Trastuzumab Treatment in Multiple Lines: Current Data and Future Directions

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 Trastuzumab (Herceptin, Genentech Inc, South San Francisco, CA, USA) is a humanized recombinant monoclonal antibody directed against the extracellular domain of human epidermal growth factor receptor 2 (HER2) and has been used for more than 10 years to treat HER2-positive breast cancer. Adjuvant trastuzumab improves diseasefree survival (DFS) and overall survival (OS) when combined with chemotherapy1-3 or when used as monotherapy following chemotherapy.4,5 When combined with chemotherapy in the neoadjuvant setting, trastuzumab improves pathologic complete response and DFS.6,7 In metastatic breast cancer (MBC), first-line trastuzumab plus chemotherapy improves response rate, time to progression (TTP), and OS.8 Second- or third-line trastuzumab monotherapy produces durable objective responses for women progressing on chemotherapy.9

University of Miami Sylvester Comprehensive Cancer Center, Miami, FL Submitted: April 21, 2011; Revised: July 22, 2011; Accepted: July 25, 2011 Address for correspondence: Mark Pegram, MD, University of Miami Sylvester Comprehensive Cancer Center, Biomedical Research Building (BRB) 731 - 1501 N.W. 10th Ave. - Miami, FL 33136. Tel: 305-243-8823; fax: 305-243-6170; e-mail contact: [email protected]

10

Clinical Breast Cancer February 2012

In metastatic disease, a chemotherapy regimen is generally administered until disease progression, and then replaced with another agent. A similar approach was adopted with trastuzumab in clinical trials. However, as a molecularly targeted drug, there may be more effective ways of using trastuzumab in clinical practice. Although anecdotal clinical and preclinical evidence suggests that trastuzumab beyond disease progression may be beneficial, as described later, it has been challenging to test this hypothesis in randomized trials within the United States (US). Nevertheless, many patients are receiving trastuzumab beyond disease progression in clinical practice.10 Furthermore, the current National Comprehensive Cancer Network (NCCN) Practice Guidelines recommend continuing HER2 blockade for HER2-positive disease progressing on first-line, trastuzumab-based regimens, using a trastuzumab-based regimen, lapatinib plus capecitabine, or trastuzumab and lapatinib.11 This review addresses the available evidence for the use of trastuzumab beyond progression and discusses a growing number of studies—including randomized prospective clinical trials of trastuzumab regimens beyond disease progression—in patients with HER2-positive MBC.

1526-8209/$ - see frontmatter © 2012 Published by Elsevier Inc. doi: 10.1016/j.clbc.2011.07.003

Preclinical Rationale for Using Trastuzumab Beyond Disease Progression Designing preclinical studies to evaluate trastuzumab beyond disease progression is difficult because it is challenging to transform a trastuzumab-sensitive cell line into a resistant cell line and to develop experimental models that mimic the clinical setting. However, preclinical evidence supports the concept of continuing trastuzumab beyond disease progression. Pietras et al12 showed that trastuzumab decreased tumor growth in breast cancer xenografts in a dose-dependent manner. When trastuzumab was discontinued, its cytostatic effect ceased and rapid tumor regrowth occurred, suggesting that optimal inhibition may require continued application. Another preclinical study in a murine model of MBC found that trastuzumab added to taxanes synergistically inhibits tumor growth, even after disease progression following initial trastuzumab monotherapy.13

Clinical Evaluation of Trastuzumab Efficacy Beyond Disease Progression The potential clinical utility of trastuzumab in multiple lines of therapy was supported by an extension study of 247 patients enrolled in the original pivotal trial of trastuzumab in MBC.14 Patients continuing trastuzumab beyond disease progression in this trial achieved only modest responses to treatment. The overall response rate (ORR) was 11%, and the clinical benefit rate (CBR) was 22%. Responses were observed both with trastuzumab alone (n ⫽ 71) and in combination with chemotherapy (n ⫽ 176). These results led investigators in the United States to initiate randomized trials of trastuzumab in multiple lines of therapy. In a trial at the MD Anderson Cancer Center (MDACC DM99-135/ H2132n), patients whose disease had progressed following a trastuzumab-based regimen were randomized to trastuzumab plus vinorelbine or vinorelbine monotherapy.15 This trial was closed early because of poor accrual (only 16 patients enrolled at five study centers during a 20-month period); this was partly attributed to physician and patient concerns about randomization to the non–trastuzumab-containing arm.15 A similar trial was initiated by the Southwest Oncology Group (S0347/NCT00103233). Patients who had progressed following treatment with a taxane plus trastuzumab were randomized to trastuzumab plus vinorelbine or vinorelbine alone (ClinicalTrials.gov). The projected accrual for this trial was 292 patients; unfortunately, accrual was also slow, and the trial closed early.15

