Background

Neratinib (N), an irreversible pan-HER TKI, is approved in the EU for extended adjuvant treatment of early-stage HR+ HER2+ breast cancer (BC) after adjuvant trastuzumab (T)-based therapy. The CONTROL trial (NCT02400476) investigated pre-emptive antidiarrheal prophylaxis or dose escalation (DE) for prevention of diarrhea, the most frequent side effect of N.

Methods

CONTROL is an international, multi-cohort, open-label, phase 2 study. Patients (pts) ≥18y with stage I–IIIc HER2+ BC received oral N (240 mg/d for 1y) after T-based adjuvant therapy. Pts were enrolled sequentially into separate cohorts: 1) mandatory loperamide prophylaxis; 2) budesonide + loperamide; 3) colestipol + loperamide; 4) colestipol + loperamide PRN; 5) DE + loperamide PRN (2 cohorts). DE1 schedule: N 120 mg/d x w1, 160 mg/d x w2, then 240 mg/d from w3 to 12m. DE2 schedule: N 160 mg/d x w1&2, 200 mg/d x w3&4, then 240 mg/d from w5 to 12m. Primary endpoint: incidence of grade ≥3 diarrhea.

Results

563 pts were enrolled. All preventive strategies reduced grade 3 diarrhea vs ExteNET (historical control: 39%). Median cumulative duration of grade 3 diarrhea ranged from 2–3.5d in CONTROL (vs 5.0d for ExteNET). The proportion of pts discontinuing N because of diarrhea was decreased in CONTROL vs ExteNET. Key diarrhea outcomes in all CONTROL cohorts are presented in the table and will be fully detailed during the congress. Table: 73P

Patient disposition and diarrhea characteristics: All CONTROL cohorts

Conclusions

These final findings from CONTROL show improved tolerability of N with all diarrhea prophylaxis strategies and suggest that DE1 with loperamide PRN allows pts to stay on treatm.ent longer and receive full benefit from N.

Clinical trial identification

NCT02400476.

Editorial acknowledgement

Editorial/writing assistance for this abstract was provided by Lee Miller (Miller Medical Communications Ltd.). This work was funded by the study sponsor (Puma Biotechnology Inc.).

Legal entity responsible for the study

Puma Biotechnology Inc.

Funding

Puma Biotechnology Inc.

Disclosure

A. Brufsky: Financial Interests, Personal, Advisory Role, Consulting fees: Puma Biotechnology Inc. A.J. Chien, R. Bose: Financial Interests, Institutional, Research Grant: Puma Biotechnology Inc. B. Pistilli: Financial Interests, Personal, Advisory Role, Consulting fees: Puma Biotechnology Inc.; Financial Interests, Personal, Advisory Role, Consulting fees: Pierre Fabre; Financial Interests, Institutional, Research Grant: Puma Biotechnology Inc. D. Diprimeo, N. Foruzan, L.M. McCulloch: Financial Interests, Personal, Full or part-time Employment: Puma Biotechnology Inc.; Financial Interests, Personal, Stocks/Shares: Puma Biotechnology Inc. All other authors have declared no conflicts of interest.

Background

Brain metastases (BM) are a frequent and devastating complication of HER2-positive breast cancer (BC). T-DXd is an antibody-drug conjugate with high activity in pretreated pts but information regarding activity in active BM is limited. Therefore, the prospective, single-arm, phase II TUXEDO-1 trial investigated T-DXd in HER2-positive BC pts with active BM.

Methods

TUXEDO-1 included adult pts with HER2-positive BC and newly diagnosed untreated BM or BM progressing after local therapy, prior exposure to trastuzumab and pertuzumab, and no indication for immediate local therapy. The primary endpoint was intracranial response rate (RR) centrally assessed by Response Assessment in Neuro-Oncology (RANO)-BM criteria. Secondary endpoints consisted of extracranial RR, progression-free survival (PFS), overall survival, safety, and quality-of-life. Based on a Simon’s two-stage design (RR under alternative hypothesis >60%; RR under null hypothesis <26%), a total number of 15 pts were enrolled. The null hypothesis was to be rejected with a type I error rate of 5% and a power of 80% if at least 7 responses were observed.

