Over 90% of patients with breast cancer are diagnosed with early breast cancer (EBC). While many patients with HR+ disease will not recur or have distant relapse with standard therapies, up to 30% of patients whose cancer has high risk clinical and/or pathological features may experience distant relapse, many in the first 2 years. Novel treatment options are needed to prevent early recurrences and development of metastases for these patients. Abemaciclib is an oral, continuously dosed CDK4 & 6 inhibitor approved for use in HR+, HER2- advanced breast cancer (ABC). Efficacy and safety of abemaciclib in ABC supported phase III evaluation in the adjuvant setting.
monarchE, an open-label, phase III study, included patients with HR+, HER2-, high risk EBC, who completed primary treatment. Patients with ≥4 positive nodes, or 1-3 nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3, or central Ki-67 ≥20%, were eligible, and randomized (1:1) to abemaciclib (150 mg BID for 2 years) plus endocrine therapy (ET) or ET alone. A prespecified interim analysis was planned at ∼293 IDFS events. The primary endpoint was invasive disease-free survival (IDFS) per STEEP criteria. Secondary endpoints included distant relapse-free survival (DRFS), overall survival, and safety.
5,637 patients were randomized. With 323 IDFS events observed in the intent-to-treat population, positive efficacy required a 2-sided p-value <0.0264. Abemaciclib plus ET demonstrated a statistically significant improvement in IDFS versus ET alone (p=.0096, HR: 0.747, 95% CI: 0.598, 0.932), corresponding to a 25.3% reduction in the risk of an IDFS event. The 2-year IDFS rates were 92.2% vs 88.7%, respectively. A similar improvement was observed for DRFS (HR: 0.717, 95% CI: 0.559, 0.920) with 2-year DRFS rates of 93.6% and 90.3%, respectively. Consistent benefit was seen in all prespecified subgroups. The most frequent AEs were diarrhea, neutropenia and fatigue in the abemaciclib arm and arthralgia, hot flush and fatigue in the control arm. Safety was consistent with the known profile of abemaciclib.
Abemaciclib when combined with ET is the first CDK4 & 6 inhibitor to demonstrate a statistically significant improvement in IDFS in patients with HR+, HER2-, high risk EB.
NCT03155997.
Sarah C Nabinger from Eli Lilly and Company has provided writing support.
Eli Lilly and Company.
Eli Lilly and Company.
S.R.D. Johnston: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly and Company; Puma technology; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Pfizer; Speaker Bureau/Expert testimony: Eisai; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Roche/Genentech. N. Harbeck: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): AstraZeneca; Eli Lilly and Company; Novartis; Pfizer; Shareholder/Stockholder/Stock options: West German Study Group. M. Toi: Honoraria (self), Research grant/Funding (institution): Chugai; Takeda; Pfizer; Eisai; AstraZeneca; Taiho; Nippon Kayaku; Research grant/Funding (institution): Kyowa-Hakko-Kirin; Astellas; AFI technologies; Research grant/Funding (institution), Officer/Board of Directors: JBCRG association; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Shimadzu; Daiichi-Sankyo; Honoraria (self): Eli Lilly and Company; MSD; Honoraria (self): Genomic Health; Novartis; Yakult; Advisory/Consultancy: Konica Minolta; BMS; Athenex Oncology; Officer/Board of Directors: Organisation for Oncology and Translational Research; Kyoto Breast cancer Research Network. M. Martin: Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Amgen; Pfizer; Advisory/Consultancy: Taiho Oncology; PharmaMar; Eli Lilly and Company; Daiichi Sankyo; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Roche/Genentech; Novartis; Advisory/Consultancy, Research grant/Funding (institution): PUMA; M. Campone: Advisory/Consultancy, Fees to the Institution: AstraZeneca; Sanofi; Servier; AbbVie; ACCORD; Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy: Eli Lilly and Company; GT1. E. Hamilton: Speaker Bureau/Expert testimony, Research grant/Funding (institution), speaker's bureau (no personal compensation accepted): Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution), advisory board (no personal compensation accepted): Eli Lilly and Company; Pfizer; Novartis; Mersana; Advisory/Consultancy: Flatiron Health; Advisory/Consultancy, Research grant/Funding (institution), consulting (no personal compensation accepted): Cascadian Therapeutics; Daiichi; AstraZeneca; Silverback Therapeutics; Black Diamond; Research grant/Funding (institution): Hutchinson MediPharma; OncoMed; MedImmune; StemCentrx; AbbVie; Curis; Verastem; Zymeworks; Syndax; Lycera; Rgenix; TapImmune; BerGenBio; Tesaro; Medivation; Kadmon; Boehringer Ingelheim; Eisai; H3 Biomedicine; Radius Health; Acerta; Takeda; Macrogenics; Immunomedics; FujiFilm; Effector; Syros; Unum; Sutro; Aravive; Deciphera; Clovis; Sermonix; Zenith; Arvinas; ArQule; Torque; Harpoon; Fochon; Orinove; Molecular Template; Seattle Genetics. J. Sohn: Research grant/Funding (institution): MSD; Roche; Novartis; AstraZeneca; Eli Lilly and Company; Pfizer; Bayer; GSK; CONTESSA; Daiichi Sankyo. V. Guarneri: Advisory/Consultancy, Speaker Bureau/Expert testimony: Eli Lilly and