The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 (HER2) –positive metastatic breast cancer (BC) is unknown.

The MA.31 trial compared a combination of first-line anti-HER2 therapy (lapatinib or trastuzumab) and taxane therapy for 24 weeks, followed by the same anti-HER2 monotherapy until progression. Stratification was by prior (neo)adjuvant anti-HER2 therapy, prior (neo)adjuvant taxane, planned taxane, and liver metastases. The primary end point was intention-to-treat (ITT) progression-free survival (PFS), defined as time from random assignment to progression by RECIST (version 1.0) criteria, or death for patients with locally assessed HER2-positive tumors. The primary test statistic was a stratified log-rank test for noninferiority. PFS was also assessed for patients with centrally confirmed HER2-positive tumors.

From July 17, 2008, to December 1, 2011, 652 patients were accrued from 21 countries, resulting in 537 patients with centrally confirmed HER2-positive tumors. Median follow-up was 21.5 months. Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab. By ITT analysis, PFS was inferior for lapatinib compared with trastuzumab, with a stratified hazard ratio (HR) of 1.37 (95% CI, 1.13 to 1.65; P = .001). In patients with centrally confirmed HER2-positive tumors, median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab (HR, 1.48; 95% CI, 1.20 to 1.83; P < .001). More grade 3 or 4 diarrhea and rash were observed with lapatinib (P < .001). PFS results were supported by the secondary end point of overall survival, with an ITT HR of 1.28 (95% CI, 0.95 to 1.72; P = .11); in patients with centrally confirmed HER2-positive tumors, the HR was 1.47 (95% CI, 1.03 to 2.09; P = .03).

As first-line therapy for HER2-positive metastatic BC, lapatinib combined with taxane was associated with shorter PFS and more toxicity compared with trastuzumab combined with taxane.

Amplification or overexpression of human epidermal growth factor receptor (EGFR) 2 (HER2) predicts aggressive breast cancer (BC) behavior and response to anti-HER2 therapy.1 Trastuzumab targets the HER2 receptor and, in combination with chemotherapy, improves outcome for early and metastatic BC.210 Despite impressive gains in tumor control and survival, HER2-positive BC remains a major problem.

Lapatinib, an orally bioavailable small-molecule tyrosine kinase inhibitor that inhibits the activity of HER2 and related tumor receptor HER1 (EGFR), is licensed for use in metastatic HER2-positive BC.11 Phase III studies have demonstrated improved time to progression when combined with capecitabine in the refractory setting and improved overall survival (OS) when added to paclitaxel in the first-line setting.1215 Combined with trastuzumab, there is increased efficacy compared with lapatinib monotherapy,16 and more recent data have demonstrated activity of lapatinib and capecitabine in brain metastases, including the phase II LANDSCAPE study.17 Studies in early BC comparing lapatinib with trastuzumab or with dual therapy (combination or sequence)1820 have been launched based on preclinical and clinical data. We conducted the first randomized trial to our knowledge to directly compare efficacy and safety of lapatinib versus trastuzumab in combination with taxane as first-line therapy in women with HER2-positive metastatic BC.

Study Design

The NCIC Clinical Trials Group (CTG) MA.31 study was a randomized open-label international phase III trial. Patients with HER2-positive metastatic BC were required to have centrally confirmed HER2-positive tumors, although they could be randomly assigned with locally or centrally confirmed tumors. Patients were randomly assigned at a 1:1 ratio to receive either lapatinib plus taxane followed by lapatinib or trastuzumab plus taxane followed by trastuzumab. Enrollment used dynamic minimization,21 stratifying by prior receipt of (neo)adjuvant HER2-targeted therapy (yes v no), (neo)adjuvant taxane chemotherapy (yes v no), planned taxane treatment (paclitaxel once per week v docetaxel once every 3 weeks), and liver metastasis (yes v no).

Taxane choice was discretionary: intravenous paclitaxel 80 mg/m2 once per week on days 1, 8, and 15 of a 28-day schedule or docetaxel 75 mg/m2 once every 3 weeks. The lapatinib dose was 1,250 mg, administered daily orally when combined with taxane for 24 weeks; it was then increased to 1,500 mg daily as monotherapy. To enhance compliance with protocol therapy administration and in keeping with the previously evaluated dosing schedule by Slamon et al,2 intravenous trastuzumab was administered once per week for 24 weeks with once-per-week paclitaxel (4 mg/kg bolus followed by 2 mg/kg maintenance) or on a once-every-3-week basis (8 mg/kg bolus followed by 6 mg/kg maintenance) when combined with docetaxel once every 3 weeks. During monotherapy, patients received trastuzumab 6 mg/kg once every 3 weeks.

Higher-than-anticipated rates of febrile neutropenia and diarrhea with lapatinib led in February 2010 to the requirement of granulocyte colony-stimulating factor (GCSF) for treatment with lapatinib and docetaxel and rigorous diarrhea management guidelines. The protocol is provided in the Data Supplement.

Study Oversight

An international academic steering committee and the faculty at NCIC CTG, in collaboration with GlaxoSmithKline, designed the MA.31 trial. Health regulatory authorities and local ethics review boards approved the protocol and amendments. Data were held and analyzed by the NCIC CTG. The NCIC CTG Data Safety Monitoring Committee reviewed study conduct, safety, and efficacy on a once-every-6-month basis. The manuscript was written with the NCIC CTG central office faculty. All authors contributed to and approved the final manuscript.

Study Patients

Patient eligibility criteria were as follows: HER2-positive metastatic BC, Eastern Cooperative Oncology Group performance status 0 to 2, no prior therapy with cytotoxics or biologics for recurrent or advanced disease, baseline left ventricular ejection fraction (LVEF) ≥ 50% (determined by echocardiography or multiple-gated acquisition scanning), measurable or nonmeasurable disease defined by RECIST (version 1.0) criteria,22 and no major end-organ disease. Prior (neo)adjuvant treatment with anti-HER2 agent and/or taxane was allowed provided the last dose was ≥ 12 months before random assignment. Prior endocrine therapy or radiotherapy was permitted provided ≥ 2 weeks had elapsed from cessation. Brain computed tomography or magnetic resonance imaging was required within 4 weeks before random assignment; patients with brain metastases were ineligible.

Mandated central testing for HER2, estrogen receptor (ER), progesterone receptor (PgR), and other biomarkers (ie, KI67, EGFR, and cytokeratin 5/6) was performed by the Clinical Laboratory Improvement Amendments–certified Centre for Translational and Applied Genomics in Vancouver, British Columbia, Canada.2325 HER2 and ER/PgR results are presented to clinically characterize patients (Data Supplement); detailed biomarker reporting will occur later.