Results

As of December 29^th, 2021, all 15 pts had received at least one dose of T-DXd (60% progressive BM, 70% prior T-DM1). One patient initially assessed as having parenchymal BM was found to have dural metastasis upon restaging and was excluded from efficacy analyses. In the intention-to-treat population, intracranial RR was 73.3% (11/15) (per protocol population: 78.6% [11/14]). At 11 months median follow-up, PFS was 14 months (95% CI 8.48-19.52); two pts died from disease progression. Main non-haematological toxicities consisted of grade 1/2 fatigue (86.7%), nausea (46.7%), and diarrhoea (26.7%). Dose reductions were required in 9 pts; 4 pts had serious adverse events. Grade 2 interstitial lung disease and a symptomatic drop of left-ventricular ejection fraction were observed in one patient each.

Conclusions

In the TUXEDO-1 study, T-DXd yielded high intracranial response rates. Data suggest that T-DXd achieves significant therapeutic effects in the central nervous system and should thus be further explored in this context.

Clinical trial identification

NCT04752059.

Legal entity responsible for the study

Medical University of Vienna, Department of Medicine 1.

Funding

Daiichi Sankyo.

Disclosure

R. Bartsch: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Daiichi; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Institutional, Funding, Investigator Initiated Trial: Daiichi; Financial Interests, Institutional, Invited Speaker, Drug support for investigator initiated trial: MSD. M. Marhold: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Daiichi; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: MEDmedia; Financial Interests, Personal and Institutional, Other: Amgen; Financial Interests, Personal and Institutional, Other: Novartis; Financial Interests, Personal and Institutional, Other: Pierre Fabre; Financial Interests, Personal and Institutional, Other: Daiichi; Financial Interests, Personal and Institutional, Other: Roche; Financial Interests, Personal and Institutional, Other: Eisai. Z.A. Bago-Horvath: Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal and Institutional, Other: Daiichi. T. Fuereder: Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: Accord; Financial Interests, Personal, Invited Speaker: Merck Darmstadt; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Merck Darmstadt. C.F. Singer: Financial Interests, Personal, Other, consultancy: Amgen; Financial Interests, Personal, Advisory Board, ADVISORY FUNCTION: NOVARTIS; Financial Interests, Personal, Advisory Board, ADVISORY ROLE: ROCHE; Financial Interests, Personal, Other, STUDY SUPPORT: PFITZER; Financial Interests, Personal, Advisory Board, ADVISORY, SPEAKER HONORARIES, STUDY SUPPORT: ASTRAZENECA; Financial Interests, Personal, Invited Speaker, STUDY COORDINATOR: AMGEN; Non-Financial Interests, Principal Investigator, STUDY: AMGEN; Non-Financial Interests, Principal Investigator, STUDY: ASTRAZENECA; Non-Financial Interests, Project Lead, REGISTER: PFITZER. M. Preusser: Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: GLG; Financial Interests, Personal, Invited Speaker: CMC contrast; Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Personal, Invited Speaker: Mundipharma; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Other: BMJ journals; Financial Interests, Personal, Writing Engagements: MedMedia; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: MEDahead; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Tocagen; Financial Interests, Personal, Invited Speaker: Adastra; Financial Interests, Personal, Invited Speaker: Gan & Lee Pharmaceuticals. All other authors have declared no conflicts of interest.

Background

In 1L setting, RIB is the only CDK4/6 inhibitor that showed a significant overall survival benefit across three phase 3 trials. REACH AUT — the only non-interventional trial on a CDK4/6 inhibitor in Austria to date, evaluated the RW clinical experience of RIB+ET (aromatase inhibitor [AI] or Fulvestrant [FUL]) in pre-, peri- or postmenopausal patients (pts) with HR+, HER2– MBC.

Methods

Pts with HR+, HER2‒ MBC with no prior ET for advanced disease were enrolled at 13 sites in Austria. Up to 1L chemotherapy (CT) for MBC was allowed.

