Live introduction (ID 238)
63O - Letrozole and palbociclib versus 3rd generation chemotherapy as neoadjuvant treatment in luminal breast cancer: survival results of the UNICANCER-NeoPAL study (ID 239)
Abstract
Background
The NeoPAL trial compared letrozole-palbociclib (LETPAL) combination to standard chemotherapy (CT) as neoadjuvant treatment in patients with high-risk LBC. Both LETPAL and CT were associated with poor pathological response, and equivalent clinical responses, while LETPAL let to encouraging biomarker responses in Prosigna®-defined high-risk LBC. We now evaluate the survival outcomes of both groups.
Methods
NeoPAL (UCBG104, NCT02400567) is a randomized, parallel, non-comparative phase II study. Postmenopausal women with ER-positive, HER2-negative, Prosigna®-defined luminal B, or luminal A and node-positive, stage II-III BC, were randomly assigned to either letrozole (2.5 mg daily) and palbociclib (125 mg daily, 3 weeks/4) during 19 weeks (LETPAL), or to FEC100 (5FU 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2) x3 21-day courses followed by docetaxel 100 mg/m2 x3 21-day courses (CT). Secondary endpoints included progression-free survival (PFS) and invasive-disease free survival (iDFS), all measured from the date of randomization. Exploratory objectives aimed at evaluating the impact of PEPI score and residual cancer burden (RCB) on survival outcomes in both arms.
Results
53 pts were randomized in each arm. 23 of the 53 pts in the LETPAL arm received postoperative adjuvant chemotherapy. Median follow-up is 40.4 months [0-56.6]. 11 progressions have been observed, of which 3 were in the LETPAL and 8 in the control arm. Two additional iDFS events were observed in the LETPAL arm (secondary malignancies). PFS (HR = 1.01; 95%CI [0.36; 2.90], p=0.98) and iDFS (HR= 0.83; 95%CI [0.31; 2.23], p=0.71) did not differ between both arms. 40 months PFS rate is 86.7% (78.0-96.4) and 87.2% (78.1-97.4) in LETPAL and CT arms respectively. PEPI (PEPI II/II vs I: HR 0.80, 95%CI 0.18-3.67) and RCB scores (RCB II/III vs 0/I: HR 1.36; 95%CI 0.17-10.6) did not appear as independent predictors of PFS or iDFS.
Conclusions
Despite its small size, NeoPAL suggests that a neoadjuvant LETPAL strategy, together with selected postoperative administration of chemotherapy, may spare chemotherapy in some pts with LBC while allowing good long-term outcomes.
Clinical trial identification
NCT02400567.
Legal entity responsible for the study
UNICANCER.
Funding
Pfizer, NanoString Technologies.
Disclosure
S. Delaloge: Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Orion; Research grant/Funding (institution): Daiichi; Research grant/Funding (institution): Puma; Research grant/Funding (institution): Pierre Fabre. H. Manduzio, J. Lemonnier, P.H. Cottu: Research grant/Funding (institution): Pfizer. All other authors have declared no conflicts of interest.
91O - Pooled analysis of patient (pt)-reported outcomes (PROs) in the MONALEESA (ML)-2, -3, and -7 trials: additional results and key subgroup findings (ID 240)
Abstract
Background
The phase III ML-2, -3, and -7 trials assessed ribociclib (RIB) with different endocrine therapy (ET) partners in pts with hormone receptor–positive, HER2-negative (HR+/HER2−) advanced breast cancer (ABC). Quality-of-life (QOL) results were previously reported for each ML trial and as a pooled analysis. Here, we report on individual dimensions of the EORTC QLQ-C30 PROs, including relevant pt subgroup data from a pooled analysis of the ML trials.
Methods
PROs were collected with EORTC QLQ-C30 questionnaires. QOL was assessed for all pts in ML-2, pts without prior ET for ABC in ML-3, and pts receiving RIB or placebo (PBO) + a nonsteroidal aromatase inhibitor in ML-7. A linear effects model was used to calculate the least-squares mean changes from baseline in global health status (GHS), nausea and vomiting, diarrhea, and anxiety/depression, and these were interpreted using minimally important differences. GHS was also assessed for pt subgroups including age, race, and molecular subtype by PAM50.
Results
A total of 1528 pts were included. Time to definitive deterioration (TDD) for diarrhea and anxiety/depression was prolonged for RIB vs PBO (Table). Diarrhea, anxiety/depression, and GHS across subgroups were improved or maintained from cycle 3 to end of treatment. Median TDD of GHS was longer for RIB vs PBO in pts regardless of age. Median TDD of GHS for RIB vs PBO was longer for White pts, similar for Asian pts, and shorter for pts of other races, although the n in the latter group was small. Median TDD of GHS for RIB vs PBO was longer in pts with luminal subtypes and was more than doubled for the HER2-enriched (HER2E; 30.4 vs 14.8 mo) subtype.