Study End Points

The primary end point was progression-free survival (PFS), defined as time from random assignment to disease progression (PD; as assessed by RECIST [version 1.0] criteria) or death. Patients were censored at the last disease assessment date, at last prior assessment with > one missed visit, or at day 1 without postrandomization assessment (or death before first scheduled assessment).

Secondary end points included OS, defined as time from random assignement to death, with censoring at the date of the longest follow-up. In addition, the incidence of and time to magnetic resonance imaging or computed tomography brain metastases at first PD were assessed, with censoring at day 1 for patients with baseline CNS metastases. Response end points for evaluable patients with ≥ one measurable baseline lesion were overall response rate (ORR; complete [CR] or partial response [PR]); time to response, from random assignment to date of first CR or PR; duration of response, from first CR or PR until PD or death; and clinical benefit response (CBR), defined as the best overall response of CR, PR, or stable disease at 24 weeks. Adverse event (AE) profiles were compiled according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). Quality of life (QOL) was measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 (QLQ-C30); a trial-specific checklist covered treatment-related items not covered by the QLQ-C30, skin rash, and oral versus intravenous administration of anti-HER2 therapy. AE reporting and QOL assessments were scheduled with RECIST assessments.

Assessments

For all patients, RECIST assessments were conducted every 12 weeks until week 96 and then every 24 weeks thereafter. We examined whether outcome was affected by the greater frequency of medical contact experienced by patients receiving trastuzumab during intravenous monotherapy administration with a protocol-specified sensitivity analysis, which reversed the indicator for censored and progressed to assess censoring pattern by trial arm.26 Six other sensitivity analyses examined the effects of different algorithms for dating events and censoring, including one where patients who crossed over to the alternate arm before PD, who were not withdrawn for being off protocol therapy, were censored at last RECIST assessment before crossover. For combination and monotherapy phases, we report mean and median daily doses of lapatinib before PD and, for all drugs, duration of therapy and dose modifications.

Statistical Analysis

The primary analysis was an intention-to-treat (ITT) population examination of whether lapatinib PFS was noninferior to trastuzumab PFS; the null hypothesis was H0:hazard ratio (HR) = 1.25, with the alternative hypothesis of H1:HR = 0.9. However, in designing MA.31, we ensured adequate power in the centrally confirmed HER2-positive group. With 390 PFS events in the HER2-positive population, the study would have 90% power and one-sided alpha of 2.5% for the test of noninferiority. Then, if lapatinib were found noninferior to trastuzumab, we would perform a superiority test, which would have approximately 80% power with two-sided alpha of 5.0% to support H0:HR = 1.0 or to reject in favor of H1:HR = 0.75. Comparisons between arms used the stratified log-rank test, adjusted for stratification factors. Unadjusted analyses were also performed. Graphical depiction was with Kaplan-Meier plots.

The target sample size was 536 patients with centrally confirmed HER2-positive tumors, derived from anticipated 600 ITT patients. The HER2-positive patient data were checked for imbalances in treatment and stratification factors with Fisher's exact test. The protocol-specified per protocol population analysis was not performed because of lapatinib inferiority.

The interim analysis was a two-sided test of superiority using the ITT population, which was planned for when the HER2-positive confirmed population had 50% (n = 195) of the PFS events. The interim analysis occurred when 263 patients with HER2-positive tumors had PFS events. The Lan-DeMets O'Brien-Fleming–type boundary for the final analysis was 0.023147 to maintain noninferiority nominal alpha level of 0.025. We added a stratified Cox multivariable examination of ER and PgR effects on PFS results for patients with HER2-positive disease.

AEs (by Common Terminology Criteria for Adverse Events [version 3.0]) were classified by worst grade (0 to 2 v 3 to 5) after ≥ one treatment dose; effects were compared with Fisher's exact test. AEs are reported if toxicity was grade ≥ 3 or if protocol specified as dose limiting or dose modifying. Liver dysfunction was reported as drug-induced liver injury assessment.

QOL was assessed before PD, classified by treatment received. The primary objective was testing for 12-week treatment differences in mean EORTC QLQ-C30 global score. The t test had 80% power to detect a 10-point mean difference with two-sided alpha of 5%. NCIC CTG standard response analysis27 and exploratory repeated measures longitudinal assessment examined change after baseline.

Study Population

From July 17, 2008, to December 1, 2011, 652 patients were enrolled in 21 countries (326 per arm), resulting in 537 patients with centrally confirmed HER2-positive disease (CONSORT diagram provided in Fig 1). Ninety-seven percent of patients underwent central HER2 review (93% after random assignment). Nine patients receiving lapatinib and five receiving trastuzumab were ineligible for MA.31, including four who had CNS metastases at random assignment. Eleven patients receiving lapatinib and four receiving trastuzumab had no PFS assessment after random assignment. The clinical cutoff for the final analysis was August 1, 2012, with a data lock on February 14, 2013.

Stratification factors and patient characteristics were similar by arm (Table 1). Most patients had Eastern Cooperative Oncology Group performance status of 0 (61%) and no prior (neo)adjuvant anti-HER2 therapy (82%) or taxane therapy (79%) and were ER positive (65%). A total of 42% had metastatic disease at diagnosis; docetaxel therapy was planned in 55% of patients; 46% had liver metastases.

Table

Table 1. Baseline Demographic and Clinical Characteristics of ITT Patient Population

Table 1. Baseline Demographic and Clinical Characteristics of ITT Patient Population