Company; Novartis; Advisory/Consultancy, Research grant/Funding (institution): Roche. J. Cortes: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Celgene; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Cellestia; Biothera Pharmaceutical; Merus; Seattle Genetics; Erytech; Athenex; Polyphor; Servier; GSK; Leuko; Bioasis; Clovis Oncology; Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Eli Lilly and Company; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck; Sharp&Dohme; Honoraria (self), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Eisai; Pfizer; Honoraria (self): Samsung Bioepis; Research grant/Funding (institution): Ariad pharmaceuticals; Baxalta GMBH/Servier Affaires; Bayer healthcare; F.Hoffman-La Roche; Guardanth health; Piqur Therapeutics; Puma C; Queen Mary University of London; Shareholder/Stockholder/Stock options: MedSIR. P. Neven: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Eli Lilly and Company. F. Boyle: Honoraria (self), Advisory/Consultancy: Roche; Pfizer; Eli Lilly and Company; Novartis. I. Smith: Full/Part-time employment, was a full time employee of Eli Lilly during the conduct of the study: Eli Lilly and Company. M. Frenzel; R. Wei; J. Cox: Shareholder/Stockholder/Stock options, Full/Part-time employment: Eli Lilly and Company. D. Headley: Shareholder/Stockholder/Stock options, Full/Part-time employment: Eli Lilly and Company; Shareholder/Stockholder/Stock options: Novartis; Takeda; Varian Medical systems; Utah Medical Products; Zoetis; Bayer; Roche; Evgen; AstraZeneca; Johnston&Johnston; Pfizer; Varex Imaging; Zimmer BioMet; Amgen; Chugai Pharma; Merck. J. O'Shaughnessy: Honoraria (self), Advisory/Consultancy: AbbVie Inc; Agendia; Amgen Biotechnology; AstraZeneca; Bristol-Myers Squibb; Celgene Corporation; Eisai; Genentech; Genomic Health; GRAIL; Immunomedics; Heron Therapeautics; Ipsen Biopharmaceuticals; Jounce Therapeutics; Eli Lilly and Company; Merck; Myriad; Novartis; Ondonate Therapeutics; Pfizer; Puma Biotechnology; Prime Oncology; Roche; Seattle Genetics; Takeda; Syndax Pharmaceuticals. P. Rastogi: Travel/Accommodation/Expenses: AstraZeneca; Genentech/Roche; Eli Lilly and Company. All other authors have declared no conflicts of interest.
Approximately 90% of patients with breast cancer are diagnosed at an early stage. While the risk of recurrence for many patients with HR+, HER2- early breast cancer (EBC) is relatively low, certain clinical and/or pathological features such as number of lymph nodes involved, tumor size, histologic grade, and proliferation index may increase the risk of recurrence. Thus, patients with high risk features may benefit from additional adjuvant treatment. monarchE, an open-label, phase 3 trial, randomized (1:1) patients with EBC at high risk of recurrence to receive standard of care endocrine therapy (ET) with or without abemaciclib (150mg BID for up to 2 years). Patients with breast cancer from Asian countries are known to have different clinical characteristics compared to Western countries. We report baseline characteristics of patients from Asia enrolled in monarchE to characterize the demographics and disease characteristics of this population.
Eligible women and men had ≥4 positive nodes, or 1-3 nodes and either tumor size ≥5 cm, histologic grade 3, or central Ki-67 ≥20%. Patients with HR+, HER2-, node-positive, high risk, EBC were randomized by an interactive web response system and stratified by prior treatment, menopausal status and region (North America/Europe vs Asia vs Other).
Between July 2017 and August 2019, 1155 patients were enrolled from Asia: Japan (n=377), China (n=357), Korea (n=245), Taiwan (n=124), Singapore (n=32), and Hong Kong (n=20). Patients from Asia were younger, more commonly premenopausal and had a higher incidence of ≥4 positive nodes.
| Patients from Asia | Patients from non-Asia | ||||
|---|---|---|---|---|---|
| Category | abemaciclib + ET N=573, n (%) | ET alone N=582, n (%) | abemaciclib + ET N=2235, n (%) | ET alone N=2247, n (%) | |
| Age | Median (range) | 48 (23-87) | 48 (23-84) | 52 (25-89) | 52 (22-86) |
| Gender | Female | 572 (99.8) | 580 (99.7) | 2215 (99.1) | 2234 (99.4) |
| Menopausal status (per IWRS) | premenopausal | 336 (58.6) | 340 (58.4) | 885 (39.6) | 892 (39.7) |
| Number of positive lymph nodes | 1-3 | 199 (34.7) | 201 (34.5) | 920 (41.2) | 942 (41.9) |
| ≥4 | 373 (65.1) | 380 (65.3) | 1307 (58.5) | 1299 (57.8) | |
To our knowledge, these are the first reported baseline characteristics in patients from Asia with high risk EBC in a CDK4 & 6 inhibitor adjuvant study. These characteristics suggest that patients from Asia may have a higher risk of recurrence than patients from non-Asia and would benefit from additional adjuvant treatment.
NCT03155997
Writing and editorial support was provided by Sarah C. Nabinger (Eli Lilly and Company)
In the phase III ML-7 trial, ribociclib (RIB) + endocrine therapy (ET) prolonged progression-free survival (PFS) and overall survival (OS) vs placebo (PBO) + ET in premenopausal pts with HR+, HER2− ABC. The RIB benefit was observed irrespective of ET partner (nonsteroidal aromatase inhibitor [NSAI] or tamoxifen [TAM]). Here we report outcomes in Asian pts enrolled in the ML-7 trial receiving an NSAI + RIB or PBO.
