Two studies show CDK4/6 inhibitors improve overall survival in advanced breast cancer

Barcelona, Spain, 29 September 2019 – New data from two studies reported at the ESMO Congress 2019 have shown that treatment with a CDK4/6 inhibitor plus fulvestrant improves overall survival in women with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) advanced breast cancer. (1,2,3)

The two studies included different patient populations as well as different CDK4/6 inhibitors used as different lines of therapy: Monarch 2 evaluated abemaciclib plus fulvestrant in patients with advanced breast cancer after failure of endocrine therapy and regardless the menopausal status; the Monaleesa-3 study investigated ribociclib plus fulvestrant as first- or second-line only in postmenopausal patients.

The results give the treating physician the full spectrum of choice of CDK4/6 inhibitor for each individual patient, although the two CDK4/6 inhibitors have slightly different management requirements and toxicity profiles.

Monaleesa-3

Results of the Monaleesa-3 (1) trial have shown that first-line, as well as second-line, treatment with the CDK4/6 inhibitor ribociclib plus fulvestrant significantly improves overall survival in postmenopausal patients with HR+ HER2- advanced breast cancer. The benefits with ribociclib plus fulvestrant were seen in women not previously treated with hormonal therapy as well as in those who had become resistant to endocrine therapy.

“This is a significant, practice-changing report, in that we are now saying that patients with advanced breast cancer will have an overall survival benefit if they get the CDK4/6 inhibitor ribociclib upfront at the time of their recurrence, even if they have not had any prior endocrine therapy at the time of presenting with metastatic disease,” said study author Prof Dennis Slamon, University of California Los Angeles, USA.

“The argument has always been by some experts that you should first treat with endocrine therapy alone and then if patients recur, you would add something like a CDK4/6 inhibitor. In other words, you get what you can out of endocrine therapy alone – and save a CDK4/6 inhibitor until the subsequent recurrence. The data from Monaleesa-3 clearly show that if postmenopausal patients receive this right up front there is a very significant benefit – not only in progression free survival, which had already been published – but now with this new report in overall survival – which is the hardest endpoint to reach, and the most important one in terms of making an impact on the disease,” Slamon explained.

Commenting on the new data, Dr Matteo Lambertini, IRCCS Policlinico San Martino Hospital, University of Genoa, Italy, said, “Monaleesa-3 reports remarkable results that further confirm the major improvement in the care of patients with HR+/HER2- advanced disease obtained with the combination of endocrine therapy and CDK4/6 inhibition; this treatment should be made widely available to all our patients in this setting. Uniquely, Monaleesa-3 is the only trial with a CDK4/6 inhibitor to include patients with endocrine sensitive as well as those with endocrine resistant disease. This is the first time we have seen improved overall survival with a combination of a CDK4/6 inhibitor plus fulvestrant in first line.”

Monarch 2

A second trial reported at the ESMO Congress 2019, Monarch 2, showed statistically and clinically meaningful improvement in overall survival with the CDK4/6 inhibitor abemaciclib plus fulvestrant in pre-, and peri- as well as in postmenopausal women patients with HR+ HER2- advanced breast cancer resistant to hormonal therapy (2).

“Results from Monarch 2 study presented two years ago (4) showed significant improvement in progression free survival for patients treated with the combination of abemaciclib plus fulvestrant compared to fulvestrant alone. Now, with further follow-up we have overall survival data showing a statistically significant and clinically meaningful improvement in overall survival with the combination,” said study first author Prof George Sledge, Stanford University School of Medicine, USA.

He suggested, “The main take-home message from this study – and from other similar studies – is that CDK4/6 inhibitors significantly prolong the time patients remain in remission and significantly improve overall survival. Therefore it is very reasonable to think of these as standard of care options for patients with metastatic breast cancer.”

Commenting on the relevance of the new studies, Prof Nadia Harbeck, University of Munich, Germany, said, “The results of Monarch 2 nicely complement those reported in Monaleesa-3. Abemaciclib is the third CDK4/6 inhibitor to show an overall survival benefit in advanced HR+ HER2- breast cancer. Together with the data we have seen before with palbociclib (5) and ribociclib, these new data strengthen the argument that we should start treatment in the metastatic setting with a CDK4/6 inhibitor plus endocrine therapy because these drugs substantially improve patient outcomes compared to anti-hormonal treatment alone.”

