- Giuseppe Curigliano (Milan, Italy)
Introduction
96O - Adjuvant trastuzumab emtansine (T-DM1) vs trastuzumab (T) in patients (pts) with residual invasive disease after neoadjuvant therapy for HER2+ breast cancer: Subgroup analysis from KATHERINE
- Sibylle Loibl (Neu-Isenburg, Germany)
- Sibylle Loibl (Neu-Isenburg, Germany)
- Chiun-Sheng Huang (Taipei, Taiwan)
- Max S. Mano (Sao Paulo, Brazil)
- Terry P. Mamounas (Orlando, FL, United States of America)
- Charles E. Geyer (Richmond, United States of America)
- Michael Untch (Berlin, Germany)
- Gunter Von Minckwitz (Neu-Isenburg, Germany)
- Jean-Christophe Thery (Rouen, France)
- Ingo Schwaner (Berlin, Germany)
- Steven Limentani (Charlotte, United States of America)
- Niklas Loman (Lund, Sweden)
- Kristina Lübbe (Hannover, Germany)
- Jennifer C. Chang (Houston, United States of America)
- Thomas Hatschek (Solna, Sweden)
- David Tesarowski (South San Francisco, United States of America)
- Thomas Boulet (Basel, Switzerland)
- Claudia Wiese (Basel, Switzerland)
- Chunyan Song (South San Francisco, United States of America)
- Norman Wolmark (Pittsburgh, United States of America)
Abstract
Background
In the phase 3 KATHERINE study (NCT01772472) adjuvant T-DM1 reduced the risk of invasive disease recurrence or death by 50% compared to adjuvant T in pts with residual invasive breast cancer after neoadjuvant chemotherapy plus HER2-targeted therapy. Here we present subgroup analyses: adjuvant radiotherapy (ART) vs no-ART; hormone receptor (HR)+ vs HR−/unknown disease; and HER2− status on retesting of a surgical specimen.
Methods
Pts were randomized to 14 q3w cycles of adjuvant T-DM1 (3.6 mg/kg) or T (6 mg/kg) with ART and hormonal therapy (HT) administered per local standards. Efficacy is reported according to tumor HR status; and safety according to HT received. The primary endpoint was invasive disease-free survival (IDFS). HER2 status was centrally assessed on available paired pre-neoadjuvant and surgical samples.
Results
Most pts received ART (82%) and/or HT (71%). IDFS benefit was consistent regardless of ART or HR status (Table). There were more grade ≥3 AEs (27.4% vs 16.2%) and serious AEs (13.2% vs 10.3%) with T-DM1 in the ART vs no-ART group. There were similar rates of grade ≥3 AEs (24.9% vs 26.0%) and serious AEs (12.2% vs 12.9%) with T-DM1 in the no-HT and HT groups. Of 845 pts with paired pre-neoadjuvant biopsy and surgical HER2 status data, 70 (8.3%) had residual disease which was considered HER2− (ie, HER2− or IHC 0-1+/ISH unk) on retesting. In this group, there have been no IDFS events among pts randomized to T-DM1 (n=28), and 11 events in pts randomized to T (n=42).
3-yr IDFS (95% CI) Unstratified hazard ratio (95%CI) T ART 77.4% (73.8–83.9) 0.50 (0.38–0.66) T-DM1 ART 88.3% (85.5–91.0) T no-ART 75.5% (67.6–83.5) 0.50 (0.27–0.93) T-DM1 no-ART 88.2% (82.2–94.2) T HR+ 80.7% (77.2–84.3) 0.48 (0.35–0.67) T-DM1 HR+ 90.7% (88.1–93.4) T HR−/unknown 66.6% (59.5–73.6) 0.50 (0.33–0.74) T-DM1 HR−/unknown 82.1% (76.7–87.5)
Conclusions
No new safety signals were observed with concomitant ART or HT. Exploratory HER2 analysis of paired specimens, suggests that T-DM1 should not be withheld in pts with HER2− residual disease at surgery. Thus HER2 retesting of residual disease may be unnecessary in this population.
Clinical trial identification
NCT01772472.
