Background

We planned an individual patient data (IPD) meta-analysis of non-inferiority (NI) RCTs to determine if a duration of less than the standard of 12 months (m) of adjuvant trastuzumab is non-inferior for treatment outcomes in HER-2 positive early breast cancer patients.

Methods

A systematic review identified five NI RCTs, and trial groups agreed a meta-analysis collaboration. PERSEPHONE, PHARE and HORG compared 12m v 6m; SOLD and Short-HER compared 12m v 9weeks[w]. Primary outcome was invasive disease-free survival (IDFS). Secondary outcomes were distant relapse-free survival (DRFS); overall survival (OS) and breast cancer specific survival (BCSS). Analysis was intention-to-treat (ITT). Random effects modelling evaluated prognostic effects of patient and tumour characteristics, treatment and trial. Heterogeneity between studies was assessed using the Cochran’s Q statistic. For the comparison of 12m v less (n≈11,500 pts), a 1-sided 2.5% significance was used. For the analyses of 12m v 6m (n≈8,000 pts) and 12m v 9w (n≈3,500 pts), 1-sided 5% significance was utilised.

Results

To date, IPD has been obtained from 4 trials and published data has been used from PHARE. For ITT analysis of the primary outcome of IDFS, non-inferiority limits for absolute 2% margins were calculated as 1.19 for all 5 trials, 1.20 for 3 trials comparing 12m v 6m and 1.25 for 2 trials comparing 12m v 9w. For 12m v less (all 5 trials combined), 5-year IDFS rates were 88.46% and 86.87% respectively. The adjusted HR for treatment was 1.14 (95% credibility interval (CI) 0.88-1.47), non-inferiority p=0.37. For 12m v 6m, 5-year IDFS rates were 89.26% and 88.56% respectively. The adjusted HR for treatment was 1.07 (90% CI 0.98-1.17), non-inferiority p=0.02. For 12m v 9w, 5-year IDFS rates were 91.40% and 89.22% respectively. The adjusted HR for treatment was 1.27 (90% CI 1.07-1.49), non-inferiority p=0.56. Cochran’s Q is 5.5 for all 5 trials, 0.91 for the 3 trials comparing 12m v 6m and 1.1 for the 2 trials comparing 12m v 9w.

Conclusions

Six months trastuzumab is non-inferior to 12months, although nine weeks is not.

Legal entity responsible for the study

The authors.

Funding

Part-funded by NIHR Senior Investigator Award to Professor Janet Dunn, University of Warwick Clinical Trials Unit.

