Randomized Phase II Study of the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody Cetuximab With Cisplatin Versus Cisplatin Alone in Patients With Metastatic Triple-Negative Breast Cancer

Abstract

Purpose

Epidermal growth factor receptor is overexpressed in metastatic triple-negative breast cancers (mTNBCs), an aggressive subtype of breast cancer. Our randomized phase II study investigated cisplatin with or without cetuximab in this setting.

Patients and Methods

Patients who had received no more than one previous chemotherapy regimen were randomly assigned on a 2:1 schedule to receive no more than six cycles of cisplatin plus cetuximab or cisplatin alone. Patients receiving cisplatin alone could switch to cisplatin plus cetuximab or cetuximab alone on disease progression. The primary end point was overall response rate (ORR). Secondary end points studied included progression-free survival (PFS), overall survival (OS), and safety profiles. Analyses included a significance level of α = .10 with no adjustments for multiplicity.

Results

The full analysis set comprised 115 patients receiving cisplatin plus cetuximab and 58 receiving cisplatin alone; 31 patients whose disease progressed on cisplatin alone switched to cetuximab-containing therapy. The ORR was 20% (95% CI, 13 to 29) with cisplatin plus cetuximab and 10% (95% CI, 4 to 21) with cisplatin alone (odds ratio, 2.13; 95% CI, 0.81 to 5.59; P = .11). Cisplatin plus cetuximab resulted in longer PFS compared with cisplatin alone (median, 3.7 v 1.5 months; hazard ratio [HR], 0.67; 95% CI, 0.47 to 0.97; P = .032). Corresponding median OS was 12.9 versus 9.4 months (HR, 0.82; 95% CI, 0.56 to 1.20; P = .31). Common grade 3/4 adverse events included acne-like rash, neutropenia, and fatigue.

Conclusion

While the primary study end point was not met, adding cetuximab to cisplatin doubled the ORR and appeared to prolong PFS and OS, warranting further investigation in mTNBC.

INTRODUCTION

Triple-negative breast cancer (TNBC), which is defined as estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) –negative disease, accounts for 11% to 17% of all breast cancers.^1,2 The incidence of this type of breast cancer is greater among young patients and African American patients.² TNBC has a more aggressive clinical course than other types of breast cancer, with a much shorter median time from recurrence to death.³ In addition, these tumors lack expression of hormone receptors and HER2 and they are not responsive to hormonal or anti-HER2 therapy. The only available therapy for advanced TNBC is cytotoxic chemotherapy⁴ and bevacizumab in combination with chemotherapy in European countries, but prognosis generally remains poor,⁵ especially for metastatic disease. Thus, investigation of novel ways to treat patients with this subtype of breast cancer is of particular importance.

Epidermal growth factor receptor (EGFR) has been shown to be highly expressed in TNBC cell lines,⁶ and TNBC cell lines overexpressing the receptor are growth inhibited by the anti-EGFR monoclonal antibody cetuximab.⁷ In addition, a majority of patients with TNBC comprise basal-like molecular characteristics and often have defects in BRCA1-regulated DNA repair pathways and thus may be particularly sensitive to DNA damaging agents such as cisplatin.^4,8 Clinical studies have shown that the use of platinum-based chemotherapy is associated with tumor response in both nonmetastatic⁹ and metastatic TNBC (mTNBC).^10,11

In vitro studies have demonstrated that the EGFR-targeting monoclonal antibody cetuximab potentiates the effects of oxaliplatin¹² and radiation¹³ by impairing DNA repair. Cetuximab has also been shown to enhance the demonstrated antitumor activity of cisplatin and carboplatin.^14–16 The safety and efficacy of the combination of cetuximab with platinum-based regimens has been demonstrated clinically in other tumor types.^17–19

Although at the molecular level, patients with TNBC comprise a heterogeneous subgroup, in the absence of predictive biomarkers to identify patients who would benefit from cetuximab treatment we investigated all patients with mTNBC.^4,20 Based on the high EGFR expression levels in TNBC, the sensitivity of these tumors to DNA-damaging agents, the observed impairment of DNA repair by cetuximab, and the strong preclinical evidence for a synergistic effect of cetuximab and cisplatin, we performed this randomized phase II study evaluating the efficacy and safety of cisplatin plus cetuximab versus cisplatin alone in patients with mTNBC.

