Review

Trastuzumab Treatment in Multiple Lines:

Current Data and Future Directions
M. Pegram, J. Liao

Abstract
Trastuzumab improves response rate, time to progression, and overall survival when combined with first-line
chemotherapy in patients with human epidermal growth factor receptor 2–positive (HER2-positive) metastatic
breast cancer (MBC). However, the benefits of continuing trastuzumab beyond disease progression have not
been clearly established. The literature was reviewed to obtain data on trastuzumab use beyond disease
progression. In general, data from retrospective and observational studies suggest that there may be clinical
benefit when trastuzumab is used beyond disease progression. These results are supported by prospective
non-randomized studies. Response rates and survival outcomes have generally been superior in patients who
have continued trastuzumab after disease progression compared with those who have not. Moreover, recent
data from two prospective randomized phase III trials have shown that adding trastuzumab to the treatment
regimen in patients with MBC who have progressed on trastuzumab-based therapy significantly prolongs
progression-free survival. Emerging evidence from randomized controlled trials supports the potential clinical
utility of continuing trastuzumab-based therapy beyond progression and supports the National Comprehensive
Cancer Network recommendation to consider this treatment approach. Future treatment of HER2-positive MBC
may involve trastuzumab being used in successive regimens in combination with other targeted therapies.

Clinical Breast Cancer, Vol. 12, No. 1, 10-8 © 2012 Published by Elsevier Inc.
Keywords: Breast cancer, Disease progression, HER2, Metastases, Trastuzumab

Introduction In metastatic disease, a chemotherapy regimen is generally ad-

Trastuzumab (Herceptin, Genentech Inc, South San Francisco, CA, ministered until disease progression, and then replaced with an-
USA) is a humanized recombinant monoclonal antibody directed other agent. A similar approach was adopted with trastuzumab in
against the extracellular domain of human epidermal growth factor re- clinical trials. However, as a molecularly targeted drug, there may
ceptor 2 (HER2) and has been used for more than 10 years to treat be more effective ways of using trastuzumab in clinical practice.
HER2-positive breast cancer. Adjuvant trastuzumab improves disease- Although anecdotal clinical and preclinical evidence suggests that
free survival (DFS) and overall survival (OS) when combined with che- trastuzumab beyond disease progression may be beneficial, as de-
motherapy1-3 or when used as monotherapy following chemother- scribed later, it has been challenging to test this hypothesis in
apy.4,5 When combined with chemotherapy in the neoadjuvant setting, randomized trials within the United States (US). Nevertheless,
trastuzumab improves pathologic complete response and DFS.6,7 In many patients are receiving trastuzumab beyond disease progres-
metastatic breast cancer (MBC), first-line trastuzumab plus chemother- sion in clinical practice.10 Furthermore, the current National
apy improves response rate, time to progression (TTP), and OS.8 Sec- Comprehensive Cancer Network (NCCN) Practice Guidelines
ond- or third-line trastuzumab monotherapy produces durable objective recommend continuing HER2 blockade for HER2-positive dis-
responses for women progressing on chemotherapy.9
ease progressing on first-line, trastuzumab-based regimens, using
a trastuzumab-based regimen, lapatinib plus capecitabine, or tras-
University of Miami Sylvester Comprehensive Cancer Center, Miami, FL tuzumab and lapatinib.11
Submitted: April 21, 2011; Revised: July 22, 2011; Accepted: July 25, 2011
This review addresses the available evidence for the use of tras-
tuzumab beyond progression and discusses a growing number of
Address for correspondence: Mark Pegram, MD, University of Miami Sylvester
Comprehensive Cancer Center, Biomedical Research Building (BRB) 731 - 1501 studies—including randomized prospective clinical trials of tras-
N.W. 10th Ave. - Miami, FL 33136. tuzumab regimens beyond disease progression—in patients with
Tel: 305-243-8823; fax: 305-243-6170; e-mail contact: MPegram@med.miami.edu
HER2-positive MBC.

1526-8209/$ - see frontmatter © 2012 Published by Elsevier Inc.

