Background

Abemaciclib, an oral, selective CDK4 & 6 inhibitor, significantly improved PFS in HR+, HER2+ advanced breast cancer (ABC; locoregionally recurrent or metastatic) when combined with fulvestrant and trastuzumab, compared to trastuzumab plus chemotherapy in monarcHER (Tolaney 2020, Lancet Oncol.) Here, we report the OS results at the prespecified final analysis.

Methods

monarcHER (NCT02675231) is a randomized, multicenter, open-label phase 2 trial. Randomization was 1:1:1 to arm A (abemaciclib 150mg PO BID, trastuzumab IV, fulvestrant 500mg IM), arm B (abemaciclib, trastuzumab), and arm C (trastuzumab, SOC chemotherapy). Stratification factors were number of prior systemic regimens for ABC and measurable disease. Exploratory biomarker analyses were also conducted, including evaluation of intrinsic subtypes by RNAseq.

Results

At the time of data cutoff (31 Mar 2022), of the 237 patients enrolled, 157 deaths had occurred across the treatment arms, 50 deaths (63%) arm A, 54 deaths (68%) arm B, and 53 deaths (67%) arm C. Median follow-up was 52.9 months. mOS was 30.3 months in arm A, 31.43 months in arm B and 22.7 months in arm C (A v C: HR 0.75 [95% CI 0.47, 1.21]; nominal 2-sided p-value 0.243; B v C: HR 0.73 [95% CI 0.46, 1.15]; nominal 2-sided p-value 0.177). In exploratory RNAseq analyses, luminal subtypes were associated with longer PFS (8.6 v 5.4 months [HR 0.54, 95% CI 0.38, 0.79]) and OS (31.7 v. 19.7 months [HR 0.68, 95% CI 0.46, 1]) compared to non-luminal. Updated PFS and safety findings were consistent with the primary analysis (data cutoff 8 Apr 2019).

Conclusions

Abemaciclib plus trastuzumab ± fulvestrant numerically improved OS in women with HR+, HER2+ ABC compared to chemotherapy plus trastuzumab with a manageable safety profile.

Clinical trial identification

NCT02675231.

Editorial acknowledgement

Medical writing support was provided by Trish Huynh and Nicholas Pulliam, employees of Eli Lilly and Company.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

F. André: Financial Interests, Institutional, Research Grant: Roche, Eli Lilly and Company, Pfizer, Novartis, Daiichi Sankyo, AstraZeneca. H. Denys: Other, Institutional, Advisory Board: Pfizer, Roche, PharmaMar, AstraZeneca, Eli Lilly and Company, Novartis, Amgen, GSK, Seagen; Other, Institutional, Other, Travel, Accomodations, Expenses: Pfizer, Roche, PharmaMar, Teva, AstraZeneca. S. Goel: Other, Advisory Board: Eli Lilly and Company, Pfizer; Other, Research Grant, Lab research funding: Eli Lilly and Company, G1 Therapeutics. L.M. Litchfield: Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company; Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company. A. Appiah: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. Y. Chen: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. S.M. Tolaney: Financial Interests, Personal, Principal Investigator, Institutional Research Funds; honorarium: AstraZeneca, Eli Lilly and Company, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Gilead, Exelixis, Bristol Myers Squibb, Eisai, Nanostring, Sanofi; Financial Interests, Personal, Advisory Board, Institutional Research Funds; honorarium: AstraZeneca, Eli Lilly and Company, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Bristol Myers Squibb, Eisai, Nanostring, Sanofi; Financial Interests, Personal, Other, Steering Committee, Institutional Research Funds; honorarium: Eli Lilly and Company; Financial Interests, Personal, Advisory Role, Institutional Research Funds; honorarium: Gilead; Financial Interests, Personal, Advisory Board, Honorarium: Puma, Oncopep, Kyowa Kirin Pharmaceuticals, Samsung Bioepsis Inc., Mersana Therapeutics, Ellipses Pharma, 4D Pharm, OncoSec Medical Incorporated, BeyondSpring Pharmaceuticals, Zymeworks, Zentalis, Reveal Genomics, ARC Therapeutics; Financial Interests, Personal, Principal Investigator, Institutional Research Funds: Cyclacel, Odonate; Financial Interests, Personal, Other, Consultant/Steering Committee: Odonate; Financial Interests, Personal, Principal Investigator, Consultant; Institutional Research Funds; honorarium: Seattle Genetics; Financial Interests, Personal, Other, Consultant; honorarium: Daiichi Sankyo, Athenex; Financial Interests, Personal, Other, Consulting/honorarium: Oncopep; Financial Interests, Personal, Other, Steering Committee/Consultant; Honorarium: CytomX; Financial Interests, Personal, Other, Honorarium: Chugai Pharmaceuticals, OncXerna, Zetagen; Financial Interests, Personal, Other, Consulting/Honorarium: Blueprint Medicines. All other authors have declared no conflicts of interest.

Background

Pyrotinib (pyro, an irreversible pan-HER inhibitor) plus capecitabine has demonstrated antitumor activity as 2L treatment in HER2-positive metastatic breast cancer (mBC) (Lancet Oncol 2021). Pertuzumab combined with trastuzumab (H) and docetaxel (T) is the standard 1L dual anti-HER2 therapy for HER2-positive mBC. Here, we report the efficacy and safety of dual anti-HER2 regimen of Pyro+H+T (PyroHT) compared with placebo+H+T (HT) in untreated HER2-positive mBC.

Methods

Eligible pts were randomized (1:1) to receive oral Pyro (400 mg QD) or placebo, both combined with intravenous H (8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles) and T (75 mg/m²) on day 1 of each 21-day cycle. The primary endpoint was PFS per investigator (INV). Data cutoff for this prespecified interim analysis was May 25, 2022.