PATIENTS AND METHODS

Patients

Eligible patients were ages 18 years or older with a histologically confirmed diagnosis of metastatic (stage IV) TNBC. ER-negative, PgR-negative, and HER2-negative status were determined locally, and tumor receptor status of the primary lesion was permitted for inclusion. Other main inclusion criteria were: no more than one previous chemotherapeutic regimen for the treatment of metastatic breast cancer, at least one measurable lesion by magnetic resonance imaging or computed tomography according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.0),²¹ Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, and tumor tissue available for EGFR expression assessment. Main exclusion criteria were: prior therapy with a platinum agent or mitomycin; previous exposure to monoclonal antibody therapy, signal transduction inhibitors, or EGFR-targeting therapy; known history of brain metastases; and other cancers except for basal-cell skin carcinoma or preinvasive cervical carcinoma.

The protocol was approved by independent ethics committees of the participating centers and the study was carried out in accordance with the Declaration of Helsinki. All patients provided written informed consent.

Study Design

This open-label, randomized phase II study was conducted in Europe, Australia, and Israel. Eligible patients were randomly assigned in a 2:1 ratio to receive cisplatin with or without cetuximab. Randomization was performed centrally using an Interactive Voice Response System with stratification according to the line of treatment (first or second).

The primary end point was the best overall response rate (ORR), defined as the proportion of patients with a confirmed complete response or partial response according to RECIST version 1. Secondary end points included progression-free survival (PFS), overall survival, time to response, and safety. The rate of disease control, defined as the proportion of patients with a complete response, partial response, or stable disease for at least 6 weeks as best response, was assessed in a post hoc analysis. Planned exploratory subgroup analyses were used to investigate the association between best ORR and baseline patient and disease characteristics and any association between first-cycle acne-like rash and response in patients receiving cisplatin plus cetuximab who were undergoing treatment at day 21.

Treatment and Assessments

In the cisplatin plus cetuximab group, patients were to receive an initial dose of cetuximab (Merck KGaA, Darmstadt, Germany) 400 mg/m² by intravenous infusion followed by 250 mg/m² once weekly. Patients were also to receive intravenous cisplatin 75 mg/m² on day 1, every 3 weeks, for six cycles. Patients benefiting from treatment could continue to receive weekly cetuximab 250 mg/m² alone following the six cycles of cisplatin until first relapse, unacceptable toxicity, or withdrawal of consent.

Patients in the cisplatin-alone group were to receive cisplatin 75 mg/m² on day 1 every 3 weeks for six cycles. On disease progression, patients had the option to switch to cisplatin plus cetuximab as above or cetuximab alone, depending on whether the patient's disease progression was reported during or after the six cisplatin cycles, respectively.

Tumor response was assessed by local investigators every 6 weeks until disease progression according to RECIST version, 1.0. After disease progression, data on survival status and further anticancer treatment use was collected systematically every 3 months after the end of study visit. Adverse events were recorded at treatment visits, the final tumor assessment, and the end of study visit and were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.

ER, PgR, and HER2 expression status was determined by immunohistochemistry of patient tumor sections. The IHC cutoff for ER-negative and PgR-negative status was ≤ 10% of staining in the nuclei. HER2-negative status was less than 3+ by immunohistochemistry (based on staining intensity).²² HER2-negative status was confirmed in 1+ or 2+ expressing cells by fluorescence in situ hybridization analysis (confirming the absence of gene amplification).²³

Statistical Analysis

The statistical analysis was based on the objective of showing superiority of cisplatin plus cetuximab over cisplatin alone in terms of overall response together with showing that the overall response for cisplatin plus cetuximab was above a prespecified clinically relevant threshold of 0.2. Two null hypotheses were tested simultaneously, that is, to test whether the ORR was equal in both treatment groups and to test if the ORR was less than or equal to 20% in the cisplatin plus cetuximab group. The simultaneous null hypothesis would be rejected if both single null hypotheses were rejected. A planned sample size of 180 was based on the following assumptions: an increase of at least 18% in ORR with cisplatin plus cetuximab compared with cisplatin alone (from 14% to 32%); an ORR of more than 20% in the cisplatin plus cetuximab group; 2:1 randomization ratio for cisplatin plus cetuximab versus cisplatin alone; a two-sided α of .10; an 80% power for the rejection of both single null hypotheses; and a 5% dropout rate. A randomization ratio of 2:1 was applied to increase both exposure in the experimental group and the power for testing the ORR in this group against 20%.