10 Clinical Breast Cancer February 2012 doi: 10.1016/j.clbc.2011.07.003
Preclinical Rationale for Using patients at three Italian institutions found favorable response rates
Trastuzumab Beyond Disease with trastuzumab following disease progression.17 Patients receiving
Progression at least two trastuzumab-containing lines for metastatic disease com-
Designing preclinical studies to evaluate trastuzumab beyond dis- pared with one line survived significantly longer (median 62.4
ease progression is difficult because it is challenging to transform a months versus 38.5 months; P ⫽ .01). Additional data obtained
trastuzumab-sensitive cell line into a resistant cell line and to develop from single-institution analyses also support the continuation of tras-
experimental models that mimic the clinical setting. However, pre- tuzumab treatment beyond progression. In one study, Tokajuk et al
clinical evidence supports the concept of continuing trastuzumab reported that patients receiving two or more trastuzumab-containing
beyond disease progression. Pietras et al12 showed that trastuzumab regimens survived significantly longer than those who discontinued
decreased tumor growth in breast cancer xenografts in a dose-depen- trastuzumab at disease progression (P ⫽ .02).18 Another study ana-
dent manner. When trastuzumab was discontinued, its cytostatic lyzed response data from 93 patients who had received additional
effect ceased and rapid tumor regrowth occurred, suggesting that trastuzumab treatment following progression (either after adjuvant
optimal inhibition may require continued application. Another pre- therapy or following one line of treatment for advanced disease).19
clinical study in a murine model of MBC found that trastuzumab The CBR in these patients was 60%, the median TTP was 24 weeks
added to taxanes synergistically inhibits tumor growth, even after (95% confidence interval [CI] 21-28 weeks), and the median OS was
disease progression following initial trastuzumab monotherapy.13 19 months (95% CI, 12-24 months).
Although, in theory, the anti-tumor effect of trastuzumab may
Clinical Evaluation of Trastuzumab continue across multiple lines of therapy, clinical outcomes and TTP
Efficacy Beyond Disease do tend to worsen with each subsequent line. The Hellenic Cooper-
Progression ative Oncology Group reviewed medical records of 80 patients.20
The potential clinical utility of trastuzumab in multiple lines of When trastuzumab was used in two lines of therapy, 24% of patients
therapy was supported by an extension study of 247 patients enrolled achieved an objective response (including 3 complete responses
in the original pivotal trial of trastuzumab in MBC.14 Patients con- [CRs]) versus 14% with three lines of therapy (including 1 CR).
tinuing trastuzumab beyond disease progression in this trial achieved Partial responses (PRs) were reported in 19% and 8% of patients
only modest responses to treatment. The overall response rate (ORR) receiving four and five lines of trastuzumab, respectively. Across the
was 11%, and the clinical benefit rate (CBR) was 22%. Responses patient population, the median OS was 22.2 months. Decreasing
were observed both with trastuzumab alone (n ⫽ 71) and in combi- response rates with subsequent trastuzumab lines were also reported
nation with chemotherapy (n ⫽ 176). in a Spanish review of hospital records,21 although TTP remained
These results led investigators in the United States to initiate ran- relatively constant at 4 to 5 months across treatment lines. Multivar-
domized trials of trastuzumab in multiple lines of therapy. In a trial iate analysis found that response to the first line of trastuzumab was
at the MD Anderson Cancer Center (MDACC DM99-135/ significantly associated with response to subsequent lines (odds ratio
H2132n), patients whose disease had progressed following a trastu- 3.84; 95% CI, 1.07-14.64; P ⫽ .04). A single-center Italian study
zumab-based regimen were randomized to trastuzumab plus vinore- also found notable CBRs and improved TTP with a second trastu-
lbine or vinorelbine monotherapy.15 This trial was closed early zumab-based regimen beyond progression.22 In an extension of this
because of poor accrual (only 16 patients enrolled at five study cen- study, it was found that a longer TTP during the first line of trastu-
ters during a 20-month period); this was partly attributed to physi- zumab predicted longer TTP (P ⫽ .009) and post-progression sur-
cian and patient concerns about randomization to the non–trastu- vival (P ⫽ .04) during the second trastuzumab-containing regi-
zumab-containing arm.15 A similar trial was initiated by the men.26 Another Italian retrospective analysis found a trend for better
Southwest Oncology Group (S0347/NCT00103233). Patients who survival from the start of trastuzumab in patients continuing beyond
had progressed following treatment with a taxane plus trastuzumab disease progression compared with those who halted the drug (hazard
were randomized to trastuzumab plus vinorelbine or vinorelbine ratio [HR], 0.78; 95% CI, 0.58-1.32).23
alone (ClinicalTrials.gov). The projected accrual for this trial was Two retrospective studies have reported no clinical benefit from
292 patients; unfortunately, accrual was also slow, and the trial continuing trastuzumab beyond progression in MBC.24,25 In one
closed early.15 study, 112 patients who discontinued trastuzumab were compared
with 83 patients who continued trastuzumab.24 No significant dif-
Retrospective Studies ferences were observed in terms of ORR (28% versus 30%; P ⫽ .5),
The lack of data from randomized trials led investigators to per- median time to second progression (8.4 months versus 7.0 months;
form studies retrospectively. In general, these studies support the P ⫽ .24), or median post-progression OS (20.6 months versus 15.4
hypothesis that continuation of trastuzumab after disease progres- months; P ⫽ .29). In the other study, vinorelbine-based salvage
sion may potentiate the effects of further cytotoxic regimens. How- therapies were retrospectively investigated in 60 patients pro-
ever, the results are somewhat heterogeneous (Table 1).16-25 A ret- gressing during initial treatment with a trastuzumab-based regi-
rospective analysis of medical charts from 13 centers in Europe, men.25 Of these, 29 patients receiving vinorelbine-based salvage
Australia, and Canada16 found that ORRs with a second trastu- treatment and continued trastuzumab had an ORR of 21% and a
zumab-based regimen compared favorably to those obtained with the CBR of 48%. In the 31 patients who stopped trastuzumab, the
first. Moreover, some women who did not respond to first-line tras- ORR was 36% and the CBR was 58%. Similarly, TTP did not
tuzumab responded to second-line trastuzumab. Similarly, data from differ significantly during salvage therapy between patients who

Clinical Breast Cancer February 2012 11

 Trastuzumab Treatment in Multiple Lines
Table 1 Summary of Outcomes From Retrospective Studies Evaluating Trastuzumab Beyond Disease Progression in MBC

Median OS
Author Treatment Line Patients (n) ORR (%) CBR (%) Median TTP (Months)
(Months)
1 77 39 69 5.4
Gelmon et al16 29
2 65 32 54 6
1 23 57 NR 7.4
Stemmler et al17 62.4
2 23 39 NR NR
1 27 56 NR 5.8
Tokajuk et al18 2 14 50 NR 5.1 Not reached
3 to 5 6 67 NR NR
Wadell et al19 After adjuvant or 1 93 NR 60 6 19
2 80 24 52 5.2
3 49 14 38 3.5
Fountzilas et al20 22.2
4 26 19 50 4.9
5 12 8 33 3.9
1 93 46 71 5
2 47 30 51 4
21
García-Sáenz et al 3 21 38 62 4 NR
4 10 20 40 4
5 5 0 60 NR
1 59 59 83 9.5
2 37 27 62 6.7
Fabi et al22 37
3 16 0 19 4
4 9 0 33 4.5
1 57 35 74 7.25 29.9
2 55 16 53 5.25
Cancello et al23
3 26 15 60 5.25 42.3
4 12 0 17 3.75
1 112 28 NR 7.0 15.4
Montemurro et al24
2 or more 83 30 NR 8.4 20.6
1 31 36 58 7.1 NR
Montemurro et al25
Salvage 29 21 48 6.1 NR

Abbreviations: CBR ⫽ clinical benefit rate (complete responses ⫹ partial responses ⫹ stable disease); MBC ⫽ metastatic breast cancer; NR ⫽ not reported; ORR ⫽ overall response rate (complete
responses ⫹ partial responses); OS ⫽ overall survival; TTP ⫽ time to progression.

