, University of California at Los Angeles, Los Angeles/US
  • 9 Medical Oncology, Massachusetts General Hospital Cancer Center, Boston/US
  • 10 Medical Oncology, University of Ulsan College of Medicine, Seoul/KR
  • 11 Medical Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago/US
  • 12 Medical Oncology, Hospital Araújo Jorge, Goiânia/BR
  • 13 Medical Oncology, Centro Regional Integrado de Oncologia, Fortaleza/BR
  • 14 Biostatistics, Puma Biotechnology Inc., Los Angeles/US
  • 15 Clinical Science And Clinical Pharmacology, Puma Biotechnology Inc., Los Angeles/US
  • 16 Translational Medicine, Puma Biotechnology Inc., Los Angeles/US
  • 17 Translational Medicine And Diagnostics, Puma Biotechnology Inc., Los Angeles/US
  • 18 Medical Oncology, Institut Gustave Roussy, Villejuif/FR
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Resources

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Abstract 1O

Background

The irreversible pan-HER tyrosine kinase inhibitor neratinib had a significant progression-free survival (PFS) benefit in NALA (NCT01808573), a randomized, phase 3 trial comparing neratinib + capecitabine (1500 mg, N+C) vs lapatinib + capecitabine (2000 mg, L+C) in 621 patients (pts) with HER2+ (either IHC3+ or IHC2+/FISH+) metastatic breast cancer (MBC) who received ≥2 prior HER2-directed regimens in the metastatic setting. Here we explore biomarker (PIK3CA or ERBB2 mutations, HER2 protein expression) associations with PFS changes.

Methods

PIK3CA and ERBB2 mutations were evaluated by next-generation sequencing on either primary (67.4%, 283/420) or metastatic/lymph node samples (32.6%, 137/420) and confirmed by ddPCR pending tissue availability. HER2 protein expression was evaluated by central IHC, H-score, and HERmark. Hazard ratios (95% CI) for subgroups were estimated using unstratified Cox proportional hazards model.

Results

PIK3CA and ERBB2 mutations were detected at incidences of 35.0% (148/420) and 6.2% (26/420), respectively. PIK3CA mutations were associated with decreased PFS (wt vs mut: HR=0.81; 95% CI 0.64–1.02; p=0.077). ERBB2 mutation trended with better PFS, but sample size was limited (wt vs mut: HR=1.68, CI 0.97–3.29, p=0.086). Higher HER2 protein expression was prognostic of increased PFS when treatment arms were grouped (IHC3+ vs 2+: HR=0.67, CI 0.54–0.82, p<0.001; H-score above vs below median HR=0.77, CI 0.63–0.92, p=0.005; HERmark positive vs equivocal or negative HR=0.71, CI 0.52–0.98, p=0.006). Pts whose tumors had higher HER2 protein expression evaluated by any of the three methods appeared to have derived consistent benefit from N+C vs L+C (HER2 IHC3+: HR=0.64, CI 0.51–0.81, p<0.001; H-score ≥median (240): HR=0.54, CI 0.41–0.72, p<0.001; HERmark positive: HR=0.65, CI 0.50– 0.84, p<0.001).

Conclusions

PIK3CA mutations associate with decreased PFS for pts enrolled in the NALA trial. Higher HER2 protein expression associates with increased PFS in the overall study population, and a greater benefit from N+C vs. L+C.

Clinical trial identification

NCT01808573.

Editorial acknowledgement

Lee Miller, Miller Medical Communications Ltd.

Legal entity responsible for the study

Puma Biotechnology Inc.

Funding

Puma Biotechnology Inc.

Disclosure

C. Saura: Advisory/Consultancy: Puma Biotechnology Inc.; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Celgene; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Eisai; Advisory/Consultancy: Genomic; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Synthon; Advisory/Consultancy: Piqur Therapeutics; Advisory/Consultancy: Sanofi. A. Vivancos: Advisory/Consultancy: Guardant Health; Advisory/Consultancy: Novartis; Advisory/Consultancy: Bayer. H. Wildiers: Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Amgen; Advisory/Consultancy: Lilly; Advisory/Consultancy: Novartis; Advisory/Consultancy: AbbVie; Advisory/Consultancy: Vifor Pharma; Advisory/Consultancy: Celldex therapeutics; Advisory/Consultancy: Janssen-CILAG; Advisory/Consultancy: TRM Oncology; Advisory/Consultancy: Puma Biotechnology Inc.; Advisory/Consultancy: ORION corporation. A.M. Brufsky: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Genentech/Roche; Advisory/Consultancy: Agendia; Advisory/Consultancy: Celgene; Advisory/Consultancy: Novartis; Advisory/Consultancy: Bayer; Advisory/Consultancy: Lilly; Advisory/Consultancy: bioTheranostics; Advisory/Consultancy: NanoString Technologies; Advisory/Consultancy: Genomic Health; Advisory/Consultancy: Puma Biotechnology Inc. M. Oliveira: Advisory/Consultancy: Puma Biotechnology Inc.; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: GlaxoSmithKline; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Pierre-Fabre; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: GP Pharma; Travel/Accommodation/Expenses: Grunenthal. S. Waters: Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche. B. Moy: Honoraria (self): Medscape Education; Spouse/Financial dependant: Motus GI. S-B. Kim: Advisory/Consultancy: Enzychem; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Odonate; Advisory/Consultancy: Beigene; Research grant/Funding (institution): Sanofi-Genzyme; Research grant/Funding (institution): Dongkook. W.J. Gradishar: Advisory/Consultancy: Genentech/Roche. J. Bebchuk: Full/Part-time employment: Puma Biotechnology Inc. K. Keyvanjah: Full/Part-time employment: Puma Biotechnology Inc. A.S. Lalani: Shareholder/Stockholder/Stock options, Full/Part-time employment: Puma Biotechnology Inc. L.D. Eli: Shareholder/Stockholder/Stock options, Full/Part-time employment: Puma Biotechnology Inc. S. Delaloge: Honoraria (self), Advisory/Consultancy, Licensing/Royalties: Pfizer; Honoraria (self), Advisory/Consultancy, Licensing/Royalties: Novartis; Honoraria (self), Advisory/Consultancy, Licensing/Royalties: Puma Biotechnology Inc.; Honoraria (self), Advisory/Consultancy, Licensing/Royalties: AstraZeneca; Honoraria (self), Advisory/Consultancy: Lilly; Advisory/Consultancy: Orion; Honoraria (self), Advisory/Consultancy: Roche. All other authors have declared no conflicts of interest.

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