Disclosure

H.M. Earl: Financial Interests, Personal, Invited Speaker, Invited speaker on topic of duration of adjuvant trastuzumab and the Persephone Trial: Asian Society of Continuing Medical Education and Intas Pharmaceuticals. P.F. Conte: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Advisory Board, For alpelisb trial: Novartis; Financial Interests, Personal, Expert Testimony, Drug approval with AIFA: Roche; Financial Interests, Institutional, Research Grant: Merck KGaAa,; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Roche. V. Guarneri: Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: BMS; Financial Interests, Institutional, Principal Investigator: Eli Lilly; Financial Interests, Institutional, Principal Investigator: MSD; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: Roche; Financial Interests, Institutional, Principal Investigator: Synton Biopharmaceuticals. H. Joensuu: Financial Interests, Personal, Advisory Board: Maud Kuistila Foundation; Financial Interests, Personal, Advisory Board: Neutron Therapeutics; Financial Interests, Personal, Advisory Board: Orion Pharma; Financial Interests, Personal, Full or part-time Employment, Until Aug 31, 2020: Orion Pharma; Financial Interests, Personal, Stocks/Shares: Orion Pharma; Financial Interests, Personal, Stocks/Shares: Sartar Therapeutics. D. Cameron: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: Pfizer; Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Advisory Board: SeaGen; Financial Interests, Institutional, Advisory Board: Synthon; Financial Interests, Institutional, Advisory Board: Zymeworks; Non-Financial Interests, Institutional, Principal Investigator, Non-financial, Funding and drug for participation in Novartis study.: Novartis; Financial Interests, Institutional, Advisory Role, Consultancy role: Novartis. D.W. Miles: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Exact Science; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Advisory Board: Gilead. A.M. Wardley: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Boehringer-Ingleheim; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Easai; Financial Interests, Personal, Writing Engagements, From contracted research and related (unremunerated): Eli Lilly; Financial Interests, Personal, Advisory Board, Remunerated: Eli Lilly; Financial Interests, Personal, Invited Speaker, Remunerated: Eli Lilly; Financial Interests, Personal, Advisory Board: Genomic Health/Exact Sciences; Financial Interests, Personal, Other, Scientific Review Committee. Expenses paid: INCa; Financial Interests, Personal, Other, Travel support - conference: MSD; Financial Interests, Personal, Advisory Board: MDS; Financial Interests, Personal, Writing Engagements, Papers from contracted research and related. Unremunerated writing: Novartis; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker, Papers from contracted research: Novartis; Financial Interests, Personal, Other, Joint working project access to secondary breast cancer in Greater Manchester. Unremunerated: Novartis/iQIVA; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Other, Outreach Research and Innovation Group (not for profit): Public Health England; Financial Interests, Personal, Writing Engagements, Papers from contracted research. Unremunerated writing: Roche; Financial Interests, Personal, Invited Speaker, Several: Roche; Financial Interests, Personal, Advisory Board, Numerous remunerated advisory boards: Roche; Financial Interests, Personal, Advisory Board: Simon-Kucher; Financial Interests, Personal, Other, Internal company training on breast cancer: Takeda; Financial Interests, Personal, Member of the Board of Directors, Company for private medical income and payment of advisory engagements: Andrew Wardley Limited; Financial Interests, Personal, Full or part-time Employment, As of 11 January 2021: AstraZeneca; Financial Interests, Personal, Member of the Board of Directors: Manchester Cancer Academy; Financial Interests, Institutional, Member of the Board of Directors, Not for profit organisation to improve cancer care across the UK and internationally: Outreach Research & Innovation Group Limited; Financial Interests, Personal, Other, SAB: Athenex; Financial Interests, Institutional, Principal Investigator: Daiichi Sankyo; Financial Interests, Institutional, Principal Investigator: Eli Lilly; Financial Interests, Personal and Institutional, Other, Steering Committee Member: Eli Lilly; Financial Interests, Institutional, Principal Investigator: Medivation; Financial Interests, Institutional, Principal Investigator: NIHR; Financial Interests, Institutional, Research Grant: NIHR; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: Pfizer, Local; Financial Interests, Institutional, Principal Investigator: Roche; Non-Financial Interests, Leadership Role, Strategy Director 2018-2021: ACP; Non-Financial Interests, Leadership Role, Breast Research Group Member, Early Breast cancer sub-group 2014-21 Chair 2020-2021: NCRI; Non-Financial Interests, Advisory Role, 2013-2021: NHSE Chemotherapy Clinical reference group; Non-Financial Interests, Advisory Role, 2013-2021: PHE Chemotherapy Clinical Intelligence Group; Non-Financial Interests, Other, Committee member, NICE liaison, until 2020: UKBCG; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Leadership Role, 2013 to 2021 EBC subgroup; lead for development of HER2-RADiCAL trial: NCRI; Non-Financial Interests, Member, Until 2021: UKBCG; Other, Raised protected public interest Disclosures - into former employer The Christie Hospital: NHSI. All other authors have declared no conflicts of interest.

Background

Studies testing addition of lapatinib (L) to neoadjuvant trastuzumab (T) plus chemotherapy reported an increase in pathologic complete response (pCR) rates but were discordant on the effect of treatment on survival, mainly due to suboptimal power. We here leverage the meta-analytic approach to resolve these inconsistencies.