Editorial acknowledgement
Medical writing support, funded by F. Hoffmann–La Roche, was provided by Holly Strausbaugh, PhD,and Sheena Hunt, PhD, on behalf of Twist Medical.
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd.
Funding
F. Hoffmann-La Roche Ltd.
Disclosure
S. Loibl: Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): AbbVie; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Amgen; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): AstraZeneca; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Celgene; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: Seattle Genetics; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: PriME/Medscape; Honoraria (self), Speaker Bureau/Expert testimony: Chugai; Research grant/Funding (institution): Teva; Research grant/Funding (institution): Vifor; Honoraria (institution), Research grant/Funding (institution): Daiichi-Sankyo; Honoraria (institution), Speaker Bureau/Expert testimony: Lilly; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: Samsung; Honoraria (institution), Advisory/Consultancy: Eirgenix. C-S. Huang: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Research grant/Funding (institution): EirGenix; Research grant/Funding (institution): OBI Pharma; Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Daiichi Sankyo. M.S. Mano: Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Lilly-Imlcone; Honoraria (self): Oncologia Brasil; Advisory/Consultancy: Amgen; Honoraria (self): DASA; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: AstraZeneca; Shareholder/Stockholder/Stock options: Biotoscana; Shareholder/Stockholder/Stock options: Hypera; Shareholder/Stockholder/Stock options: Fleury. T.P. Mamounas: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Genentech/Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Exact Sciences (Genomic Health); Advisory/Consultancy: Merck; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Biotheranostics. C.E. Geyer: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, Non-remunerated activity/ies, Medical writing and uncompensated advisory boards: Genentech/Roche; Advisory/Consultancy, Travel/Accommodation/Expenses, Non-remunerated activity/ies, Uncompensated consulting and advisory board: Daiichi-Sankyo; Advisory/Consultancy, Travel/Accommodation/Expenses, Uncompensated advisory board: AstraZeneca; Advisory/Consultancy, Non-remunerated activity/ies, Uncompensated advisory board: Seattle Genetics; Non-remunerated activity/ies, Medical writing: AbbVie; Advisory/Consultancy, Non-remunerated activity/ies, Uncompensated consulting: Athenex. M. Untch: Advisory/Consultancy, all fees to the employer/institution: AbbVie; Honoraria (institution), Advisory/Consultancy, all fees to the employer/institution: AstraZeneca; Honoraria (institution), Advisory/Consultancy, all fees to the employer/institution: Celgene; Advisory/Consultancy, all fees to the employer/institution: Daiichi Sankyo; Honoraria (institution), Advisory/Consultancy, all fees to the employer/institution: Amgen; Honoraria (institution), Advisory/Consultancy, all fees to the employer/institution: Lilly; Advisory/Consultancy, all fees to the employer/institution: MSD Merck; Honoraria (institution), Advisory/Consultancy, all fees to the employer/institution: Mundipharma; Honoraria (institution), Advisory/Consultancy, all fees to the employer/institution: Myriad Genetics; Advisory/Consultancy, all fees to the employer/institution: Odonate; Honoraria (institution), Advisory/Consultancy, all fees to the employer/institution: Pfizer; Advisory/Consultancy, all fees to the employer/institution: Puma Biotechnology; Honoraria (institution), Advisory/Consultancy, all fees to the employer/institution: Roche Pharma; Honoraria (institution), Advisory/Consultancy, all fees to the employer/institution: Sanofi Aventis; Honoraria (institution), Advisory/Consultancy, all fees to the employer/institution: Novartis; Honoraria (institution), Advisory/Consultancy, all fees to the employer/institution: Pierre Fabre; Honoraria (institution), Advisory/Consultancy, all fees to the employer/institution: Clovis. G. von Minckwitz: Shareholder/Stockholder/Stock options: Cara GmbH. J-C. Thery: Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution), Travel/Accommodation/Expenses: Mundi Pharma; Travel/Accommodation/Expenses: Eisai; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: PharmaMar; Travel/Accommodation/Expenses: GSK. I. Schwaner: Advisory/Consultancy: AbbVie; Advisory/Consultancy: Amgen; Advisory/Consultancy, Travel/Accommodation/Expenses: Celgene; Advisory/Consultancy: Hexal; Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Servier. N. Loman: Honoraria (institution): Roche; Honoraria (institution): Pierre Fabre; Honoraria (institution): AstraZeneca; Honoraria (institution): MSD. K. Lübbe: Advisory/Consultancy: Roche; Advisory/Consultancy: Lilly; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer. J.C. Chang: Advisory/Consultancy: Lilly USA; Advisory/Consultancy: Genentech; Advisory/Consultancy: Celgene. T. Hatschek: Honoraria (self), Advisory/Consultancy: Roche Sweden; Honoraria (self), Advisory/Consultancy: Pfizer Sweden; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Research grant/Funding (institution): Pfizer. D. Tesarowski: Full/Part-time employment: Genentech. T. Boulet: Full/Part-time employment: F. Hoffmann-La Roche. C. Wiese: Shareholder/Stockholder/Stock options, Full/Part-time employment: F. Hoffmann-La Roche. C. Song: Shareholder/Stockholder/Stock options, Full/Part-time employment: F. Hoffmann-La Roche. All other authors have declared no conflicts of interest.