Pre/perimenopausal pts (≤ 1 line of prior chemotherapy; no prior ET for ABC) who received RIB or PBO + NSAI (letrozole or anastrozole) were included in this analysis. The primary end point was PFS, with a prespecified subset analysis in Asian pts. OS, overall response rate (ORR), clinical benefit rate (CBR), QOL, and safety were secondary end points.
166 pts (34% of the total NSAI cohort) were included (RIB, n=82; PBO, n=84); 31% of pts had de novo metastatic disease, and 4% and 66% had a DFI ≤ 12 mo and > 12 mo, respectively. As of 30 Nov 2018, 33 and 16 pts in the RIB and PBO arms, respectively, were still receiving treatment; the primary cause of discontinuation was disease progression (50% for RIB vs 70% for PBO). A consistent PFS and OS benefit with RIB vs PBO was observed in Asian pts vs the intention-to-treat population (Table). ORR and CBR favored RIB + NSAI vs PBO + NSAI in Asian pts with measurable disease at baseline. The EORTC QLQ-C30 global health score was generally maintained throughout RIB treatment. The only grade 3/4 adverse event occurring in > 20% of pts in either arm was neutropenia (78% for RIB vs 4% for PBO).
These findings indicate that treatment with RIB + NSAI improved PFS nearly 3-fold and prolonged OS with a relative reduction in risk of death of 56% vs PBO + NSAI in Asian pts with HR+/HER2− ABC. Safety findings in Asian pts were consistent with the overall population, and QOL was maintained during RIB + NSAI treatment. a ORR = CR+PR in pts with measurable disease (RIB, n = 65; PBO, n = 76) b CBR = CR+PR or SD or non-CR/non-PD ≥ 24 weeks in pts with measurable disease.
ML-7 Asian subset RIB + NSAI n = 82 PBO + NSAI n = 84 Age, median (range), yrs 43 (27-58) 45 (29-58) Weight, mean (SD), kg 59.9 (12.1) 55.8 (9.1) PFS events, n/N 42/82 60/84 PFS, median (95% CI), mo 30.4 (24.6-37.7) 11.0 (7.4-14.7) HR (95% CI) 0.47 (0.31-0.71) OS events, n/N 15/82 30/84 OS, median (95% CI), mo NE (NE-NE) NE (31.6-NE) HR (95% CI) 0.44 (0.23-0.81) 36-Mo OS, % (95% CI) 78.9 (66.9-86.9) 61.5 (49.0-71.8) 42-Mo OS, % (95% CI) NE (NE-NE) 50.7 (33.4-65.8) ORR, n (%)a 43 (66.2) 28 (36.8) CBR, n (%)b 56 (86.2) 48 (63.2)
NCT02278120.
Medical editorial assistance was provided by Casey Nielsen of MediTech Media, Ltd.
Novartis Pharmaceuticals Corporation.
Novartis Pharmaceuticals Corporation.
Y-S. Lu: Research grant/Funding (self), Clinical trial study fee: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Research grant/Funding (institution), Grant for clinical study for ESR1 mutation detected by cell free DNA; Advisory board consultation fee; Speaker fee: Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Consultation fee; Contracted research: Pfizer; Honoraria (self), Advisory/Consultancy, Consultation fee: Boehringer Ingelheim; Research grant/Funding (institution), Contracted research: Roche; Research grant/Funding (institution), Contracted research: Merck Sharp & Dohme; Honoraria (self), Speaker Bureau/Expert testimony, Speaker Fee: Eisai. J. Sohn: Research grant/Funding (institution): MSD; Roche; Novartis; AstraZeneca; Lilly; Pfizer; Bayer; GlaxoSmithKline; Contessa; Daiichi Sankyo. K.S. Lee: Honoraria (self), Advisory/Consultancy, Consulting or advisory role: Eli Lilly; Novartis; Pfizer; Roche; Research grant/Funding (institution), Research Funding: Dong-A Socio. K.H. Jung: Honoraria (self): Novartis. M-C. Liu: Honoraria (self), Advisory/Consultancy, Advisory Board: Pfizer; Honoraria (self), Advisory/Consultancy, Advisory Board: Roche; Honoraria (self), Advisory/Consultancy, Advisory Board: Novartis; Travel/Accommodation/Expenses, Travel Fee: Itnl Congress on Clinical Trials Hemo-Oncology. Y.S. Yap: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Honoraria, consultancy, research support: Novartis; Honoraria (self), Advisory/Consultancy, Consulting or advisory role: Pfizer; Travel/Accommodation/Expenses: Eisai; Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Consulting or advisory role: Roche. A. Gaur: Full/Part-time employment: Novartis. Y. Wang: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. M. Gao: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. S-A. Im: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Research grant, advisory board role: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses, Advisory Board Role, travel support: Novartis; Honoraria (self), Advisory/Consultancy, Advisory Board role: Hanmi; Honoraria (self), Advisory/Consultancy, Advisory Board role: Pfizer; Honoraria (self), Advisory/Consultancy, Participation in advisory meetings: Eisai; Honoraria (self), Advisory/Consultancy, Participation in advisory meetings: Amgen; Honoraria (self), Advisory/Consultancy, Participation in advisory meetings: MediPacto; Honoraria (self), Advisory/Consultancy, Participation in advisory meetings: Roche; Honoraria (self), Advisory/Consultancy, Participation in advisory meetings: Lilly. All other authors have declared no conflicts of interest.