Results

At data cutoff (8-Oct-2021), out of 283 analyzed pts (12.4% pre/peri- and 85.2% postmenopausal, 2.4% not known) 52.3% pts received ongoing treatment on RIB+ET. Median duration of follow-up was 14.4 months. Median age was 63 years (<65, n=158; ≥65, n=125); ECOG PS 0: 72.4%; 1: 14.8%; 2: 1.4% 3: 0.4%. Visceral (lung, liver) metastases (mets) were recorded in 116 pts (41.0%) and bone only mets in 81 pts (28.6%). De novo disease was reported in 38.5% pts. Prior adjuvant therapy was received by 48.1% pts (AI: n=72 [25.4%]; tamoxifen: n=62 [21.9%]; CT: n=52 [18.4%]). In the advanced setting, 49 pts (17.3%) received RIB+FUL and 222 pts (78.4%) RIB+AI. Prior CT was received by 5 pts (1.8%). In pts evaluable for response, the objective response rate was 31.4%, clinical benefit rate 45.9% and disease control rate 61.1%. Median progression-free survival (mPFS) was 29.7 months in the overall population and 32.7 months in pts with visceral mets. The 12-month OS rate was 90.3%. Majority of adverse events (AEs) were grade 1 (51.9%) or grade 2 (29.7%). Grade 1 AEs were seen in 214 pts (75.6%), grade 2 in 202 pts (71.4%), grade 3 in 140 pts (49.5%), and grade 4 in 13 pts (4.6%). The most common AE was neutropenia (45.9%). 11.7% pts had hepatobiliary AEs (grade 1: n=9 [3.2%]; grade 2: n=14 [4.9%]; grade 3: n=21 [7.4%]). 11.0% of pts had QTcF prolongation (grade 1: n=24 [8.5%]; grade 2: n=10 [3.5%]; grade 3: n=1 [0.4%]). Therapy interruption was needed in 152 pts (53.7%) and ≥1 dose reduction in 113 pts (39.9%).

Conclusions

In RW setting, RIB+ET shows tolerable safety and a mPFS for 1L pts that is in line with MONALEESA trials. The study follow up is immature to show median OS.

Clinical trial identification

CLEE011AAT01.

Editorial acknowledgement

The authors wish to thank Priscilla Joys MDS and Moumita Samanta PhD of Novartis Healthcare Pvt Ltd (Hyderabad, India), for providing medical editorial assistance in the preparation of this abstract.

Legal entity responsible for the study

Novartis Pharma GmbH, Vienna, Austria.

Funding

Novartis Pharma GmbH, Vienna, Austria.