Results

Between May 2019 and Jan 2022, 590 eligible pts from 40 centers were randomized and treated (297 with PyroHT and 293 with HT). Median follow-up was 15.8 mo and 14.9 mo, respectively. PFS per INV of PyroHT was significantly longer than HT (median, 24.3 mo [95% CI 19.1-33.0] vs 10.4 mo [95% CI 9.3-12.3]; HR, 0.41 [95% CI 0.32-0.53]; P < 0.0001; subgroup results are in Table 1), which was consistent with PFS per IRC (median, 33.0 vs 10.4 mo; HR, 0.35 [95% CI 0.27-0.46]). The most common grade ≥3 TRAEs were decreased neutrophil count (62.6% vs 65.2%), decreased WBC count (53.2% vs 50.9%), and diarrhea (46.5% vs 3.1%). Grade 3 diarrhea occurred mainly during cycle 1 and substantially decreased in cycle 2 and thereafter. No grade 4 or 5 diarrheas occurred. Serious TRAEs occurred in 24.9% vs 6.1% of pts and treatment-related deaths occurred in 0 vs 0.3% of pts, respectively. Table: LBA19

Subgroup analyses of PFS per INV

Conclusions

PyroHT significantly prolonged PFS over HT in pts with HER2-positive mBC. The safety is manageable. To our knowledge, this is the second phase 3 trial to demonstrate PFS benefit from dual HER2 inhibition in 1L treatment of HER2-positive mBC.

Clinical trial identification

NCT03863223.

Legal entity responsible for the study

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Funding

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Disclosure

B. Xu: Non-Financial Interests, Personal, Advisory Role: Novartis; Non-Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Pfizer, Roche, Eisai; Financial Interests, Personal, Advisory Role: Roche.. F. Dong: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals Co., Ltd. S. Wu: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals Co., Ltd. X. Zhu: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals Co., Ltd. All other authors have declared no conflicts of interest.

Background

Acquired ESR1 mutations cause endocrine resistance, driving metastasis and poor prognosis in patients with ER+/HER2- mBC. A phase 2 trial of LAS plus abemaciclib (ELAINE 2) showed efficacy in heavily pretreated patients with ESR1-mutated mBC post-CDK4/6i (ASCO 2022). Here we describe ELAINE 1, a randomized trial of LAS vs Fulv in a post-CDK4/6i second-line setting.

Methods

Women with ER+/HER2-/ESR1-mutated mBC and progression on prior (≥12 mos) AI plus CDK4/6i (n=103) were randomized to oral LAS 5 mg (n=52) daily or IM Fulv 500 mg (n=51) days 1, 15, and 29, then every 4 weeks, until disease progression or severe toxicity. Imaging occurred every 2 mos (or if clinically indicated). Primary endpoint was progression-free survival (PFS).

Results

Mean age was 60.8 yr (33-84); 83% were white, 66% had visceral disease, 71% (n=73) had measurable disease. For LAS vs Fulv, median PFS was 6.04 mos (95% CI, 2.82–8.04) vs 4.04 mos (95% CI, 2.93–6.04), P=0.138 (HR, 0.699 [95% CI, 0.445–1.125]); PFS at 12 mos was 30.7% vs 14.1%; clinical benefit rate was 36.5% vs 21.6%, P=0.12. Objective response rate for LAS vs Fulv was 13.2% vs 2.9%, P=0.12, with 1 complete response (60-week duration) and 4 partial responses (PR) in the LAS arm versus 1 PR in the Fulv arm. PFS was numerically and consistently greater with LAS vs Fulv when visceral metastasis and/or Y537S ESR1 mutation subgroups were analyzed. Clearance of ctDNA also favored LAS over Fulv. Most common adverse events were fatigue, nausea, arthralgias, and hot flushes; most were Grade 1/2. No thrombotic events occurred.

Conclusions

ELAINE 1 is the first clinical trial comparing LAS with Fulv in ESR1-mutated mBC patients with progression on CDK4/6i and demonstrating activity of a novel SERM in this setting. All clinical outcomes numerically favored LAS vs Fulv in this signal-seeking study. LAS may be a new treatment option following endocrine/CDK4/6i therapies if efficacy is confirmed in a larger, adequately powered clinical study. A phase 3 combination study of LAS and abemaciclib is planned based on encouraging efficacy/safety in ELAINE 2.

Clinical trial identification

NCT03781063.

Editorial acknowledgement

Medical writing assistance was provided by Kathleen Ohleth, PhD of Precise Publications, LLC.

Legal entity responsible for the study

Sermonix Pharmaceuticals.

Funding

Sermonix Pharmaceuticals.