Characteristic LTax/L (n = 326)
TTax/T (n = 326)
Total (N = 652)
No. % No. % No. %
Age at random assignment, years
    ≤ 39 28 9 21 6 49 8
    40-49 71 22 102 31 173 27
    50-59 117 36 110 34 227 35
    60-69 77 24 66 20 143 22
    ≥ 70 33 10 27 8 60 9
    Median 55.4 54.4 54.9
Race
    Missing 0 0 1 0 1 0
    White 246 75 234 72 480 74
    Black or African American 5 2 8 2 13 2
    Native Hawaiian or other Pacific Islander 1 0 0 0 1 0
    Asian 67 21 74 23 141 22
    American Indian or Alaskan Native 4 1 4 1 8 1
    Not reported 1 0 3 1 4 1
    Unknown 2 1 2 1 4 1
ECOG PS
    0 196 60 204 63 400 61
    1 118 36 112 34 230 35
    2 12 4 10 3 22 3
Received prior (neo)adjuvant anti-HER2/neu–targeted therapy 59 18 59 18 118 18
Received prior (neo)adjuvant taxane chemotherapy 65 20 69 21 134 21
Received prior (neo)adjuvant anthracyclines 128 39 140 43 268 41
Received prior (neo)adjuvant other chemotherapy 146 45 161 49 307 47
Prior (neo)adjuvant/metastatic endocrine therapy
    Yes 122 37 127 39 249 38
    No 204 63 198 61 402 62
    Missing 0 0 1 0 1 0
Prior (neo)adjuvant/metastatic radiotherapy
    Yes 138 42 149 46 287 44
    No 187 57 176 54 363 56
    Missing 0 0 1 0 1 0
    Unknown 1 0 0 0 1 0
Prior (neo)adjuvant other therapy
    Yes 5 2 2 1 7 1
    No 321 98 323 99 644 99
    Missing 0 0 1 0 1 0
Planned taxane treatment
    Paclitaxel once per week 146 45 146 45 292 45
    Docetaxel once every 3 weeks 180 55 180 55 360 55
Liver metastases 149 46 150 46 299 46
Disease status
    Metastatic BC at primary diagnosis 138 42 138 42 276 42
    Metastatic BC relapse after curative-intent therapy 187 57 187 57 374 57
    Missing 1 0 1 0 2 0
Metastatic disease measurable 286 88 288 88 574 88
Central review HER2/neu status
    Positive 270 83 267 82 537 82
    Equivocal 9 3 5 2 14 2
    Negative 36 11 46 14 82 13
    Unknown 11 3 8 2 19 3
Central review ER status
    Positive 213 65 208 64 421 65
    Negative 96 29 107 33 203 31
    Missing 17 5 11 3 28 4
Central review PgR status
    Positive 116 36 104 32 220 34
    Negative 190 58 204 63 394 60
    Missing 20 6 18 6 38 6

Abbreviations: BC, breast cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; ITT, intention to treat; LTax/L, lapatinib plus taxane followed by lapatinib; PgR, progesterone receptor; TTax/T, trastuzumab plus taxane followed by trastuzumab.

Median follow-up was 21.5 months. A total of 574 discontinued protocol therapy permanently (Appendix Table A1, online only), a majority because of PD (lapatinib, 70.4%; trastuzumab, 63.4%). Toxicity-related treatment discontinuations were more frequent with lapatinib (15%) than trastuzumab (8%).

Treatment Exposure Data

Patients receiving lapatinib were administered a mean daily dose of 1,106 mg during combination therapy, with 25% requiring dose modification (Table 2), and a mean daily dose of 1,342 mg during monotherapy, with 10% requiring dose modification. Among patients receiving trastuzumab, 23% and 3% required dose modification during combination therapy and monotherapy, respectively. Docetaxel modifications occurred in 46% of patients receiving lapatinib and 40% receiving trastuzumab. Paclitaxel modifications occurred in 62% of patients receiving lapatinib and 57% receiving trastuzumab. Using the ITT population as the denominator, 22% of the lapatinib arm and 28% of the trastuzumab arm went off protocol therapy for reasons other than PD or death (Appendix Table A1, online only). Drug compliance was 75% for lapatinib in the combination phase and 90% in the monotherapy phase. Compliance with trastuzumab was 77% in the combination phase and 97% in the monotherapy phase.

Table

Table 2. Treatment Compliance Before Disease Progression*

Table 2. Treatment Compliance Before Disease Progression*

Characteristic Lapatinib Arm (n = 322)
Trastuzumab Arm (n = 325)
Lapatinib Paclitaxel Docetaxel Trastuzumab Paclitaxel Docetaxel
Anti-HER2/neu

Treatment duration, weeks
    Median 36.6 36.4
    Range 0.1 to 167.9 0.0 to 186.0
Combination therapy
    Daily dose, mg
        Median 1,250.0
        Range 250.0 to 1,500.0
    No. of doses
        Median 8
        Range 1 to 27
    Patients with ≥ one dose modification, % 25 23
Monotherapy
    Daily dose, mg
        Median 1,500.0
        Range 750.0 to 1,750.0
    No. of doses
        Median 9
        Range 1 to 53
    Patients with ≥ one dose modification, % 10 3

Taxane

Paclitaxel
    No. of cycles
        Median 6 6
        Range 1 to 6 1 to 7
    Patients receiving all 18 doses, % 71 82
    Patients receiving ≤ eight doses/< 50% planned, % 14 7
    Patients with dose modifications, % 62 57
Docetaxel
    No. of cycles
        Median 8 8
        Range 1 to 8 1 to 8
    Patients receiving all eight doses, % 72 78
    Patients receiving ≤ three doses/< 50% planned, % 14 10
    Patients with dose modifications, % 46 40

Abbreviation: HER2, human epidermal growth factor receptor 2.

*Patients received some treatment, as treated allocations.

†Includes data from one lapatinib-treated patient from June 22, 2012, to August 1, 2012, after commencement of open-label trastuzumab on June 22, 2012.

PFS

At the interim analysis, lapatinib had inferior PFS compared with trastuzumab (HR, 1.33; 95% CI, 1.06 to 1.67; P = .01)28,29; the NCIC CTG Data Safety Monitoring Committee recommended external disclosure and notification of patients. Continued data collection allowed for a final analysis, when 395 patients with centrally confirmed HER2-positive disease had experienced PFS events. At the protocol-specified final analysis, the ITT median PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab (stratified HR, 1.37; 95% CI, 1.13 to 1.65; P = .001; Fig 2; centrally confirmed HER2 positive: Appendix Fig A1, online only). Noninferiority was excluded, because the upper bound of the 95% CI exceeded the noninferiority margin of 1.25. Sensitivity analyses did not indicate an effect of schedule on outcome (Appendix Table A2, online only). In neither the ITT nor centrally confirmed HER2-positive population did adjusting for ER or PgR have a substantive impact on treatment effect (ITT: HR of lapatinib to trastuzumab, 1.41; 95% CI, 1.16 to 1.71; P = .001). In patients with centrally confirmed HER2-positive disease, higher values of continuous ER were associated with better PFS (P = .04); PgR was not associated with PFS (P = .45); neither factor had a significant interaction with treatment (P = .14 and .79, respectively). De novo stage IV disease did not affect PFS (ITT univariable stratified log-rank P = .57).