continued trastuzumab treatment and those who stopped (6.1 disease progression. Median duration of treatment was 28 weeks for
months versus 7.1 months; P ⫽ .10). paclitaxel and 59 weeks for trastuzumab, producing an ORR of 62%
In summary, of 10 retrospective studies, 8 suggested a possible (2 CRs and 14 PRs). Median OS exceeded 34 months, which com-
benefit when continuing trastuzumab beyond disease progres- pared favorably with OS in the pivotal randomized study evaluating
sion, whereas two did not. However, these findings needed to be trastuzumab plus chemotherapy until disease progression (25
tested in an adequately powered prospective study in order to be months in women with HER2-positive disease receiving paclitaxel
confirmed. every 3 weeks).8 In another prospective study, clinical benefits, in-
Prospective Non-Randomized Studies cluding two CRs, were reported in 69% of the 54 patients who
Data from several completed and ongoing, non-comparative stud- received second-line treatment with a trastuzumab-based regimen.28
ies indicate responses and clinical benefit from continuing trastu- In addition, TTP (6 months) did not decrease significantly from
zumab beyond disease progression (Table 2).14,27-40 Christodoulou first-line to beyond second-line treatment.
et al27 evaluated trastuzumab plus weekly paclitaxel after disease pro- Clinical benefit beyond progression has also been reported when
gression in 26 women with metastatic disease. Treatment was only trastuzumab is combined with chemotherapeutic agents (Table 2),
stopped in the event of unacceptable toxicity or death, irrespective of including paclitaxel,27 metronomic low-dose cyclophosphamide and

12 Clinical Breast Cancer February 2012

 M. Pegram, J. Liao
Table 2 Summary of Outcomes From Prospective (Non-Randomized) Studies Evaluating Trastuzumab Beyond Disease
Progression in MBC

Patients ORR CBR Median TTP

Author Treatment Line Median OS (Months)
(n) (%) (%) (Months)
Use of T beyond disease progression
Christodoulou et al27 26 62 NR 11 ⬎34
(⫹ paclitaxel)
Use of T beyond disease progression
Tripathy et al14 93 11 22 NR NR
(monotherapy or ⫹ chemotherapy)
First-line (⫹ chemotherapy) 54 43 85 6
Use of T beyond disease progression
54 26 69 6
Bartsch et al28 (⫹ second-line chemotherapy) Not reached at 24 months
Use of T beyond disease progression
33 30 58 6
(⫹ 3⫺6-line chemotherapy)
Use of T beyond disease progression
Orlando et al29 11 18 27 NR NR
(⫹ cyclophosphamide ⫹ methotrexate)
Use of T beyond disease progression ⫹
10 40 3
vinorelbine
Use of T beyond disease progression ⫹
Bangemann et al30 17 53 NR 3 NR
capecitabine
Use of T beyond disease progression ⫹
9 33 3.5
docetaxel
Use of T beyond disease progression
Chollet et al31 17 29 53 NR NR
(⫹ vinorelbine)
Use of T beyond disease progression
Bartsch et al32 29 19 46 3 17
(⫹ gemcitabine)
Use of T beyond disease progression
Morabito et al33 7 29 57 NR NR
(⫹ vinorelbine ⫹ gemcitabine)
Use of T beyond disease progression
Bartsch et al, 200734 40 20 70 8 24
(⫹ capecitabine)
Use of T beyond disease progression
André et al35 13 46 83 NR NR
(⫹ paclitaxel ⫹ everolimus)
Use of T beyond disease progression
6 NR NR NR 20
(⫹ docetaxel)
Montemurro et al36
Halt T at disease progression (then
23 17% 50 NR 19
continue docetaxel)
Use of T beyond disease progression
Baselga et al37 66 24 50 5.5 NR
(⫹ pertuzumab)
Use of T beyond disease progression Not reached at 27.8
107 NR NR 10.1
(first-line)‡ months
Halt T at disease progression
70 NR NR 7.1 16.8
(first-line)‡
Antoine et al38
Use of T beyond disease progression
87 NR NR 7.6 27.1
(second-line)
Halt T at disease progression
30 NR NR 5.6 15.6
(second-line)
Use of T beyond disease progression
107 NR NR 10.2 ⬎ 27.8 (21.3†)
Extra et al39 (first-line)
Halt T at disease progression (first-line) 70 NR NR 7.1 16.8 (4.6†)
Use of T beyond disease progression
527 NR NR NR 21.1†
Rugo et al40 (first-line)
Halt T at disease progression (first-line) 115 NR NR NR 5.9†

Abbreviations: CBR ⫽ clinical benefit rate (complete responses ⫹ partial responses ⫹ stable disease); NR ⫽ not reported; ORR ⫽ overall response rate (complete responses ⫹ partial responses);
OS ⫽ overall survival; T ⫽ trastuzumab; TTP ⫽ time to progression.
†
Median OS beyond progression.
‡
Updated analysis published by Extra et al.39