Disclosure

M.P. Goetz: Financial Interests, Institutional, Advisory Role: Mayo Clinic, Biovica, Biotheranostics, Blueprint Medicines, Eagle Pharmaceuticals, Lily, Novartis, Pfizer, Sanofi Genzyme, Sermonix; Financial Interests, Personal, Invited Speaker: Research to Practice, Clinical Education Alliance, Medscape, Total Health Conferenceing, Curio Science; Financial Interests, Institutional, Research Grant: Mayo Clinic, Pfizer, Sermonix. P. Plourde: Financial Interests, Personal, Full or part-time Employment: Sermonix; Financial Interests, Personal, Stocks/Shares: Sermonix. D.G. Stover: Financial Interests, Personal, Advisory Board: Novartis. N. Bagegni: Financial Interests, Institutional, Research Grant: Ambrx Inc, AstraZeneca Pharmaceuticals LP, Biovica International AB, Daiichi Sankyo, Novartis, Pfizer, Sarah Cannon Development Innovations LLC, Seattle Genetics, Sermonix, Xcovery Hholdings Company LLC. G.A. Vidal: Financial Interests, Personal and Institutional, Advisory Role: Roche/Genetech, Novartis, Eli-Lilly, Gilead, Puma, Pfizer, AstraZeneca, Biotheranautics, Daiichi Sankyo, Concerto Al; Financial Interests, Personal, Training: Eli-Lilly; Financial Interests, Institutional, Research Grant: Roche/Genetech, Puma, Celcuity, Merck, BMS, Eli-Lilly, AstraZeneca, Pfizer, Gilead, GSK; Financial Interests, Personal, Ownership Interest: Oncodisc. A. Brufsky: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer, Novartis, Lilly, Genentech/Roche, SeaGen, Daiichi Sankyo, Merck, Agendia, Sanofi, Puma; Financial Interests, Institutional, Research Grant: Agendia, AstraZeneca. H.S. Rugo: Financial Interests, Institutional, Research Grant: Pfizer, Merck, Novartis, Lilly, Roche, Daiichi, Seattle Genetics, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, AstraZeneca, Ayala, Astellas, Gilead; Financial Interests, Personal, Other, Honoraria: Puma, Samsung, NAPO. D.J. Portman: Financial Interests, Personal, Full or part-time Employment: Sermonix; Financial Interests, Personal, Stocks/Shares: Sermonix. E. Gal-Yam: Financial Interests, Personal, Other, Honoraria: Eli-Lilly, Novartis, Pfizer, Roche, AstraZeneca, MSD.

Background

ET is the mainstay management for ER+ BC; guidelines recommend ET before chemotherapy in LA/mBC. Giredestrant, a highly potent, non-steroidal, oral selective ER antagonist and degrader (SERD), achieves robust ER occupancy and was well tolerated and active as a single agent and in combination with palbociclib, regardless of ESR1 mutation, in phase I/II studies. acelERA BC (NCT04576455) compares giredestrant and PCET for ER+, HER2– LA/mBC in the 2^nd/3^rd line. We report the primary results.

Methods

Post- and pre-/peri-menopausal women, or men, ≥18 years with measurable disease or evaluable bone lesions, who progressed after 1–2 lines of systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomised 1:1 to giredestrant (30 mg PO QD) or fulvestrant/aromatase inhibitor per local guidelines (+LHRH agonist in pre-/peri-menopausal women, and men) until disease progression/unacceptable toxicity. Stratification was by visceral vs non-visceral disease, prior CDK4/6 inhibitor (yes/no) and prior fulvestrant (yes/no). The primary endpoint was investigator-assessed progression-free survival (INV-PFS).

Results

At cut-off (18/02/22), median follow-up was 7.89 months; 39% of pts had baseline ESR1 mutations; 71%/28% had 1/2 prior therapy lines. Efficacy/safety are shown in the table. Updated data with longer follow-up will be presented. Table: 211MO

Conclusions

While acelERA BC did not meet its primary endpoint of INV-PFS, giredestrant showed a numerical improvement vs PCET. A higher CBR and ORR was also observed in favour of giredestrant. In pts with higher dependence on ER activity, such as those with ESR1 mutations, the PFS benefit was more pronounced. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known ET risks. Giredestrant continues to be investigated in other studies.

Clinical trial identification

NCT04576455 (October 6, 2020).

Editorial acknowledgement

Support for third-party writing assistance for this abstract, furnished by Daniel Clyde, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