Efficacy analyses were performed on the full analysis set. Because of the exploratory nature of the study, all statistical tests used a significance level of α = .10, and no adjustments were made for multiplicity. The ORR in the cisplatin plus cetuximab group was tested against .20 using a one-sided z test at a significance level of α/2 = .05.

Best ORRs were compared using a two-sided Cochran-Mantel-Haenszel test stratified by line of treatment. The odds ratio (cisplatin plus cetuximab v cisplatin alone) between treatment groups and ORR per group are presented with the corresponding 95% CI.

Time-to-event variables were compared using a two-sided log-rank test stratified by line of treatment. Kaplan-Meier curves (except for time to response) and median values with corresponding two-sided 95% CIs are presented. Hazard ratios (cisplatin plus cetuximab v cisplatin alone) were calculated by Cox's proportional hazards model stratified by line of treatment and presented with 95% CI.

Data cutoff times for analyses were 6 months after the last patient had been randomly assigned for best overall response, PFS, and time to response; times for analyses for overall survival were after two thirds of the randomly assigned patients had died.

The safety population included all patients to whom any dose of study treatment was administered. Analysis of safety end points was performed according to the actual treatment received. Adverse events were categorized according to the Medical Dictionary for Regulatory Activities (version 12.0) system organ classes and preferred terms, as well as predefined special adverse event categories in which the preferred terms were pooled.

RESULTS

From June 2007 to February 2009, 181 patients were randomly assigned from 47 sites (Fig 1). Significant deviations from the Good Clinical Practice guidelines were identified at one site that resulted in a lack of credibility of the data and a subsequent mandate from the national health authority to exclude all their eight patients from the analysis. This gave a full analysis set of 173 patients. One hundred and fifteen patients were randomly assigned to receive cisplatin plus cetuximab and 58 were assigned to receive cisplatin alone. Thirty-one (53%) of 57 patients in the cisplatin-alone group switched to cetuximab on disease progression: 21 patients switched to cisplatin plus cetuximab and 10 switched to cetuximab alone. Two patients who did not receive study treatment were excluded from the safety population.

Fig 1.

CONSORT diagram.

In the safety population, the cisplatin plus cetuximab group had a median duration of 13.1 weeks and 13.6 weeks of cetuximab and of cisplatin treatments, respectively. A relative dose intensity of at least 90% for cetuximab and cisplatin was attained in 81 (71%) of 114 patients and 90 (80%) of 113 patients, respectively. The cisplatin-alone group had a median treatment duration of cisplatin of 12.7 weeks. Patients switching to cetuximab after progression had a median treatment duration of cetuximab of 5.9 weeks.

The study groups were well balanced for performance status, line of treatment, and median time to metastasis (Table 1). Overall, the majority of patients had infiltrating ductal carcinoma (150 of 173; 86%), had received study treatment as first-line therapy (126 of 173; 73%), and had an ECOG performance status of 0 (111 of 173; 64%). The patients' median age was 52.0 years. Altogether, 82 (71%) of 115 patients in the cisplatin plus cetuximab group and 35 (60%) of 58 patients in the cisplatin-alone group received anticancer therapy poststudy treatment.

Table 1.

Baseline Patient Characteristics

Characteristic	Cisplatin Plus Cetuximab (n = 115)		Cisplatin Alone (n = 58)
	No. of Patients	%	No. of Patients	%
Age, years
Median	53.0		52
Standard deviation	12.5		10.7
< 65	93	81	51	88
≥ 65	22	19	7	12
ECOG performance status
0	72	63	39	67
1	37	32	17	29
2	6	5	2	3
Line of treatment*
First line	84	73	42	72
Second line	31	27	16	28
Time to metastasis, months†
Median	15.7		15.4
No. of patients	108		55
Interquartile range, Q1-Q3	5.0-26.4		1.8-29.7
Site of metastasis‡
Liver	36	31	17	29
Lung	64	56	26	45
Bone	37	32	20	34
Lymph nodes	49	43	22	38
Skin	20	17	8	14
Other	15	13	9	16
Previous anticancer therapy§	101	88	53	91
Neoadjuvant	46	40	12	21
Adjuvant	75	65	41	71
Local therapy	53	46	26	45
No previous chemotherapy	19	17	10	17
Naturally postmenopausal	64	56	36	62

Abbreviation: ECOG, Eastern Cooperative Oncology Group.