Clinical Breast Cancer February 2012 13

 Trastuzumab Treatment in Multiple Lines
methotrexate,29 vinorelbine,30,31 gemcitabine,32 gemcitabine and (8.2 months versus 5.6 months; HR, 0.69; two-sided log rank
vinorelbine,33 capecitabine,30,34 and paclitaxel and everolimus.35 P ⫽ .0338; one-sided log rank P ⫽ .0169), ORR (48.1% versus
However, OS was not improved in an analysis of six patients partic- 27.0%; P ⫽ .0115) and CBR (75.3% versus 54.1%; P ⫽ .0068),41
ipating in a phase II study of docetaxel plus trastuzumab who con- although no significant difference in OS was reported (24.9 months
tinued trastuzumab beyond disease progression.36 Median OS in versus 20.6 months; P ⫽ .73).42 In a post hoc analysis of this study,
these patients was 20 months, similar to the 19 months observed in however, patients who received third-line anti-HER2 therapy (either
patients who halted trastuzumab. trastuzumab or lapatinib) experienced longer median OS than those
Non-randomized, observational cohort studies have compared re- who did not (18.8 months versus 13.3 months; HR, 0.63; P ⫽.02),
sponse rates and survival outcomes in patients receiving trastuzumab suggesting that there may be additional benefit in continuing anti-
after disease progression with those who have halted trastuzumab. In HER2 treatment across even further lines of therapy.42 Enrollment
an analysis of the Hermine Cohort study of trastuzumab use in rou- in this study (n ⫽ 156) was lower than what was originally targeted
tine clinical practice, 194 patients who continued trastuzumab-based (n ⫽ 482), which may have affected its statistical power. However,
therapy in multiple lines were compared with 100 patients who trastuzumab combined with capecitabine is a recommended option
stopped trastuzumab at progression.38 Continuing trastuzumab be- in the NCCN Practice Guidelines for HER2-positive disease pro-
yond disease progression in first-line MBC was an independent prog- gressing on previous trastuzumab-based treatment.11
nostic factor for survival (HR, 0.062; 95% CI, 0.02-0.26); and TTP The relatively low number of patients enrolled in the GBG 26/
was also prolonged in patients continuing trastuzumab beyond pro- BIG 03-05 trial was probably a result of the US Food and Drug
gression the second line (Table 2). The final results of the Hermine Administration approval of lapatinib (Tykerb; GlaxoSmithKline,
study were recently published,39 including the subanalysis of trastu- Research Triangle Park, NC, USA), which is indicated for patients
zumab treatment beyond progression in the 177 patients who re- who have received prior therapy, including an anthracycline, a tax-
ceived first-line trastuzumab and either continued trastuzumab for ane, and trastuzumab. Lapatinib approval was based on a phase III,
30 days following progression or stopped trastuzumab at or before randomized trial of capecitabine plus lapatinib versus capecitabine
progression (Table 2). Median OS from treatment initiation and monotherapy in 324 patients with progressive HER2-positive dis-
TTP were longer for patients who continued trastuzumab (⬎27.8 ease who had previously been treated with an anthracycline, a taxane,
months and 21.3 months, respectively) than for those who stopped and trastuzumab.43 The primary end-point was TTP and the sec-
trastuzumab (10.2 months and 7.1 months, respectively). However, ondary end-points were progression-free survival (PFS), OS, ORR,
it was noted that patients who continued trastuzumab beyond pro- and CBR. Adding lapatinib to capecitabine resulted in a TTP of 8.4
gression initially had a better prognosis than those who did not con- months compared with 4.4 months with capecitabine monotherapy,
tinue treatment. and the risk of disease progression was reduced by 51% (HR, 0.49;
In a large observational cohort study of 1023 patients with P ⬍ .001). Adding lapatinib to capecitabine did not significantly
HER2-positive MBC (registHER), 879 patients (87%) received improve ORR (22% versus 14%; P ⫽ .09) or OS (HR, 0.92;
trastuzumab in the first-line setting, either as monotherapy or in P ⫽ .72).
combination with hormone therapy and/or chemotherapy. A The 51% reduction in risk of progression with lapatinib use
multivariate analysis found that the unadjusted HR for survival in reported by Geyer et al43 is higher than the 31% reduction in risk
patients receiving trastuzumab beyond first progression (n ⫽ 527, reported by von Minckwitz et al41 (Table 3).41-43 Conversely, the
21.1 months) compared with those who did not (n ⫽ 115) was ORR in the trastuzumab plus capecitabine group in the GBG
0.25, suggesting improved survival for those who did continue 26/BIG 3-05 study (48%)41 is higher than that reported for the
trastuzumab40 (Table 2). This HR was unchanged when lapatinib lapatinib plus capecitabine group reported in the study by Geyer
use was considered. The findings of prospective non-randomized et al (22%).43 However, it is not possible to make a direct com-
studies must be interpreted with caution because of the bias in- parison between the results from these trials because of substan-
herent in selecting patients who should continue trastuzumab tive differences between the patient populations. For example, the
treatment. This would be avoided by randomizing patients to study populations differ in terms of their treatment with prior
different treatment arms in controlled prospective studies, and anthracyclines (97% versus 69%) and taxanes (97% versus 85%),
data from such studies are now available. and the percentage of patients who had estrogen receptor–nega-
tive/progesterone receptor–negative disease (49% versus 38%, re-
Prospective Randomized Studies spectively; Table 4).41-43 Furthermore, whereas disease stage (ie,
The German Breast Group (GBG) 26/BIG 3-05 phase III study MBC or stage IIIB/IIIC disease) was reported in the Geyer study,
prospectively evaluated whether trastuzumab should continue be- only disease stage at first diagnosis (subdivided as T stage, N stage,
yond disease progression.41,42 Patients with HER2-positive, locally and M stage) was reported for GBG 26/BIG 3-05. Thus, it is not
advanced or MBC who received trastuzumab previously (either ad- possible, based on the available data, to ascertain which of these
juvant or first-line), were randomized to capecitabine alone (n ⫽ 78) approaches is most suitable.
or capecitabine plus trastuzumab (n ⫽ 78) until progression. The The activity of a different HER2 inhibitor (lapatinib) and of
primary objective was to compare TTP between the two groups. trastuzumab, each combined with chemotherapy, after progres-
Secondary end-points included ORR, CBR, and OS. Over a me- sion on trastuzumab-containing therapy suggests that these tu-
dian follow-up of 15.6 months, continuing trastuzumab im- mors continue to be dependent on the HER2 pathway after pro-
proved the efficacy of second-line capecitabine in terms of TTP gression. Thus, these data provide a rationale for combining

14 Clinical Breast Cancer February 2012

 M. Pegram, J. Liao
Table 3 Comparison of Two Prospective Studies Assessing the Addition of Lapatinib (Geyer et al43) or Trastuzumab
(von Minckwitz et al41,42) to Capecitabine in Patients Who Had Previously Progressed on Trastuzumab-Containing
Regimens, in Terms of Clinical Benefit