Methods

We conducted a meta-analysis to combine findings from published or unpublished randomised phase 2 and 3 studies testing L in combination with neoadjuvant T plus chemotherapy for HER2+ early breast cancer. Pooled hazard ratios (HRs) were obtained for the effect of L plus T compared to T only, pCR compared to no pCR in the whole study populations, and pCR compared to no pCR in the hormone receptor-negative or positive cohorts.

Results

The meta-analysis included four studies (CALGB40601, CHER-LOB, NSABP-B41, NeoALTTO) for an overall population of 1410 patients. Patients received either T and L or T alone, in combination with paclitaxel or anthracyclines. Relapse-free survival (RFS) was higher with the combination of L plus T than with T only (HR 0.62, 95% CI 0.46-0.85). Dual blockade also led to improved overall survival (OS) (HR 0.65, 95% CI 0.43-0.98). For all treatments combined, patients achieving a pCR had better RFS and OS than those with residual disease at surgery (HR 0.45, 95% CI 0.34-0.60, and HR 0.34, 95% CI 0.23-0.51, for RFS and OS, respectively). In patients with hormone receptor-negative tumours, pCR was associated with a 65% reduction of risk of relapse (HR 0.35, 95% CI 0.23-0.53) and a 73% reduction of risk of death (HR 0.27, 95% CI 0.15-0.47). Patients with hormone receptor-positive tumours also had improved RFS if they achieved pCR (HR 0.60, 95% CI 0.37-0.97), but the benefit was smaller than in hormone receptor-negative disease.

Conclusions

These findings further validate the role of pCR as a strong predictor of outcome in patients with HER2+, especially in hormone receptor-negative disease. Moreover, we here provide robust evidence that dual blockade with L in combination with T and chemotherapy prolongs overall survival, suggesting that L could be repurposed in early settings.

Legal entity responsible for the study

University of Padua - Department of Surgery, Oncology and Gastroenterology.

Funding

University of Padua – Department of Surgery, Oncology and Gastroenterology: BIRD 2019 (to VG, MVD, PFC) and BIRD 2020 (to VG, MVD, GG).

Disclosure

V. Guarneri: Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Institutional, Principal Investigator, Local PI: AstraZeneca; Financial Interests, Institutional, Principal Investigator, Local PI: BMS; Financial Interests, Institutional, Principal Investigator, Local PI: Eli Lilly; Financial Interests, Institutional, Principal Investigator, Local PI: MSD; Financial Interests, Institutional, Principal Investigator, Local PI: Novartis; Financial Interests, Institutional, Principal Investigator, Local PI: Roche; Financial Interests, Institutional, Principal Investigator, Local PI: Synton Biopharmaceuticals .G. Griguolo: Other, Other, Travel Support: Novartis; Other, Other, Travel Support: Amgen; Other, Other, Trave Support: Pfizer; Other, Other, Travel Support: Daiichi Sankyo. P.F. Conte: Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Tesaro; Financial Interests, Personal, Other, Honoraria: BMS; Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests, Personal, Other, Honoraria: Eli Lilly; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Merck-KGa; Financial Interests, Institutional, Research Grant: Italian Ministry of Health; Financial Interests, Institutional, Research Grant: Veneto Secretary; Financial Interests, Institutional, Research Grant: University of Padua. M.V. Dieci: Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Genomic Health; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Celgene. All other authors have declared no conflicts of interest.

Background

The benefit of extended adjuvant therapy with aromatase inhibitors (AIs) in postmenopausal hormone-receptor positive breast cancer patients treated with tamoxifen for 2-3 years followed by an AI for 2-3 years is still controversial. We aimed to determine whether, after 2-3 years of tamoxifen, 5 years of letrozole is more effective than the standard duration of 2-3 years.