Conclusions
In this pooled analysis of the ML trials, RIB + ET showed delayed deterioration in QOL scores. TDD for GHS favored RIB vs PBO across most subgroups. These results support prior QOL analyses showing the value of RIB + ET in maintaining QOL for pts with HR+/HER2− ABC. aGHS by ≥10% NE, not estimable.
TDD, median mo RIB + ET (n=819) PBO + ET (n=709) HR (95% CI) All pts Nausea/vomiting ≥12 points 57.9 NE 1.04 (0.82-1.31) Diarrhea ≥10 points NE 55.2 0.76 (0.59-1.00) Anxiety/depression ≥30% 52.0 49.7 0.78 (0.63-0.96) Age (n)a <40 y (171) 35.9 23.0 0.78 (0.46-1.30) 40 - <55 y (531) 34.2 27.7 0.75 (0.57-0.99) ≥55 y (826) 42.6 35.9 0.82 (0.65-1.05) Race (n)a Asian (254) 35.9 35.8 0.94 (0.60-1.46) White (1131) 41.5 32.2 0.73 (0.59-0.89) Other (143) 33.2 46.9 1.11 (0.61-2.00) Molecular subtype (n)a Luminal A + B (628) 41.7 35.9 0.86 (0.65-1.14) HER2E (105) 30.4 14.8 0.59 (0.29-1.20) Basal-like (49) 16.5 22.4 0.84 (0.34-2.06) Normal-like (152) 47.2 50.6 0.74 (0.41-1.32)
Clinical trial identification
NCT01958021, NCT02422615, NCT02278120.
Editorial acknowledgement
This abstract was developed with editorial assistance provided by Casey Nielsen, PhD of MediTech Media, LLC. Editorial support was funded by Novartis Pharmaceuticals Corporation.
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation.
Funding
Novartis Pharmaceuticals Corporation.
Disclosure
P.A. Fasching: Research grant/Funding (institution): BioNTech; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Celgene; Honoraria (self), Speaker Bureau/Expert testimony: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy: Macrogenics; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Puma; Research grant/Funding (institution): Cepheid; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy: AstraZeneca. A. Bardia: Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Research grant/Funding (institution): Radius Health; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Immunomedics/Gilead; Advisory/Consultancy, Research grant/Funding (institution): Biothernostics Inc.; Advisory/Consultancy, Travel/Accommodation/Expenses: Taiho; Advisory/Consultancy: Daiichi Pharma/AstraZeneca; Advisory/Consultancy: Puma; Advisory/Consultancy, Travel/Accommodation/Expenses: Phillips; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy: Mersana. A. Nusch: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Amgen. G. Jerusalem: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self): AbbVie; Honoraria (self): Daiichi Sankyo; Advisory/Consultancy: MedImmune; Advisory/Consultancy: Merck. N.S. El Saghir: Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Eli Lilly. E. Alba Conejo: Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): NanoString; Travel/Accommodation/Expenses: Celgene; Research grant/Funding (institution): Sysmex. S-A. Im: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Hanmi; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Eisai; Advisory/Consultancy: Amgen; Advisory/Consultancy: MediPacto; Research grant/Funding (institution): Roche; Honoraria (self): Lilly; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: GSK; Research grant/Funding (institution): Daewoong Pharm. W. Janni: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis. D. Chandiwana, B.R. Lanoue, A. Thuerigen, E. Gu: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. N. Harbeck: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca. All other authors have declared no conflicts of interest.
Invited Discussant 63O and 91O (ID 241)
Q&A and live discussion (ID 242)
1O - Detection of homologous recombination repair deficiency (HRD) in treatment-naive early triple negative breast cancer (TNBC) by RAD51 foci and comparison with DNA-based tests (ID 243)
Abstract
Background
PARP inhibitors (PARPi) are approved for the treatment of metastatic breast cancers (BC) associated with germline BRCA1/BRCA2 (gBRCA) mutations. Tumours from these patients are defective in double strand break DNA repair, namely homologous recombination repair (HRR). HRR alterations also exist beyond gBRCA mutation in 60% of TNBC. HRR results in RAD51 foci formation. Here, we aimed to evaluate the functional status of HRR with an immunofluorescence (IF) tissue-based test, to identify tumours lacking RAD51 foci, and correlate this with genomic HRD tests or treatment activity.