OS

More deaths (ITT) occurred in the lapatinib arm compared with the trastuzumab arm (102 v 82), as well as in the confirmed HER2-positive population (84 v 56). Median OS was not observed. In the ITT population, patients receiving lapatinib did not have significantly different OS from those receiving trastuzumab (HR, 1.28; 95% CI, 0.95 to 1.72; P = .11; Fig 3). Among patients with centrally confirmed HER2-positive disease, those receiving lapatinib had worse OS (stratified HR, 1.47; 95% CI, 1.03 to 2.09; P = .03; Appendix Fig A2, online only).

CNS Metastases

Four patients were ineligible, with baseline CNS metastases; CNS metastases at first progression for the ITT population were 18% for the lapatinib group versus 24% for the trastuzumab group (Appendix Table A3, online only). The HER2-positive population incidence was 20% for lapatinib and 28% for trastuzumab. The ITT-stratified HR for time to CNS metastasis as first site of PD (lapatinib v trastuzumab) was 1.13 (95% CI, 0.74 to 1.73; P = .58) for the ITT population; patients with HER2-positive disease had similar results (P = .68).

Response

ORR was assessed in 257 ITT patients receiving lapatinib and 270 receiving trastuzumab, with responses seen in 139 (54%) in the lapatinib group and 148 (55%) in the trastuzumab group. ITT CBR was 75.8% for lapatinib and 75.9% for trastuzumab. Patients with centrally confirmed HER2-positive disease had similar ORR and CBR results.

QOL

In the primary QOL analysis, patients receiving lapatinib experienced a 2.74 lower mean 12-week EORTC QLQ-C30 global score than those receiving trastuzumab (P = .25); mean patient change at 12 weeks was 0.30 (standard deviation, 24.74) for lapatinib and 2.45 (standard deviation, 20.61) for trastuzumab (P = .57). Mean change in EORTC QLQ-C30 global score between arms was not significantly different in the combination-therapy period, from baseline to 24 weeks. Lapatinib-treated patients had significantly worse QLQ-C30 scores for diarrhea (P < .001), appetite loss (P = .03), social function (P = .04), and trial-specific checklist skin rash (P = .001) than trastuzumab-treated patients.

Toxicity

A total of 647 patients were included in the safety analyses. Table 3 lists AEs of note (ie, grade ≥ 3 or protocol prespecified as dose limiting or dose modifying). Incidences of rash and diarrhea were higher in the lapatinib arm, but most were grade 1 or 2. During combination therapy, grade 3 or 4 rash occurred in 8% of patients receiving lapatinib compared with 0% of those receiving trastuzumab (P < .001), and grade 3 or 4 diarrhea was reported in 19% of those receiving lapatinib compared with 1% of those receiving trastuzumab (P < .001). With 188 patients enrolled, higher febrile neutropenia rates were seen with lapatinib plus docetaxel (17.3%) compared with trastuzumab plus docetaxel (2.0%). The protocol was modified to mandate prophylactic GCSF in patients receiving lapatinib plus docetaxel; similar febrile neutropenia incidence were then seen in both arms (P = .17).

Table

Table 3. Adverse Events

Table 3. Adverse Events

Adverse Event Lapatinib Arm (n = 322)
Trastuzumab Arm (n = 325)
P
Grade*
Grade*
1 to 2 3 to 5 Total
1 to 2 3 to 5 Total
No. % No. %
Combination Therapy Phase of Acute Therapy

Allergy
    Allergic reaction 25 6 31 10 39 4 43 13 .544
Cardiac (general)
    Left ventricular diastolic dysfunction 0 0 0 0 1 1 2 1 1.000
    Left ventricular systolic dysfunction 6 1§ 7 2 12 1 13 4 1.000
Dermatology/skin
    Rash 169 26 186 58 113 0 113 35 .000
    Ulceration 8 0 8 2 2 1 3 1 1.000
GI
    Diarrhea 194 60 254 79 122 4 126 39 .000
    Nausea 146 7 153 48 131 4 135 42 .382
    Vomiting 86 10 96 30 59 6 65 20 .324
Hepatobiliary/pancreas
    Liver dysfunction 0 0 0 0 1 0 1 0
    Hepatobiliary (other) 1 0 1 0 1 0 1 0
Infection
    Febrile neutropenia 0 17 17 5 0 10 10 3 .174
Lymphatics
    Edema (limb) 77 4 81 25 104 3 107 33 .724
Neurology
    Neuropathy (sensory) 161 3 164 51 154 5 159 49 .725
Pain
    Joint 68 1 69 21 69 7 76 23 .069
    Muscle 71 5 76 24 72 1 73 22 .122
Pulmonary/upper respiratory
    ARDS 0 0 0 0 0 1 1 0 1.000
    Pneumonitis 2 4 6 2 2 2 4 1 .449

Monotherapy Phase of Acute Therapy

Cardiac (general)
    Left ventricular systolic dysfunction 8 0 8 2 15 1 16 5 1.000
    Right ventricular dysfunction 0 0 0 0 0 1 1 0 1.000
Dermatology/skin
    Rash 79 5 84 26 39 0 39 12 .030
GI
    Diarrhea 93 3 96 30 24 2 26 8 .685
    Nausea 39 39 12 25 2 27 8 .499
    Vomiting 16 16 5 14 3 17 5 .249
Hepatobiliary/pancreas
    Liver dysfunction 2 0 2 1 1 0 1 0
    Hepatobiliary (other) 0 0 0 0 1 1 2 1 1.000
Pain
    Joint 30 2 32 10 50 4 54 17 .686
    Muscle 23 1 24 7 27 27 8 .498
Pulmonary/upper respiratory
    Pneumonitis 2 0 2 1 2 2 4 1

Delayed Therapy

Cardiac (general)
    Left ventricular systolic dysfunction 1 1 2 1 5 3 8 2 .624

Abbreviation: ARDS, —acute respiratory distress syndrome.

*Adverse events graded according to Common Toxicity Criteria (version 3.0).

P value is based on Fisher's exact test for differences between arms (grade 0 to 2 v 3 to 5).

‡Selected treatment-related adverse events grade ≥ 3 or dose limiting by protocol criteria during acute therapy (combination therapy or monotherapy), and delayed therapy (after protocol therapy, including data from one laptinib-treated patient from June 22, 2012, to August 1, 2012, after commencement of open-label trastuzumab on June 22, 2012). Organ-specific reporting of adverse event data where there was incidence of any-grade toxicity ≥ 5% in ≥ one trial arm is publically available for MA.31 trial.28

§Grade 5.

