Background

Neoadjuvant atezolizumab plus docetaxel, trastuzumab and pertuzumab therapy showed favorable efficacy and safety profiles in HER2-positive early breast cancer (EBC) in NEO-PATH phase 2 study, which provided evidence of combining immunotherapy and anti-HER2 treatment as a potential new therapeutic option. We evaluated potential genomic biomarkers in NEO-PATH trial.

Methods

Tumor tissue were collected before neoadjuvant chemotherapy from all enrolled patients and at surgery in patients who did not achieve pathologic complete response (pCR). Targeted sequencing using FoundationOne CDx^TM and whole transcriptome sequencing (WTS) were performed. The association between genomic features and pCR achievement was analyzed by Fisher's exact test for the enrichment test by mutations and by differential gene expression analysis using edgeR package. A p-value or false discovery rate (FDR) less than 0.05 were considered as statistically significant.

Results

Targeted sequencing result were obtained from 63 patients(T1) and 15 patients(T3), respectively. Pre-treatment RAD21 amplification (p=0.0002), MYC amplification (p=0.0095) and MYC pathway mutations (p=0.0095) were more frequently detected in non-pCR group (n=23) compared to pCR group (n=40), and co-amplification of ERBB2 and MYC were enriched in non-pCR group (p=0.01687). When genomic mutations were compared before and after neoadjuvant chemotherapy, ERBB2 amplification (p= 0.0026) and CDK12 amplification (p=0.0006) were enriched in pre-treatment tumors and PTPRO mutation (p=0.0229) was enriched in residual tumor tissue. WTS result were obtained from 62 patients(T1) and 10 patients(T3), respectively. Luminal subtypes were enriched in non-pCR group (p = 0.0558). In patients with non-pCR, LRP1B (FDR=4.04e-04), ESR1 (FDR=1.07e-4) and RAD21 (FDR=2.05e-03) were highly expressed and ESR1, luminal and MYC related genesets showed higher expression (FDR<0.05).

Conclusions

Luminal subtype and MYC amplification were associated with non-pCR in patients with HER2-positive EBC who were treated with immunotherapy and anti-HER2 treatment combination. Further evaluation of the predictive role of these mutations are warranted.

Clinical trial identification

NCT03881878.

Legal entity responsible for the study

Yeon Hee Park.

Funding

This work was supported by a grant from the Ministry of Health and Welfare, Republic of Korea (HA17C0055) and by the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1720150). The study drugs were provided by Roche (trastuzumab, pertuzumab, and atezolizumab), Sanofi (docetaxel), and Dong-A ST (tripegfilgrastim).

Disclosure

H.K. Ahn: Non-Financial Interests, Institutional, Principal Investigator: AstraZeneca, Roche, Boehringer Ingelheim, MSD, Pfizer, Eli Lilly; Financial Interests, Personal, Invited Speaker: MSD Boehringer Ingelheim. S. Im: Financial Interests, Personal, Invited Speaker: Merck, AstraZeneca, Eisai, GSK, Hanmi, Eli Lilly, MSD, Pfizer, Novartis; Financial Interests, Institutional, Research Grant: Roche, AstraZeneca, Pfizer, Dae Woong; K.H. Jung: Non-Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Novartis, BiXink, Takeda. Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer, Roche, Novartis, MSD, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Roche, Novartis, MSD; Financial Interests, Institutional, Other, Research Grant: AstraZeneca, Pfizer, Roche, MSD; Non-Financial Interests, Principal Investigator: AstraZeneca, Pfizer, Novartis, MSD, Lilly, Roche, Daiichi Sankyo. All other authors have declared no conflicts of interest.

Background

LUCY interim findings confirmed the clinical effectiveness of olaparib 300 mg twice daily in patients with metastatic breast cancer (mBC) in a real world setting. Findings were consistent with the OlympiAD trial of olaparib vs chemotherapy of physician’s choice. We report results of the final planned analysis.