Considering possible limitations of the studies, Harbeck said, “All three of the CDK4/6 inhibitors powered their studies for progression-free survival and not for overall survival. Nevertheless, I think the data are strong enough, taken together, to give us certainty that this is really the way forward in this disease – to go for endocrine-based therapy plus CDK4/6 inhibition and not just endocrine therapy alone.” She added that she would like to see detailed quality of life data from Monarch 2 to accompany the survival data and hoped this will be made available in the future. Moreover, she stated that these results make the doctors and patients hopeful for the results of the CDK 4/6 inhibitor studies in early breast cancer – the first ones of which will be reported in the near future.

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Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO Congress 2019

Official Congress Hashtag: #ESMO19

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References

1 LBA7_PR ‘Overall survival (OS) results of the phase III MONALEESA-3 trial of postmenopausal patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) advanced breast cancer (ABC) treated with fulvestrant (FUL) + ribociclib (rib)’ will be presented by Dennis Slamon during the Presidential Symposium II on Sunday, 29 September 2019, 16:30-18:00 in Barcelona Auditorium (Hall 2).

Annals of Oncology

, Volume 30, Supplement 5, October 2019

2 LBA6_PR ‘Monarch 2: overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2- advanced breast cancer’ will be presented by George Sledge during the Presidential Symposium II on Sunday, 29 September 2019, 16:30-18:00 in Barcelona Auditorium (Hall 2).

Annals of Oncology

, Volume 30, Supplement 5, October 2019

3

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/

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esmo.

org/

Conferences/

ESMO-Congress-2019

4 Sledge GW, Toi M, Neven P et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced cancer who had progressed while receiving endocrine therapy. JCO 2017; 35: 2875-2884

5 Turner N, Slamon D, Ro J et al Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer.

N Engl J Med

2018; 379:1926-1936. DOI: 10.1056/NEJMoa1810527

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LBA6_PR – MONARCH 2: Overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2- advanced breast cancer

G.W. Sledge1, M. Toi2, P. Neven3, J. Sohn4, K. Inoue5, X. Pivot6, O. Burdaeva7, M. Okera8, N. Masuda9, P.A. Kaufman10, H. Koh11, E.-M. Grischke12, P.F. Conte13, Y. Lu14, S. Barriga15, K. Hurt16, M. Frenzel17, S.R.D. Johnston18, A. Llombart-Cussac19

1Medicine – Med/oncology, Stanford University School of Medicine, Stanford, United States of America, 2Breast Cancer Unit, Kyoto University Hospital, Kyoto, Japan, 3Vesalius Research Center – Vib, University Hospitals Leuven, Ku Leuven, University of Leuven, Leuven, Belgium, 4Medical Oncology Dept, Yonsei University, Seoul, Korea, Republic of, 5Cancer Center, Saitama Cancer Center, Kita-adachi Ina, Japan, 6Medical Oncology, Centre Paul Strauss, INSERM 110, Strasbourg, France, 7Oncology, Arkhangelsk Regional Clinical Oncology Dispensary, Arkhangelsk, Russian Federation, 8Medical Oncology, Adelaide Cancer Centre, Adelaide, Australia, 9Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka, Japan, 10Medicine, Division Of Hematology/oncology, University of Vermont Cancer Center, Burlington, United States of America, 11Hematology/oncology, Kaiser Permanente Medical Group, Bellflower, United States of America, 12Dept. Fur Frauengesundheit, Universitats Frauenklinik Tubingen, Eberhard Karls University, Tubingen, Germany, 13Department Of Oncology, Istituto Oncologico Veneto IRCCS, Padova, Italy, 14Global Statistical Sciences – Oncology, Eli Lilly and Company, Indianapolis, United States of America, 15Clinical Development – Oncology, Eli Lilly and Company, Windlesham, United Kingdom, 16Clinical Development – Oncology, Eli Lilly and Company, Indianapolis, United States of America, 17Statistics – Oncology, Eli Lilly and Company – Global Headquarters, Indianapolis, United States of America, 18Department Of Medicine, Royal Marsden Hospital, London, United Kingdom, 19Medical Oncology, Hospital Universitario Arnau de Vilanova, Valencia, Spain

Background: Abemaciclib is an oral, selective cyclin-dependent kinase 4 & 6 inhibitor, approved for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) as monotherapy for endocrine refractory disease (US) and with endocrine therapy (ET) for initial treatment and after progression on ET. In the MONARCH 2 trial, abemaciclib + fulvestrant (F) significantly improved PFS compared to placebo (P) + F (median: 16.4 m vs 9.3 m; HR: 0.553) with a generally tolerable safety profile. Here we report the OS results of the prespecified interim.

