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Breast Cancer
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Lapatinib or Trastuzumab Plus Taxane Therapy for Human Epidermal Growth Factor Receptor 2–Positive Advanced Breast Cancer: Final Results of NCIC CTG MA.31
Abstract
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).
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.2–10 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.12–15 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)18–20 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.
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.
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.
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.23–25 HER2 and ER/PgR results are presented to clinically characterize patients (Data Supplement); detailed biomarker reporting will occur later.
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.
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.
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.
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.
Fig 1. CONSORT diagram. HER2, human epidermal growth factor receptor 2; ITT, intention to treat; PD, progressive disease; PFS, progression-free survival.
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.
|
| 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%).
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.
|
| 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.
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).
Fig 2. Kaplan-Meier estimates of intention-to-treat progression-free survival. HR, hazard ratio; LTax/L, lapatinib plus taxane followed by lapatinib; TTax/T, trastuzumab plus taxane followed by trastuzumab.
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).
Fig 3. Kaplan-Meier estimates of intention-to-treat overall survival. HR, hazard ratio; LTax/L, lapatinib plus taxane followed by lapatinib; TTax/T, trastuzumab plus taxane followed by trastuzumab.
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).
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.
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.
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).
|
| 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.
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
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| 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. |
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.
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Leadership: Vector Oncology
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|
| 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.
|
| 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.
|
| 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.
|
| 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.
Fig A1. Kaplan-Meier estimates of centrally confirmed human epidermal growth factor receptor 2–positive progression-free survival. HR, hazard ratio; LTax/L, lapatinib plus taxane followed by lapatinib; TTax/T, trastuzumab plus taxane followed by trastuzumab.
Fig A2. Kaplan-Meier estimates of centrally confirmed human epidermal growth factor receptor 2–positive overall survival. HR, hazard ratio; LTax/L, lapatinib plus taxane followed by lapatinib; TTax/T, trastuzumab plus taxane followed by trastuzumab.