Methods

Eligible adults had germline (g) or somatic (s) BRCA1- and/or BRCA2-mutated (BRCAm), HER2-negative mBC and had received taxane and/or anthracycline in early or metastatic settings and ≤2 previous lines of chemotherapy for mBC. Pts with hormone receptor-positive (HR+) mBC had previously completed ≥1 line of endocrine therapy (ET) in any setting or were unsuitable for further ET. Primary endpoint: investigator-assessed progression-free survival (PFS; gBRCAm cohort). Overall survival (OS) and safety were secondary endpoints. Final analysis was planned at 130 OS events (gBRCAm). Results are in all pts (gBRCAm and sBRCAm). Prespecified subgroups (gBRCAm only): HR status (HR+ vs triple-negative breast cancer [TNBC]); line of therapy (1st line vs 2nd line+).

Results

During 2018, 255 pts were enrolled (252 gBRCAm, 3 sBRCAm; median [m] age: 45.0 [range 22–75] years; 98.4% female). mPFS: 8.2 months (95% CI 7.0–9.2; 208 events, 81.6%). mOS: 24.9 months (95% CI 21.1–27.9; 142 events, 55.7%). OS rate at 30 months: 41.7% (95% CI 35.2–48.1). Treatment-related adverse events (AEs, >10% pts): nausea (47.8%), anaemia (34.5%), asthenia (20.8%), fatigue (18.0%), vomiting (17.6%), neutropenia (15.3%) and diarrhoea (11.0%). Grade ≥3 AEs (17.6% pts) included anaemia (11.8%). Few pts (4.3%) discontinued treatment due to an AE. Post study therapies will be reported.

Conclusions

The benefit of olaparib was similar across HR status and treatment lines. mOS was longer than reported in OlympiAD. No new safety signals were observed. These results strongly support olaparib as a chemotherapy-free alternative for gBRCAm, HER2-negative mBC. Table: 174P

Subgroup analyses (full analysis set)

Editorial acknowledgement

Medical writing assistance was provided by Elizabeth Gandhi, PhD of PharmaGenesis Cambridge, Cambridge, UK, with funding from AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Legal entity responsible for the study

AstraZeneca.

Funding

This study was funded by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

J. Balmana: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: MedSir. P.A. Fasching: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Merck, Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Merck, Sharp & Dohme; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Hecal; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Personal, Advisory Board: Agendia; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Invited Speaker: BioNTech; Financial Interests, Institutional, Invited Speaker: Cepheid; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member: Arbeitsgemeinschaft für Gynäkologische Onkologie e.V.; Non-Financial Interests, Member: Translational Research in Oncology; Non-Financial Interests, Member: Deutsche Gesellschaft für Senologie e.v. S. Delaloge: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Exact Sciences; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Advisory Board: Pierre Fabre; Financial Interests, Institutional, Advisory Board: Orion; Financial Interests, Institutional, Advisory Board: Sanofi; Financial Interests, Institutional, Advisory Board: Rappta; Financial Interests, Institutional, Advisory Board: Cellectis; Financial Interests, Institutional, Advisory Board: Isis/Servier; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Seagen; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Advisory Board, ad board: Besins Healthcare; Financial Interests, Institutional, Invited Speaker: Roche Genentech; Financial Interests, Institutional, Invited Speaker: BMS; Financial Interests, Institutional, Invited Speaker: Puma; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Orion; Financial Interests, Institutional, Invited Speaker: Sanofi; Financial Interests, Institutional, Funding: GE; Financial Interests, Institutional, Invited Speaker: Pfizer; 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. Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Other, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Other, Research Grant: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Research Grant: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Institutional, Other, Research Grant: MSD; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Non-Financial Interests, Principal Investigator: AstraZeneca; Non-Financial Interests, Principal Investigator: Pfizer; Non-Financial Interests, Principal Investigator: Novartis; Non-Financial Interests, Principal Investigator: MSD; Non-Financial Interests, Principal Investigator: Lilly; Non-Financial Interests, Principal Investigator: Roche; Non-Financial Interests, Principal Investigator: Daiichi Sankyo. J. Sohn: Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim. S. Aksoy: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Merck, Merck Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Merck, Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche. C.V. Timcheva: Financial Interests, Personal, Invited Speaker, Presentation during national scientific conference: Roche Bulgaria; Financial Interests, Personal, Advisory Board, Discussion on the place of CDK4/6 inhibitors in the treatment of metastatic breast cancer: Eli Lilly; Financial Interests, Personal, Advisory Board, The role of PARP inhibitors in the treatment of breast and ovarian cancer: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker, PI for several clinical trials performing in the hospital: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker, PI for several clinical trials performing in the hospital: Parexel; Financial Interests, Personal and Institutional, Invited Speaker, Pi for several clinical trials perforing in the hospital: Roche; Financial Interests, Personal and Institutional, Invited Speaker, PI for some clinical trials performing in the hospital: Novartis; Financial Interests, Personal and Institutional, Invited Speaker, PI for the clinical trial performing in the hospital: I3Research; Non-Financial Interests, Principal Investigator, Investigator initiated trial on metastatic CRC: Merck; Non-Financial Interests, Member, Created in 2012, Head of BAMO until 2020: Bulgarian Association for Medical Oncology (BAMO). T. Park-Simon: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pizer; Financial Interests, Personal, Advisory Board: Daiichi; Financial Interests, Personal, Invited Speaker: Daiichi; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Invited Speaker: Gilead; Financial Interests, Personal, Advisory Board: Exact Sciences; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis. E. John: Financial Interests, Institutional, Full or part-time Employment: AstraZeneca. K. Baria: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. G. Walker: Financial Interests, Institutional, Other, I work as a consultant to the company: AstraZeneca. K.A. Gelmon: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Advisory Board: Ayala; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: BMS. All other authors have declared no conflicts of interest.