Geyer et al, 200643 von Minckwitz et al, 2009, 201041,42

Measure Capecitabine ⴙ Capecitabine ⴙ
Capecitabine Capecitabine
Lapatinib Trastuzumab
(n ⴝ 161) (n ⴝ 78)
(n ⴝ 163) (n ⴝ 78)
Response Rate, % (95% CI) 14 (9-21) 22 (16-29) 27 (17-39) 48 (37-60)*
CBR, % (95% CI, if reported) 18 27† 54 (42-66) 75.3 (64-84)*
HR for Progression (95% CI) 0.49 (0.34-0.71) in favor of lapatinib arm* 0.69 (0.48-0.97) in favor of trastuzumab arm*
Median TTP, Months (95% CI, if
4.4 8.4* 5.6 (4.2-6.3) 8.2 (7.3-11.2)†
reported)
HR for Death (95% CI) 0.92 (0.58-1.46) in favor of lapatinib arm 0.94 (0.65-1.35) in favor of trastuzumab arm
Median Survival, Months (95% CI) NR NR 20.4 (17.8-24.7) 25.5 (19.0-30.7)†

Abbreviations: CBR ⫽ clinical benefit rate (complete responses ⫹ partial responses ⫹ stable disease ⱖ6 months43 or ⬎24 months41,42); CI ⫽ confidence interval; HR ⫽ hazard ratio; NR ⫽ not
reported; TTP ⫽ time to progression.
* statistically significant difference P ⬍ .05; † P value not reported.

Table 4 Comparison of Two Prospective Studies Assessing the Addition of Lapatinib (Geyer et al43) or Trastuzumab (von
Minckwitz et al41,42) to Capecitabine in Patients Who Had Previously Progressed on Trastuzumab-Containing Regimens,
in Terms of Patient Characteristics

von Minckwitz et al, 2009,

Geyer et al, 200643
201041,42
Characteristic Capecitabine ⴞ Lapatinib
Capecitabine ⴞ Trastuzumab
(n ⴝ 324)
(n ⴝ 156)
Previous Therapy with Anthracyclines, % 97 69
Previous Therapy with Taxanes 97 85
Estrogen Receptor– and Progesterone
49 38
Receptor–Negative Disease

HER2 inhibitors, thereby potentially offering a treatment option Safety of Trastuzumab Treatment
without many of the chemotherapy-related toxicities. Results Beyond Disease Progression
have recently been published from a randomized phase III study Cytotoxic chemotherapy may be stopped at disease progression to
of lapatinib alone (n ⫽ 148) versus lapatinib plus trastuzumab avoid exposing patients to unnecessary toxicity in the absence of
(n ⫽ 148) in patients with MBC who had progressed on a tras- clinical benefit. Therefore, it is important to weigh any toxicity
tuzumab-containing regimen.44 The primary end-point was PFS, against the therapeutic effect of trastuzumab beyond disease progres-
and secondary end-points included response rate, CBR (ie, CR ⫹ sion. An extension study to the pivotal trial of trastuzumab plus
PR ⫹ stable disease ⱖ 6 months), and OS. Compared with pa- chemotherapy in MBC found no unexpected adverse events with the
tients receiving lapatinib alone, patients receiving lapatinib plus use of long-term (up to 40⫹ months) trastuzumab.14 This is sup-
trastuzumab had a significantly longer duration of PFS (12 weeks ported by other safety data from clinical studies in which prolonged
versus 8.1 weeks, HR, 0.73; P ⫽ .008) and greater CBR (25% trastuzumab use was generally well-tolerated, and adverse events
versus 12%; P ⫽ .01). The response rate was not statistically could be attributed to the chemotherapy combined with trastu-
significantly different between the two groups (10% versus 7%; zumab rather than trastuzumab itself.19,27,28 Cardiac events were
P ⫽ .46). Initially, there was a trend toward improved OS with reported in a minority of patients. However, these were generally
continued trastuzumab (25% reduction in the risk of death; HR, manageable with standard treatment.
0.75; P ⫽ .106).44 With longer follow-up, these OS results have
become statistically significant with median OS of 9.5 months Ongoing Studies of Trastuzumab
with lapatinib compared with 14 months with lapatinib plus tras- Beyond Disease Progression
tuzumab (HR, 0.74; 95% CI, 0.57-0.97; P ⫽ .026).45 There are still questions about how best to use trastuzumab be-
The NCCN Practice Guidelines now list trastuzumab com- yond disease progression in patients with MBC. Given that adjuvant
bined with lapatinib as a treatment option for patients with trastuzumab is increasingly used, it is important to assess the benefit
HER2-positive disease that progresses on first-line, trastuzumab- of re-exposing patients with MBC to trastuzumab following relapse
based regimens.11 in the adjuvant setting. The Retreatment after HErceptin Adjuvant

Clinical Breast Cancer February 2012 15

 Trastuzumab Treatment in Multiple Lines
Figure 1 Designs of the (A) PANDORA Study (NCT00444587) and the (B) THOR Study (NCT0044827). Both Are Phase III, Open-
Label, Randomized Studies Evaluating the Use of Chemotherapy Plus Trastuzumab Versus Chemotherapy Alone in
Patients With Metastatic Breast Cancer That Progressed on First-Line Treatment With Trastuzumab Plus Chemotherapy

A
Second-line chemotherapy +
trastuzumab 6 mg/kg IV Primary endpoint:
every 3 weeks Time to progression
Disease progression during or
Secondary endpoints:
after previous first-line
Overall response rate
chemotherapy + trastuzumab
Clinical benefit rate
(n = 274)
Time to treatment failure
Overall survival
Second-line chemotherapy

B Second-line chemotherapy +
trastuzumab 2 mg/kg IV
every week or 6 mg/kg IV
every 3 weeks Primary endpoint:
Disease progression during or
Progression-free survival
after previous first-line
Secondary endpoints:
chemotherapy + trastuzumab
Overall response rate
(n = 300)
Overall survival
Second-line chemotherapy