An absolute decrease in LVEF of ≥ 20% measured by multiple-gated acquisition scans or echocardiograms was reported in 2.3% of patients in the trastuzumab arm and no patients receiving lapatinib (Appendix Table A4, online only). No cardiac-related deaths were reported that were attributed to therapy. One patient in the experimental arm with heart failure attributed to pre-existing factors had multiple AEs (vomiting, diarrhea, febrile neutropenia, and supraventricular arrythmias) and died shortly after discontinuing protocol therapy.

The NCIC CTG MA.31 trial was the first head-to-head comparison to our knowledge of trastuzumab and lapatinib in locally determined metastatic HER2-positive BC, with separate analysis for centrally determined HER2-positive disease. The combination of lapatinib and taxane was inferior for PFS, with OS results in the centrally confirmed HER2-positive population directionally similar to PFS results. Eighty-two percent of our population did not receive anti-HER2 therapy in the adjuvant setting. Our results support the use of trastuzumab over lapatinib in the HER2 treatment–naive first-line metastatic setting. Recently, a number of HER2 receptor–targeted therapies have shown activity in advanced disease.30,31 Research is ongoing regarding optimal combinations of these agents in the adjuvant setting, and it is noteworthy that the combination of lapatinib and trastuzumab did not significantly improve disease-free survival compared with trastuzumab in women with early HER2-positive BC.32 Access to the drugs varies internationally, and many patients are still being offered at best only older anti-HER2 treatments.

Presentation with stage IV HER2-positive disease has been associated with better outcome compared with relapsed HER2-positive cancer.30,31 This group comprised 43% of our patients, likely because of the international nature of the study conduct, associated variations in medical access and care, and aggressive biology of HER2-positive BC. Correlative scientific work may indicate factors associated with resistance to either agent.

Taxane therapy was paclitaxel once per week or docetaxel once every 3 weeks. Our docetaxel dose of 75 mg/m2 was lower than the approved single-agent dose, reflecting usual clinical practice; however, the 75-mg/m2 dose was tolerable in combination with daily oral lapatinib. Prophylactic use of GCSF was required because of high rates of febrile neutropenia.

This was an open-label study, and the primary end point was PFS. Investigator-reported clinical and radiologic assessments were performed every 12 weeks during both MA.31 combined therapy and monotherapy. However, after 24 weeks of taxane therapy, patients in the trastuzumab arm had more frequently scheduled encounters with medical personnel, with intravenous dosing every 3 weeks, compared with their counterparts receiving oral lapatinib. The primary results and extensive sensitivity analyses did not support a bias in favor of lapatinib; for both treatments, patients had similar baseline characteristics, including measurable and nonmeasurable disease and similar treatment exposures to anti-HER2 therapy and taxane. Also, the other end points of ORR and OS would not have been affected by such an imbalance and provided directionally similar results. Lapatinib was inferior to trastuzumab.

The frequency of CNS metastases was 6% to 8% lower with lapatinib; however, this difference was nonsignificant, possibly because of the low rate of CNS scans at PD despite being mandated by the protocol, low frequency of CNS events, size of the study, or PD in other sites. Other studies may provide further information about the activity of lapatinib in this setting.34

There was increased frequency of diarrhea and rash in the lapatinib arm, both expected toxicities. Decreases of ≥ 20% in LVEF, although infrequent, were seen only in the trastuzumab arm. EORTC QLQ C-30 global QOL was not significantly different between arms at 12 weeks, although patients receiving lapatinib had significantly worse toxicity for some instrument scales, with increased diarrhea, appetite loss, social functioning, and skin rash. The lack of global score difference was maintained during the 24-week combination therapy period, perhaps suggesting that the QOL differences were related to toxicities that could be successfully treated or that the global score lacks sensitivity.

In summary, the combination of lapatinib and taxane was associated with inferior PFS and more toxicity compared with trastuzumab and taxane in first-line metastatic BC. OS was worse with lapatinib in the confirmed HER2-positive group. This has implications for the treatment of patients with advanced HER2-positive BC, where dual therapy or newer agents are not available but where the older agents or biosimilars may be available and affordable.18,19,30,33 Limited access to new treatments is a reality for many women globally.

© 2015 by American Society of Clinical Oncology

See accompanying editorial on page 1530 and article on page 1564

Supported by the NCIC Clinical Trials Group through grant support from the Canadian Cancer Society Research Institute and GlaxoSmithKline.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Presented in interim analysis form at the 48th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2012.

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

Clinical trial information: NCT00667251.

Disclosures provided by the authors are available with this article at www.jco.org.

Conception and design: Karen A. Gelmon, Frances M. Boyle, Bella Kaufman, Julie Lemieux, Samuel Aparicio, Lois E. Shepherd, Susan L. Ellard, Kathleen I. Pritchard, Timothy J. Whelan, Judith-Anne W. Chapman, Wendy R. Parulekar

Provision of study materials or patients: Karen A. Gelmon, Frances M. Boyle, Bella Kaufman, Miguel Martin, Susan L. Ellard, Katia Tonkin, Timothy J. Whelan, Arnd Nusch, Robert E. Coleman

Collection and assembly of data: Karen A. Gelmon, Frances M. Boyle, David G. Huntsman, Miguel Martin, Julie Lemieux, Lois E. Shepherd, Dora Nomikos, Arnd Nusch, Hirofumi Mukai, Sergei Tjulandin, Shulamith Rizel, Anne P. Connor, Judith-Anne W. Chapman, Wendy R. Parulekar

Data analysis and interpretation: Karen A. Gelmon, Frances M. Boyle, Bella Kaufman, David G. Huntsman, Alexey Manikhas, Angelo Di Leo, Miguel Martin, Lee S. Schwartzberg, Julie Lemieux, Samuel Aparicio, Lois E. Shepherd, Susan Dent, Katia Tonkin, Kathleen I. Pritchard, Dora Nomikos, Robert E. Coleman, Sergei Tjulandin, Rustem Khasanov, Sergio L. Santillana, Judith-Anne W. Chapman, Wendy R. Parulekar