Methods

This is a prospective, open-label, phase 3 trial conducted in 64 Italian hospitals within the Gruppo Italiano Mammella (GIM). Stage I-III breast cancer patients, free of recurrence after 2-3 years of tamoxifen, were randomly allocated (1:1) with a centralized, interactive online system to receive 2-3 years (control arm) or 5 years (extended arm) of letrozole. Primary endpoint was disease-free survival (DFS) in the intention-to-treat population. Overall survival (OS) and safety were secondary endpoints.

Results

Between August 1, 2005, and October 24, 2010, we recruited 2056 patients. After a median follow-up of 11.7 years (IQR 9.5-13.1), 262 (25%) of 1030 patients in the control arm and 212 (21%) of 1026 patients in the extended arm experienced a DFS event. The 12-year DFS was 62% (95% CI 57-66) and 67% (62-71) in the control and extended arm, respectively (Hazard Ratio [HR] 0.78, 0.65-0.93; p=0.006). The effect did not change in a multivariate Cox model including nodal status, tumor size, grading, age, hormone receptor status, HER2 status, previous chemotherapy, and BMI (p=0·014). Overall, 263 (13%) deaths occurred, 147 in the control arm and 116 in the extended arm. The 12-year OS was 84% (82-87) in the control arm and 88% (86-90) in the extended arm (HR 0.77, 0.60-0.98; p=0.036). Arthralgia (31% vs 38%), myalgia (8% vs 12%), hypertension (1% vs 2%) and osteoporosis (5% vs 8%) were significantly more frequent in the experimental arm.

Conclusions

In post-menopausal breast cancer patients treated with 2-3 years of tamoxifen, extended treatment with 5 years of letrozole resulted in a significant and clinically meaningful improvement in both DFS and OS compared to the duration of 2-3 years of letrozole.

Clinical trial identification

EudraCT 2005-001212-44, NCT01064635.

Legal entity responsible for the study

The authors.

Funding

Novartis; Italian Ministry of Health.

Disclosure

L. Del Mastro: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Genomic Health; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Personal, Invited Speaker: Ipsen; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: Celgene. M. Mansutti: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Celgene; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Roche. F. Cognetti: Financial Interests, Personal, Advisory Role: Genomic Health; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Glaxo Smith Kline; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Amgen; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Merck MSD; Financial Interests, Personal, Speaker’s Bureau: BMS; Financial Interests, Personal, Speaker’s Bureau: Astellas; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly. A. Frassoldati: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Other: Pfizer; Financial Interests, Personal, Other: Eli Lilly. A. Michelotti: Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Teva; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Other, Travel grant: Ipsen. S. De Placido: Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Speaker’s Bureau: Celgene; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Eisai; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Speaker’s Bureau: Clovis; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Advisory Board: Daiichii Sankyo; Financial Interests, Personal, Advisory Board: MSD. O. Garrone: Financial Interests, Personal, Other, Consulting fees: Novartis; Financial Interests, Personal, Other, Consulting fees: MSD; Financial Interests, Personal, Other, Consulting fees: Eisai; Financial Interests, Personal, Other, Consulting fees: Eli Lilly; Financial Interests, Personal, Other, Meeting support: Roche. C. Bighin: Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly. F. Poggio: Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Speaker’s Bureau: Novartis. M. Lambertini: Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Personal, Other, Honoraria: Takeda; Financial Interests, Personal, Other, Honoraria: Sandoz. All other authors have declared no conflicts of interest.

Background

In BrighTNess, adding Cb with or without V to neoadjuvant chemotherapy significantly improved pathological complete response (pCR) with an acceptable safety profile in operable TNBC. We report EFS, OS, and second malignancies ≥4 years postsurgery.