Retrospective Studies The lack of data from randomized trials led investigators to perform studies retrospectively. In general, these studies support the hypothesis that continuation of trastuzumab after disease progression may potentiate the effects of further cytotoxic regimens. However, the results are somewhat heterogeneous (Table 1).16-25 A retrospective analysis of medical charts from 13 centers in Europe, Australia, and Canada16 found that ORRs with a second trastuzumab-based regimen compared favorably to those obtained with the first. Moreover, some women who did not respond to first-line trastuzumab responded to second-line trastuzumab. Similarly, data from

patients at three Italian institutions found favorable response rates with trastuzumab following disease progression.17 Patients receiving at least two trastuzumab-containing lines for metastatic disease compared with one line survived significantly longer (median 62.4 months versus 38.5 months; P ⫽ .01). Additional data obtained from single-institution analyses also support the continuation of trastuzumab treatment beyond progression. In one study, Tokajuk et al reported that patients receiving two or more trastuzumab-containing regimens survived significantly longer than those who discontinued trastuzumab at disease progression (P ⫽ .02).18 Another study analyzed response data from 93 patients who had received additional trastuzumab treatment following progression (either after adjuvant therapy or following one line of treatment for advanced disease).19 The CBR in these patients was 60%, the median TTP was 24 weeks (95% confidence interval [CI] 21-28 weeks), and the median OS was 19 months (95% CI, 12-24 months). Although, in theory, the anti-tumor effect of trastuzumab may continue across multiple lines of therapy, clinical outcomes and TTP do tend to worsen with each subsequent line. The Hellenic Cooperative Oncology Group reviewed medical records of 80 patients.20 When trastuzumab was used in two lines of therapy, 24% of patients achieved an objective response (including 3 complete responses [CRs]) versus 14% with three lines of therapy (including 1 CR). Partial responses (PRs) were reported in 19% and 8% of patients receiving four and five lines of trastuzumab, respectively. Across the patient population, the median OS was 22.2 months. Decreasing response rates with subsequent trastuzumab lines were also reported in a Spanish review of hospital records,21 although TTP remained relatively constant at 4 to 5 months across treatment lines. Multivariate analysis found that response to the first line of trastuzumab was significantly associated with response to subsequent lines (odds ratio 3.84; 95% CI, 1.07-14.64; P ⫽ .04). A single-center Italian study also found notable CBRs and improved TTP with a second trastuzumab-based regimen beyond progression.22 In an extension of this study, it was found that a longer TTP during the first line of trastuzumab predicted longer TTP (P ⫽ .009) and post-progression survival (P ⫽ .04) during the second trastuzumab-containing regimen.26 Another Italian retrospective analysis found a trend for better survival from the start of trastuzumab in patients continuing beyond disease progression compared with those who halted the drug (hazard ratio [HR], 0.78; 95% CI, 0.58-1.32).23 Two retrospective studies have reported no clinical benefit from continuing trastuzumab beyond progression in MBC.24,25 In one study, 112 patients who discontinued trastuzumab were compared with 83 patients who continued trastuzumab.24 No significant differences were observed in terms of ORR (28% versus 30%; P ⫽ .5), median time to second progression (8.4 months versus 7.0 months; P ⫽ .24), or median post-progression OS (20.6 months versus 15.4 months; P ⫽ .29). In the other study, vinorelbine-based salvage therapies were retrospectively investigated in 60 patients progressing during initial treatment with a trastuzumab-based regimen.25 Of these, 29 patients receiving vinorelbine-based salvage treatment and continued trastuzumab had an ORR of 21% and a CBR of 48%. In the 31 patients who stopped trastuzumab, the ORR was 36% and the CBR was 58%. Similarly, TTP did not 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 Author Gelmon et al16 Stemmler et al17

Treatment Line

Patients (n)

ORR (%)

CBR (%)

Median TTP (Months)