Manuscript writing: All authors

Final approval of manuscript: All authors

1. HJ Burstein : The distinctive nature of HER2 positive breast cancer N Engl J Med 353: 16521654,2005 Crossref, MedlineGoogle Scholar
2. DJ Slamon, B Leyland-Jones, S Shak , etal: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 N Engl J Med 344: 783792,2001 Crossref, MedlineGoogle Scholar
3. M Marty, F Cognetti, D Maraninchi , etal: Randomized phase II of the efficacy and safety of trastuzumab combined with docetaxel in patients with epidermal growth factor receptor 2–positive metastatic breast cancer administered as first line treatment: The M77001 study group J Clin Oncol 23: 42654274,2005 LinkGoogle Scholar
4. N Robert, B Leyland-Jones, L Asmar , etal: Randomized phase III study of trastuzumab, paclitaxel and carboplatin compared with trastuzumab and paclitaxel in women with HER2-overexpressing metastatic breast cancer J Clin Oncol 24: 27862792,2006 LinkGoogle Scholar
5. V Valero, J Forbes, MD Pegram , etal: Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2 gene–amplified metastatic breast cancer (BCIRG 007 study): Two highly active therapeutic regimens J Clin Oncol 29: 149156,2011 LinkGoogle Scholar
6. MJ Piccart-Gebhart, M Proctor, B Leyland-Jones , etal: Trastuzumab after adjuvant chemotherapy in HER2 positive breast cancer N Engl J Med 353: 16591672,2005 Crossref, MedlineGoogle Scholar
7. EH Romond, EA Perez, J Bryant , etal: Trastuzumab plus adjuvant chemotherapy for operable HER2 positive breast cancer N Engl J Med 353: 16731684,2005 Crossref, MedlineGoogle Scholar
8. H Joensuu, PL Kellokumpu-Lehtinen, P Bono , etal: Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer N Engl J Med 354: 809820,2006 Crossref, MedlineGoogle Scholar
9. I Smith, P Marion, RD Gelber , etal: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2 positive breast cancer: A randomized controlled trial Lancet 369: 2936,2007 Crossref, MedlineGoogle Scholar
10. D Slamon, W Eiermann, N Robert , etal: Adjuvant trastuzumab in HER2-positive breast cancer N Engl J Med 365: 12731283,2011 Crossref, MedlineGoogle Scholar
11. NL Spector, W Xia, H Burris 3rd , etal: Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies J Clin Oncol 23: 25022512,2005 LinkGoogle Scholar
12. CE Geyer, J Forster, D Lindquist , etal: Lapatinib plus capecitabine for HER2 positive advanced breast cancer N Engl J Med 355: 27332743,2006 Crossref, MedlineGoogle Scholar
13. D Cameron, M Casey, M Press , etal: A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: Updated efficacy and biomarker analyses Breast Cancer Res Treat 112: 35333543,2008 CrossrefGoogle Scholar
14. A Di Leo, HL Gomez, Z Aziz , etal: Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer J Clin Oncol 26: 55445552,2008 LinkGoogle Scholar
15. Z Guan, B Xu, ML Desilvio , etal: Randomized trial of lapatinib versus placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2–overexpressing metastatic breast cancer J Clin Oncol 31: 19471953,2013 LinkGoogle Scholar
16. KL Blackwell, HJ Burstein, AM Storniolo , etal: Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2–positive metastatic breast cancer: Final results from the EGF104900 Study J Clin Oncol 30: 25852592,2012 LinkGoogle Scholar
17. T Bachelot, G Romieu, M Campone , etal: Laptinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): A single-group phase 2 study Lancet Oncol 14: 6471,2013 Crossref, MedlineGoogle Scholar
18. J Baselga, I Bradbury, H Eidtmann , etal: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): A randomised, open-label, multicentre, phase 3 trial Lancet 379: 633640,2012 Crossref, MedlineGoogle Scholar
19. M Untch, S Loibl, J Bischoff , etal: Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane based chemotherapy (GeparQuinto, GBG 44): A randomized phase 3 trial Lancet Oncol 13: 135144,2012 Crossref, MedlineGoogle Scholar
20. BIG 2-06/N063D ALTTO (Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation) Study https://clinicaltrials.gov/ct2/show/NCT00490139 Google Scholar
21. D Tu : SC Chow Minimization procedure Encyclopedia of Biopharmaceutical Statistics 795798,2010 ed 3 New York, NY Marcel Dekker CrossrefGoogle Scholar
22. P Therasse, SG Arbuck, EA Eisenhauer , etal: New guidelines to evaluate the response to treatment in solid tumors (RECIST guidelines) J Natl Cancer Inst 92: 205216,2000 Crossref, MedlineGoogle Scholar
23. AC Wolff, ME Hammond, JN Schwartz , etal: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer J Clin Oncol 25: 118145,2007 LinkGoogle Scholar
24. DG Altman, LM McShane, W Sauerbrei , etal: Reporting recommendations for Tumor Marker Prognostic Studies (REMARK): Explanation and elaboration PLoS Med 9: e1001216,2012 Crossref, MedlineGoogle Scholar
25. ME Hammond, DF Hayes, M Dowsett , etal: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer J Clin Oncol 28: 27842795,2010 LinkGoogle Scholar
26. AG DiRienzo, SW Lagakos : Bias correction for score tests arising from misspecified proportional hazard regression models Biometrika 88: 421434,2001 CrossrefGoogle Scholar
27. D Osoba, G Rodrigues, J Myles , etal: Interpreting the significance of changes in health-related quality-of-life scores J Clin Oncol 16: 139144,1998 LinkGoogle Scholar
28. Chemotherapy and Lapatinib or Trastuzumab in Treating Women With HER2/neu-Positive Metastatic Breast Cancer http://clinicaltrials.gov/ct2/show/results/NCT00667251?sect = X40156#othr Google Scholar
29. K Gelmon, F Boyle, B Kaufman , etal: Open-label phase III randomized controlled trial comparing taxane-based chemotherapy (Tax) with lapatinib (L) or trastuzumab (T) as first-line therapy for women with HER2+ metastatic breast cancer: Interim analysis (IA) of NCIC CTG MA. 31/GSK EGF 108919 J Clin Oncol 30,2012 suppl abstr LBA671 MedlineGoogle Scholar
30. J Baselga, J Cortés, SB Kim , etal: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer N Engl J Med 366: 109119,2012 Crossref, MedlineGoogle Scholar
31. S Verma, D Miles, L Gianni , etal: Trastuzumab emtansine for HER2 positive advanced breast cancer N Engl J Med 367: 17831791,2012 Crossref, MedlineGoogle Scholar
32. MJ Piccart-Gebhart, AP Holmes, J Baselga , etal: First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC) J Clin Oncol 32: 4s,2014 suppl abstr LBA4 Google Scholar
33. S Dawood, K Broglio, J Ensor , etal: Survival differences among women with de novo stage IV and relapsed breast cancer Ann Oncol 21: 21692174,2010 Crossref, MedlineGoogle Scholar
34. X Pivot, V Semiglazov, B Zurawsky , etal: CEREBAL(EGF111438): An open label randomized phase III study comparing the incidence of CNS metastases in patients(pts) with HER2+ metastatic breast cancer (MBC), treated with lapatinib plus capecitabine (LC) versus trastuzumab plus capecitabine (TC) Ann Oncol 23: ixe1ixe30,2012 suppl 9 Google Scholar
Glossary Terms
docetaxel:

a member of the taxane group of antimitotic chemotherapy medications whose mode of action is to bind and stabilize microtubules and thus disrupt cell division.