Methods
The percentage of RAD51 foci in the S/G2-phase of the cell cycle was scored using an IF test (RAD51-IF) in baseline and end of treatment (EOT) FFPE tumour samples from 29 patients diagnosed with early TNBC, receiving the PARPi rucaparib in the RIO trial (EudraCT 2014-003319-12). The baseline RAD51 score, predefined as low if ≤10%, was correlated with trial endpoints including HRR alterations, HRDetect status, RAD51 by immunohistochemistry (RAD51-IHC) at EOT and change in ctDNA levels.
Results
The RAD51-IF test scored 17/17 baseline tumour samples (100%), and 27/28 EOT samples (96%), compared to 93% success rate for HRDetect or 73% of RAD51-IHC EOT. RAD51-IF scores increased from baseline to EOT (p=0.026), reflecting rucaparib induced RAD51-mediated repair. The prevalence of HRD according to the RAD51-IF test was 47% (8 out of 17). Six out of eight tumours with known HRR alterations had low RAD51-IF (75%). Two tumours without known HRR alterations had low RAD51-IF, suggesting the presence of underlying HRR alterations. Seven out of ten HRDetect-positive tumours had low RAD51-IF, and none of the HRDetect-negative tumours had low RAD51-IF (p=0.054). RAD51-IF low tumours had greater ctDNA suppression on rucaparib than RAD51 high tumours (n=12, p=0.052), with 4 out of 5 (80%) RAD51-low tumours undergoing a substantial decrease in ctDNA levels, similar to 78% for RAD51-IHC EOT.
Conclusions
The RAD51-IF test is feasible in treatment-naive FFPE tumour samples from early TNBC to assess the functional status of HRR and identifies PARPi-sensitive tumours.
Clinical trial identification
EudraCT 2014-003319-12.
Legal entity responsible for the study
RMH and ICR.
Funding
Instituto de Salud Carlos III, Asociación Española Contra el Cáncer. Clovis Oncology Inc., Cridlan Foundation, CRUK, Breast Cancer Now, NHS, Wellcome Trust.
Disclosure
V. Serra Elizalde: Licensing/Royalties, PCT/EP2018/086759 (WO2019122411A1): Patent; Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): Tesaro; Advisory/Consultancy: AbbVie. A. Llop-Guevara: Licensing/Royalties, PCT/EP2018/086759 (WO2019122411A1): Patent. C. Cruz: Licensing/Royalties, PCT/EP2018/086759 (WO2019122411A1): Patent. M. Castroviejo-Bermejo: Licensing/Royalties, PCT/EP2018/086759 (WO2019122411A1): Patent. H. Tovey: Research grant/Funding (self): Clovis Oncology Inc. C. Toms: Research grant/Funding (self): Clovis. R. Roylance: Honoraria (self): Pfizer. A. Tutt: Honoraria (self): Pfizer; Honoraria (self): Vertex; Honoraria (self): prIME Oncology; Honoraria (self): Artios; Honoraria (self), Shareholder/Stockholder/Stock options: InBiomotion; Honoraria (self): AstraZeneca; Honoraria (self): Medivation; Honoraria (self): Myriad Genetics; Honoraria (self): Merck Serono; Licensing/Royalties, PARP inhibitor: Institute of Cancer Research. H.R. Davies: Licensing/Royalties, WO2017191074A1: Patent. S. Nik-Zainal: Licensing/Royalties, WO2017191074A1: Patent; Honoraria (self): GTx; Honoraria (self): Radius; Honoraria (self): Orion; Honoraria (self): G1therapeutics; Speaker Bureau/Expert testimony: Myriad and; Speaker Bureau/Expert testimony: NanoString; Research grant/Funding (self): Pfizer; Research grant/Funding (self): Radius; Licensing/Royalties, Abiraterone: Institute of Cancer Research. J. Balmaña: Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Licensing/Royalties, PCT/ EP2018/086759 (WO2019122411A1): Patent. N. Turner: Research grant/Funding (self): Clovis; Honoraria (self), Research grant/Funding (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Lilly; Honoraria (self): Merck Sharpe and Dohme; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self), Research grant/Funding (self): Roche/Genentech; Honoraria (self): Tesaro; Honoraria (self): Bicycle Therapeutics; Research grant/Funding (self): BioRad; Research grant/Funding (self): Guardant Health. All other authors have declared no conflicts of interest.
2O - Association of RAD51 with Homologous Recombination Deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial (ID 244)
Abstract
Background
Current genetic and genomic tests that measure HRD show limited predictive value. We compare the performance of a functional HRD test based on scoring RAD51 nuclear foci with genetic/genomic HRD tests, and assess its capacity to select patients (pts) with primary TNBC sensitive to platinum-based neoadjuvant chemotherapy (NACT).