Methods

Women with untreated stage II/III TNBC were randomized (2:1:1) to A) paclitaxel (P) 80 mg/m² (weekly, 12 doses) + Cb area under the curve 6 mg/mL (every 3 weeks, 4 cycles) + V 50 mg orally twice a day (PCbV); B) P + Cb + V placebo (PCb); or C) P + Cb/V placebo (P). All patients (pts) then received 4 cycles of doxorubicin + cyclophosphamide every 2–3 weeks. The primary (pCR) and secondary (EFS and OS) endpoints used a fixed testing procedure that ordered PCbV vs P, then PCbV vs PCb. Efficacy was assessed in all randomized pts and safety in all who received ≥1 dose. In primary pCR analyses, PCbV was superior to P but not PCb, so subsequent secondary analyses are descriptive with nominal P values.

Results

Overall, 634 pts were randomized to PCbV (n=316), PCb (n=160), and P (n=158). Median follow-up time was 4.5 years. Hazard ratio (HR) for EFS with PCbV vs P was 0.63 (95% confidence interval [CI] 0.43‒0.92, P=0.016) and 1.12 (95% CI 0.72‒1.72, P=0.620) for PCbV vs PCb. In post hoc analysis, HR for EFS with PCb vs P was 0.57 (95% CI 0.36‒0.91, P=0.018). Deaths occurred in 38/316 (12%) with PCbV, 16/160 (10%) with PCb, and 22/158 (14%) with P. HR for OS was 0.82 (95% CI 0.48‒1.38, P=0.452) for PCbV vs P, 1.25 (95% CI 0.70−2.24, P=0.455) for PCbV vs PCb, and 0.63 (95% CI 0.33−1.21, P=0.166) for PCb vs P. See table for myelodysplastic syndromes (MDS) and second malignancies. Table: 119O

Myelodysplastic syndromes and selected second cancers

Conclusions

Adding Cb to P improved pCR and EFS without increasing MDS or acute myeloid leukemia. Addition of V did not impact pCR or EFS. Mortality rate was low, but numerically higher with P than PCbV and PCb.

Clinical trial identification

NCT02032277.

Editorial acknowledgement

Medical writing support was provided by Chun Zhou, PhD, of Fishawack Health, and was funded by AbbVie Inc.

Legal entity responsible for the study

AbbVie Inc.

Funding

AbbVie Inc. funded this study; contributed to its design, data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. All authors had access to relevant data. No honoraria or payments were made for authorship.