Disclosure

C.F. Singer: Financial Interests, Research Grant: Novartis, AstraZeneca, Amgen; Financial Interests, Advisory Role, Personal fee: Novartis, AstraZeneca, Amgen, Seagen; Financial Interests, Invited Speaker, Speakers' honorarium: Novartis, AstraZeneca, Amgen, Roche, Seagen, Daiichi Sankyo. D. Egle: Financial Interests, Advisory Role, Consulting fee: AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pfizer, Roche; Financial Interests, Speaker’s Bureau, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz; Financial Interests, Other, Support for attending meetings and/or travel: Novartis, Pfizer, Roche. R. Greil: Financial Interests, Research Grant: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo, Sanofi; Financial Interests, Other, Personal fee, Honoraria, Travel, Accommodations, Expenses: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo, Sanofi;Financial Interests, Advisory Role: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo, Sanofi. E. Petru: Financial Interests, Advisory Board, Payment or honoraria: Novartis; Financial Interests, Other, Payments for Presentations, Support for Attending Several Meetings: Novartis; Other, Member: Frauenkrebshilfe Österreich. M. Balic: Financial Interests, Research Grant: ABCSG, AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pierre Fabre, Roche, Pfizer, Samsung, Seagen;Financial Interests, Other, Consulting fees, Support for attending meetings and/or travel: AstraZeneca, Eli Lilly, MSD, Pfizer, Roche; Financial Interests, Other, Consulting fees: Daiichi Sankyo, Samsung; Financial Interests, Other, Consulting fees, Support for attending meetings and/or travel, Receipt of drugs: Novartis, Pierre Fabre; Financial Interests, Other, Consulting fees, Receipt of drugs: Seagen; Financial Interests, Speaker’s Bureau, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Samsung, Seagen; Financial Interests, Advisory Board, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen. C. Tinchon: Financial Interests, Research Grant: Novartis. G. Pfeiler: Financial Interests, Research Grant: AstraZeneca, Pfizer, Accord Healthcare, Bondimed, Roche; Financial Interests, Speaker’s Bureau, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Novartis, AstraZeneca, Daiichi, MSD, Merck, Pfizer, Amgen, Accord, Roche, UCB; Financial Interests, Expert Testimony, Payment: Novartis, AstraZeneca, Daiichi, MSD, Merck, Pfizer, Amgen, Accord, Roche, UCB; Financial Interests, Other, Support for attending meetings and/or travel: Novartis, AstraZeneca, Daiichi, MSD, Merck, Pfizer, Amgen, Accord, Roche, UCB. M. Marhold: Financial Interests, Speaker’s Bureau, Payment or Honoraria for Lectures, Presentations, Speakers Bureaus, Manuscript Writing or Educational Events: Roche, Pfizer, MSD, Eli Lilly, Novartis, AstraZeneca, Daiichi Sankyo, Medmedia; Financial Interests, Other, Support for Attending Meetings and/or Travel: Roche, Novartis, Pierre Fabre, Daiichi Sankyo, Eisai. U. Pluschnig: Financial Interests, Advisory Board, Participation in Virtual Scientific Expert Meeting and Payment or Honoraria for Expert Meeting: Novartis. F. Haslbauer: Financial Interests, Speaker’s Bureau, Payment or Honoraria for Lectures, Presentations, Speakers Bureaus, Manuscript Writing or Educational Events: Roche, BMS, Servier; Financial Interests, Other, All support for the present manuscript: Novartis. J. Flatschacher, S. Uthman: Financial Interests, Full or part-time Employment: Novartis. B. Mraz: Financial Interests, Full or part-time Employment: Novartis; Financial Interests, Stocks/Shares, Owner of stocks: Novartis. R. Bartsch: Financial Interests, Other, Personal fees: AstraZeneca, Daiichi, Eisai, Eli Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Seagen; Financial Interests, Research Grant: Daiichi; Non-Financial Interests, Other, Personal fees: Daiichi. All other authors have declared no conflicts of interest.

Background

Neratinib (N), an irreversible pan-HER TKI, is approved in the EU for extended adjuvant treatment of early-stage HR+ HER2+ breast cancer (BC) after adjuvant trastuzumab (T)-based therapy. The CONTROL trial (NCT02400476) investigated pre-emptive antidiarrheal prophylaxis or dose escalation (DE) for prevention of diarrhea, the most frequent side effect of N.

Methods

CONTROL is an international, multi-cohort, open-label, phase 2 study. Patients (pts) ≥18y with stage I–IIIc HER2+ BC received oral N (240 mg/d for 1y) after T-based adjuvant therapy. Pts were enrolled sequentially into separate cohorts: 1) mandatory loperamide prophylaxis; 2) budesonide + loperamide; 3) colestipol + loperamide; 4) colestipol + loperamide PRN; 5) DE + loperamide PRN (2 cohorts). DE1 schedule: N 120 mg/d x w1, 160 mg/d x w2, then 240 mg/d from w3 to 12m. DE2 schedule: N 160 mg/d x w1&2, 200 mg/d x w3&4, then 240 mg/d from w5 to 12m. Primary endpoint: incidence of grade ≥3 diarrhea.

Results

563 pts were enrolled. All preventive strategies reduced grade 3 diarrhea vs ExteNET (historical control: 39%). Median cumulative duration of grade 3 diarrhea ranged from 2–3.5d in CONTROL (vs 5.0d for ExteNET). The proportion of pts discontinuing N because of diarrhea was decreased in CONTROL vs ExteNET. Key diarrhea outcomes in all CONTROL cohorts are presented in the table and will be fully detailed during the congress. Table: 73P

Patient disposition and diarrhea characteristics: All CONTROL cohorts

Conclusions

These final findings from CONTROL show improved tolerability of N with all diarrhea prophylaxis strategies and suggest that DE1 with loperamide PRN allows pts to stay on treatm.ent longer and receive full benefit from N.

Clinical trial identification

NCT02400476.