(RHEA) study is a phase II, prospective, open-label, ex-US study of whose disease progressed on or following first-line trastuzumab-
first-line trastuzumab treatment with or without a taxane in patients based therapy to trastuzumab and capecitabine with or without per-
with MBC who have relapsed after initial (neo)adjuvant therapy with tuzumab.47 The primary end-point of this study is PFS assessed by
trastuzumab. The single-agent trastuzumab arm was terminated independent review. The Swiss Group for Clinical Cancer Research
because of poor enrollment, but data from the 41 patients in the is evaluating the benefits of adding paclitaxel to trastuzumab
trastuzumab combination arm were promising: ORR was 61% (NCT00004935) or letrozole to trastuzumab (NCT00238290) fol-
(all PRs), with stable disease in 7 patients (17%), and progressive lowing disease progression on first-line trastuzumab monotherapy.
disease in 6 patients (15%).46 Median duration of response was 7
months, median PFS was 8 months, median time to treatment Conclusions
failure was 8 months, and CBR was 71%. A lapatinib-containing
The synergy between trastuzumab and a variety of chemothera-
arm was not included, but it would be interesting to compare
peutic agents was first reported preclinically.48,49 Data from clinical
first-line lapatinib plus capecitabine with trastuzumab-based
studies show that this synergy can not only be exploited in the first-
combination therapy and trastuzumab alone.
line and adjuvant settings but also, perhaps, beyond disease progres-
Several other prospective clinical studies are planned or currently in
sion in pretreated patients. Data from retrospective and prospective
progress to investigate the clinical utility of trastuzumab in multiple lines
clinical studies provide an indication that the use of trastuzumab in
of therapy. Two phase III Hoffmann-La Roche–sponsored studies
multiple lines of therapy is capable of eliciting objective responses
(PANDORA and THOR) will assess chemotherapy plus trastuzumab
versus chemotherapy alone in MBC that progressed on first-line trastu- and delaying disease progression. This is supported by a recent sys-
zumab plus chemotherapy. In the open-label PANDORA study tematic review of eight retrospective and four prospective studies in
(NCT00444587), 274 patients progressing on a first-line chemotherapy which patients with HER2-positive MBC received trastuzumab be-
regimen containing trastuzumab will be randomized to second-line che- yond progression within various treatment regimens (n ⫽ 516). The
motherapy with or without trastuzumab (Figure 1A). The primary end- mean time to progression was 23.7 weeks (median 26 weeks; range,
point is TTP. The THOR study (NCT00448279) is of similar de- 13 weeks to 39 weeks); combined trastuzumab plus vinorelbine
sign (Figure 1B), with the exception of the trastuzumab dosing showed a comparatively shorter mean and median time to progres-
regimen and primary end-point (PFS). With a targeted accrual of sion (20.6 weeks and 19.6 weeks, respectively), whereas trastuzumab
300 patients, THOR is also expected to be completed in 2010. An- plus capecitabine was associated with a mean time to progression of
other Hoffmann-La Roche–sponsored study, the open-label phase II 30.3 weeks. The authors concluded that trastuzumab-based regi-
PHEREXA study (NCT01026142), will randomize 450 patients mens might have activity in HER2-positive MBC beyond progres-