CompLEEment-1 is a large phase IIIb trial in an expanded pt population with HR+, HER2– ABC (N = 3,246 pts). Here, we present safety and efficacy data for Asian pts from Hong Kong, India, Malaysia, Philippines, Singapore, Taiwan, and Thailand who participated in the study.
Pts with HR+, HER2– ABC, ≤1 line of prior chemotherapy (CT) and no prior endocrine therapy for ABC received RIB + LET. Study design has been reported previously (Lu J. et al, SABCS 2019, Poster P1-19-21). Primary endpoints were safety and tolerability, and secondary endpoint was efficacy.
Overall, 197 Asian pts were included (6.1% of the total CompLEEment-1 population); 1.5% pts were male, 84.8% pts were <65 years (median age: 52.0 years), and 34.0% pts were premenopausal. 2.5%, 65.5%, and 12.7% pts had CNS, visceral and bone-only metastasis, 3.6% had prior CT, 5.1% were ECOG2, and 18.3% had relapsed within < 2 years of adjuvant therapy. The median duration of exposure to RIB was 16.1 months, while the median relative dose intensity was 96.9%; 2 patients (1.0%) were lost to follow-up. Adverse events (AEs) and treatment-related AEs occurred in 192 (97.5%) and 177 (89.8%) pts, while grade ≥ 3 AEs and serious AEs were reported in 142 (72.1%) and 45 (22.8%) pts, respectively. The most common all-grade and grade ≥ 3 treatment-related AEs were neutropenia (66.5% and 47.7%), leukopenia (26.4% and 12.7%), and anemia (18.8% and 4.1%). Overall, 74 (37.6%) pts had ≥ 1 dose reduction of RIB; 52 (26.4%) due to AEs. 112 (56.9%) pts permanently discontinued treatment; 15 (7.6%) due to AEs. Median time to progression was 20.3 months (95% confidence interval [CI], 15.5-22.8). For the 156 pts with measurable disease, overall response rate was 44.9% (95% CI, 36.9-53.0%), and clinical benefit rate was 68.6% (95% CI, 60.7-75.8).
This subgroup analysis supports the efficacy of RIB + LET in Asian pts for first-line endocrine therapy of HR+, HER2– ABC. The safety profile associated with RIB + LET was manageable with few pts discontinuing treatment due to AEs, consistent with previous phase III trials of RIB + LET.
NCT02941926.
Medical editorial assistance was provided by Sara Henriques, PhD of Healthcare Consultancy Group, LLC, and funded by Novartis Pharmaceuticals Corporation.
Novartis Pharmaceuticals.
Novartis Pharmaceuticals.
S. Chatterjee: Research grant/Funding (institution), Site Specific Principal Investigator: Novartis; Research grant/Funding (institution), Site Specific Principal Investigator: Roche; Research grant/Funding (institution), Site Specific Principal Investigator: Alkem; Research grant/Funding (institution), Site Specific Principal Investigator: Samsung Biopsies. M. Md Yusof: Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, writing: AstraZeneca; Novartis; MSD; Astellas; Advisory/Consultancy, Speaker Bureau/Expert testimony, writing: Boeringher Ingelheim; Eli Lilly; Roche; Eisai; Sanofi; Genzyme; Mundi Pharma; Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Zuellig Pharma; Research grant/Funding (self), Principal investigator: Mundi Pharma; Honoraria (institution): Pfizer; Leadership role, executive council member: Malaysian Oncological Society; Leadership role, council member: Breast Cancer women association. T. Dejthevaporn: Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eisai; AstraZeneca; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Honoraria (institution), Advisory/Consultancy: Roche; Leadership role, Vice president: Thai Society of Clinical Oncology. W-P. Chung: Honoraria (self): Novartis; Roche; AstraZeneca; Pfizer; Amgen; Kyowa Kirin; Foundation Medicine; Chugai Pharma; Takeda; Eli Lilly; Sanofi. C.G. Galvez: Speaker Bureau/Expert testimony: Novartis; Roche; Mylan; Amgen; Leadership role, past president: Philippine Breast Cancer Society. A. Cheng: Research grant/Funding (self): AstraZeneca; Eli Lilly; Merck; Gilead Sciences; Incyte Corp.; Astellas Pharma Global Development Inc.; Ignyta; Roche; MSD; Pfizer; Novartis; Bristol-Myers Squibb; AbbVie Limited; United Therapeutics Corporation; Bayer; ARIAD Pharmaceuticals Inc. subsidiary of Takeda; Takeda; Turning Point Therapeutics Inc.. M.L.T. Abesamis-Tiambeng: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Novartis; AstraZeneca; MSD; Roche; Mylan; Eli Lilly. L. Menon-Singh; J. Wu; K. Zhou: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis Pharmaceuticals Corporation. H. Azim: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Novartis; Roche; Pfizer; AstraZeneca; Eli Lilly; Amgen; BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): MSD; Speaker Bureau/Expert testimony, Research grant/Funding (self): Janssen; Advisory/Consultancy: Hekma; Research grant/Funding (self): Bayer. All other authors have declared no conflicts of interest.
Preferred neoadj regimens for patients (pts) with early-stage (e)TNBC include taxane + anthracycline–based therapy. IMpassion031 is a global, Ph 3, multicentre, double-blind, randomised, placebo-controlled study in pts with high-risk primary invasive eTNBC evaluating the efficacy and safety of neoadj atezolizumab (A) or placebo (P) with nab-paclitaxel (nP) followed by A or P with dose-dense doxorubicin + cyclophosphamide. Here, we report the primary analysis of IMpassion031.