Editorial acknowledgement

Editorial/writing assistance for this abstract was provided by Lee Miller (Miller Medical Communications Ltd.). This work was funded by the study sponsor (Puma Biotechnology Inc.).

Legal entity responsible for the study

Puma Biotechnology Inc.

Funding

Puma Biotechnology Inc.

Disclosure

A. Brufsky: Financial Interests, Personal, Advisory Role, Consulting fees: Puma Biotechnology Inc. A.J. Chien, R. Bose: Financial Interests, Institutional, Research Grant: Puma Biotechnology Inc. B. Pistilli: Financial Interests, Personal, Advisory Role, Consulting fees: Puma Biotechnology Inc.; Financial Interests, Personal, Advisory Role, Consulting fees: Pierre Fabre; Financial Interests, Institutional, Research Grant: Puma Biotechnology Inc. D. Diprimeo, N. Foruzan, L.M. McCulloch: Financial Interests, Personal, Full or part-time Employment: Puma Biotechnology Inc.; Financial Interests, Personal, Stocks/Shares: Puma Biotechnology Inc. All other authors have declared no conflicts of interest.

Background

In 1L setting, RIB is the only CDK4/6 inhibitor that showed a significant overall survival benefit across three phase 3 trials. REACH AUT — the only non-interventional trial on a CDK4/6 inhibitor in Austria to date, evaluated the RW clinical experience of RIB+ET (aromatase inhibitor [AI] or Fulvestrant [FUL]) in pre-, peri- or postmenopausal patients (pts) with HR+, HER2– MBC.

Methods

Pts with HR+, HER2‒ MBC with no prior ET for advanced disease were enrolled at 13 sites in Austria. Up to 1L chemotherapy (CT) for MBC was allowed.

Results

At data cutoff (8-Oct-2021), out of 283 analyzed pts (12.4% pre/peri- and 85.2% postmenopausal, 2.4% not known) 52.3% pts received ongoing treatment on RIB+ET. Median duration of follow-up was 14.4 months. Median age was 63 years (<65, n=158; ≥65, n=125); ECOG PS 0: 72.4%; 1: 14.8%; 2: 1.4% 3: 0.4%. Visceral (lung, liver) metastases (mets) were recorded in 116 pts (41.0%) and bone only mets in 81 pts (28.6%). De novo disease was reported in 38.5% pts. Prior adjuvant therapy was received by 48.1% pts (AI: n=72 [25.4%]; tamoxifen: n=62 [21.9%]; CT: n=52 [18.4%]). In the advanced setting, 49 pts (17.3%) received RIB+FUL and 222 pts (78.4%) RIB+AI. Prior CT was received by 5 pts (1.8%). In pts evaluable for response, the objective response rate was 31.4%, clinical benefit rate 45.9% and disease control rate 61.1%. Median progression-free survival (mPFS) was 29.7 months in the overall population and 32.7 months in pts with visceral mets. The 12-month OS rate was 90.3%. Majority of adverse events (AEs) were grade 1 (51.9%) or grade 2 (29.7%). Grade 1 AEs were seen in 214 pts (75.6%), grade 2 in 202 pts (71.4%), grade 3 in 140 pts (49.5%), and grade 4 in 13 pts (4.6%). The most common AE was neutropenia (45.9%). 11.7% pts had hepatobiliary AEs (grade 1: n=9 [3.2%]; grade 2: n=14 [4.9%]; grade 3: n=21 [7.4%]). 11.0% of pts had QTcF prolongation (grade 1: n=24 [8.5%]; grade 2: n=10 [3.5%]; grade 3: n=1 [0.4%]). Therapy interruption was needed in 152 pts (53.7%) and ≥1 dose reduction in 113 pts (39.9%).

Conclusions

In RW setting, RIB+ET shows tolerable safety and a mPFS for 1L pts that is in line with MONALEESA trials. The study follow up is immature to show median OS.

Clinical trial identification

CLEE011AAT01.

Editorial acknowledgement

The authors wish to thank Priscilla Joys MDS and Moumita Samanta PhD of Novartis Healthcare Pvt Ltd (Hyderabad, India), for providing medical editorial assistance in the preparation of this abstract.