16 Clinical Breast Cancer February 2012

 M. Pegram, J. Liao
sion, but additional randomized phase III trials are required to eval- 3. Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus
adjuvant chemotherapy for operable human epidermal growth factor receptor
uate this further.50 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP
Another open question is whether trastuzumab should remain the B-31. J Clin Oncol 2011; 29:3366-73.
4. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant
HER2-suppressing agent throughout multiple lines of treatment or chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:1659-72.
whether clinical benefit would be increased if different HER2-tar- 5. Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adju-
vant chemotherapy in HER2-positive breast cancer: a randomised controlled trial.
geted agents were used. There are no currently available data address- Lancet 2007; 369:29-36.
ing this question. Similarly, a recent retrospective analysis showed 6. Buzdar AU, Valero V, Ibrahim NK, et al. Neoadjuvant therapy with paclitaxel
followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy
that obtaining the answers to some of the open questions may involve and concurrent trastuzumab in human epidermal growth factor receptor 2-pos-
further investigation of underlying mechanisms. In this analysis in 97 itive operable breast cancer: an update of the initial randomized study popula-
tion and data of additional patients treated with the same regimen. Clin Cancer
patients who had been treated with at least two lines of trastuzumab- Res 2007; 13:228-33.
based therapy for metastatic HER2-positive disease, second-line tras- 7. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with
trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy
tuzumab-based therapy showed activity as assessed by median alone, in patients with HER2-positive locally advanced breast cancer (the NOAH
TTP.51 However, the investigators were unable to identify a clinical trial): a randomised, controlled superiority trial with a parallel HER2-negative co-
hort. Lancet 2010; 375:377-84.
or histopathologic feature predictive of response to treatment with 8. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal
trastuzumab across multiple lines, suggesting that exploration of un- antibody against HER2 for metastatic breast cancer that overexpresses HER2.
N Engl J Med 2001; 344:783-92.
derlying mechanisms of sensitivity to and progression on trastu- 9. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and
zumab may be more useful in predicting response to trastuzumab or safety of humanized anti-HER2 monoclonal antibody in women who have HER2-
overexpressing metastatic breast cancer that has progressed after chemotherapy for
other HER2-targeted agents. metastatic disease. J Clin Oncol 1999; 17:2639-48.
In practice, trastuzumab has become a “backbone” of treatment 10. Wong Y, Ottesen R, Niland J, et al. Continued use of trastuzumab (TRZ) beyond
disease progression in the National Comprehensive Cancer Network (NCC). J Clin
across multiple lines of chemotherapy, with patients who progress Oncol 2008; 26(suppl 15):342s (abstract 6522).
during or after treatment with one trastuzumab-containing treat- 11. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncol-
ogy: Breast Cancer. V.2.2011. National Comprehensive Cancer Network [website].
ment regimen re-treated with another trastuzumab-containing regi- Available at: http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf.
men. The partnering agent(s) could be tailored to address the mech- Accessed: February 9, 2011.
12. Pietras RJ, Pegram MD, Finn RS, et al. Remission of human breast cancer xeno-
anisms that cause disease progression, such as other inhibitors of grafts on therapy with humanized monoclonal antibody to HER-2 receptor and
HER signaling (eg, lapatinib or pertuzumab), tumor cell signaling DNA-reactive drugs. Oncogene 1998; 17:2235-49.
13. Fujimoto-Ouchi K, Sekiguchi F, Kazushige M. Preclinical study of continuous
(eg, protease inhibitor 3 kinase inhibitors and mammalian target of
administration of trastuzumab as combination therapy after disease progression
rapamycin inhibitors), or tumor angiogenesis (eg, bevacizumab). with trastuzumab monotherapy. Proc Am Assoc Cancer Res 2005; 46: (abstract
Adding another HER2 inhibitor, pertuzumab, to trastuzumab has 5062).
14. Tripathy D, Slamon DJ, Cobleigh M, et al. Safety of treatment of metastatic
shown activity in two phase II studies of patients who progressed on breast cancer with trastuzumab beyond disease progression. J Clin Oncol 2004;
prior trastuzumab.37,52 In the larger study by Baselga et al37 (Table 22:1063-70.
15. Pusztai L, Esteva FJ. Continued use of trastuzumab (Herceptin) after progression on
2), the ORR was 24% (5 CRs and 11 PRs of 66 evaluable patients), prior trastuzumab therapy in HER-2-positive metastatic breast cancer. Cancer Invest
and a further 17 patients had stable disease lasting ⱖ 6 months, 2006; 24:187-91.
16. Gelmon KA, Mackey J, Verma S, et al. Use of trastuzumab beyond disease progres-
resulting in a CBR of 50%. The median duration of response was 5.8 sion: observations from a retrospective review of case histories. Clin Breast Cancer
months, and median PFS was 5.5 months. Pertuzumab combined 2004; 5:52-8.
17. Stemmler HJ, Kahlert S, Siekiera W, et al. Prolonged survival of patients receiving
with trastuzumab is being evaluated in the ongoing, phase II trastuzumab beyond disease progression for HER2 overexpressing metastatic breast
PHEREXA trial described previously, as well as in the phase III, cancer (MBC). Onkologie 2005; 28:582-6.
18. Tokajuk P, Czartoryska-Arlukowicz B, Wojtukiewicz MZ. Activity of trastuzumab-
global Clinical Evaluation of Pertuzumab and Trastuzumab (CLEO- based therapy beyond disease progression in heavily pretreated metastatic breast
PATRA) trial of trastuzumab plus docetaxel with or without pertu- cancer patients – single institution experience. J Clin Oncol 2006; 24(suppl 18):614s
(abstract 13159).
zumab in patients who previously received trastuzumab.53 The re- 19. Waddell T, Kotsori A, Constantinidou A, et al. Trastuzumab beyond progression in
sults of this study, as well as others evaluating trastuzumab combined HER2-positive advanced breast cancer: the Royal Marsden experience. Cancer Res
2010; 70(suppl 24):449s-50s.
with a variety of agents following disease progression during or after 20. Fountzilas G, Razis E, Tsavdaridis D, et al. Continuation of trastuzumab beyond
first-line trastuzumab-based therapy are eagerly awaited. disease progression is feasible and safe in patients with metastatic breast cancer: a
retrospective analysis of 80 cases by the Hellenic Cooperative Oncology Group. Clin
Breast Cancer 2003; 4:120-5.
Acknowledgment 21. García-Sáenz J, Martín M, Bueno C, et al. Trastuzumab associated with successive
cytotoxic therapies beyond disease progression in metastatic breast cancer. J Clin
Support for third-party writing assistance for this manuscript was Oncol 2006; 24(suppl 18):577s. (abstract 10617).
provided by Genentech, Inc. 22. Fabi A, Metro G, Ferretti G, et al. Do HER-2 positive metastatic breast cancer
patients benefit from the use of trastuzumab beyond disease progression? A mono-
institutional experience and systematic review of observational studies. Breast 2008;
Disclosure 17:499-505.
Dr. Pegram serves on the scientific advisory board of Takeda/ 23. Cancello G, Montagna E, D’Agostino D, et al. Continuing trastuzumab beyond
disease progression: outcomes analysis in patients with metastatic breast cancer.
Millennium and serves on advisory panels for Genentech/Roche, Breast Cancer Res 2008; 10:R60.
GlaxoSmithKline, and Pfizer/Wyeth. Dr. Liao has no conflicts of 24. Montemurro F, Viale G, Donadio M, et al. Retrospective evaluation of clinical out-
comes in patients with HER2-positive advanced breast cancer progressing on trastu-
interest to disclose. zumab-based therapy in the pre-lapatinib era. Clin Breast Cancer 2008; 8:436-42.
25. Montemurro F, Redana S, Nolè F, et al. Vinorelbine-based salvage therapy in
HER2-positive metastatic breast cancer patients progressing during trastuzumab-
References containing regimens: a retrospective study. BMC Cancer 2008; 8:209.
1. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy 26. Metro G, Fabi A, Giannarelli D, et al. Time to first tumor progression as outcome
for operable HER2-positive breast cancer. N Engl J Med 2005; 353:1673-84. predictor of a second trastuzumab-based therapy beyond progression in HER-2
2. Slamon DJ, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive positive metastatic breast cancer. J Clin Oncol 2008; 26(suppl 15s):58s. (abstract
breast cancer. N Engl J Med 2011; 365:1273-83. 1071).