Background

The phase II trial of the pan-HER inhibitor poziotinib (NCT02418689) demonstrated the clinical effectiveness of poziotinib 12 mg p.o. once daily (QD) in patients with HER2-positive metastatic breast cancer (mBC) in a heavily pretreated setting with median progression free survival (PFS) of 4 months from the primary analysis. Diarrhea and stomatitis were the major toxicities. We now report the results from the final planned analysis of overall survival (OS).

Methods

Eligible patients have received anticancer chemotherapy including taxane and ≥2 prior HER2-directed regimens including trastuzumab. PFS was the primary endpoint. Secondary endpoints included OS and objective response rate (ORR), and safety was evaluated. The database was locked on October 1, 2021 including data from the last patient who received poziotinib for 104 cycles (72.7 months) and transferred to the early access program. The final OS analysis was planned when ≥ 54 deaths occurred. The final OS analysis occurred after 68 deaths.

Results

From April 2015 to February 2016, 106 patients were enrolled at seven sites in Korea. At data cut off on 1 October 2021, the full analysis set included 102 patients. Median age was 51.0 (range 30–76) years. Median number of treatment regimens before poziotinib was 4 (2-16). At the data cut-off, median PFS (95% CI) was 4.0 (3.0–4.4) months. Median OS (95% CI) was 17.7 (95% CI 12.4–20.8) months (68/102 events; 66.7%). OS rate (95% CI) at 36 and 60 months was 18 (10-28)% and 14 (7-24)%, respectively. Most frequent all-grade adverse events (AEs) considered to be treatment related were: diarrhea (96.2%), stomatitis (92.5%), pruritus (63.2%), rash (63.2%), dry skin (38.7%), dermatitis acneiform (32.1%), and decreased appetite (26.4%). Grade ≥3 AEs and serious AEs occurred in 45.3% and 8.5% of patients, respectively.

Conclusions

Poziotinib showed clinically meaningful OS benefit for patients with HER2-positive mBC and the safety profile was as expected for tyrosine kinase inhibitors(TKIs). This encouraging result provide an important update on the clinical effectiveness and safety of poziotinib in HER2-positive mBC patients who were previously heavily treated.

Clinical trial identification

NCT02418689.

Legal entity responsible for the study

The authors.

Funding

Hanmi.