97O - PREDIX HER2 trial: Event-free survival and pathologic complete response in clinical subgroups and stromal TILs levels
- Thomas Hatschek (Solna, Sweden)
- Thomas Hatschek (Solna, Sweden)
- Anne Andersson (Umeå, Sweden)
- Judith Bjöhle (Solna, Sweden)
- Ana Bosch (Lund, Sweden)
- Lena Carlsson (Sundsvall, Sweden)
- Anne C. Dreifaldt (Örebro, Sweden)
- Zakaria Einbeigi (Göteborg, Sweden)
- Ellinor Elinder (Stockholm, Sweden)
- Hanna Fredholm (Solna, Sweden)
- Erika Isaksson-Friman (Stockholm, Sweden)
- Mats Hellström (Stockholm, Sweden)
- Hemming Johansson (Stockholm, Sweden)
- Tobias Lekberg (Stockholm, Sweden)
- Henrik Lindman (Uppsala, Sweden)
- Ioannis Zerdes (Solna, Sweden)
- Theodoros Foukakis (Solna, Sweden)
- Johan Hartman (Stockholm, Sweden)
- Yvonne Brandberg (Stockholm, Sweden)
- Jonas Bergh (Solna, Solna, Sweden)
Abstract
Background
Neoadjuvant treatment with Trastuzumab-emtansine was associated with similar rates of pathological complete remission (pCR) as standard therapy with docetaxel, trastuzumab and pertuzumab in the PREDIX HER2 trial. Here, results of event-free survival (EFS), and pCR rates in key clinical-pathological subgroups and biomarkers including the abundance of stromal tumor infiltrating lymphocytes (TILs) are presented.
Methods
PREDIX HER2 is a randomized, multicenter, open-label, phase 2 study involving 9 Swedish sites. Patients with HER2 positive breast cancer, verified by ISH, T >20 mm and/or verified lymph node metastases were randomized to six three-weekly courses of either docetaxel, trastuzumab SC and pertuzumab (group A), or trastuzumab emtansine (T-DM1, group B). Switch of treatment to the opposite arm was allowed in case of lack of response or severe toxicity. Radiological evaluation included 18F-FDG PET/CT. Patients in both groups received adjuvant chemotherapy with epirubicin and cyclophosphamide. TILs were evaluated using standard methodology, median 10%.
Results
In total 197 pts. were evaluable, 99 in group A, and 98 in group B. pCR (ypT0/is ypN0) was achieved in 90 pts, 45.7%, with no significant difference between the two treatment groups. pCR rates were lower in the group of patients with hormone receptor (HR)–positive compared with HR-negative tumors but similar in both treatment groups. pCR rates did not differ between the two treatments in subgroups defined by age, menopausal status, tumor grade, T size, node status, HR-status, HER2 status and Ki67. Progressive disease was observed in 3 pts. (3%) during treatment with T-DM1, none in group A. After a median follow-up of 2.4 years 13 EFS events occurred, with no significant differences between the treatment groups. The presence of ≥10% TILs predicted pCR significantly (p=0.009), similar in both treatment groups. We also found that a decrease of SUVmax by more than 80% was highly predictive of pCR. HRQoL was significantly better in pts. receiving T-DM1.