^*According to Interactive Voice Response System.

^†Duration from initial diagnosis to date of metastasis, Q1-Q3 interquartile range (25% quartile to 75% quartile).

^‡Patients could have metastases at more than one site.

^§Patients could have received more than one type of therapy.

The best ORR was 20% (95% CI, 13 to 29; 23 of 115) and 10% (95% CI, 4 to 21; six of 58) in the cisplatin plus cetuximab and cisplatin-alone groups, respectively (odds ratio, 2.13; 95% CI, 0.81 to 5.59; P = .11). Thus, the primary end point was not met (Table 2).

Table 2.

Efficacy of Study Treatment

Response	Cisplatin Plus Cetuximab (n = 115)		Cisplatin Alone (n = 58)
	No. of Patients	%	No. of Patients	%
Complete response	2	2	1	2
Partial response	21	18	5	9
Stable disease	48	42	18	31
Progressive disease	34	30	31	53
Not evaluable	10	9	3	5
Best overall response rate	23	20	6	10
95% CI	13 to 29		4 to 21
Odds ratio*	2.13
95% CI	0.81 to 5.59

NOTE. Complete responses, partial responses, and stable disease were defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0.

^*Stratified Cochran-Mantel-Haenszel test, P = .11.

Median PFS was significantly longer in the cisplatin plus cetuximab group than in the cisplatin-alone group (3.7 months v 1.5 months; hazard ratio [HR], 0.67; 95% CI, 0.47 to 0.97; P = .032; Fig 2A). Median overall survival was 12.9 months in the cisplatin plus cetuximab group and 9.4 months in the cisplatin-alone group (HR, 0.82; 95% CI, 0.56 to 1.20; P = .31; Fig 2B). Median time to response was 1.4 months and 1.3 months in the cisplatin plus cetuximab and cisplatin-alone groups, respectively (HR, 0.75; 95% CI, 0.26 to 2.17; P = .60).

Fig 2.

Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS). (A) Median PFS was significantly longer in patients who received cisplatin plus cetuximab compared with patients who received cisplatin alone (3.7 months [mos] v 1.5 months; hazard ratio [HR], 0.67; 95% CI, 0.47 to 0.97; P = .032). (B) Median OS was 12.9 months in the cisplatin plus cetuximab group and 9.4 months in the cisplatin-alone group (HR, 0.82; 95% CI, 0.56 to 1.20; P = .31).

In the exploratory subgroup analyses regarding ORR, odds ratios in favor of cisplatin plus cetuximab over cisplatin alone seemed highest in postmenopausal patients and in patients receiving study treatment as second-line therapy (Fig 3). Among patients undergoing treatment at day 21 in the cisplatin plus cetuximab group with (n = 64) and without (n = 43) first-cycle acne-like rash, there seemed to be no difference in the ORR (with acne-like rash, 20%; 13 of 64; without acne-like rash, 23%; 10 of 43).

Fig 3.

Odds ratios for best overall response rate in subgroup analyses. ECOG PS, Eastern Cooperative Oncology Group performance status.

All 171 patients experienced at least one adverse event. Altogether, 69 (61%) of 114 patients in the cisplatin plus cetuximab group and 24 (42%) of 57 patients in the cisplatin-alone group experienced at least one grade 3 or 4 adverse event. Grade 3 or 4 adverse events occurring in at least 5% of patients in the cisplatin plus cetuximab or cisplatin-alone groups are listed in Table 3and included neutropenia (11 [10%] of 114 v three [5%] of 57), fatigue (10 [9%] of 114 v four [7%] of 57), dyspnea (seven [6%] of 114 v one [2%] of 57), and acne-like rash (17 [15%] of 114 v 0%). In the cisplatin plus cetuximab group, grade 3 or 4 dyspnea was associated with clinical deterioration and disease progression in all patients. Other grade 3/4 adverse events with cisplatin plus cetuximab and cisplatin alone were sepsis (two [2%] of 114 v 0%), hypertension (four [4%] of 114 v 0%), and hypomagnesemia (four [4%] of 114 v one [2%] of 57). Any grade and grade 3 infusion-related reactions occurred in 15 (13%) of 114 and three (3%) of 114 patients in the cisplatin plus cetuximab group, respectively, and in no patients in the cisplatin-alone group. There were no treatment-related adverse events leading to death.

Table 3.