Disclosure

Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Other, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Other, Research Grant: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Research Grant: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Institutional, Other, Research Grant: MSD; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Non-Financial Interests, Principal Investigator: AstraZeneca; Non-Financial Interests, Principal Investigator: Pfizer; Non-Financial Interests, Principal Investigator: Novartis; Non-Financial Interests, Principal Investigator: MSD; Non-Financial Interests, Principal Investigator: Lilly; Non-Financial Interests, Principal Investigator: Roche; Non-Financial Interests, Principal Investigator: Daiichi Sankyo. J. Sohn: Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim. K.S. Lee: Financial Interests, Institutional, Research Grant: Ono. J.H. Kim: Financial Interests, Institutional, Research Grant: Ono. E. Baek: Financial Interests, Personal and Institutional, Other, Employee: Hanmi. H. Han: Financial Interests, Personal and Institutional, Other, Employee: Hanmi. S. Im: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Institutional, Principal Investigator: MSD; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: Prizer; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Research Grant: Hanmi; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Institutional, Principal Investigator: Lilly; Financial Interests, Institutional, Principal Investigator: Novartis. All other authors have declared no conflicts of interest.

Background

The phase II trial of the pan-HER inhibitor poziotinib (NCT02418689) demonstrated the clinical effectiveness of poziotinib 12 mg p.o. once daily (QD) in patients with HER2-positive metastatic breast cancer (mBC) in a heavily pretreated setting with median progression free survival (PFS) of 4 months from the primary analysis. Diarrhea and stomatitis were the major toxicities. We now report the results from the final planned analysis of overall survival (OS).

Methods

Eligible patients have received anticancer chemotherapy including taxane and ≥2 prior HER2-directed regimens including trastuzumab. PFS was the primary endpoint. Secondary endpoints included OS and objective response rate (ORR), and safety was evaluated. The database was locked on October 1, 2021 including data from the last patient who received poziotinib for 104 cycles (72.7 months) and transferred to the early access program. The final OS analysis was planned when ≥ 54 deaths occurred. The final OS analysis occurred after 68 deaths.

Results

From April 2015 to February 2016, 106 patients were enrolled at seven sites in Korea. At data cut off on 1 October 2021, the full analysis set included 102 patients. Median age was 51.0 (range 30–76) years. Median number of treatment regimens before poziotinib was 4 (2-16). At the data cut-off, median PFS (95% CI) was 4.0 (3.0–4.4) months. Median OS (95% CI) was 17.7 (95% CI 12.4–20.8) months (68/102 events; 66.7%). OS rate (95% CI) at 36 and 60 months was 18 (10-28)% and 14 (7-24)%, respectively. Most frequent all-grade adverse events (AEs) considered to be treatment related were: diarrhea (96.2%), stomatitis (92.5%), pruritus (63.2%), rash (63.2%), dry skin (38.7%), dermatitis acneiform (32.1%), and decreased appetite (26.4%). Grade ≥3 AEs and serious AEs occurred in 45.3% and 8.5% of patients, respectively.

Conclusions

Poziotinib showed clinically meaningful OS benefit for patients with HER2-positive mBC and the safety profile was as expected for tyrosine kinase inhibitors(TKIs). This encouraging result provide an important update on the clinical effectiveness and safety of poziotinib in HER2-positive mBC patients who were previously heavily treated.

Clinical trial identification

NCT02418689.

Legal entity responsible for the study

The authors.

Funding

Hanmi.

Disclosure

Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Other, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Other, Research Grant: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Research Grant: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Institutional, Other, Research Grant: MSD; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Non-Financial Interests, Principal Investigator: AstraZeneca; Non-Financial Interests, Principal Investigator: Pfizer; Non-Financial Interests, Principal Investigator: Novartis; Non-Financial Interests, Principal Investigator: MSD; Non-Financial Interests, Principal Investigator: Lilly; Non-Financial Interests, Principal Investigator: Roche; Non-Financial Interests, Principal Investigator: Daiichi Sankyo. J. Sohn: Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim. K.S. Lee: Financial Interests, Institutional, Research Grant: Ono. J.H. Kim: Financial Interests, Institutional, Research Grant: Ono. E. Baek: Financial Interests, Personal and Institutional, Other, Employee: Hanmi. H. Han: Financial Interests, Personal and Institutional, Other, Employee: Hanmi. S. Im: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Institutional, Principal Investigator: MSD; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: Prizer; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Research Grant: Hanmi; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Institutional, Principal Investigator: Lilly; Financial Interests, Institutional, Principal Investigator: Novartis. All other authors have declared no conflicts of interest.