Legal entity responsible for the study

Novartis Pharma GmbH, Vienna, Austria.

Funding

Novartis Pharma GmbH, Vienna, Austria.

Disclosure

C.F. Singer: Financial Interests, Research Grant: Novartis, AstraZeneca, Amgen; Financial Interests, Advisory Role, Personal fee: Novartis, AstraZeneca, Amgen, Seagen; Financial Interests, Invited Speaker, Speakers' honorarium: Novartis, AstraZeneca, Amgen, Roche, Seagen, Daiichi Sankyo. D. Egle: Financial Interests, Advisory Role, Consulting fee: AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pfizer, Roche; Financial Interests, Speaker’s Bureau, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz; Financial Interests, Other, Support for attending meetings and/or travel: Novartis, Pfizer, Roche. R. Greil: Financial Interests, Research Grant: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo, Sanofi; Financial Interests, Other, Personal fee, Honoraria, Travel, Accommodations, Expenses: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo, Sanofi;Financial Interests, Advisory Role: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo, Sanofi. E. Petru: Financial Interests, Advisory Board, Payment or honoraria: Novartis; Financial Interests, Other, Payments for Presentations, Support for Attending Several Meetings: Novartis; Other, Member: Frauenkrebshilfe Österreich. M. Balic: Financial Interests, Research Grant: ABCSG, AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pierre Fabre, Roche, Pfizer, Samsung, Seagen;Financial Interests, Other, Consulting fees, Support for attending meetings and/or travel: AstraZeneca, Eli Lilly, MSD, Pfizer, Roche; Financial Interests, Other, Consulting fees: Daiichi Sankyo, Samsung; Financial Interests, Other, Consulting fees, Support for attending meetings and/or travel, Receipt of drugs: Novartis, Pierre Fabre; Financial Interests, Other, Consulting fees, Receipt of drugs: Seagen; Financial Interests, Speaker’s Bureau, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Samsung, Seagen; Financial Interests, Advisory Board, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen. C. Tinchon: Financial Interests, Research Grant: Novartis. G. Pfeiler: Financial Interests, Research Grant: AstraZeneca, Pfizer, Accord Healthcare, Bondimed, Roche; Financial Interests, Speaker’s Bureau, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Novartis, AstraZeneca, Daiichi, MSD, Merck, Pfizer, Amgen, Accord, Roche, UCB; Financial Interests, Expert Testimony, Payment: Novartis, AstraZeneca, Daiichi, MSD, Merck, Pfizer, Amgen, Accord, Roche, UCB; Financial Interests, Other, Support for attending meetings and/or travel: Novartis, AstraZeneca, Daiichi, MSD, Merck, Pfizer, Amgen, Accord, Roche, UCB. M. Marhold: Financial Interests, Speaker’s Bureau, Payment or Honoraria for Lectures, Presentations, Speakers Bureaus, Manuscript Writing or Educational Events: Roche, Pfizer, MSD, Eli Lilly, Novartis, AstraZeneca, Daiichi Sankyo, Medmedia; Financial Interests, Other, Support for Attending Meetings and/or Travel: Roche, Novartis, Pierre Fabre, Daiichi Sankyo, Eisai. U. Pluschnig: Financial Interests, Advisory Board, Participation in Virtual Scientific Expert Meeting and Payment or Honoraria for Expert Meeting: Novartis. F. Haslbauer: Financial Interests, Speaker’s Bureau, Payment or Honoraria for Lectures, Presentations, Speakers Bureaus, Manuscript Writing or Educational Events: Roche, BMS, Servier; Financial Interests, Other, All support for the present manuscript: Novartis. J. Flatschacher, S. Uthman: Financial Interests, Full or part-time Employment: Novartis. B. Mraz: Financial Interests, Full or part-time Employment: Novartis; Financial Interests, Stocks/Shares, Owner of stocks: Novartis. R. Bartsch: Financial Interests, Other, Personal fees: AstraZeneca, Daiichi, Eisai, Eli Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Seagen; Financial Interests, Research Grant: Daiichi; Non-Financial Interests, Other, Personal fees: Daiichi. All other authors have declared no conflicts of interest.