1

77

39

69

5.4

2

65

32

54

6

1

23

57

NR

7.4

2

23

39

NR

NR

1

27

56

NR

5.8

Tokajuk et al18

2

14

50

NR

5.1

3 to 5

6

67

NR

NR

Wadell et al19

After adjuvant or 1

93

NR

60

6

2

80

24

52

5.2

3

49

14

38

3.5

4

26

19

50

4.9

5

12

8

33

3.9

1

93

46

71

5

2

47

30

51

4

3

21

38

62

4

4

10

20

40

4

Fountzilas et al20

21

García-Sáenz et al

Fabi et al22

Cancello et al23

Montemurro et al24 Montemurro et al25

5

5

0

60

NR

1

59

59

83

9.5

2

37

27

62

6.7

3

16

0

19

4

4

9

0

33

4.5

1

57

35

74

7.25

2

55

16

53

5.25

3

26

15

60

5.25

Median OS (Months) 29

62.4

Not reached

19

22.2

NR

37

29.9

42.3

4

12

0

17

3.75

1

112

28

NR

7.0

15.4

2 or more

83

30

NR

8.4

20.6

1

31

36

58

7.1

NR

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 months versus 7.1 months; P ⫽ .10). In summary, of 10 retrospective studies, 8 suggested a possible benefit when continuing trastuzumab beyond disease progression, whereas two did not. However, these findings needed to be tested in an adequately powered prospective study in order to be confirmed.

Prospective Non-Randomized Studies Data from several completed and ongoing, non-comparative studies indicate responses and clinical benefit from continuing trastuzumab beyond disease progression (Table 2).14,27-40 Christodoulou et al27 evaluated trastuzumab plus weekly paclitaxel after disease progression in 26 women with metastatic disease. Treatment was only stopped in the event of unacceptable toxicity or death, irrespective of

12

Clinical Breast Cancer February 2012

disease progression. Median duration of treatment was 28 weeks for paclitaxel and 59 weeks for trastuzumab, producing an ORR of 62% (2 CRs and 14 PRs). Median OS exceeded 34 months, which compared favorably with OS in the pivotal randomized study evaluating trastuzumab plus chemotherapy until disease progression (25 months in women with HER2-positive disease receiving paclitaxel every 3 weeks).8 In another prospective study, clinical benefits, including two CRs, were reported in 69% of the 54 patients who received second-line treatment with a trastuzumab-based regimen.28 In addition, TTP (6 months) did not decrease significantly from first-line to beyond second-line treatment. Clinical benefit beyond progression has also been reported when trastuzumab is combined with chemotherapeutic agents (Table 2), including paclitaxel,27 metronomic low-dose cyclophosphamide and

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

Patients (n)

ORR (%)

CBR (%)

Median TTP (Months)

Median OS (Months)

Use of T beyond disease progression (⫹ paclitaxel)

26

62

NR

11

⬎34

Tripathy et al14

Use of T beyond disease progression (monotherapy or ⫹ chemotherapy)

93

11

22

NR

NR

First-line (⫹ chemotherapy)

54

43

85

6

Bartsch et al28

Use of T beyond disease progression (⫹ second-line chemotherapy)

54

26

69

6

Use of T beyond disease progression (⫹ 3⫺6-line chemotherapy)

33

30

58

6

Use of T beyond disease progression (⫹ cyclophosphamide ⫹ methotrexate)

11

18

27

NR

Use of T beyond disease progression ⫹ vinorelbine

10

40

Use of T beyond disease progression ⫹ capecitabine

17

53

Use of T beyond disease progression ⫹ docetaxel

9

33

Chollet et al31

Use of T beyond disease progression (⫹ vinorelbine)

17

29

53

NR

NR

Bartsch et al32

Use of T beyond disease progression (⫹ gemcitabine)

29

19

46

3

17

Morabito et al33

Use of T beyond disease progression (⫹ vinorelbine ⫹ gemcitabine)

7

29

57

NR

NR

Bartsch et al, 200734

Use of T beyond disease progression (⫹ capecitabine)

40

20

70

8

24

André et al35

Use of T beyond disease progression (⫹ paclitaxel ⫹ everolimus)

13

46

83

NR

NR

Use of T beyond disease progression (⫹ docetaxel)

6

NR

NR

NR

20

Halt T at disease progression (then continue docetaxel)

23

17%

50

NR

19

Use of T beyond disease progression (⫹ pertuzumab)

66

24

50

5.5

NR

Use of T beyond disease progression (first-line)‡

107

NR

NR

10.1

Not reached at 27.8 months

Halt T at disease progression (first-line)‡

70

NR

NR

7.1

16.8

Use of T beyond disease progression (second-line)