Conclusions
Our data suggest that neoadjuvant T-DM1 may be as effective as standard neoadjuvant treatment in all clinical subgroups evaluated. Both TILs and PET/CT showed potential to predict pCR.
Clinical trial identification
NCT02568839.
Legal entity responsible for the study
Karolinska University Hospital, Region Stockholm.
Funding
Swedish Cancer Society, Research funds at Radiumhemmet, Karolinska Institutet, Region Stockholm, Roche Sweden AB.
Disclosure
T. Hatschek: Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche Sweden; Advisory/Consultancy: Pfizer Sweden; Advisory/Consultancy: Pierre Fabre Sweden. T. Foukakis: Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Pfizer. J. Hartman: Travel/Accommodation/Expenses: Roche Sweden. J. Bergh: Research grant/Funding (institution): Amgen; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Sanofi-Aventis. All other authors have declared no conflicts of interest.
Invited discussant abstracts: 96O and 97O
- Valentina Guarneri (Padova, Italy)
- Valentina Guarneri (Padova, Italy)
138O - CNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses
- Guy Jerusalem (Liège, Belgium)
- Guy Jerusalem (Liège, Belgium)
- Yeon Hee Park (Seoul, Korea, Republic of)
- Toshinari Yamashita (Yokohama, Japan)
- Sara A. Hurvitz (Santa Monica, CA, United States of America)
- Shuquan Chen (Basking Ridge, United States of America)
- Jillian Cathcart (Basking Ridge, United States of America)
- Caleb Lee (Basking Ridge, United States of America)
- Christophe Perrin (Rennes, France)
Abstract
Background
Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable linker and a cytotoxic topoisomerase I inhibitor. In the pivotal DESTINY-Breast01 trial (NCT03248492), efficacy of T-DXd for HER2-positive metastatic breast cancer (mBC) was demonstrated with an objective response rate (ORR) of 60.9% and median PFS of 16.4 months. We report data on T-DXd for patients (pts) with CNS metastases at baseline and CNS status upon disease progression.
Methods
DESTINY-Breast01 was a single-group, open-label, phase 2 trial of T-DXd (5.4 mg/kg) in 184 pts with HER2-positive mBC previously treated with T-DM1. Pts with CNS metastases that were treated and asymptomatic were allowed on trial. Comparison of subgroup variables was descriptive.
Results
Of 184 pts enrolled at the 5.4 mg/kg dose, 24 had CNS metastases at baseline. Demographics were well matched although CNS pts were likely to have ECOG 0 status (62.5%) and hormone receptor negative disease (58.3%). Similar to the total population, the CNS subgroup was heavily pretreated (median 6 prior lines of therapy). Efficacy was seen in the CNS subgroup: ORR, 58.3% [95% CI: 36.6, 77.9]; mPFS, 18.1 months [95% CI: 6.7, 18.1]. CNS response was observed, case report of 55% regression of a metastatic brain lesion will be presented. At a median 11.1 mo follow-up, 26% of pts (48/184) had progressive disease prior to data cutoff date (01 Aug 2019); 33% (8/24) in the CNS subgroup. The most common sites of progression were in the liver, lung, or lymph nodes and were similar among all pts and the CNS subgroup. Progression involving the brain occurred in only 4 of 48 pts, including 2 of 8 pts with baseline CNS metastases. The 2 CNS progression events in the baseline CNS subgroup occurred at 78 and 85 days of treatment while those in pts without a history of CNS metastases occurred late, at 323 and 498 days.
Conclusions
T-DXd demonstrated efficacy in pts who had a history of CNS metastases at baseline that was similar to the overall population, including one who experienced an in-brain response on therapy. Progression in the brain was noted at time of progression in only 8% of pts with non-CNS disease at time of enrolment.
Clinical trial identification
NCT03248492.
Legal entity responsible for the study
Daiichi Sankyo, Inc.
Funding
Daiichi Sankyo, Inc.