M. Martin Jimenez: Financial Interests, Personal, Other, Consulting/advisory: F. Hoffmann-La Roche Ltd/ Genentech, Novartis, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Lilly/ImClone, Roche/Genentech, Pierre Fabre; Financial Interests, Personal, Other, Honoraria: Roche/Genentech, Lilly, Pfizer, Novartis, Pierre Fabre, Seattle Genetics ; Financial Interests, Institutional, Funding: Novartis, Roche, PUMA Biotechnology; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. E. Lim: Financial Interests, Personal, Other, Consulting/advisory: Lilly, Novartis, Pfizer, Roche; Financial Interests, Institutional, Funding: Novartis, Roche; Financial Interests, Personal, Other, Patents/royalties/IP: Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737: Walter & Eliza Hall Institute of Medical Research; Financial Interests, Personal, Other, Travel/accommodation/expenses: Lilly; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. M. Chavez Mac Gregor: Financial Interests, Personal, Full or part-time Employment: MD Anderson Physician's Network; Financial Interests, Personal, Other, Consulting/advisory: Roche/Genentech, Novartis, Pfizer, Asofarma, Roche/Genentech, Exact Sciences, AstraZeneca/ Daiichi Sankyo, AstraZeneca; Financial Interests, Personal, Other, Travel/accommodation/expenses: Pfizer; Financial Interests, Personal, Expert Testimony: Abbott Laboratories, Pfizer; Financial Interests, Personal, Other, Honoraria: Pfizer, Eisai; Financial Interests, Institutional, Funding: Novartis, Genentech/Roche, Pfizer; Non-Financial Interests, Personal, Member of the Board of Directors, Volunteer-Member, Board of Directors: Legacy Healthcare Services, The Hope Foundation ; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. A. Bardia: Financial Interests, Personal, Other, Consulting/advisory: Novartis, Genentech, Pfizer, Spectrum Pharmaceuticals, BioTheranostics, Merck, Radius Health, Immunomedics, Sanofi, Puma Biotechnology, Daiichi Sankyo/AstraZeneca, Foundation Medicine, Philips ; Financial Interests, Institutional, Other, Consulting/advisory: Immunomedics, Novartis, Genentech/Roche, Pfizer, Radius Health, Innocrin Pharma; Financial Interests, Institutional, Funding: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, AstraZeneca/Daiichi Sankyo; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. J. Wu: Financial Interests, Institutional, Funding: National Natural ScienceFoundation, Roche; Financial Interests, Personal, Other, Honoraria: Lilly, Roche, AstraZeneca, Pfizer; Financial Interests, Personal, Proprietary Information, Microvascular anastomosis support dilator; degradable breast-conserving stent: Fudan University Shanghai Cancer Center; Non-Financial Interests, Personal, Leadership Role, Chairman: Chinese Breast Cancer Society; Non-Financial Interests, Personal, Leadership Role, Vice chairman: Breast Surgeon Committee; Non-Financial Interests, Personal, Leadership Role: Chinese College of Surgeons; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. Q. Zhang: Financial Interests, Institutional, Funding: Roche; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. Z. Nowecki: Financial Interests, Personal, Other, Travel/accommodation/expenses: F. Hoffmann-La Roche Ltd/ Genentech; Financial Interests, Institutional, Funding: F. Hoffmann-La Roche Ltd; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. F. Cruz: Financial Interests, Institutional, Funding: Roche; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. R. Safin: Financial Interests, Personal, Speaker’s Bureau: F. Hoffmann-La Roche Ltd; Financial Interests, Institutional, Funding: F. Hoffmann-La Roche Ltd; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. S. Kim: Financial Interests, Institutional, Other, Consulting/advisory: Lilly; Financial Interests, Personal, Other, Consulting/advisory: Novartis, AstraZeneca, Dae Hwa Pharmaceutical Co, Ltd, ISU Abxis, Daiichi Sankyo; Financial Interests, Personal, Other, Honoraria: Novartis, AstraZeneca, Lilly; Financial Interests, Institutional, Funding: Novartis, Dongkook Pharm Co, Sanofi-Aventis, Roche; Financial Interests, Personal, Other, Consulting/advisory: Data safety monitoring/advisory board: Novartis, AstraZeneca, Lilly, Daiichi Sankyo; Non-Financial Interests, Personal, Leadership Role, Co-Chair: ESMO Breast 2021-2022; Financial Interests, Personal, Stocks/Shares: Genopeaks, Neogene TC; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. C. Schem: Financial Interests, Institutional, Funding: Roche; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. A. Montero: Financial Interests, Personal, Other, Consulting/advisory: New Century Health, Welwaze; Financial Interests, Personal, Other, Honoraria: Celgene, AstraZeneca, OncoSec; Financial Interests, Institutional, Funding: F. Hoffmann-La Roche Ltd; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. S. Khan: Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Institutional, Funding: Roche; Financial Interests, Personal, Other, Travel/accommodation/expenses: Novartis; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. R. Bandyopadhyay: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. M. Shivhare: Financial Interests, Personal, Full or part-time Employment: Roche Products Limited; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. M. Patre: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. J. Martinalbo: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. L. Roncoroni: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. P.D. Pérez-Moreno: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd. J. Sohn: Financial Interests, Institutional, Funding: Roche, MSD, AstraZeneca, Lilly, Pfizer, GSK, Daiichi Sankyo, Sanofi, Boehringer Ingelheim; Non-Financial Interests, Personal, Funding, Medical writing support: F. Hoffmann-La Roche Ltd.

Background

AMC (SAR439859), an optimized oral selective ER degrader (SERD), showed encouraging antitumor activity and favorable safety in a phase I/II study of ER+/HER2– aBC pts who progressed after endocrine-based therapy.

Methods

AMEERA-3 (NCT04059484), an open-label phase II randomized study, enrolled postmenopausal women, or premenopausal women or men taking a GnRH agonist, with ER+/HER2− aBC who received ≤ 2 prior lines of ET and ≤ 1 prior chemotherapy or ≤ 1 targeted therapy for aBC. Pts were randomized 1:1 to AMC 400 mg QD (4 x 100 mg capsules) or single agent TPC (fulvestrant, aromatase inhibitor, or tamoxifen) and stratified for the presence of visceral metastasis, prior CDK4/6 inhibitor (i), and ECOG performance status 0 or 1. The primary endpoint was progression-free survival (PFS) assessed by independent central review (ICR). Key secondary endpoints included overall survival (OS) and safety. PFS was compared using a stratified log-rank test at one-sided significance of α = 0.025.

Results

AMEERA-3 randomized 290 pts to AMC (n = 143) or TPC (n = 147). Baseline characteristics were balanced across arms. 79% of pts received prior CDK4/6i for aBC. In the TPC arm, 90% of pts received fulvestrant. AMEERA-3 did not meet its primary objective; PFS per ICR was numerically similar between AMC and TPC (median PFS 3.6 vs 3.7 months; HR = 1.051 [95% CI: 0.789, 1.4]; P = 0.6437). Results for PFS per investigator assessment and in key prespecified subgroups were generally consistent with the primary analysis. OS was numerically similar (data not mature). Common (≥ 5% in either arm) treatment-related adverse events (TRAEs) with AMC vs TPC were mostly Grade 1/2: nausea (14.0% vs 4.1%), vomiting (8.4% vs 1.4%), hot flush (8.4% vs 7.5%), asthenia (7.0% vs 1.4%), fatigue (5.6% vs 6.1%), and injection site pain (0% vs 6.8%); 4.9% vs 0.7% of pts had Grade ≥ 3 TRAEs.

Conclusions

AMC showed numerically similar PFS as TPC in pts with endocrine-resistant ER+/HER2− aBC. The safety profile of AMC was consistent with earlier studies. Clinical development of AMC continues, with a focus on earlier-line breast cancer indications for pts with endocrine-sensitive disease in AMEERA-5 and -6.