Methods: MONARCH 2 (NCT02107703) was a global, randomized, double-blind phase 3 trial of abemaciclib + F or P + F in pre- or perimenopausal (with ovarian suppression) and postmenopausal women with advanced ET resistant HR+, HER2- ABC. 669 patients were randomized 2:1, stratified based on site of metastasis (visceral, bone-only, or other) and resistance to prior ET (primary vs secondary). Abemaciclib or P 150 mg was dosed Q12H, and F 500 mg was administered per label. The primary objective was investigator-assessed PFS. OS was a gated secondary endpoint. The boundary p-value for the interim analysis was 0.0208.

Results: At the prespecified interim analysis, 338 deaths (77% of the planned 441 events) were observed in the ITT population with a median OS of 46.7 m for abemaciclib + F and 37.3 m for P + F (HR: 0.757; 95% CI: 0.606, 0.945; P = 0.0137). These results met the predefined boundary for significance and are thus definitive. OS benefit was consistent in all stratification factors; among stratification factors, more pronounced effects were observed in subgroups of visceral disease (HR: 0.675) and primary resistance to prior ET (HR: 0.686). PFS2 (HR: 0.675; 95% CI: 0.558, 0.816) and time to chemotherapy (HR: 0.622; 95% CI: 0.499, 0.775) were also significantly improved. Safety data were consistent with known abemaciclib safety profile.

Conclusions: Treatment with abemaciclib plus fulvestrant provided a statistically significant and clinically meaningful median OS benefit of 9.4 months to pre- or perimenopausal and postmenopausal patients with HR+, HER2- ABC who progressed on ET with no new safety signals observed.

Clinical trial identification: NCT02107703

Editorial acknowledgement: Scientific writing support was provided by Sarah C. Nabinger, employee of Eli Lilly and Company.

Legal entity responsible for the study: Eli Lilly and Company

Funding: Eli Lilly and Company

Disclosure: G.W. Sledge: Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly and Company.

M. Toi: Honoraria (self), Research grant / Funding (institution), lecture honoraria: Chugal; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Takeda; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Pfizer; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Kyowa-Hakko-Kirin; Honoraria (self), Research grant / Funding (institution), lecture honoraria: C & C Res Lab; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Talho; Research grant / Funding (institution), Officer / Board of Directors: JBCRG association; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Eisai; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Dallchl-Sankyo; Honoraria (self), Research grant / Funding (institution), lecture honoraria: AstraZeneca; Honoraria (self), lecture honoraria: Eli Lilly and Company; Honoraria (self): MSD; Honoraria (self), lecture honoraria: Novartis; Honoraria (self), Honoraria for a meeting: Konica Minorta; Honoraria (self), Honoraria for a meeting: Genomic Health; Officer / Board of Directors: Organisation for Oncology and Translational Research; Officer / Board of Directors: Kyoto Breast Cancer Research Network.

P. Neven: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Honoraria (institution), Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy: Roche; Research grant / Funding (self): Kom op Tegan Kanker; Honoraria (institution): Benelux.

K. Inoue: Honoraria (self), Research grant / Funding (institution): Eli Lilly and Company; Honoraria (self), Honoraria (institution): Esal; Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Chugal; Research grant / Funding (institution): Dailchl Sankyo; Research grant / Funding (institution): Parexel/Puma Biotechnology; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Bayer.