Disclosure
G. Jerusalem: Research grant/Funding (self), Non-remunerated activity/ies, personal fees and non-financial support: Daiichi Sankyo; Research grant/Funding (self), Research grant/Funding (institution), Non-remunerated activity/ies, grants, personal fees and non-financial support: Novartis; Research grant/Funding (self), Research grant/Funding (institution), Non-remunerated activity/ies, grants, personal fees and non-financial support: Roche; Research grant/Funding (self), Research grant/Funding (institution), Non-remunerated activity/ies, grants, personal fees and non-financial support: Pfizer; Research grant/Funding (self), Non-remunerated activity/ies, personal fees and non-financial support: Lilly; Research grant/Funding (self), Non-remunerated activity/ies, personal fees and non-financial support: Amgen; Research grant/Funding (self), Non-remunerated activity/ies, personal fees and non-financial support: BMS; Research grant/Funding (self), Non-remunerated activity/ies, personal fees and non-financial support: AstraZeneca; Research grant/Funding (self), personal fees: AbbVie; Non-remunerated activity/ies, non-financial support: Med-Immune; Non-remunerated activity/ies, non-financial support: Merck KGaA. Y.H. Park: Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (self): Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Eisai; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Merck; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Novartis; Honoraria (self): Samsung Bioepis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Licensing/Royalties: Hanmi; Advisory/Consultancy: Lilly. T. Yamashita: Honoraria (self), Research grant/Funding (institution): Chugai Pharma; Honoraria (self): Eisai; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Kyowa Hakko Kirin; Honoraria (self): Pfizer; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical; Honoraria (self): Lilly; Research grant/Funding (institution): Nihonkayaku. S.A. Hurvitz: Research grant/Funding (self), Travel: Eli Lilly; Research grant/Funding (self), Travel: Novartis; Research grant/Funding (self), Travel: OBI Pharma; Research grant/Funding (self): Pfizer; Research grant/Funding (self): Pieris; Research grant/Funding (self): PUMA; Research grant/Funding (self): Roche; Research grant/Funding (self): Seattle Genetics; Research grant/Funding (self): Medivation; Research grant/Funding (self): Merrimack; Research grant/Funding (self): Dignitana; Research grant/Funding (self): Genentech; Research grant/Funding (self): GlaxoSmithKline; Research grant/Funding (self): Eli Lilly; Research grant/Funding (self): Macrogenics; Research grant/Funding (self): Biomarin; Research grant/Funding (self): Cascadian; Research grant/Funding (self): Daiichi Sankyo; Research grant/Funding (self): Ambryx; Research grant/Funding (self): Amgen; Research grant/Funding (self): Bi Pharma; Research grant/Funding (self): Bayer. S. Chen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Daiichi Sankyo Inc. J. Cathcart: Full/Part-time employment: Daiichi Sankyo Inc. C. Lee: Shareholder/Stockholder/Stock options, Full/Part-time employment: Daiichi Sankyo Inc. All other authors have declared no conflicts of interest.
137O - Tucatinib vs placebo added to trastuzumab and capecitabine in previously treated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB)
- Giuseppe Curigliano (Milan, Italy)
- Giuseppe Curigliano (Milan, Italy)
- Rashmi Murthy (Houston, United States of America)
- Sherene Loi (Melbourne, VIC, Australia)
- Alicia Okines (London, United Kingdom)
- Elisavet Paplomata (Atlanta, United States of America)
- Erika P. Hamilton (Nashville, United States of America)
- Sara A. Hurvitz (Santa Monica, CA, United States of America)
- David Cameron (Edinburgh, Midlothian, United Kingdom)
- Virgina Borges (Aurora, United States of America)
- Philippe Bedard (Toronto, Ontario, Canada)
- Ana Mafalda Antunes De Melo e Oliveira (Barcelona, Spain)
- Erik H. Jakobsen (Vejle, Denmark)
- Thomas Bachelot (Lyon, France)
- Schlomit S. Shachar (Haifa, Israel)
- Volkmar Mueller (Hamburg, Germany)
- Lisa A. Carey (Chapel Hill, NC, United States of America)
- Sibylle Loibl (Neu-Isenburg, Germany)
- Wentao Feng (Bothell, United States of America)
- Luke N. Walker (Seattle, United States of America)
- Eric Winer (Boston, MA, United States of America)
Abstract
Background
Tucatinib (TUC) is an investigational oral TKI that is highly selective for HER2 with minimal EGFR inhibition. It has shown antitumor activity in preclinical models of HER2+ breast cancer (BC) and intracranial tumors.