87

NR

NR

7.6

27.1

Halt T at disease progression (second-line)

30

NR

NR

5.6

15.6

Use of T beyond disease progression (first-line)

107

NR

NR

10.2

⬎ 27.8 (21.3†)

Halt T at disease progression (first-line)

70

NR

NR

7.1

16.8 (4.6†)

Use of T beyond disease progression (first-line)

527

NR

NR

NR

21.1†

Halt T at disease progression (first-line)

115

NR

NR

NR

5.9†

Author Christodoulou et al27

Orlando et al29

Bangemann et al30

Montemurro et al36

Baselga et al37

Antoine et al38

Extra et al39

Rugo et al40

Not reached at 24 months

NR

3 NR

NR

3 3.5

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 vinorelbine,33 capecitabine,30,34 and paclitaxel and everolimus.35 However, OS was not improved in an analysis of six patients participating in a phase II study of docetaxel plus trastuzumab who continued trastuzumab beyond disease progression.36 Median OS in these patients was 20 months, similar to the 19 months observed in patients who halted trastuzumab. Non-randomized, observational cohort studies have compared response rates and survival outcomes in patients receiving trastuzumab after disease progression with those who have halted trastuzumab. In an analysis of the Hermine Cohort study of trastuzumab use in routine clinical practice, 194 patients who continued trastuzumab-based therapy in multiple lines were compared with 100 patients who stopped trastuzumab at progression.38 Continuing trastuzumab beyond disease progression in first-line MBC was an independent prognostic factor for survival (HR, 0.062; 95% CI, 0.02-0.26); and TTP was also prolonged in patients continuing trastuzumab beyond progression the second line (Table 2). The final results of the Hermine study were recently published,39 including the subanalysis of trastuzumab treatment beyond progression in the 177 patients who received first-line trastuzumab and either continued trastuzumab for 30 days following progression or stopped trastuzumab at or before progression (Table 2). Median OS from treatment initiation and TTP were longer for patients who continued trastuzumab (⬎27.8 months and 21.3 months, respectively) than for those who stopped trastuzumab (10.2 months and 7.1 months, respectively). However, it was noted that patients who continued trastuzumab beyond progression initially had a better prognosis than those who did not continue treatment. In a large observational cohort study of 1023 patients with HER2-positive MBC (registHER), 879 patients (87%) received trastuzumab in the first-line setting, either as monotherapy or in combination with hormone therapy and/or chemotherapy. A multivariate analysis found that the unadjusted HR for survival in patients receiving trastuzumab beyond first progression (n ⫽ 527, 21.1 months) compared with those who did not (n ⫽ 115) was 0.25, suggesting improved survival for those who did continue trastuzumab40 (Table 2). This HR was unchanged when lapatinib use was considered. The findings of prospective non-randomized studies must be interpreted with caution because of the bias inherent in selecting patients who should continue trastuzumab treatment. This would be avoided by randomizing patients to different treatment arms in controlled prospective studies, and data from such studies are now available.

Prospective Randomized Studies The German Breast Group (GBG) 26/BIG 3-05 phase III study prospectively evaluated whether trastuzumab should continue beyond disease progression.41,42 Patients with HER2-positive, locally advanced or MBC who received trastuzumab previously (either adjuvant or first-line), were randomized to capecitabine alone (n ⫽ 78) or capecitabine plus trastuzumab (n ⫽ 78) until progression. The primary objective was to compare TTP between the two groups. Secondary end-points included ORR, CBR, and OS. Over a median follow-up of 15.6 months, continuing trastuzumab improved the efficacy of second-line capecitabine in terms of TTP