Eligible pts were ≥ 18 years old with previously untreated, centrally confirmed, invasive stage II-III eTNBC and tumour size > 2 cm. Pts (n = 333) were randomized 1:1 to receive A 840 mg or P q2w + nP 125 mg/m2 qw for 6 doses of A/P followed by A 840 mg or P q2w + doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 q2w for 4 doses of A/P followed by surgery. After surgery, pathologic complete response (pCR; ypT0/isN0) was assessed in all pts and investigators were unblinded to study treatment. Stratification was by diagnosis stage (II vs III) and PD-L1 expression on tumour-infiltrating immune cells (IC; ≥ 1% vs < 1%). Co-primary endpoints were locally assessed pCR in ITT or PD-L1+ (PD-L1 IC ≥ 1%) pts. Event-free survival (EFS) was a secondary endpoint. Safety was assessed.
333 pts were assigned to A-chemo (n = 165) or P-chemo (n = 168). Median follow-up was 20.6 mos in the A-chemo arm and 19.8 mos in the P-chemo arm (data cutoff 3 Apr 2020). pCR was seen in 57.6% (95% CI: 49.7, 65.2) of pts in the A-chemo arm and 41.1% (33.6, 48.9) in the P-chemo arm (Δ16.5%; 5.9, 27.1; 1-sided P = 0.0044 [significance boundary, 0.0184], P = 0.0085 for the intersection hypothesis of ITT and PD-L1+ populations). In PD-L1+ pts (n=152), pCR was seen in 68.8% (57.3, 78.9) vs 49.3% (37.6, 61.1) of pts (Δ19.5%; 4.2, 34.8; 1-sided P = 0.021; not significant). Median EFS was not reached in either arm (HR, 0.76; 95% CI: 0.40, 1.44). In the neoadj phase, Grade 3/4 adverse events (AEs) were balanced, treatment-related serious AEs occurred in 22.6% (A-chemo) and 15.6% (P-chemo), and 1 pt per arm had an unrelated Grade 5 AE.
In pts with eTNBC, A + neoadj chemo significantly improved pCR rates regardless of PD-L1 status with an acceptable safety profile.
NCT03197935.
Medical writing assistance for this abstract was provided by Christopher Lum, PhD of Health Interactions, Inc.
F. Hoffmann-La Roche, Ltd.
F. Hoffmann-La Roche, Ltd.
S. Saji: Advisory/Consultancy, Speaker Bureau/Expert testimony: Kyowa Kirin; Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Chugai; Speaker Bureau/Expert testimony: AstraZeneca; Pfizer; Novartis; Eisai; Takeda; Speaker Bureau/Expert testimony, Research grant/Funding (institution): MSD; Research grant/Funding (institution): Daiichi Sankyo; Taiho. E. Mittendorf: Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies: F. Hoffmann-La Roche/Genentech; Research grant/Funding (institution): GlaxoSmithKline; EMD Serono; Galena Biopharma; Honoraria (self): Physician Education Resource; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Exact Sciences; Merck; Peregrine Pharmaceuticals; Sellas Lifesciences; TapImmune; Non-remunerated activity/ies: BMS; Non-remunerated activity/ies: Lilly. N. Harbeck: Research grant/Funding (self): AstraZeneca; BMS; Merck Sharpe & Dohme; Research grant/Funding (self), Non-remunerated activity/ies: Roche. H. Zhang: Advisory/Consultancy, Non-remunerated activity/ies: F. Hoffman-La Roche. C.H. Barrios: Advisory/Consultancy, Research grant/Funding (self): Pfizer, Merck, AstraZeneca, Novartis, BI, Roche/Genentech, GSK; Advisory/Consultancy: Eisai; Research grant/Funding (self): Amgen; Research grant/Funding (self): Abraxis; Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (self): AB Science; Research grant/Funding (self): Eli Lilly; Research grant/Funding (self): Sanofi; Research grant/Funding (self): Taiho; Research grant/Funding (self): Mylan; Research grant/Funding (self): Merrimack; Research grant/Funding (self): Daiichi Sankyo; Research grant/Funding (self): AbbVie; Research grant/Funding (self): Astellas; Research grant/Funding (self): Biomarin; Research grant/Funding (self): Asana Biosciences; Research grant/Funding (self): Medivation; Research grant/Funding (self): Exelixis; Research grant/Funding (self): ImClone Systems; Advisory/Consultancy, Non-remunerated activity/ies: Roche. R. Hegg: Non-remunerated activity/ies: F. Hoffman La Roche. A. Koehler: Travel/Accommodation/Expenses: Roche, Novartis, Celgene, Amgen. J. Sohn: Research grant/Funding (institution): Merck Sharpe & Dohme, Roche, Novartis, AstraZeneca, Lilly, Pfizer, Bayer, GSK, Contessa, and Daiichi Sankyo. H. Iwata: Advisory/Consultancy, Research grant/Funding (self), Non-remunerated activity/ies: F. Hoffman-La Roche; Honoraria (self), Advisory/Consultancy: Novartis, AstraZeneca, Pfizer, Eli Lilly, Daiichi Sankyo; Non-remunerated activity/ies: Chugai. M.L. Telli: Research grant/Funding (self), Non-remunerated activity/ies, Personal Fees: AbbVie, Pfizer, Merck, Tesaro and Roche/Genentech; Research grant/Funding (self): PharmaMar, Bayer, Vertex, AstraZeneca, Calithera Biosciences, Biothera, OncoSec Medical and EMD Serono; Advisory/Consultancy, Personal Fees: Lilly, Immunomedics, G1 Therapeutics, Daiichi Sankyo, Aduro, Celldex; Non-remunerated activity/ies, Personal Fees: Celgene. C. Ferrario: Research grant/Funding (self), Non-remunerated activity/ies, Personal Fees: Bayer, Novartis; Research grant/Funding (self), and Personal Fees: Astellas, Genomic Health, RochePfizer, AstraZeneca, and Merck; Research grant/Funding (self), Non-remunerated activity/ies, Personal Fees: Roche; Research grant/Funding (self): Amgen, Cascadian Therapeutics, Lilly, Janssen Oncology and Zymeworks. K. Punie: Honoraria (institution): Pfizer, Lilly, Roche, Novartis, Mundi Pharma, AstraZeneca, Lilly, Pierre Fabre, Vifor Pharma, Teva; Travel/Accommodation/Expenses: Roche, AstraZeneca, PharmaMar, Pfizer and Novartis; Research grant/Funding (institution): Sanofi, Pfizer. F. Penault Llorca: Research grant/Funding (self), and Personal Fees: Myriad, NanoString, AstraZeneca, Roche; Travel/Accommodation/Expenses, Personal Fees: Genomic Health, Novartis and Pfizer; Non-remunerated activity/ies: Roche. S. Patel; A. Nguyen Duc: Full/Part-time employment: F. Hoffman La Roche. M. Liste Hermoso: Full/Part-time employment: F. Hoffmann-La Roche, Ltd. V. Maiya; L. Molinero; S. Chui: Shareholder/Stockholder/Stock options, Full/Part-time employment: F. Hoffman La Roche. K.H. Jung: Advisory/Consultancy: AstraZeneca; Roche; Novartis; Takeda; Celgene.
Based on findings from IMpassion130, international guidelines now recommend atezolizumab (A) + nab-paclitaxel (nP) for patients (pts) with locally advanced or metastatic TNBC (mTNBC) whose tumours express PD-L1 on tumour-infiltrating immune cells (IC). Here we report prespecified final OS and long-term safety results.
The study design and final PFS analysis have been reported (Schmid NEJM 2018). Pts were randomised 1:1 to A + nP or placebo (P) + nP. Co-primary endpoints were PFS (tested in parallel in ITT and PD-L1+ pts) and OS (tested hierarchically in ITT and, if significant, in PD-L1+ pts).
As of 14 April 2020, 666/902 pts (73.8%) had died; median OS follow-up was 18.8 mo (IQR, 8.9-34.7 mo). 6% of pts in the A + nP arm and 2% in the P + nP arm remained on any treatment. OS data are in the table. 460 A + nP arm pts and 430 P + nP arm pts were safety evaluable, of whom 8% and 3%, respectively, received nP for up to 24 mo. Similarly, 5% in the A + nP arm received nP for ≥ 24 mo (vs 1% in the P + nP arm). Respectively, 51% vs 43% had a G 3-4 AE; ≈ 1% per arm had a G 5 AE (no new G 5 AEs since last analysis; no patterns seen); 24% vs 19% had a serious AE, and 59% vs 42% had an AE of special interest (G 3-4 in 8% vs 5%). No confirmed or suspected COVID-19 AEs were reported. 19% in the A + nP arm and 8% in the P + nP arm had an AE leading to treatment discontinuation (most commonly due to neuropathy); in 18% and 8%, respectively, AEs led to nP discontinuation, and in 8% and 1%, AEs led to A or P discontinuation.
While OS differences for A + nP vs P + nP in the IMpassion130 ITT population were not statistically significant, precluding formal testing, clinically meaningful OS benefit was observed in PD-L1+ pts (7.5-mo median OS improvement). A + nP remained safe and tolerable with longer follow-up. Results from this final and mature OS analysis are consistent with prior interim analyses. Final OS analysis a Stratified by: prior taxane use, liver metastases, PD-L1 status b Not significant c PD-L1 positivity defined as PD-L1–stained IC on ≥ 1% of the tumour area (VENTANA SP142 IHC assay) d P value not shown since PD-L1+ OS not formally tested per hierarchical study design.
ITT population A + nP (n = 451) P + nP (n = 451) Events, n (%) 322 (71) 344 (76) Median OS (95% CI), mo 21.0 (19.0, 23.4) 18.7 (16.9, 20.8) OS HRa (95% CI); log-rank P 0.87 (0.75, 1.02); 0.0770b 3-year OS (95% CI), % 28 (24, 32) 25 (21, 29) (n = 185) (n = 184) Events, n (%) 120 (65) 139 (76) Median OS (95% CI), mo 25.4 (19.6, 30.7) 17.9 (13.6, 20.3) OS HRa (95% CI) 0.67 (0.53, 0.86)d 3-year OS (95% CI), % 36 (29, 43) 22 (16, 28)
NCT02425891.
Medical writing assistance for this abstract was provided by Ashley J. Pratt, PhD, CMPP of Health Interactions, Inc.