Methods
HER2CLIMB (NCT02614794) is a randomized double-blind trial in pts with metastatic HER2+ BC (MBC) previously treated with trastuzumab (T), pertuzumab (P), and T-DM1, including pts with untreated, treated stable, or treated progressing brain metastases (BM). Pts were randomized 2:1 to TUC (300 mg BID) or placebo, in combination with T and capecitabine (C). Primary endpoint was progression free survival (PFS, defined as disease progression or death) per RECIST 1.1 (blinded independent review) in the first 480 pts. Multiplicity-adjusted secondary endpoints were overall survival (OS,) PFS in pts with BM, and confirmed objective response rate (ORR). Clinical benefit rate (CBR), defined as CR + PR + SD>6 months, was evaluated in all pts. Ad hoc time to response (TTR) was assessed in pts with measurable disease.
Results
Baseline characteristics for the 612 pts were balanced across arms, including 48% of pts with BM. In the TUC arm, risk of progression or death was reduced by 46% (HR: 0.54; 95% CI: 0.42, 0.71; P<0.00001), risk of death was reduced by 34% (HR: 0.66; 95% CI: 0.50, 0.88; P=0.0048), and risk of progression or death in BM pts was reduced by 52% (HR: 0.48; 95% CI: 0.34, 0.69; P<0.00001). With TUC, PFS at 1 year was 20.8% higher and OS at 2 years was 18.3% higher. In pts with measurable disease at baseline, ORR was 41% in the TUC arm vs 23% in the control arm. Median TTR was 1.4 mo for both arms. CBR was 60% in the TUC arm vs 38% in the control arm. Most common AEs in the TUC arm were diarrhea, palmar-plantar erythrodysesthesia (PPE), nausea, fatigue, and vomiting. Grade ≥3 AEs higher in the TUC arm were diarrhea, PPE, and increased AST and ALT.
Conclusions
Adding TUC to T and C significantly prolonged PFS and OS in heavily pretreated pts with HER2+ MBC, including pts with BM. If approved, tucatinib in combination with trastuzumab and capecitabine has the potential to become a new standard of care in pts who previously received 3 HER2-targeted agents.
Clinical trial identification
NCT02614794.
Editorial acknowledgement
Editorial assistance provided by Laurie LaRusso, Chestnut Medical Communications, paid for by Seattle Genetics.
Legal entity responsible for the study
Seattle Genetics.
Funding
Seattle Genetics.
Disclosure
G. Curigliano: Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Roche; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Lilly. R. Murthy: Research grant/Funding (institution), Travel/Accommodation/Expenses: Seattle Genetics; Honoraria (self), Research grant/Funding (institution): Daiichi Sankyo; Honoraria (self), Research grant/Funding (institution): Genentech; Honoraria (self), Research grant/Funding (institution): Puma. S. Loi: Research grant/Funding (institution), Non-remunerated activity/ies: Bristol Meyers Squibb; Research grant/Funding (institution), Non-remunerated activity/ies: Roche-Genentech; Research grant/Funding (institution): Puma Biotechnology; Research grant/Funding (institution), Non-remunerated activity/ies: Pfizer; Research grant/Funding (institution), Non-remunerated activity/ies: Seattle Genetics; Research grant/Funding (institution), Non-remunerated activity/ies: Novartis; Research grant/Funding (institution), Non-remunerated activity/ies: Merck; Research grant/Funding (institution): Eli Lilly; Honoraria (institution): Aduro Biotech; Honoraria (institution): G1 Therapeutics; Research grant/Funding (institution), Non-remunerated activity/ies: AstraZeneca. A. Okines: Speaker Bureau/Expert testimony, Payment for a lecture: Roche; Travel/Accommodation/Expenses: Leo Pharmaceuticals. E. Paplomata: Research grant/Funding (institution), Non-remunerated activity/ies, non-remunerated: writing support: Seattle Genetics; Research grant/Funding (institution), Non-remunerated activity/ies, non-remunerated: food: Genentech; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies, non-remunerated: food: Novartis; Research grant/Funding (institution), Non-remunerated activity/ies, non-remunerated: food: Merck; Research grant/Funding (institution), Non-remunerated activity/ies, non-remunerated: writing support: Hoosier Cancer Research Network; Research grant/Funding (institution), Non-remunerated activity/ies, non-remunerated: food: Corcept; Research grant/Funding (institution), Non-remunerated activity/ies, non-remunerated: food: AbbVie; Honoraria (self), Advisory/Consultancy, Non-remunerated activity/ies, non-remunerated: food: R-Pharm; Honoraria (self), Advisory/Consultancy, Non-remunerated activity/ies, non-remunerated: food: Pfizer; Honoraria (self), Advisory/Consultancy, Non-remunerated activity/ies, non-remunerated: food: Mylan; Non-remunerated activity/ies, non-remunerated: food: Amgen; Non-remunerated activity/ies, non-remunerated: food: Tesaro. E. Hamilton: Grants from Seattle Genetics, during the conduct of the study; grants and other from Pfizer, grants, non-financial support and other from Genentech/Roche, grants, non-financial support and other from Lilly, grants and other from Puma Biotechnology, grants, non-financial support and other from Daiichi Sankyo, grants and other from Mersana, grants and other from Boehringer Ingelheim, grants and other from Cascadian Therapeutics, grants, non-financial support and other from AstraZeneca, grants from Hutchinson MediPharma, grants from OncoMed, grants from MedImmune, grants from Stem CentRx, grants from Curis, grants from Verastem, grants from Zymeworks, grants from Syndax, grants from Lycera, grants from Rgenix, grants from Millennium, grants from TapImmune, grants from BerGenBio, grants from Medivation, grants and non-financial support from Tesaro, grants, non-financial support and other from Eisai, grants from H3 Biomedicine, grants and non-financial support from Radius Health, grants from Acerta Pharma, grants from Takeda, grants from Macrogenics, grants from AbbVie, grants from Immunomedics, grants from Fujifilm, grants from eFFECTOR Therapeutics, grants from Merus, grants from Nucana, grants from Regeneron, grants from Leap Therapeutics, grants from Taiho Pharmaceutical, grants and non-financial support from EMD Serono, grants from Syros, grants and non-financial support from Clovis, grants from CytomX, grants from InventisBio, non-financial support from Amgen, non-financial support from Bayer, non-financial support from Bristol-Myers Squibb, non-financial support from Genzyme, non-financial support from Helsinn Therapeutics, non-financial support from HERON, non-financial support from Lexicon, non-financial support from Medivation, non-financial support from Merck, grants, non-financial support and other from Novartis, non-financial support from Roche, non-financial support from Sysmex, non-financial support from Guardant Health, non-financial support from Foundation Medicine, grants from Deciphera, grants and other from Silverback, grants and other from Black Diamond, grants from ArQule, grants from Sermonix Pharmaceuticals, grants from Sutro Biopharma, grants from Zenith Epigenetics, grants from Arvinas, grants from Torque Therapeutics, grants from Harpoon Therapeutics, grants from Fochon Pharmaceuticals, grants from Orinove, grants from Molecular Templates, grants from Unum Therapeutics, grants from Aravive, other from NanoString, grants from Compugen, grants from Dana Farber Cancer Institute, grants from G1 Therapeutics, grants from Karyopharm Therapeutics, grants from Torque Therapeutics, outside the submitted work. S.A. Hurvitz: Grants and non-financial support from Seattle genetics, during the conduct of the study; grants from Amgen, grants from Ambrx, grants from Bayer, grants and non-financial support from Daiichi-Sankyo, grants and non-financial support from Genentech/Roche, grants from GSK, grants from Immunomedics, grants and non-financial support from Lilly, grants from Macrogenics, grants from Novartis, grants and non-financial support from Pfizer, grants and non-financial support from OBI Pharma, grants from Pieris, grants and non-financial support from PUMA, grants from Radius, grants from sanofi, grants and non-financial support from Dignitana, grants from Radius, grants from Arvinas, outside the submitted work. D. Cameron: Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (institution), Advisory/Consultancy: Synthon; Honoraria (institution), Advisory/Consultancy: Daiichi-Sankyo; Honoraria (institution), Advisory/Consultancy: Samsung Bioepsis; Honoraria (institution), Advisory/Consultancy: PUMA; Honoraria (institution), Advisory/Consultancy, unrelated to this study