X. Pivot: Research grant / Funding (institution): Eli Lilly and Company.

N. Masuda: Honoraria (self), Research grant / Funding (institution), Lecture fees (Honoraria): Chugai; Honoraria (self), Research grant / Funding (institution), Lecture fees (Honoraria): AstraZeneca; Honoraria (self), Research grant / Funding (institution), Lecture fees (Honoraria): Pfizer; Honoraria (self), Research grant / Funding (institution), Lecture fees (Honoraria): Eli Lilly and Company; Honoraria (self), Research grant / Funding (institution), Lecture fees (Honoraria): Eisai; Honoraria (self), Lecture fees (Honoraria): Takeda; Research grant / Funding (institution): Kyowa-Kirin; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Daiichi Sankyo; Officer / Board of Directors: Japan Breast Cancer Research Group Association.

P.A. Kaufman: Honoraria (self), Research grant / Funding (institution): Eli Lilly and Company; Honoraria (self): AstraZeneca; Research grant / Funding (institution): Novartis.

H. Koh: Research grant / Funding (institution): Eli Lilly and Company.

E. Grischke: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly and Company.

P.F. Conte: Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, travel grant: Eli Lilly and Company; Research grant / Funding (institution): Roche; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self), travel grant: Celgene; Honoraria (self), travel grant: Tesaro.

Y. Lu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company.

S. Barriga: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company.

K. Hurt: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company.

M. Frenzel: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company.

S.R.D. Johnston: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Puma Biotechnology; Speaker Bureau / Expert testimony: Elsal.

A. Llombart-Cussac: Shareholder / Stockholder / Stock options: MedSIR; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company; Honoraria (self), Research grant / Funding (institution): Celgene; Honoraria (self), Research grant / Funding (institution): Plere Fabre; Research grant / Funding (institution): Genomic Health; Research grant / Funding (institution): Puma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Non-financial support: AstraZeneca; Research grant / Funding (institution): TESARO; Research grant / Funding (institution): ELSAI; Honoraria (self): Ferrer Incode – Agendia.

LBA7_PR – Overall survival (OS) results of the phase III MONALEESA-3 trial of postmenopausal patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) advanced breast cancer (ABC) treated with fulvestrant (FUL) + ribociclib (rib)

D.J. Slamon1, P. Neven2, S. Chia3, P.A. Fasching4, M. De Laurentiis5, S.-A. Im6, K. Petrakova7, G.V. Bianchi8, F.J. Esteva9, M. Martin10, A. Nusch11, G.S. Sonke12, L. De la Cruz-Merino13, J.T. Beck14, X. Pivot15, M. Sondhi16, Y. Wang17, A. Chakravartty16, K. Rodriguez-Lorenc16, G. Jerusalem18

1Department Of Medicine, University of California Los Angeles, Santa Monica, United States of America, 2Vesalius Research Center – Vib, University Hospitals Leuven, Ku Leuven, University of Leuven, Leuven, Belgium, 3Department Of Medicine, University of British Columbia, Vancouver, Canada, 4Gynecology And Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany, 5Fondazione G. Pascale, Istituto Nazionale Tumori, Naples/Italy, 6Internal Medicine, SNUH-Seoul National University Hospital, Seoul/Korea, Republic of, 7Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic, 8Istituto Nazionale Dei Tumori, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy, 9Medical Oncology, NYU Langone Health, New York, United States of America, 10Centro De Investigacion Biomedica En Red De Cancer, Grupo Espanol De Investigacion En Cancer De Mama, Universidad Complutense, Instituto de Investigacion Sanitaria Gregorio Maranon, Madrid, Spain, 11Onkologie, Praxis fur Hamatologie und internistische Onkologie, Ratingen, Germany, 12Borstkanker Onderzoek Groep Study Center, Netherlands Cancer Institute, Amsterdam, Netherlands, 13Oncology, Hospital Universitario Virgen Macarena, Seville, Spain, 14Oncology, Highlands Oncology Group, Fayetteville, United States of America, 15Medical Oncology, Centre Paul Strauss, INSERM 110, Strasbourg, France, 16Oncology, Novartis Pharmaceuticals Corporation, East Hanover, United States of America, 17Oncology, Novartis Pharma AG, Basel, Switzerland, 18Oncology, Centre Hospitalier Universitaire de Liege, Liege, Belgium

Background: The Phase III MONALEESA-3 trial (NCT02422615; N = 726) investigated RIB, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, + FUL as first-line (1L) or second-line (2L) treatment for postmenopausal pts with HR+/HER2- ABC. Here we report OS and 1L progression-free survival (PFS) results.