F. Hoffmann-La Roche, Ltd.
F. Hoffmann-La Roche, Ltd.
H. Iwata: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies, uncompensated IMpassion130 study steering committee member, editorial support: Roche; Non-remunerated activity/ies, editorial support: Chugai; Honoraria (self), Advisory/Consultancy: Novartis; AstraZeneca; Pfizer; Eli Lilly; Daiichi Sankyo. L. Emens: Honoraria (self): AbbVie; Amgen; Celgene; Chugai; Gritstone; MedImmune; Peregrine; Shionogi; Syndax; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Bayer; MacroGenics; Replimune; Vaccinex; Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS; Research grant/Funding (institution), Travel/Accommodation/Expenses, Non-remunerated activity/ies, editorial support, uncompensated IMpassion130 study and KATE2 study steering committee chairs: Genentech/Roche; Shareholder/Stockholder/Stock options, Potential for stock in future: Molecuvax; Research grant/Funding (institution), Licensing/Royalties: Aduro Biotech; Research grant/Funding (institution): Breast Cancer Research Foundation; Research grant/Funding (institution): Bolt Therapeutics, Corvus, US Dept of Defense, EMD Serono, Maxcyte, Merck, National Cancer Institute, NSABP Foundation, Translational Breast Cancer Research Consortium, Tempest, HeritX. S. Adams: Advisory/Consultancy, Research grant/Funding (institution), uncompensated advisory/consulting: BMS; Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies, uncompensated advisory/consulting, editorial support: Roche/Genentech; Advisory/Consultancy, Research grant/Funding (institution), uncompensated advisory/consulting: Merck; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Novartis. C.H. Barrios: Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Novartis; Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Boehringer Ingelheim; GlaxoSmithKline; Advisory/Consultancy, Research grant/Funding (institution), editorial support: Roche/Genentech; Research grant/Funding (institution): Eli Lily; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Taiho Pharmaceutical; Research grant/Funding (institution): Mylan; Research grant/Funding (institution): Merrimack; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Astellas, BioMarin; Advisory/Consultancy: Eisai, Bayer; Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy: Merck Sharp and Dohme; Research grant/Funding (institution): Abraxis BioScience, AB Science, Asana BioSciences, Medivation, Exelexis, ImClone Systems, LEO Pharma, Millennium. V. Diéras: Advisory/Consultancy, editorial support: Roche/Genentech; Advisory/Consultancy: Pfizer; Eli Lilly; Novartis; Daiichi Sankyo; AstraZeneca; AbbVie; MSD; Seattle Genetics; Odonate. S. Loi: Advisory/Consultancy, Research grant/Funding (institution), Unpaid consultant: Novartis; Advisory/Consultancy, Research grant/Funding (institution): BMS; Research grant/Funding (institution), Unpaid consultant: Merck; Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies, Unpaid consultant, editorial support: Roche/Genentech; Research grant/Funding (institution): Puma; Advisory/Consultancy, Research grant/Funding (institution), Unpaid consultant: Pfizer; Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy, Unpaid consultant: Seattle Genetics; Advisory/Consultancy, Unpaid consultant: AstraZeneca; Advisory/Consultancy, Consulting fees paid to institution: Aduro Biotech. H.S. Rugo: Research grant/Funding (institution), Travel/Accommodation/Expenses, Non-remunerated activity/ies, editorial support: Roche/Genentech; Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Merck; Research grant/Funding (institution): OBI; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Plexxikon; Travel/Accommodation/Expenses: MacroGenics; Travel/Accommodation/Expenses: Puma; Travel/Accommodation/Expenses: Mylan; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution), Travel/Accommodation/Expenses: Daiichi Sankyo; Honoraria (self): Celltrion. A. Schneeweiss: Honoraria (self), Research grant/Funding (institution): Celgene; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, Non-remunerated activity/ies, editorial support: Roche; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Molecular Partners; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Merck Sharp and Dohme; Honoraria (self): Tesaro; Honoraria (self): Eli Lilly; Honoraria (self), Travel/Accommodation/Expenses: Pfizer. E.P. Winer: Honoraria (self): Eli Lilly; Honoraria (self), Advisory/Consultancy: Leap; Honoraria (self): Genentech; Honoraria (self): Infinite MD; Honoraria (self): Carrick Therapeutics; Honoraria (self): GlaxoSmithKline; Honoraria (self): Jounce; Honoraria (self): Genomic Health; Honoraria (self): Merck; Honoraria (self): Seattle Genetics; Non-remunerated activity/ies, editorial support: Roche. S. Patel: Full/Part-time employment, Non-remunerated activity/ies, editorial support: Roche/Genentech. V. Henschel: Shareholder/Stockholder/Stock options, Full/Part-time employment, Non-remunerated activity/ies, editorial support: Roche. A. Swat: Full/Part-time employment, Non-remunerated activity/ies, editorial support: Roche. M. Kaul: Full/Part-time employment, Non-remunerated activity/ies, editorial support: Roche/Genentech. L. Molinero: Shareholder/Stockholder/Stock options, Full/Part-time employment, Non-remunerated activity/ies, Use patent to disclose with Roche/Genentech, editorial support: Roche/Genentech. S.S. Chui: Shareholder/Stockholder/Stock options, Full/Part-time employment, Non-remunerated activity/ies, Use patent to disclose with Roche/Genentech, editorial support: Roche/Genentech. P. Schmid: Research grant/Funding (institution), Spouse/Financial dependant: Genentech; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Spouse/Financial dependant, Non-remunerated activity/ies, editorial support, uncompensated steering committee member: F. Hoffmann-La Roche; Honoraria (self): Medscape; Honoraria (self), Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Merck; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Bayer; Advisory/Consultancy: Eisai; Advisory/Consultancy: Celgene; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Puma; Honoraria (self): GI Therapeutics; Research grant/Funding (institution): OncoGenex.