14

Clinical Breast Cancer February 2012

(8.2 months versus 5.6 months; HR, 0.69; two-sided log rank P ⫽ .0338; one-sided log rank P ⫽ .0169), ORR (48.1% versus 27.0%; P ⫽ .0115) and CBR (75.3% versus 54.1%; P ⫽ .0068),41 although no significant difference in OS was reported (24.9 months versus 20.6 months; P ⫽ .73).42 In a post hoc analysis of this study, however, patients who received third-line anti-HER2 therapy (either trastuzumab or lapatinib) experienced longer median OS than those who did not (18.8 months versus 13.3 months; HR, 0.63; P ⫽.02), suggesting that there may be additional benefit in continuing antiHER2 treatment across even further lines of therapy.42 Enrollment in this study (n ⫽ 156) was lower than what was originally targeted (n ⫽ 482), which may have affected its statistical power. However, trastuzumab combined with capecitabine is a recommended option in the NCCN Practice Guidelines for HER2-positive disease progressing on previous trastuzumab-based treatment.11 The relatively low number of patients enrolled in the GBG 26/ BIG 03-05 trial was probably a result of the US Food and Drug Administration approval of lapatinib (Tykerb; GlaxoSmithKline, Research Triangle Park, NC, USA), which is indicated for patients who have received prior therapy, including an anthracycline, a taxane, and trastuzumab. Lapatinib approval was based on a phase III, randomized trial of capecitabine plus lapatinib versus capecitabine monotherapy in 324 patients with progressive HER2-positive disease who had previously been treated with an anthracycline, a taxane, and trastuzumab.43 The primary end-point was TTP and the secondary end-points were progression-free survival (PFS), OS, ORR, and CBR. Adding lapatinib to capecitabine resulted in a TTP of 8.4 months compared with 4.4 months with capecitabine monotherapy, and the risk of disease progression was reduced by 51% (HR, 0.49; P ⬍ .001). Adding lapatinib to capecitabine did not significantly improve ORR (22% versus 14%; P ⫽ .09) or OS (HR, 0.92; P ⫽ .72). The 51% reduction in risk of progression with lapatinib use reported by Geyer et al43 is higher than the 31% reduction in risk reported by von Minckwitz et al41 (Table 3).41-43 Conversely, the ORR in the trastuzumab plus capecitabine group in the GBG 26/BIG 3-05 study (48%)41 is higher than that reported for the lapatinib plus capecitabine group reported in the study by Geyer et al (22%).43 However, it is not possible to make a direct comparison between the results from these trials because of substantive differences between the patient populations. For example, the study populations differ in terms of their treatment with prior anthracyclines (97% versus 69%) and taxanes (97% versus 85%), and the percentage of patients who had estrogen receptor–negative/progesterone receptor–negative disease (49% versus 38%, respectively; Table 4).41-43 Furthermore, whereas disease stage (ie, MBC or stage IIIB/IIIC disease) was reported in the Geyer study, only disease stage at first diagnosis (subdivided as T stage, N stage, and M stage) was reported for GBG 26/BIG 3-05. Thus, it is not possible, based on the available data, to ascertain which of these approaches is most suitable. The activity of a different HER2 inhibitor (lapatinib) and of trastuzumab, each combined with chemotherapy, after progression on trastuzumab-containing therapy suggests that these tumors continue to be dependent on the HER2 pathway after progression. Thus, these data provide a rationale for combining

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 Capecitabine ⴙ Trastuzumab (n ⴝ 78)

Capecitabine (n ⴝ 161)

Capecitabine ⴙ Lapatinib (n ⴝ 163)

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)*

Measure

HR for Progression (95% CI) Median TTP, Months (95% CI, if reported) HR for Death (95% CI) Median Survival, Months (95% CI)

0.49 (0.34-0.71) in favor of lapatinib arm* 4.4

8.4*

0.92 (0.58-1.46) in favor of lapatinib arm NR

NR

Capecitabine (n ⴝ 78)

0.69 (0.48-0.97) in favor of trastuzumab arm* 8.2 (7.3-11.2)†

5.6 (4.2-6.3)

0.94 (0.65-1.35) in favor of trastuzumab arm 25.5 (19.0-30.7)†

20.4 (17.8-24.7)

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 Geyer et al, 200643 Capecitabine ⴞ Lapatinib (n ⴝ 324)

von Minckwitz et al, 2009, 201041,42 Capecitabine ⴞ Trastuzumab (n ⴝ 156)