Methods: Postmenopausal pts with HR+/HER2-ABC were randomized 2:1 to receive RIB + FUL or PBO + FUL in 1L and 2L settings. This is the 2nd of 3 protocol-specified OS analyses.

Results: At the data cutoff (3 Jun 2019), 153 pts were still on treatment (RIB, n = 121 [25.0%]; PBO, n = 32 [13.2%]); OS was evaluated after 275 deaths (RIB, 167 [34.5%]; PBO, 108 [44.6%]). Median follow-up was 39.4 mo. RIB + FUL demonstrated a statistically significant OS prolongation over PBO + FUL (median, NR vs 40.0 mo; HR, 0.724, 95% CI, 0.568-0.924, P = 0.00455). The result crossed the prespecified Lan DeMets (O’Brien Fleming) stopping boundary (P = 0.01129) for superior efficacy. Per protocol, these OS results will be considered final. OS benefit with RIB vs PBO was consistent across all subgroups, including the 1L subgroup (median, NR vs 45.1 mo; HR, 0.700 [95% CI, 0.479-1.021]) and the early-relapse/2L subgroup (median, 40.2 vs 32.5 mo; HR, 0.730 [95% CI, 0.530-1.004]). In pts receiving 1L treatment, the median PFS (descriptive analysis) with RIB + FUL vs PBO + FUL was 33.6 vs 19.2 mo (HR, 0.546 [95% CI, 0.415-0.718]). Time to progression on next-line therapy or death (PFS2) was also longer with RIB vs PBO (median, 39.8 vs 29.4 mo; HR, 0.670 [95% CI, 0.542-0.830]). The safety profile was consistent with previously published analyses.

Conclusions: There was a statistically significant OS prolongation with RIB over PBO, which was consistent across all subgroups. The median PFS with RIB in the 1L setting is the longest reported in a Phase III trial in HR+/HER2- ABC. These data, combined with results from MONALEESA-7, confirm RIB benefit with multiple combination partners in pre- and postmenopausal pts, and support RIB as a recommended CDK4/6 inhibitor as 1L and 2L treatment in pts with HR+/HER2- ABC.

Clinical trial identification: NCT02422615

Editorial acknowledgement: Editorial assistance in the writing of this abstract was provided by Tara Wabbersen, PhD, of MediTech Media, LLC, through funding by Novartis Pharmaceuticals Corporation.

Legal entity responsible for the study: Novartis Pharmaceuticals Corporation

Funding: Novartis Pharmaceuticals Corporation

Disclosure: D.J. Slamon: Leadership role, Travel / Accommodation / Expenses: Biomarin; Research grant / Funding (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy: Eli Lilly.

S. Chia: Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Hoffman LaRoche; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly.

P.A. Fasching: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy: Myelo Therapeutics GmbH; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Puma Biotechnology; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Teva; Research grant / Funding (institution): BioNTech AG.

M. De Laurentiis: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen.

S. Im: Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Hanmi; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eisai.

K. Petrakova: Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Travel / Accommodation / Expenses: BMS.

F.J. Esteva: Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Genentech/Roche; Advisory / Consultancy: Celltrion Healthcare ; Advisory / Consultancy: Seattle Genetics; Research grant / Funding (self): GlaxoSmithKline.

M. Martin: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy: Roche-Genentech; Honoraria (self), Advisory / Consultancy: GlaxoSmithKline; Honoraria (self), Advisory / Consultancy: Pharmamar; Honoraria (self), Advisory / Consultancy: Taiho Oncology ; Research grant / Funding (self): Roche.

A. Nusch: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy: Amgen.

G.S. Sonke: Honoraria (institution), Research grant / Funding (institution), institutional reimbursement for patient accrual; institutional reimbursement for education and steering committee activities: Novartis; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Roche.

J.T. Beck: Research grant / Funding (institution): Novartis .

M. Sondhi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis Pharmaceuticals Corporation.

Y. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis Pharmaceuticals Corporation.

A. Chakravartty: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis Pharmaceuticals Corporation.

K. Rodriguez-Lorenc: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis Pharmaceuticals Corporation.

G. Jerusalem: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Puma Biotechnology.