Clinical trial identification

NCT04059484.

Editorial acknowledgement

Editorial support was provided by Amanda Sheldon, PhD, CMPP, of inScience Communications (Philadelphia, PA, USA), funded by Sanofi.

Legal entity responsible for the study

Sanofi.

Funding

Sanofi.

Disclosure

S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Novartis, Gilead, Genentech/Roche, Eisai, Sanofi, SeaGen, Daichii Sankyo, 4D Pharma, Puma, ARC Therapeutics; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Other, Consultant: Nektar, Nanostring, Athenex, Blueprint Medicines; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol-Myers Squibb, OncoPep, OncoSec, Certara, Mersana Therapeutics, Ellipses Pharma; Financial Interests, Personal, Advisory Board, Ad board participant/consultant/DSMC: Odonate; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Invited Speaker, Invited speaker for pharma supported educational activity: Chugai Pharmaceuticals; Financial Interests, Personal, Advisory Board, Advisory board participant: G1 Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory Board participation: Zentalis, OncXerna; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pfizer, Sanofi, SeaGen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Invited Speaker: CytomX. K. Petrakova: Financial Interests, Personal, Advisory Role: Novartis, AstraZeneca, Elli Lilly, Roche, Pfizer; Financial Interests, Personal, Speaker’s Bureau: Novartis, AstraZeneca, Elli Lilly, Roche. S. Delaloge: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Pierre fabre, Orion, Sanofi, Rappta, Cellectis, Isis/servier; Financial Interests, Institutional, Invited Speaker: Exact Sciences, Pfizer, Seagen, Lilly, AstraZeneca, MSD, Roche Genentech, BMS, Puma, AstraZeneca, Orion, Sanofi, Pfizer; Financial Interests, Institutional, Advisory Board, ad board: Besins Healthcare; Financial Interests, Institutional, Funding: GE; Financial Interests, Institutional, Invited Speaker, clinical research funding to my institution: Taiho; Non-Financial Interests, Invited Speaker, Société Française de Sénologie et Pathologie Mammaire: SFSPM. M. Campone: Financial Interests, Personal, Advisory Role: Amgen, Gilead, Novartis, MSD, Pfizer, Lilly, Pierre Fabre, Sanofi, Seagen, GSK; Financial Interests, Personal, Speaker’s Bureau: Novartis, Lilly. H. Iwata: Financial Interests, Personal, Other, Honoraria: Daiichi Sankyo, Chugai, AstraZeneca, Lilly, MSD, Pfizer; Financial Interests, Personal, Advisory Role: Daiichi Sankyo, Chugai, AstraZeneca, Lilly, MSD, Pfizer, Novartis, Sanofi; Financial Interests, Personal, Research Grant: Daiichi Sankyo, Chugai, AstraZeneca, Lilly, MSD, Pfizer, Amgen, Novartis. P.A. Kaufman: Financial Interests, Personal, Advisory Role: Polyphor, Roche/Genentech, Lilly, Eisai, Macrogenics, Pfizer, Merck, AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Lilly; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Lilly, Polyphor, Macrogenics; Financial Interests, Personal, Stocks/Shares: Amgen; Financial Interests, Personal, Other, Honoraria: Lilly, Polyphor, Macrogenics, Eisai; Financial Interests, Institutional, Research Grant: Eisai, Polyphor, Roche/Genentech, Lilly, Novartis, Macrogenics, Pfizer, Sanofi. E. de Kermadec: Financial Interests, Personal, Full or part-time Employment: Sanofi; Financial Interests, Personal, Stocks/Shares: Sanofi; Financial Interests, Personal, Other, Spouse working in Sanofi Oncology (but cope not related to the trial): Sanofi. Q. Liu: Financial Interests, Personal, Full or part-time Employment: Sanofi; Financial Interests, Personal, Stocks/Shares: Sanofi. P. Cohen: Financial Interests, Personal, Full or part-time Employment: Sanofi; Financial Interests, Personal, Stocks/Shares: Sanofi. G. Paux: Financial Interests, Personal, Full or part-time Employment: Sanofi; Financial Interests, Personal, Stocks/Shares: Sanofi; Financial Interests, Personal, Other, Patents, Royalties, Other Intellectual Property: Sanofi. S. Im: Financial Interests, Personal, Research Grant: AstraZeneca, Eisai, Daewoong, Roche, Pfizer; Financial Interests, Personal, Advisory Role: AstraZeneca, Amgen, Eisai, GSK, MSD, Lilly, Novartis, Roche, Pfizer, Daiichi Sankyo, Hanmi; Financial Interests, Personal, Other: Roche. All other authors have declared no conflicts of interest.

Background

A subgroup of triple negative breast cancer (TNBC) expresses the androgen receptor (AR). In this trial we evaluated the efficacy and tolerability of the AR inhibitor darolutamide (D) or capecitabine (C) in patients (pts) with advanced AR-positive TNBC (NCT03383679).

Methods

Pts with centrally reviewed AR-positive (≥ 10% by immunohistochemistry) TNBC treated with up to one line of chemotherapy for advanced disease were eligible. They were randomized in a 2:1 ratio to receive D 600 mg twice daily or C 1000 mg/m² twice daily 2-weeks on/ 1-week off, until progression or unacceptable toxicity. Primary endpoint was clinical benefit rate (CBR) at 16 weeks and was assessed in the eligible population and in the sensitivity analysis population (pts with delayed tumour assessment performed in the context of COVID pandemic). Main secondary endpoints included objective response rate, overall survival, progression-free survival (PFS) and safety.