Previous Therapy with Anthracyclines, %

97

69

Previous Therapy with Taxanes

97

85

Estrogen Receptor– and Progesterone Receptor–Negative Disease

49

38

Characteristic

HER2 inhibitors, thereby potentially offering a treatment option without many of the chemotherapy-related toxicities. Results have recently been published from a randomized phase III study of lapatinib alone (n ⫽ 148) versus lapatinib plus trastuzumab (n ⫽ 148) in patients with MBC who had progressed on a trastuzumab-containing regimen.44 The primary end-point was PFS, and secondary end-points included response rate, CBR (ie, CR ⫹ PR ⫹ stable disease ⱖ 6 months), and OS. Compared with patients receiving lapatinib alone, patients receiving lapatinib plus trastuzumab had a significantly longer duration of PFS (12 weeks versus 8.1 weeks, HR, 0.73; P ⫽ .008) and greater CBR (25% versus 12%; P ⫽ .01). The response rate was not statistically significantly different between the two groups (10% versus 7%; P ⫽ .46). Initially, there was a trend toward improved OS with continued trastuzumab (25% reduction in the risk of death; HR, 0.75; P ⫽ .106).44 With longer follow-up, these OS results have become statistically significant with median OS of 9.5 months with lapatinib compared with 14 months with lapatinib plus trastuzumab (HR, 0.74; 95% CI, 0.57-0.97; P ⫽ .026).45 The NCCN Practice Guidelines now list trastuzumab combined with lapatinib as a treatment option for patients with HER2-positive disease that progresses on first-line, trastuzumabbased regimens.11

Safety of Trastuzumab Treatment Beyond Disease Progression Cytotoxic chemotherapy may be stopped at disease progression to avoid exposing patients to unnecessary toxicity in the absence of clinical benefit. Therefore, it is important to weigh any toxicity against the therapeutic effect of trastuzumab beyond disease progression. An extension study to the pivotal trial of trastuzumab plus chemotherapy in MBC found no unexpected adverse events with the use of long-term (up to 40⫹ months) trastuzumab.14 This is supported by other safety data from clinical studies in which prolonged trastuzumab use was generally well-tolerated, and adverse events could be attributed to the chemotherapy combined with trastuzumab rather than trastuzumab itself.19,27,28 Cardiac events were reported in a minority of patients. However, these were generally manageable with standard treatment.

Ongoing Studies of Trastuzumab Beyond Disease Progression There are still questions about how best to use trastuzumab beyond disease progression in patients with MBC. Given that adjuvant trastuzumab is increasingly used, it is important to assess the benefit of re-exposing patients with MBC to trastuzumab following relapse 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, OpenLabel, 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 every 3 weeks Disease progression during or after previous first-line chemotherapy + trastuzumab (n = 274) Second-line chemotherapy

B

Disease progression during or after previous first-line chemotherapy + trastuzumab (n = 300)

Second-line chemotherapy + trastuzumab 2 mg/kg IV every week or 6 mg/kg IV every 3 weeks

Primary endpoint: Time to progression Secondary endpoints: Overall response rate Clinical benefit rate Time to treatment failure Overall survival

Primary endpoint: Progression-free survival Secondary endpoints: Overall response rate Overall survival

Second-line chemotherapy

(RHEA) study is a phase II, prospective, open-label, ex-US study of first-line trastuzumab treatment with or without a taxane in patients with MBC who have relapsed after initial (neo)adjuvant therapy with trastuzumab. The single-agent trastuzumab arm was terminated because of poor enrollment, but data from the 41 patients in the trastuzumab combination arm were promising: ORR was 61% (all PRs), with stable disease in 7 patients (17%), and progressive disease in 6 patients (15%).46 Median duration of response was 7 months, median PFS was 8 months, median time to treatment failure was 8 months, and CBR was 71%. A lapatinib-containing arm was not included, but it would be interesting to compare first-line lapatinib plus capecitabine with trastuzumab-based combination therapy and trastuzumab alone. Several other prospective clinical studies are planned or currently in progress to investigate the clinical utility of trastuzumab in multiple lines of therapy. Two phase III Hoffmann-La Roche–sponsored studies (PANDORA and THOR) will assess chemotherapy plus trastuzumab versus chemotherapy alone in MBC that progressed on first-line trastuzumab plus chemotherapy. In the open-label PANDORA study (NCT00444587), 274 patients progressing on a first-line chemotherapy regimen containing trastuzumab will be randomized to second-line chemotherapy with or without trastuzumab (Figure 1A). The primary endpoint is TTP. The THOR study (NCT00448279) is of similar design (Figure 1B), with the exception of the trastuzumab dosing regimen and primary end-point (PFS). With a targeted accrual of 300 patients, THOR is also expected to be completed in 2010. Another Hoffmann-La Roche–sponsored study, the open-label phase II PHEREXA study (NCT01026142), will randomize 450 patients

16

Clinical Breast Cancer February 2012

whose disease progressed on or following first-line trastuzumabbased therapy to trastuzumab and capecitabine with or without pertuzumab.47 The primary end-point of this study is PFS assessed by independent review. The Swiss Group for Clinical Cancer Research is evaluating the benefits of adding paclitaxel to trastuzumab (NCT00004935) or letrozole to trastuzumab (NCT00238290) following disease progression on first-line trastuzumab monotherapy.