Grade 3 or 4 Adverse Events

Event	Cisplatin Plus Cetuximab (n = 114)		Cisplatin Alone (n = 57)
	No. of Patients	%	No. of Patients	%
Any grade 3 or 4 event	69	61	24	42
Any grade 4 event	12	11	4	7
Grade 3 or 4 adverse events in ≥ 5% patients in either treatment arm
Neutropeni a	11	10	3	5
Fatigue	10	9	4	7
Dyspnea	7	6	1	2
Nausea	5	4	3	5
Vomiting	5	4	3	5
Asthenia	3	3	3	5
General physical health deterioration	0		3	5
Special adverse events*
Acne-like rash	17	15	0
Infusion-related reaction	3	3	0
Cardiac event (arrhythmia)	0		1	2

^*Special adverse events are of composite categories of preferred terms that were prospectively defined in the study protocol according to Medical Dictionary for Regulatory Activities (MedDRA; version 12); all were grade 3.

DISCUSSION

This randomized phase II study demonstrated that cisplatin plus cetuximab doubled the ORR achieved with cisplatin alone (from 10% to 20%) in patients with mTNBC. The primary end point of the study was not met and this is therefore a negative trial. However, it is possible that this may not accurately represent the true activity of this combination regimen as, unlike other randomized phase II studies, the primary end point was based on two null hypotheses; on the one hand, superiority of the cetuximab arm and, on the other, an ORR of greater than 20%. Therefore, the observed doubling of the ORR with the addition of cetuximab to cisplatin should not be ignored when considering the potential of anti-EGFR agents in mTNBC.

The addition of cetuximab significantly prolonged median PFS from 1.5 months with cisplatin alone to 3.7 months with cisplatin plus cetuximab. There was a nonsignificant improvement in median survival of 3.5 months observed with cisplatin plus cetuximab, although the sample size was small and 31 (53%) of 57 patients in the cisplatin-alone group switched to a cetuximab-containing therapy on disease progression. It is not possible to accurately assess the impact of this cross-over on outcome, as response was not protocol-specified in these patients.

The tolerability profile of cisplatin plus cetuximab was as expected, with no new safety concerns. The more frequent grade 3 or 4 adverse events in the cisplatin plus cetuximab compared with the cisplatin alone group are mainly owing to grade 3 acne-like rash associated with cetuximab, which was generally manageable. In addition, patients in the cisplatin plus cetuximab group had a slightly higher incidence of grade 3 or 4 neutropenia than patients in the cisplatin-alone group as well as some grade 3/4 infusion-related reactions. Infusion-related reactions are a known adverse effect of cetuximab treatment and severe neutropenia or neutropenic complications, such as sepsis, have been noted to occur more frequently in patients receiving cetuximab plus platinum-based therapy compared with platinum-based therapy alone in phase III trials in other tumor types.^18,24,25

Other phase II studies have reported clinical activity for cetuximab in mTNBC, supporting the concept that this may be a worthwhile approach for the treatment of this disease. In a randomized phase II trial conducted by the Translational Breast Cancer Research Consortium (TBCRC 001), in which 54% of patients had received prior chemotherapy for mTNBC, though cetuximab alone (n = 31) demonstrated low activity with a response rate of 6%, the combination of cetuximab and carboplatin (n = 71) led to a response rate of 17% and a clinical benefit rate of 31%.²⁶ In a second study of patients with metastatic breast cancer who were randomly assigned to receive irinotecan followed by carboplatin with or without cetuximab as first- or second-line treatment, among a subgroup of 78 patients with mTNBC, a higher response rate was reported in the group receiving cetuximab (49% v 30%).²⁷ These data suggest that the addition of cetuximab to platinum-based chemotherapy may offer clinical benefit for patients with mTNBC. The data also highlight the importance of an appropriate control group in cetuximab studies. For example, the 18% response rate reported for the combination of cetuximab and carboplatin in TBCRC 001 may appear disappointingly low, particularly when compared with historical data of response rates with platinum salts in mTNBC.^10,11 However, the response rate with the combination is similar to the response rate that was observed in our cetuximab-containing arm and superior to the one observed with cisplatin alone in our study.