or therapeutic area: Seattle Genetics; Honoraria (institution), Advisory/Consultancy: Zymeworks. V. Borges: Research grant/Funding (institution): Cascadian/Seattle Genetics; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Biothera; Research grant/Funding (institution): Pfizer. P. Bedard: Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution), Non-remunerated activity/ies, Uncompensated advisory boards: Bristol Meyers Squibb; Research grant/Funding (institution), Non-remunerated activity/ies, Uncompensated advisory boards: Sanofi; Research grant/Funding (institution), Non-remunerated activity/ies, Uncompensated advisory boards: Genentech/Roche; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Nektar Therapeutics; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Servier; Research grant/Funding (institution): PTC Therapeutics; Non-remunerated activity/ies, Uncompensated advisory boards: Pfizer. M. Oliveira: Grants from Seattle Genetics, during the conduct of the study; grants, personal fees and non-financial support from Roche, grants and personal fees from Genentech, grants and personal fees from GSK, grants and personal fees from PUMA Biotechnology, grants and personal fees from AstraZeneca, grants and personal fees from Seattle Genetics, grants from Immunomedics, grants from Boehringer-Ingelheim, non-financial support from Pierre-Fabre, non-financial support from Eisai, non-financial support from GP Pharma, non-financial support from Grünenthal, grants, personal fees and non-financial support from Novartis, outside the submitted work. E.H. Jakobsen: Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Novartis. T. Bachelot: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy: Seattle Genetics. S.S. Shachar: Honoraria (institution): Seattle Genetics; Honoraria (self), Speaker Bureau/Expert testimony: Novartis; Honoraria (self), Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Honoraria (self), Speaker Bureau/Expert testimony: Pfizer. V. Mueller: Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Celgene; Honoraria (self), Advisory/Consultancy: Daiichi-Sankyo; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self): Pfizer; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self): Teva; Advisory/Consultancy: Genomic Health; Advisory/Consultancy: Hexal; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: ClinSol; Advisory/Consultancy: Lilly; Advisory/Consultancy: Tesaro; Advisory/Consultancy: Nektar; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Genentech. S. Loibl: Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): AbbVie; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Amgen; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): AstraZeneca; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Celgene; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: Seattle Genetics; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: PriME/Medscape; Honoraria (self), Speaker Bureau/Expert testimony: Chugai; Research grant/Funding (institution): Teva; Research grant/Funding (institution): Vifor; Honoraria (institution), Research grant/Funding (institution): Daiichi-Sankyo; Honoraria (institution), Speaker Bureau/Expert testimony: Lilly; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: Samsung; Honoraria (institution), Advisory/Consultancy: Eirgenix. C-S. Huang: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Research grant/Funding (institution): EirGenix; Research grant/Funding (institution): OBI Pharma; Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Daiichi Sankyo. W. Feng: Full/Part-time employment: Seattle Genetics. L.N. Walker: Licensing/Royalties, Full/Part-time employment, Named inventor on patents: Seattle Genetics. E. Winer: Honoraria (self), Advisory/Consultancy: Carrick Pharmaceuticals; Honoraria (self), Advisory/Consultancy: Genentech/Roche; Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy: GSK; Honoraria (self), Advisory/Consultancy: Jounce; Honoraria (self), Advisory/Consultancy: Leap; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: G1 Therapeutics. All other authors have declared no conflicts of interest.
Invited discussant abstracts: 138O and 137O
- Antonio Llombart Cussac (Lleida, Spain)
- Antonio Llombart Cussac (Lleida, Spain)