Conclusions The synergy between trastuzumab and a variety of chemotherapeutic agents was first reported preclinically.48,49 Data from clinical studies show that this synergy can not only be exploited in the firstline and adjuvant settings but also, perhaps, beyond disease progression in pretreated patients. Data from retrospective and prospective clinical studies provide an indication that the use of trastuzumab in multiple lines of therapy is capable of eliciting objective responses and delaying disease progression. This is supported by a recent systematic review of eight retrospective and four prospective studies in which patients with HER2-positive MBC received trastuzumab beyond progression within various treatment regimens (n ⫽ 516). The mean time to progression was 23.7 weeks (median 26 weeks; range, 13 weeks to 39 weeks); combined trastuzumab plus vinorelbine showed a comparatively shorter mean and median time to progression (20.6 weeks and 19.6 weeks, respectively), whereas trastuzumab plus capecitabine was associated with a mean time to progression of 30.3 weeks. The authors concluded that trastuzumab-based regimens might have activity in HER2-positive MBC beyond progres-

M. Pegram, J. Liao sion, but additional randomized phase III trials are required to evaluate this further.50 Another open question is whether trastuzumab should remain the HER2-suppressing agent throughout multiple lines of treatment or whether clinical benefit would be increased if different HER2-targeted agents were used. There are no currently available data addressing this question. Similarly, a recent retrospective analysis showed that obtaining the answers to some of the open questions may involve further investigation of underlying mechanisms. In this analysis in 97 patients who had been treated with at least two lines of trastuzumabbased therapy for metastatic HER2-positive disease, second-line trastuzumab-based therapy showed activity as assessed by median TTP.51 However, the investigators were unable to identify a clinical or histopathologic feature predictive of response to treatment with trastuzumab across multiple lines, suggesting that exploration of underlying mechanisms of sensitivity to and progression on trastuzumab may be more useful in predicting response to trastuzumab or other HER2-targeted agents. In practice, trastuzumab has become a “backbone” of treatment across multiple lines of chemotherapy, with patients who progress during or after treatment with one trastuzumab-containing treatment regimen re-treated with another trastuzumab-containing regimen. The partnering agent(s) could be tailored to address the mechanisms that cause disease progression, such as other inhibitors of HER signaling (eg, lapatinib or pertuzumab), tumor cell signaling (eg, protease inhibitor 3 kinase inhibitors and mammalian target of rapamycin inhibitors), or tumor angiogenesis (eg, bevacizumab). Adding another HER2 inhibitor, pertuzumab, to trastuzumab has shown activity in two phase II studies of patients who progressed on prior trastuzumab.37,52 In the larger study by Baselga et al37 (Table 2), the ORR was 24% (5 CRs and 11 PRs of 66 evaluable patients), and a further 17 patients had stable disease lasting ⱖ 6 months, resulting in a CBR of 50%. The median duration of response was 5.8 months, and median PFS was 5.5 months. Pertuzumab combined with trastuzumab is being evaluated in the ongoing, phase II PHEREXA trial described previously, as well as in the phase III, global Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trial of trastuzumab plus docetaxel with or without pertuzumab in patients who previously received trastuzumab.53 The results of this study, as well as others evaluating trastuzumab combined with a variety of agents following disease progression during or after first-line trastuzumab-based therapy are eagerly awaited.

Acknowledgment Support for third-party writing assistance for this manuscript was provided by Genentech, Inc.

Disclosure Dr. Pegram serves on the scientific advisory board of Takeda/ Millennium and serves on advisory panels for Genentech/Roche, GlaxoSmithKline, and Pfizer/Wyeth. Dr. Liao has no conflicts of interest to disclose.

References 1. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:1673-84. 2. Slamon DJ, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365:1273-83.