Methods
A retrospective, blinded analysis from the GeparSixto randomized trial was conducted on TNBC pts who received neoadjuvant paclitaxel plus non-pegylated liposomal doxorubicin (Myocet®) and bevacizumab (PM) or PM plus carboplatin (PMCb). Functional HRD biomarkers (RAD51, BRCA1 and yH2AX nuclear foci) were quantified in formalin-fixed paraffin-embedded (FFPE) tumor samples on a tissue microarray format (TMA). Concordance analyses were performed between the RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (myChoice® CDx). Associations with clinical outcomes were studied by logistic (pathological complete response, pCR) and Cox (disease-free survival, DFS) regression models. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low).
Results
RAD51, BRCA1 and yH2AX were successfully scored in 133/200 TMA cores (67%). Functional HRD by RAD51-low was evidenced in 81/133 tumors (62%). The RAD51 test identified 93% of tBRCA-mutated tumors and 45% of the non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% (95%CI 79-93%). In pts with RAD51-high tumors, the pCR rate was similar between treatment arms (PMCb 31% vs PM 39%, odds ratio (OR) 0.71, 0.23-2.24, p=0.561). Pts with RAD51-low tumors benefited from PMCb (66% vs 33%, OR 3.96, 1.56-10.05, p=0.004; interaction test p=0.023). The addition of Cb showed a trend towards better DFS in both RAD51-high (hazard ratio (HR) 0.40, 0.12-1.29, p=0.125) and RAD51-low (HR 0.45, 0.16-1.25, p=0.124) groups.
Conclusions
The RAD51 test is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51-testing in the clinical decision making.
Clinical trial identification
NCT01426880.
Legal entity responsible for the study
Violeta Serra, ERAPERMED.
Funding
Has not received any funding.
Disclosure
A. Llop-Guevara: Research grant/Funding (self): AECC (INVES20095LLOP); Research grant/Funding (self): La Caixa Foundation and European Institute of Innovation and Technology/Horizon 2020 (LCF/TR/CC19/52470003). A. Schneeweiss: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses, Non-remunerated activity/ies, Medical writing grant: Roche; Research grant/Funding (institution): AbbVie; Honoraria (self), Speaker Bureau/Expert testimony: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Tesaro; Honoraria (self): Lilly. G. Villacampa: Honoraria (self): MSD; Honoraria (self): AstraZeneca. P. Jank: Research grant/Funding (institution): EU funding EraPerMed JTC2019 \"RAD51predict\"; Research grant/Funding (institution), Shareholder/Stockholder/Stock options: Myriad Genetics, Inc. M. van Mackelenbergh: Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Genomic Health; Honoraria (self): Mylan; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): Roche. P.A. Fasching: Honoraria (self): Novartis; Research grant/Funding (institution): Biontech; Honoraria (self): Pfizer; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Eisai; Honoraria (self): Merck Sharp & Dohme; Research grant/Funding (institution): Cepheid; Honoraria (self): Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Seattle Genetics; Honoraria (self): Roche; Honoraria (self): Hexal. F. Marmé: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Clovis; Honoraria (self): GSK/Tesaro; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): Celgene; Honoraria (self): Seagen; Honoraria (self): Myriad Gen; Honoraria (self): PharmaMar; Honoraria (self): Eisai; Honoraria (self): Janssen-Cilag. R. Dienstmann: Honoraria (self): Roche; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Merck Sharp Dohme; Honoraria (self): Amgen; Honoraria (self): Sanofi; Honoraria (self): Servier; Honoraria (self): Ipsen. J. Balmaña: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer. C. Denkert: Research grant/Funding (institution): European Commission H2020; Research grant/Funding (institution): German Cancer Aid Translational Oncology; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): MSD Oncology; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Research grant/Funding (institution): Myriad; Honoraria (self): Merck; Shareholder/Stockholder/Stock options: Sividon diagnostics; Licensing/Royalties, patent royalties: MScope digital pathology software; Licensing/Royalties, patent pending: WO2020109570A1 - cancer immunotherapy; Licensing/Royalties, patent issued: WO2015114146A1 and WO2010076322A1- therapy response. S. Loibl: Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Honoraria (institution): Seagen; Research grant/Funding (institution): Immunomedics/Gilead Sciences Inc; Honoraria (institution): prIME/Medscape; Honoraria (institution): Eirgenix; Research grant/Funding (self), Research grant/Funding (institution): DSI; Honoraria (institution): BMS; Honoraria (institution): Merck; Honoraria (institution): Puma; Speaker Bureau/Expert testimony: Chugai; Licensing/Royalties, patent pending: EP14153692.0-Immunsignature in TNBC. V. Serra: Research grant/Funding (institution): ISCIII (CPII19/00033); Research grant/Funding (institution): TRANSCAN-2 (AC15/00063; Research grant/Funding (institution): AECC (LABAE16020PORTT); Research grant/Funding (institution): ERAPERMED2019-215. All other authors have declared no conflicts of interest.