Disclosure

S. Loibl: Financial Interests, Institutional, Research Grant: AbbVie, Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Immunomedics, Novartis, Pfizer, Roche, Cepheid; Other, Personal, Research Grant: Pfizer, Novartis, Immunomedics, SeaGen, Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Novartis, Pfizer, Roche; Financial Interests, Personal, Invited Speaker: Prime/Medscape; Financial Interests, Institutional, Advisory Board: AbbVie, Amgen, AstraZeneca, Celgene, Pfizer, Roche, Seattle Genetics, Merck KG, Eirgenix, DSI, BMS, Lilly, GSK, Pierre Fabre; Financial Interests, Personal, Invited Speaker, Lectures: Chugai; Financial Interests, Institutional, Writing Engagements, Medical writing role: AbbVie, Daiichi-Sankyo, Novartis, Pfizer, and Roche; Financial Interests, Personal, Full or part-time Employment, CEO: GBG Forschungs GmbH; Financial Interests, Institutional, Royalties, Ki67: VM Scope GmbH; Other, Institutional, Royalties, EP14153692.0: Patent; Non-Financial Interests, Personal, Principal Investigator: PI Aphinity; Other, Personal, Member of the Board of Directors: BIG; Other, Personal, Member: AGO, DKG, ASCO, ESMO; Financial Interests, Personal, Invited Speaker: Prime/Medscape. W. Sikov: Non-Financial Interests, Personal, Other, unpaid Member of Steering Committee: AbbVie. J. Huober: Financial Interests, Personal, Research Grant: Celgene, Hexal, and Novartis; Financial Interests, Personal, Other, Honoraria: AbbVie, AstraZeneca, Celgene, Eisai, Lilly, MSD, Novartis, Pfizer, and Roche; Financial Interests, Personal, Advisory Role, Consulting and Advisory role: AbbVie, AstraZeneca, Celgene, Lilly, Hexal, MSD, Novartis, and Roche; Financial Interests, Personal, Other, Travel expenses: Celgene, Daiichi, Novartis, Pfizer, and Roche. H.S. Rugo: Financial Interests, Institutional, Research Grant, Research support for clinical trials through the University of California: AstraZeneca, Boehringer Ingelheim, Daiichi, Eisai, Genentech, Immunomedics, Lilly, Macrogenics, Merck, Novartis, Odonate, Pfizer, Polyphor, Seattle Genetics, and Sermonix; Financial Interests, Personal, Other, Honoraria: Mylan, Puma, and Samsung. J. O'Shaughnessy: Financial Interests, Personal, Advisory Role, Honoraria for consulting and/or advisory boards: AbbVie, Agendia, and Amgen Biotechnology, Aptitude Health, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene Corporation, Clovis Oncology, Daiichi Sankyo, Eisai, G1 Therapeutics, Genentech, Gilead Sciences, GRAIL, Halozyme Therapeutics, Heron Therapeutics. D. Maag: Financial Interests, Personal, Full or part-time Employment: AbbVie; Financial Interests, Personal, Stocks/Shares, may hold stock or options: AbbVie. M. Untch: Financial Interests, Personal, Advisory Board, Lectures and advisory boards: AbbVie, Agendia, Amgen, AstraZeneca, BioNTech, BMS, Celgene, Daiichi-Sankyo, Eisai, GSK, Jansen Cilag, Johnson & Johnson, Lilly, Molecular Health, MSD, Mundipharma, Myriad, Novartis, Pfizer, Pierre Fabre, Roche, and Seagen; Financial Interests, Personal, Other, Consulting: AbbVie. M. Golshan: Non-Financial Interests, Personal, Other, unpaid Member of Steering Committee: AbbVie. O. Metzger: Financial Interests, Personal, Other, Consulting: AbbVie and G1 Therapeutics; Financial Interests, Personal, Research Grant: AbbVie, Genentech, Pfizer, and Roche; Financial Interests, Personal, Other, Travel expenses: AbbVie and Group Oncoclinicas; Non-Financial Interests, Personal, Advisory Board, Uncompensated co-chair of advisory board: Pfizer. M. Dunbar: Financial Interests, Personal, Full or part-time Employment: AbbVie; Financial Interests, Personal, Stocks/Shares, may hold stock or options: AbbVie. W.F. Symmans: Financial Interests, Personal, Stocks/Shares, Founder shares: Delphi Diagnostics; Financial Interests, Personal, Proprietary Information, Intellectual property: Delphi Diagnostics; Financial Interests, Personal, Stocks/Shares, Public Company shares: Eiger Biopharmaceuticals and IONIS Pharmaceuticals; Financial Interests, Personal, Advisory Board, Compensated advisory boards: Merck; Non-Financial Interests, Personal, Advisory Board, Uncompensated advisory boards: Delphi Diagnostics and Roche. C. Geyer: Financial Interests, Personal, Other, Travel funding: AstraZeneca, Daiichi-Sankyo, Genentech, and Roche; Financial Interests, Personal, Writing Engagements, Medical writing role: AbbVie and Roche; Non-Financial Interests, Personal, Advisory Board, Uncompensated advisory board: Daiichi-Sankyo, Genentech, Roche, and Seattle Genetics; Financial Interests, Personal, Advisory Board, Compensated advisory boards: Exact Sciences; Non-Financial Interests, Personal, Other, Uncompensated consulting role: Daiichi-Sankyo; Financial Interests, Personal, Other, Compensated consulting role: Athenex. All other authors have declared no conflicts of interest.