Results

A total of 254 pts from 45 centres were screened; 94 pts were randomized (61 in D arm, 33 in C arm) from April 2018 to July 2021. A clinical benefit was observed in D arm in 13 of 53 evaluable pts (CBR at 16 weeks 24.5%; 95% CI: 12.9%-36.1%) including 2 PR and 1 CR and in C arm in 11 of 23 evaluable pts (CBR at 16 weeks 47.8%; 95% CI: 27.4%-68.2%). In the sensitivity analysis, a clinical benefit was observed in D arm in 17 of 58 evaluable patients (CBR ≥ 16 weeks 29.3%; 95% CI: 17.6%-41.0%) and in C arm in 19 of 32 evaluable patients (CBR ≥ 16 weeks 59.4%; 95% CI: 42.3%-76.4%). 7 pts presented with drug-related serious adverse events: 3 in D arm and 4 in C arm. In D arm, asthenia (26.7%), nausea (25%) and ASAT increase (21.7%) were the most common adverse events, the majority being grade 1 or 2, similar to previous safety data. Median PFS were 1.8 months (CI 95% 1.7-3.1) and 3.6 months (1.8-9.1) in D arm and C arm respectively. Other secondary endpoints will be presented at the meeting.

Conclusions

Despite not reaching the pre-specified CBR, darulotamide demonstrated clinical activity with significant benefit for a group of patients. A research program to identify predictive biomarkers of sensitivity is ongoing.

Clinical trial identification

EudraCT: 2017-002284-18 NCT03383679.

Legal entity responsible for the study

UNICANCER.

Funding

BAYER.

Disclosure

All authors have declared no conflicts of interest.

Background

Tumors with HER2 IHC1+ or IHC2+ combined with a negative in situ hybridization (ISH) test are described as HER2-Low. SG, a novel Trop-2–directed antibody-drug conjugate, is approved for patients (pts) with metastatic triple-negative breast cancer in the second-line or greater setting. In the TROPiCS-02 study, SG demonstrated a 34% reduction in risk of progression or death vs treatment of physician’s choice (TPC) in heavily pretreated, endocrine-resistant HR+/HER2– MBC (Rugo H, et al. ASCO 2022; LBA1001). In this TROPiCS-02 post hoc analysis, we describe SG efficacy in HER2 IHC0 and HER2-Low HR+/HER2– MBC.

Methods

Pts with HR+/HER2– unresectable locally advanced or MBC and 2-4 prior chemotherapy regimens for MBC were randomized 1:1 to receive SG (10 mg/kg IV on d 1 and 8, every 21 d) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until unacceptable toxicity or disease progression. Primary endpoint was progression-free survival (PFS) per RECIST 1.1 by central review. Pts with known HER2-positive disease were ineligible, with HER2 status (IHC and ISH) assessed locally. Table: 214MO

Results

In the intent-to-treat (ITT) population and in each treatment arm, 92% of pts were HER2 IHC0 or HER2-Low. Baseline characteristics between HER2 IHC0 and HER2-Low were comparable and similar to that of the ITT population. Median PFS was improved with SG vs TPC in the HER2 IHC0 and HER2-Low groups (HR 0.72, P=0.05 and 0.58, P<0.001, respectively; Table). The safety profile of the subgroups was consistent with that of the overall safety population.

Conclusions

Clinical benefit with SG vs TPC in HER2 IHC0 and HER2-Low HR+/HER2- MBC was consistent with that of the TROPiCS-02 ITT population. SG should be considered an effective treatment option for pts with HR+/HER2- MBC, regardless of HER2 status.

Clinical trial identification

NCT03901339.

Legal entity responsible for the study

Gilead Sciences, Inc.

Funding

Gilead Sciences, Inc.