HER2/neu (human epidermal growth factor receptor 2):

also called ErbB2. HER2/neu belongs to the epidermal growth factor receptor (EGFR) family and is overexpressed in several solid tumors. Like EGFR, it is a tyrosine kinase receptor whose activation leads to proliferative signals within the cells. On activation, the human epidermal growth factor family of receptors are known to form homodimers and heterodimers, each with a distinct signaling activity. Because HER2 is the preferred dimerization partner when heterodimers are formed, it is important for signaling through ligands specific for any members of the family. It is typically overexpressed in several epithelial tumors.

lapatinib:

a dual tyrosine kinase inhibitor. Lapatinib has been developed as an inhibitor of the tyrosine kinase activities of ErbB1 (EGFR) and ErbB2. Like other tyrosine kinase inhibitors, it competes with ATP binding to the intracellular regions of the receptors that are activated after tyrosine phosphorylation.

overall survival:

the duration between random assignment and death.

progression-free survival:

time from random assignment until death or first documented relapse, categorized as either locoregional (primary site or regional nodes) failure or distant metastasis or death.

RECIST (Response Evaluation Criteria in Solid Tumors):

a model proposed by the Response Evaluation Criteria Group by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment.

trastuzumab:

a humanized anti-ErbB2 monoclonal antibody approved for treating patients whose breast cancers overexpress the ErbB2 protein or demonstrate ErbB2 gene amplification. It is currently being tested in combination with other therapies.

Lapatinib or Trastuzumab Plus Taxane Therapy for Human Epidermal Growth Factor Receptor 2–Positive Advanced Breast Cancer: Final Results of NCIC CTG MA.31

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.

Karen A. Gelmon

Consulting or Advisory Role: Novartis, Roche/Genentech, Pfizer, GlaxoSmithKline

Frances M. Boyle

Consulting or Advisory Role: Roche, Pfizer, Eisai

Bella Kaufman

Consulting or Advisory Role: Roche, AstraZeneca, Novartis, Pfizer, Teva, Abvvie

Speakers' Bureau: Roche, AstraZeneca, Pfizer

Travel, Accommodations, Expenses: Medison, Novartis, Roche, Teva

David G. Huntsman

No relationship to disclose

Alexey Manikhas

No relationship to disclose

Angelo Di Leo

Honoraria: Roche, Novartis, Pfizer, AstraZeneca, Genomic Health, Eisai

Consulting or Advisory Role: Roche, Novartis, Pfizer, AstraZeneca, Pierre Fabre

Travel, Accommodations, Expenses: Roche, Novartis, Pfizer, AstraZeneca, Eisai

Miguel Martin

Honoraria: Roche/Genentech, GlaxoSmithKline

Consulting or Advisory Role: Roche, GlaxoSmithKline

Speakers' Bureau: Roche, GlaxoSmithKline

Lee S. Schwartzberg

Leadership: Vector Oncology

Consulting or Advisory Role: Eisai, Teva, Amgen

Speakers' Bureau: Eisai, Genentech, Novartis

Research Funding: Eisai

Julie Lemieux

Honoraria: Roche

Travel, Accommodations, Expenses: Roche

Samuel Aparicio

No relationship to disclose

Lois E. Shepherd

No relationship to disclose

Susan Dent

Consulting or Advisory Role: Roche, Amgen

Travel, Accommodations, Expenses: Celgene

Susan L. Ellard

Stock or Other Ownership: Pfizer, GlaxoSmithKline

Katia Tonkin

Honoraria: Roche, Amgen, GlaxoSmithKline

Consulting or Advisory Role: GlaxoSmithKline, Roche, Novartis, Amgen

Research Funding: Amgen (Inst)

Travel, Accommodations, Expenses: Roche, Amgen, Novartis, GlaxoSmithKline

Kathleen I. Pritchard

Honoraria: Roche, Novartis, Pfizer, Celgene

Consulting or Advisory Role: Roche, Novartis, Pfizer

Speakers' Bureau: Novartis

Research Funding: GlaxoSmithKline (Inst), Novartis (Inst), AstraZeneca (Inst), Eisai (Inst)

Travel, Accommodations, Expenses: Novartis, AstraZeneca

Timothy J. Whelan

No relationship to disclose

Dora Nomikos

No relationship to disclose

Arnd Nusch

No relationship to disclose

Robert E. Coleman

Expert Testimony: Novartis

Hirofumi Mukai

Honoraria: Chugai Pharma, AstraZeneca, Eisai, Novartis, Daiichi Sankyo, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical

Research Funding: Chugai Pharma (Inst), Daiichi Sankyo (Inst), Eisai (Inst), Nippon Kayaku (Inst), Novartis (Inst), Pfizer (Inst), sanofi-aventis (Inst)

Sergei Tjulandin

Speakers' Bureau: AstraZeneca, Pfizer, Eisai, sanofi-aventis

Research Funding: AstraZeneca

Rustem Khasanov

No relationship to disclose

Shulamith Rizel

No relationship to disclose

Anne P. Connor

Employment: GlaxoSmithKline

Stock or Other Ownership: GlaxoSmithKline

Sergio L. Santillana

Employment: GlaxoSmithKline, Takeda Pharmaceuticals

Stock or Other Ownership: GlaxoSmithKline, Takeda Pharmaceuticals

Travel, Accommodations, Expenses: GlaxoSmithKline, Takeda Pharmaceuticals

Judith-Anne W. Chapman

No relationship to disclose

Wendy R. Parulekar

No relationship to disclose

Table

Table A1. Off-Protocol Treatment for Treated Patients

Table A1. Off-Protocol Treatment for Treated Patients

Reason LTax/L (n = 287)
TTax/T (n = 287)
No. % No. %
Death 6 2.1 11 3.8
Intercurrent illness 5 1.7 6 2.1
Progressive disease 202 70.4 182 63.4
Toxicity 43 15.0 22 7.7
Refused treatment 7 2.4 4 1.4
Symptomatic progression 7 2.4 3 1.0
Other* 17 5.9 59 20.6

Abbreviations: LTax/L, lapatinib plus taxane followed by lapatinib; TTax/T, trastuzumab plus taxane followed by trastuzumab.