The JCOG0306 was a phase II study of preoperative sequential chemoradiation therapy for the nonsurgical treatment of early breast cancer. In JCOG0306 trial, we employed the representative cut surface sampling (R method) for evaluating pathological therapeutic effect and pathological complete response (pCR) rate. In addition, therapeutic effect was also evaluated for whole tumor bed sampling in case the primary tumor grossly disappeared by referring to the pretreatment imaging findings (T method). pCR was evaluated by central pathology review and defined as disappearance of invasive carcinoma component.
We compared pCR rates and prognostic significance of pCR between R and T methods to validate the use of R method in the trial.
Totally, 103 (95%) of 108 invasive cancer patients enrolled were evaluated. Median age was 51 (23-69), cStage I/IIA/IIB/IIIA were 1/50/48/4, and ER and HER2 positive were 63 and 33, respectively. %pCR were 37.9% (n = 39) by R method and 24.3% (n = 25) by T method, and their concordance rate was 86.4% (89/103). Almost all discordant cases were histologically Grade 2b (only a small number of invasive cancer cells remained). With a median follow up period of 11.6 years, among node-negative patients, OS significantly differed between pCR and non-pCR patients (10yOS: pCR 94.3% vs. non-pCR 75.7%; 10yrRFS: 90.9% vs. 66.6%, p = 0.047), whereas there was no significant difference by T (10yOS: 95.2% vs. 78.7%, p = 0.13). When pCR and Grade 2b patients were combined, pCR/Grade 2b patients and others showed significantly different clinical outcomes for OS and RFS by both R and T methods.
R method provided stronger stratification of prognosis between pCR and non-pCR patients than T method and the use of R method was proved to be reasonable for the evaluation of therapeutic effect. The combination of pCR and Grade 2b appeared to be more sensitive to identify the patient group who received chemoradiation therapy and showed better clinical outcome in both R and T methods.
The authors.
the National Cancer Center Research and Development Fund (29-A-3).
T. Shien: Honoraria (self): Chugai; AstraZeneca; Novartis; Kirin; Allergan; Pfizer; Honoraria (self): Daiichi Sankyo; Eizai. N. Hayashi: Honoraria (self): Chugai; Novartis; AstraZeneca; Kirin; Genomic Health; Allergan; Devixcor Japan; Pfizer. N. Masuda: Honoraria (self), Research grant/Funding (self): Chugai; AstraZeneca; Pfizer; Eli-Lilly; Eisai; Takeda; Research grant/Funding (self): MSD; Kyowa-Kirin; Novartis; Nihon-Kayaku; Daiichi Sankyo. All other authors have declared no conflicts of interest.
There are no satisfying ways to distinguish high- from low-risk patients with early-stage breast cancer. We aimed to develop a MRI radiomic-based signature for predicting prognosis and discriminating of high-risk relapse patients with different molecular subtypes (RBC-01 study).
Machine learning intratumoral and peritumoral radiomics to develop the radiomic signature for DFS prediction in 799 patients from Sun Yat-sen Memorial Hospital and Sun Yat-sen University Cancer Center (training cohort). Clinical-radiomic nomogram was constructed by integrating radiomic signature with significant clinical risk factors. The performance of the model was validated in prospective phase III trials [NCT01503905] (internal validation cohort, n=105), and Shunde Hospital of Southern Medical University and Tungwah Hospital of Sun Yat-Sen University (external validation cohort, n=180).
In the training cohort, the radiomic signature comprising intratumoral and peritumoral features showed an improved performance, with 1-, 2-, 3-year AUCs of 0.97, 0.95, and 0.98 over intratumoral or peritumoral radiomics alone. The clinical-radiomic nomogram achieved the highest 1-, 2-, 3-year AUCs of 0.97, 0.96, and 0.98, it was also found to be significantly associated with DFS (HR 0.027, 95% CI 0.010-0.077, p<0.001). The prognostic value was validated in the internal and external cohorts. The clinical-radiomic nomogram could also discriminate high- from low-risk patients in different molecular subtypes (P<0.001 for Luminal A; P<0.001 for Luminal B; P=0.007 for HER2+; P<0.001 for TNBC). Neoadjuvant chemotherapy improved DFS compared with patients who received adjuvant chemotherapy (P=0.048), among high-risk patients of Luminal subtype. No significance was observed between neoadjuvant chemotherapy and adjuvant chemotherapy in patient with low-risk (P=0.400).
The clinical-radiomic nomogram we developed which shows the potential to be served as a convenient tool for DFS prediction in patients with early-stage breast cancer and identify patients who might benefit from neoadjuvant chemotherapy.
NCT04003558; ChiCTR1900024020.
Sun Yat-sen Memorial Hospital, Sun Yat-sen University.
National Natural Science Foundation of China;National Major Science and Technology Projects of China; Medical Artificial Intelligence Project of Sun Yat-Sen Memorial Hospital; Natural Science Foundation of Guangdong Province; Guangzhou Science and Technology Major Program; Sun Yat-Sen University Clinical Research 5010 Program; Sun Yat-Sen Clinical Research Cultivating Program; Guangdong Science and Technology Department.
All authors have declared no conflicts of interest.