Disclosure

P. Schmid: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma, Roche, Daiichi Sankyo, Eisai; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche, Medivation; Other, Other, Spouse - Employee: Roche. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, Astrazeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp& Dohme, GSK, LEUKO, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp& Dohme, Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, Astrazeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma B, Queen Mary University of London; Other, Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo. F. Marmé: Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK/Tesaro, Clovis, Pfizer, Lilly; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Novartis, Roche, Gilead/immunomedics, EISAI, PharmaMar, GenomicHealth, Myriad, Seagen; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis, Roche, Eisai, Gilead/Immunomedics, MSD, German Breast Group, AGO Research GmbH, Vaccibody, GSK; Financial Interests, Institutional, Funding: AstraZeneca. H.S. Rugo: Financial Interests, Personal, Invited Speaker: PUMA, mylan; Financial Interests, Personal, Advisory Board: samsung; Financial Interests, Institutional, Invited Speaker: Novartis, Lilly, Pfizer, OBI Pharma, Immunomedics, Macrogenics, Daiichi, AstraZeneca, Roche, Merck, Odonate, sermonix, seattle genetics, polyphor, Boehringer Ingelheim; Non-Financial Interests, Advisory Role, I advise a number of companies without compensation: various. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Novartis, Gilead, Genentech/Roche, Eisai, Sanofi, SeaGen, Daichii Sankyo, 4D Pharma, Puma, ARC Therapeutics; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Other, Consultant: Nektar, Nanostring, Athenex, Blueprint Medicines; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol-Myers Squibb, OncoPep, OncoSec, Certara, Mersana Therapeutics, Ellipses Pharma; Financial Interests, Personal, Advisory Board, Ad board participant/consultant/DSMC: Odonate; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Invited Speaker, Invited speaker for pharma supported educational activity: Chugai Pharmaceuticals; Financial Interests, Personal, Advisory Board, Advisory board participant: G1 Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory Board participation: Zentalis, OncXerna; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pfizer, Sanofi, SeaGen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Invited Speaker: CytomX. M. Oliveira: Financial Interests, Personal, Advisory Board: Roche, GSK, PUMA Biotechnology, AstraZeneca; Financial Interests, Personal, Invited Speaker: Roche, Seattle Genetics, Novartis, MSD, Guardant Health, Pfizer, AstraZeneca, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Genentech, Novartis, Immunomedics, Seattle Genetics, GSK, Boehringer-Ingelheim, Zenith Epigenetics; Financial Interests, Invited Speaker: Roche; Non-Financial Interests, Invited Speaker: SOLTI Breast Cancer Research. D. Loirat: Financial Interests, Personal, Other, honoraria: AstraZeneca, Novartis, MSD, Lilly, Amgen, EISAI, Gilead Sciences Inc.; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Pfizer, Novartis, MSD, Immunomedics, Pharma4D, Daiichi Sankyo, Lilly, Amgen, EISAI; Financial Interests, Personal, Other, travel, accommodations, expenses: Roche, AstraZeneca, Pfizer, Novartis, Gilead Sciences Inc., Amgen. O.K. Yoon: Financial Interests, Personal, Full or part-time Employment, employee, stock options: Gilead Sciences Inc. M. Motwani: Financial Interests, Personal, Full or part-time Employment: Gilead Sciences Inc.; Financial Interests, Personal, Stocks/Shares: Gilead Sciences Inc. H. Wang: Financial Interests, Personal, Full or part-time Employment, Study Biostatistician: Gilead Sciences Inc.; Financial Interests, Personal, Stocks/Shares: Gilead Sciences Inc.; Non-Financial Interests, Institutional, Advisory Board, data safety monitoring board: Gilead Sciences Inc. R.J. Delaney: Financial Interests, Personal, Full or part-time Employment, employee: Gilead Sciences Inc. A. Bardia: Financial Interests, Institutional, Research Grant: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health/Menarini, Immunomedics, Gilead, Daiichi Pharma, AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Board: Novartis, Genentech, Merck, Radius Health/Menarini, Immunomedics, Gilead, Sanofi, Daiichi Pharma, AstraZeneca, Phillips, Eli Lilly, Foundation Medicine. All other authors have declared no conflicts of interest.

Background

Immune checkpoint inhibitors have not been extensively explored in estrogen receptor-positive breast cancer (ER⁺ BC). This BC entity is considered to be immunologically “cold”. Therefore, we tested nivolumab (nivo; anti-PD1) and ipilimumab (ipi; anti-CTLA-4) in combination with anthracyclines and low-dose cyclophosphamide, which are reported to provoke immunogenic cell death and to counter immunosuppressive cells.

Methods

The trial enrolled patients with ER⁺ HER-2^- metastatic BC and maximum one previous line of chemotherapy after metastasis. Patients were randomized 2:3 into two arms (A:B). Arm A patients received only chemotherapy, i.e. pegylated liposomal doxorubicin (PLD; 20mg/m² every 2^nd week) + cyclophosphamide (cyclo; 50mg/day, 2/4 weeks). Arm B patients received PLD + cyclo + ipi (1mg/kg every 6^th week) + nivo (240mg every 2^nd week). Descriptive assessments of safety and progression-free survival (PFS) were the primary endpoints. Secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and biomarkers (PD-L1, immune gene expression, mutation burden). Hazard ratios (HR) are presented with confidence intervals (CI).

Results

82 patients were randomized to arm A (n=33) or arm B (n=49). 46% had not received previous chemotherapy in the metastatic setting. Serious adverse events occurred in 63% of the patients in arm B, versus 39% in arm A. The most common immune related adverse events in arm B were hypothyroidism (45%), hyperthyroidism (22%), hypophysitis (10%) and pneumonitis (8%). Median PFS was 5.1 months in arm B versus 3.7 months in arm A; PFS HR [95% CI] 0.94 [0.59-1.5]. Median OS was 20.9 months versus 19.9 months in arm B and arm A, respectively; OS HR 1.13 [0.65-1.98]. ORR was 32% in arm B versus 29% in arm A. CBR was 55% in arm B versus 48% in arm A. Biomarker analyses and assessments of immunological changes during therapy are ongoing.

Conclusions

The concomitant addition of ipi/nivo to chemotherapy did not show any clear benefit. Patients receiving ipi/nivo had more adverse events, but the toxicity was manageable. Biomarker analyses will be important to determine if further studies on selected subgroups are warranted.

Clinical trial identification

NCT03409198.

Legal entity responsible for the study

Oslo University Hospital.

Funding

Norwegian Health Region South-East, Bristol Myers Squibb.

Disclosure

J.A. Kyte: Other, Institutional, Research Grant: Bristol Myers Squibb, Roche. B. Gilje: Financial Interests, Personal and Institutional, Advisory Board: Daiichi Sankyo, Novartis, Eli Lilly. All other authors have declared no conflicts of interest.

Background

METEORA-II was designed to test the concept of the metronomic VEX regimen administered for as long as the pt has the possibility of deriving a benefit from it, in comparison with weekly P, for pts with ER+/HER2- MBC candidates for chemotherapy (CT). Time to treatment failure (TTF) was chosen as primary endpoint, as CT may be stopped due to lack of tolerability, lack of efficacy or pt preference.

Methods

From Sept 2017 to Jan 2021, 140 pts were randomized at 15 centers in Italy, 133 initiated VEX (n=70) or P (n=63) in 4-week cycles and entered the efficacy analysis population. CT could be delayed by a maximum of 3 weeks. TTF was defined from randomization until permanent discontinuation of P or at least 1 VEX agent for any reason, or censored at date of last dose. A total of 123 TTF events had 80% power to detect HR=0.60 (median TTF from 4.5 to 7.5 months with VEX; α=0.05). At final analysis, 128/133 pts had experienced TTF events and 61 pts had died. Median follow-up was 29 months.