Clinical Breast Cancer February 2012 17

 Trastuzumab Treatment in Multiple Lines
27. Christodoulou C, Klouvas G, Pateli A, et al. Prolonged administration of weekly 41. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in
paclitaxel and trastuzumab in patients with advanced breast cancer. Anticancer Res human epidermal growth factor receptor 2–positive advanced breast cancer: a Ger-
2003; 23:737-44. man Breast Group 26/Breast International Group 03-05 study. J Clin Oncol 2009;
28. Bartsch R, Wenzel C, Hussian D, et al. Analysis of trastuzumab and chemotherapy 27:1999-2006.
in advanced breast cancer after the failure of at least 1 earlier combination: an 42. von Minckwitz G, Schwedler K, Schmidt M, et al. Final overall survival analysis of
observational study. BMC Cancer 2006; 6:63. the TBP phase III study (GBG 26 / BIG 3-05): capecitabine vs capecitabine ⫹
29. Orlando L, Cardillo A, Ghisini R, et al. Trastuzumab in combination with metro- trastuzumab in patients with HER2-positive metastatic breast cancer progressing
nomic cyclophosphamide and methotrexate in patients with HER-2 positive met- during trastuzumab treatment. Cancer Res 2010; 70(suppl 24):459s (abstract P6-
astatic breast cancer. BMC Cancer 2006; 6:225. 14-05).
30. Bangemann N, Kuhle A, Willrodt RG, et al. Treatment of HER2 overexpressing 43. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-
metastatic breast cancer with trastuzumab (HERceptin) and chemotherapy. Breast positive advanced breast cancer. N Engl J Med 2006; 355:2733-43.
Cancer Res Treat 2000; 64:123(530a). 44. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib
31. Chollet P, Durando X, Mauriac L, et al. Clinical benefit with trastuzumab (Her- alone or in combination with trastuzumab in women with ErbB2-positive, trastu-
ceptin®) plus vinorelbine beyond disease progression in women with HER2-posi- zumab-refractory metastatic breast cancer. J Clin Oncol 2010; 28:1124-30.
tive metastatic breast cancer. Proc Breast Cancer Symp 2007; 179 (abstract 243). 45. Blackwell KL, Burstein HJ, Sledge G, et al. Updated survival analysis of a random-
32. Bartsch R, Wenzel C, Gampenrieder SP, et al. Trastuzumab and gemcitabine as ized study of lapatinib alone or in combination with trastuzumab in women with
salvage therapy in heavily pre-treated patients with metastatic breast cancer. Cancer HER2-positive metastatic breast cancer progressing on trastuzumab therapy. Cancer
Chemother Pharmacol 2008; 62:903-10. Res 2009; 69(24 suppl):499s (abstract 61).
33. Morabito A, Longo R, Gattuso D, et al. Trastuzumab in combination with gemcit- 46. Lang I, Bell R, Feng F, et al. Trastuzumab use at relapse after adjuvant trastuzumab
abine and vinorelbine as second-line therapy for HER-2/neu overexpressing meta-
therapy in HER2-positive breast cancer. J Clin Oncol 2011; 29(15s);63s (abstr 575).
static breast cancer. Oncol Rep 2006; 16:393-8.
47. Munoz-Mateu M, Urruticoechea A, Separovic R, et al. Trastuzumab plus capecit-
34. Bartsch R, Wenzel C, Altorjai G, et al. Combination of capecitabine and trastu-
abine with or without pertuzumab in patients with HER2-positive MBC whose
zumab is effective in heavily pretreated patients with metastatic breast cancer. Proc
disease has progressed during or following trastuzumab-based therapy for first-line
Breast Symp 2007: 136 (abstract 154).
metastatic disease: a multicenter, randomized, two-arm, phase II study (PHEREXA).
35. André F, Campone M, Hurvitz SA, et al. Multicenter phase I clinical trial of daily
and weekly RAD001 in combination with weekly paclitaxel and trastuzumab in J Clin Oncol 2011; 29(suppl 15):11s (abstr TPS118).
patients with HER2-overexpressing metastatic breast cancer with prior resistance to 48. Pegram M, Hsu S, Lewis G, et al. Inhibitory effects of combinations of HER-2/neu
trastuzumab. J Clin Oncol 2008; 26(suppl 15):41s (abstract 1003). antibody and chemotherapeutic agents used for treatment of human breast cancers.
36. Montemurro F, Faggiuolo R, Redana S, et al. Continuation of trastuzumab beyond Oncogene 1999; 18:2241-51.
disease progression. J Clin Oncol 2005; 23:2866-8; discussion 2868-9. 49. Pegram MD, Lopez A, Konecny G, et al. Trastuzumab and chemotherapeutics:
37. Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab drug interactions and synergies. Semin Oncol 2000; 27(Suppl 11):21-5.
in patients with human epidermal growth factor receptor 2-positive metastatic 50. Mannocci A, De Feo E, de Waure C, et al. Use of trastuzumab in HER2-positive
breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 2010; metastatic breast cancer beyond disease progression: a systematic review of pub-
28:1138-44. lished studies. Tumori 2010; 96:385-91.
38. Antoine E-C, Extra J-M, Vincent-Salomon A, et al. Favourable multiple lines of 51. Bartsch R, De Vries C, Pluschnig U, et al. Predicting for activity of second-line
trastuzumab (Herceptin®) may provide a survival benefit for women with HER2- trastuzumab-based therapy in her2-positive advanced breast cancer. BMC Cancer
positive metastatic breast cancer: data from the Hermine Cohort study. Proc Breast 2009; 9:367.
Symp 2007: 173 (abstract 230). 52. Portera C, Walshe J, Rosing D, et al. Cardiac toxicity and efficacy of trastu-
39. Extra JM, Antoine EC, Vincent-Salomon A, et al. Efficacy of trastuzumab in routine zumab combined with pertuzumab in patients with [corrected] human epider-
clinical practice and after progression for metastatic breast cancer patients: The mal growth factor receptor 2-positive metastatic breast cancer. Clin Cancer Res
Observational Hermine Study. Oncologist 2010; 15:799-809. 2008; 14:2710-16.
40. Rugo HS, Kaufman PA, Ulcickas Wood M, et al. registHER: an observational 53. Baselga J, Imadalou K, Paton V, et al. Efficacy, safety and tolerability of dual
cohort study of survival of patients with HER2-positive metastatic breast cancer and monoclonal antibody therapy with pertuzumab ⫹ trastuzumab in HER2⫹ meta-
use of trastuzumab following progression. Cancer Res 2009; 69(suppl 2):250s (ab- static breast cancer patients previously treated with trastuzumab. Cancer Res 2009;
stract 3142). 69(suppl 2):249s (abstract 3138).

18 Clinical Breast Cancer February 2012