A limitation of our study is the unavailability of data from the analysis for predictive biomarkers of cetuximab activity. The identification of patients with tumors most likely to respond to cetuximab is clearly an area deserving intense investigation. A retrospective analysis of data from patients who received subsequent-line cetuximab for colorectal cancer reported that high gene expression levels of the EGFR ligands epiregulin and amphiregulin were found to be associated with improved disease control compared with lower levels.²⁸ In addition, disease control following treatment with cetuximab was significantly higher among patients without tumor mutations in the KRAS gene,²⁸ an observation subsequently confirmed by analyses of other studies of cetuximab in combination with standard first-line therapy.^19,29 In breast cancer, however, the KRAS gene is not frequently mutated³⁰ and so is unlikely to be a useful predictive marker.

In conclusion, the primary end point of the study was not met. However, the addition of cetuximab to cisplatin was associated with a numerical doubling of the response rate and an increase in PFS when compared with cisplatin alone in patients with mTNBC who had received no more than one line of palliative chemotherapy. These results suggest that EGFR may be a suitable target in the treatment of TNBC and that cetuximab might be a potentially important addition to treatment strategies for the management of patients with TNBC. These findings warrant further investigation. Future approaches might include the identification of predictive markers for the treatment with cetuximab and the development of a more active chemotherapy-cetuximab combination regimen in mTNBC.

Appendix

The principal investigator of the BALI-1 study was J. Baselga (Boston, MA). Other investigators include: Austria: R. Greil (Salzburg), G. Steger (Wein), A. Lang (Feidkirch); Belgium: J.-P. Machiels and A. Awada (Brussels), L. Dirix (Wilrijk), J. Vermorken (Edegem), M.-P. Graas (Liège), J.-C. Goeminne (Namur), V. Cocquyt (Gent); Germany: W. Jonat (Kiel), A. Schneeweiss (Heidelberg), M. Kaufmann (Frankfurt), W. Eiermann and V. Heinemann (München), B. Gerber (Rostock), M. Warm (Köln); Ireland: J. Crown and M.J. Kennedy (Dublin); Israel: D. Geffen (Beer Sheba), I. Moshe (Tel Aviv), S. Stemmer (Petach Tiqva), B. Kaufmann (Tel Hashomer), G. Fried (Haifa), N.B. Baruch (Rehovot), B. Klein (Kfar-Saba), A. Salmon (Jerusalem); Italy: P. Pronzato (La Spezia), P. Conte (Modena); Portugal: S. Braga (Lisbon), H. Rodrigues (Porto), A. Pêgo (Coimbra); Spain: P. Gómez (Barcelona), E.M. Ciruelos Gil, A. Gonzalez and R. Colomer (Madrid), A. Lluch, M.A. Climent and M.J. Godes Sanz DeBremond (Valencia), J.I. Mayordomo (Zaragoza), G. Catalan (Palma de Mallorca), M. Garcia (Murcia); United Kingdom: A. Jones (London), A. Wardley (Manchester), P. Barrett-Lee (Cardiff), C.J. Poole (Birmingham), S. Houston (Guildford); Australia: A. Chan (Perth), P. Clingan (Wollongong), G. Richardson (Malren), R. Eek (Liverpool); New Zealand: S. Della-Fiorentina (Cambelltown), A. Simpson (Wellington), H. Winter (Palmerston North), B. Robinson (Christchurch).

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) and/or an author's immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Angela Zubel, Merck KGaA (C); Helena Melezínková, Merck KGaA (C) Consultant or Advisory Role: Richard Greil, Merck KGaA (C) Stock Ownership: None Honoraria: Richard Greil, Merck KGaA Research Funding: None Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: José Baselga, Sofia Braga, Ahmad Awada

Provision of study materials or patients: José Baselga, Patricia Gómez, Richard Greil, Miguel A. Climent, Andrew M. Wardley, Bella Kaufman, Andreas Schneeweiss, Ahmad Awada

Collection and assembly of data: Patricia Gómez, Richard Greil, Miguel A. Climent, Andrew M. Wardley, Bella Kaufman, Salomon M. Stemmer, António Pêgo, Jean-Charles Goeminne, Marie-Pascale Graas, Eva Maria Ciruelos Gil, Andreas Schneeweiss, Angela Zubel, Ahmad Awada

Data analysis and interpretation: José Baselga, Richard Greil, Salomon M. Stemmer, Arlene Chan, M. John Kennedy, Eva Maria Ciruelos Gil, Angela Zubel, Jutta Groos, Helena Melezínková, Ahmad Awada

Manuscript writing: All authors

Final approval of manuscript: All authors