Results

The 133 pts with ER+/HER2- MBC had median age 61 years (30-80); 21% were ECOG PS 1, 78% had measurable disease. In total, 16% of pts had prior CT for MBC; 56% had only prior ET for MBC usually with CDK4/6 inhibitor (47%). VEX significantly improved TTF compared with P (HR=0.61; 95% CI 0.42-0.88; p=0.008). The median TTF was 8.3 vs 5.7 months (VEX vs P) and the 12-month TTF was 34.3 vs 8.6%. The median PFS was 11.1 vs 6.9 months favoring VEX (HR=0.67; 95% CI 0.46-0.96, p=0.03). The 12-months PFS was 43.5% vs. 21.9 % (VEX vs P). There was no difference in OS (HR=0.98; 95% CI 0.59-1.63). For 56% of pts, the TTF event was progression of disease; for 23% of pts, it was AE(s). More pts assigned VEX had at least 1 grade 3+ targeted AE (42.9%; 95% CI 31.1-55.3% vs 28.6%; 95% CI 17.9-41.3); neutrophil count decrease was the most frequent grade 4 AE (9/70 VEX and 1/63 P). Three pts died during treatment (1 P; 2 VEX).

Conclusions

METEORA-II trial showed VEX significantly improved TTF compared with P. VEX metronomic oral treatment should be considered as a first-line CT regimen for pts with ER+/HER2- MBC that require CT.

Clinical trial identification

NCT02954055 EudraCT Number: 2016-002200-39.

Legal entity responsible for the study

ETOP IBCSG Partners Foundation.

Funding

ETOP IBCSG Partners Foundation.

Disclosure

E. Munzone: Financial Interests, Personal, Advisory Role: Eisai, Exact Sciences, MSD Oncology, Daiichi Sankyo/AstraZeneca, Pfizer, Seagen; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Roche, Pfizer, Lilly, Novartis. M.M. Regan: Financial Interests, Personal, Advisory Board, Also invited speaker: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board, Includes consulting.: Tolmar Pharmaceuticals; Financial Interests, Personal, Invited Speaker: WebMD; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb, Bayer; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trial supported by company: Novartis; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials supported by company: Pfizer, Ipsen, TerSera; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trial drug supply from company: Roche; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials supported or drug supply from company: AstraZeneca; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials with funding from company: Debiopharm; Non-Financial Interests, Advisory Role: Bristol-Myers Squibb. E. Montagna: Financial Interests, Personal, Advisory Role: Novartis, Pierre Fabre. L. Gianni: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Other, Travel, Accommodations, Expense: Novartis, Pfizer, Roche, Daiichi Sankyo/AstraZeneca; Financial Interests, Institutional, Funding, research funding to my Institution: Tesaro, Roche, AstraZeneca, SeattleGenetics, Puma Biotechnology; Non-Financial Interests, Member, Olympia Steering Committee: AstraZeneca. U.F.F. De Giorgi: Financial Interests, Personal, Advisory Board: Pfizer, BMS, MSD, Pharmamar, Astellas, Bayer, Ipsen, Novartis; Financial Interests, Personal, Invited Speaker: Roche, BMS, Sanofi, Astrazeneca; Financial Interests, Institutional, Research Grant: Astrazeneca, Sanofi, Roche. D. Generali: Financial Interests, Personal, Advisory Role: Novartis, Lilly, Pfizer, AstraZeneca, AstraZeneca, Roche; Financial Interests, Personal, Invited Speaker: Novartis, Lilly, Pfizer, Roche. F. Puglisi: Financial Interests, Institutional, Research Grant, Disclosure is outside the submitted work: AstraZeneca, Eisai, Roche; Financial Interests, Personal, Other, Honoraria or consultation fees / Disclosure is outside the submitted work: Amgen, AstraZeneca, Daichii Sankyo, Celgene, Eisai, Gilead, GSK, Ipsen, MSD, Novartis, Pierre Fabre, Pfizer, Seagen, Takeda, Viatris; Financial Interests, Personal, Officer, Honoraria or consultation fees / Disclosure is outside the submitted work: Eli Lilly; Financial Interests, Personal, Other, Honoraria or consultation fees / Disclosure is outside the submitted wor: Roche. C. Zamagni: Financial Interests, Personal, Advisory Board: Roche, Eisai, Novartis, AstraZeneca, Pfizer, PharmaMar, Amgen, Tesaro, QuintilesIMS, Lilly, Celgene; Financial Interests, Personal, Other, travel accommodation: Roche, Novartis, PharmaMar, Tesaro, PierreFabre, Istituto Gentili, Celgene; Financial Interests, Personal, Officer, travel accommodation: Pfizer; Financial Interests, Institutional, Funding, research funding to institution: Roche, Novartis, AstraZeneca, Pfizer, SeattleGenetics, Tesaro, PierreFabre, Istituto Gentili, Takeda, Teva, Medivation, AbbVie, Array BioPharma, Morphotek, Synthon; Non-Financial Interests, Member, Member of scientific committee of patients non-profit organization: Europa Donna Italy, Susan J Komen Emilia-Romagna, LOTO Onlus, Mamazone Sudtirol. M.A. Colleoni: Financial Interests, Institutional, Funding: Roche; Non-Financial Interests, Institutional, Leadership Role, Co-Chair Scientific Committee IBCSG: IBCSG. All other authors have declared no conflicts of interest.