*Most patients in this category went off protocol therapy before progression when trial closed; more patients in LTax/L group experienced progression than in TTax/T group.

Table

Table A2. Protocol-Specified and New Emergent PFS Sensitivity Analyses of Treatment Effect*

Table A2. Protocol-Specified and New Emergent PFS Sensitivity Analyses of Treatment Effect*

Sensitivity Analysis Stratified HR (LTax/L to TTax/T) 95% CI P
1. Progression assigned to next RECIST
    ITT 1.392 1.154 to 1.680 < .001
    HER2/neu positive 1.529 1.239 to 1.887 < .001
2. Reversal of censoring/progression
    ITT 1.157 0.826 to 1.620 .40
    HER2/neu positive 1.089 0.756 to 1.568 .65
3. Censored at last RECIST with anticancer therapy
    ITT 1.400 1.155 to 1.696 < .001
    HER2/neu positive 1.513 1.222 to 1.873 < .001
4. Censored at last RECIST with anticancer therapy or treatment discontinuation
    ITT 1.378 1.118 to 1.698 .0027
    HER2/neu positive 1.471 1.165 to 1.858 .0012
5. Event at last RECIST with anticancer therapy or treatment discontinuation
    ITT 1.304 1.078 to 1.578 .0062
    HER2/neu positive 1.383 1.119 to 1.709 .0027
6. Patient crossover censored at last RECIST§
    ITT 1.341 1.107 to 1.624 .0027
    HER2/neu positive 1.442 1.165 to 1.786 < .001
7. Patient not censored with > one missed visit
    ITT 1.366 1.134 to 1.646 .001
    HER2/neu positive 1.488 1.209 to 1.832 < .001

Abbreviations: HER2, human epidermal growth factor receptor 2; HR, hazard ratio; ITT, intention to treat; LTax/L, lapatinib plus taxane followed by lapatinib; PFS, progression-free survival; TTax/T, trastuzumab plus taxane followed by trastuzumab.

*Includes data from one lapatinib-treated patient from May 4, 2012, to August 1, 2012, after commencement of open-label trastuzumab on June 22, 2012.

†Sensitivity analyses 1 and 3 to 7 examined effects of timing of events and censoring on results; all indicated that LTax/L is inferior to TTax/T. Sensitivity analysis 2 indicated no significant difference in censoring between LTax/L and TTax/T.

P value is two-sided stratified log-rank test statistic.

§This sensitivity analysis was prespecified in final statistical analysis plan to account for potential that patients had crossed over to other treatment arm, either during trial conduct or because of data safety monitoring committee–recommended trial closure. Only one patient crossed over from lapatinib to trastuzumab.

Table

Table A3. CNS Metastasis at First Progression by ITT Allocation

Table A3. CNS Metastasis at First Progression by ITT Allocation

CNS Metastasis Lapatinib* Trastuzumab
ITT population progressions or deaths
    Yes 256 231
    No 70 95
        No post–random assignment evaluation 11 4
CNS metastasis at first ITT progression
    Total No. of first ITT progressions 242 219
    Yes 44 52
    No 134 105
    Unknown 64 62
Incidence rate of CNS metastasis at first progression§ 0.18 0.24
Central HER2/neu-positive progressions or deaths
    Yes 214 181
    No 56 86
        No post–random assignment evaluation 9 2
CNS metastasis at first central HER2/neu-positive progression
    Total No. of first central HER2/neu-positive progressions 202 172
    Yes 40 48
    No 111 80
    Unknown 51 44
Incidence rate of CNS metastasis at first progression§ 0.20 0.28

Abbreviations: CT, computed tomography; HER2, human epidermal growth factor receptor 2; ITT, intention to treat; MRI, magnetic resonance imaging.

*Includes data from one lapatinib-treated patient from May 4, 2012, to August 1, 2012, after commencement of open-label trastuzumab on June 22, 2012.

†Progression was defined by RECIST (version 1.0) disease progression or death resulting from any cause; patients were censored at time of last evaluation of disease or on day 1 if there was no post–random assignment evaluation (or death before first evaluation).

‡Four patients included in ITT assessment had CNS metastases at random assignment and were ineligible for trial and evaluation of CNS metastases; they were censored at date of random assignment (+1 day). Progression was determined radiologically by scan. CNS metastasis at first progression was determined with CT/MRI brain scan, so patients who did not undergo CT/MRI at time of first progression had unknown CNS metastasis status.

§Incidence rate of CNS metastasis at first progression: No. of CNS yes/No. of first progressions of any type.

Table

Table A4. LVEF Results

Table A4. LVEF Results

Week LTax/L
TTax/T
No. of Patients Absolute Change From Baseline (%)
No. of Patients Absolute Change From Baseline (%)
Any Increase
0 to < 20 Decrease
≥ 20 Decrease
Any Increase
0 to < 20 Decrease
≥ 20 Decrease
No. % No. % No. % No. % No. % No. %
Baseline 321 0 0 0 0 0 0 325 0 0 0 0 0 0
12 287 107 37 180 63 0 0 300 96 32 204 68 0 0
24 250 94 38 156 62 0 0 262 82 31 177 68 3 1
36 194 62 32 132 68 0 0 212 65 31 144 68 3 1
48 110 34 31 76 69 0 0 133 31 23 100 75 2 2
60 70 20 29 50 71 0 0 100 27 27 73 73 0 0
72 42 17 40 25 60 0 0 69 23 33 45 65 1 1
84 29 12 41 17 59 0 0 52 14 27 38 73 0 0
96 18 5 28 13 72 0 0 37 8 22 28 76 1 3
108 12 4 33 8 67 0 0 22 8 36 13 59 1 5
120 7 1 14 6 86 0 0 17 6 35 11 65 0 0
132 4 0 0 4 100 0 0 10 3 30 6 60 1 10
144 3 1 33 2 67 0 0 10 3 30 7 70 0 0
156 3 1 33 2 67 0 0
168 1 0 0 1 100 0 0
180 1 1 100 0 0 0 0

Abbreviations: LTax/L, lapatinib plus taxane followed by lapatinib; LVEF, left ventricular ejection fraction; TTax/T, trastuzumab plus taxane followed by trastuzumab.

Downloaded 4,943 times

COMPANION ARTICLES

No companion articles

ARTICLE CITATION

DOI: 10.1200/JCO.2014.56.9590 Journal of Clinical Oncology 33, no. 14 (May 10, 2015) 1574-1583.

Published online March 16, 2015.

PMID: 25779558

ASCO Career Center