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 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:3366-73. 4. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:1659-72. 5. Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:29-36. 6. Buzdar AU, Valero V, Ibrahim NK, et al. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res 2007; 13:228-33. 7. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised, controlled superiority trial with a parallel HER2-negative cohort. Lancet 2010; 375:377-84. 8. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783-92. 9. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17:2639-48. 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 Oncol 2008; 26(suppl 15):342s (abstract 6522). 11. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Breast Cancer. V.2.2011. National Comprehensive Cancer Network [website]. Available at: http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf. Accessed: February 9, 2011. 12. Pietras RJ, Pegram MD, Finn RS, et al. Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs. Oncogene 1998; 17:2235-49. 13. Fujimoto-Ouchi K, Sekiguchi F, Kazushige M. Preclinical study of continuous administration of trastuzumab as combination therapy after disease progression with trastuzumab monotherapy. Proc Am Assoc Cancer Res 2005; 46: (abstract 5062). 14. Tripathy D, Slamon DJ, Cobleigh M, et al. Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol 2004; 22:1063-70. 15. Pusztai L, Esteva FJ. Continued use of trastuzumab (Herceptin) after progression on prior trastuzumab therapy in HER-2-positive metastatic breast cancer. Cancer Invest 2006; 24:187-91. 16. Gelmon KA, Mackey J, Verma S, et al. Use of trastuzumab beyond disease progression: observations from a retrospective review of case histories. Clin Breast Cancer 2004; 5:52-8. 17. Stemmler HJ, Kahlert S, Siekiera W, et al. Prolonged survival of patients receiving trastuzumab beyond disease progression for HER2 overexpressing metastatic breast cancer (MBC). Onkologie 2005; 28:582-6. 18. Tokajuk P, Czartoryska-Arlukowicz B, Wojtukiewicz MZ. Activity of trastuzumabbased therapy beyond disease progression in heavily pretreated metastatic breast cancer patients – single institution experience. J Clin Oncol 2006; 24(suppl 18):614s (abstract 13159). 19. Waddell T, Kotsori A, Constantinidou A, et al. Trastuzumab beyond progression in HER2-positive advanced breast cancer: the Royal Marsden experience. Cancer Res 2010; 70(suppl 24):449s-50s. 20. Fountzilas G, Razis E, Tsavdaridis D, et al. Continuation of trastuzumab beyond 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. 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 Oncol 2006; 24(suppl 18):577s. (abstract 10617). 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 monoinstitutional experience and systematic review of observational studies. Breast 2008; 17:499-505. 23. Cancello G, Montagna E, D’Agostino D, et al. Continuing trastuzumab beyond disease progression: outcomes analysis in patients with metastatic breast cancer. Breast Cancer Res 2008; 10:R60. 24. Montemurro F, Viale G, Donadio M, et al. Retrospective evaluation of clinical outcomes in patients with HER2-positive advanced breast cancer progressing on trastuzumab-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 trastuzumabcontaining regimens: a retrospective study. BMC Cancer 2008; 8:209. 26. Metro G, Fabi A, Giannarelli D, et al. Time to first tumor progression as outcome predictor of a second trastuzumab-based therapy beyond progression in HER-2 positive metastatic breast cancer. J Clin Oncol 2008; 26(suppl 15s):58s. (abstract 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 paclitaxel and trastuzumab in patients with advanced breast cancer. Anticancer Res 2003; 23:737-44. 28. Bartsch R, Wenzel C, Hussian D, et al. Analysis of trastuzumab and chemotherapy in advanced breast cancer after the failure of at least 1 earlier combination: an observational study. BMC Cancer 2006; 6:63. 29. Orlando L, Cardillo A, Ghisini R, et al. Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer. BMC Cancer 2006; 6:225. 30. Bangemann N, Kuhle A, Willrodt RG, et al. Treatment of HER2 overexpressing metastatic breast cancer with trastuzumab (HERceptin) and chemotherapy. Breast Cancer Res Treat 2000; 64:123(530a). 31. Chollet P, Durando X, Mauriac L, et al. Clinical benefit with trastuzumab (Herceptin®) plus vinorelbine beyond disease progression in women with HER2-positive metastatic breast cancer. Proc Breast Cancer Symp 2007; 179 (abstract 243). 32. Bartsch R, Wenzel C, Gampenrieder SP, et al. Trastuzumab and gemcitabine as salvage therapy in heavily pre-treated patients with metastatic breast cancer. Cancer Chemother Pharmacol 2008; 62:903-10. 33. Morabito A, Longo R, Gattuso D, et al. Trastuzumab in combination with gemcitabine and vinorelbine as second-line therapy for HER-2/neu overexpressing metastatic breast cancer. Oncol Rep 2006; 16:393-8. 34. Bartsch R, Wenzel C, Altorjai G, et al. Combination of capecitabine and trastuzumab is effective in heavily pretreated patients with metastatic breast cancer. Proc Breast Symp 2007: 136 (abstract 154). 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 patients with HER2-overexpressing metastatic breast cancer with prior resistance to trastuzumab. J Clin Oncol 2008; 26(suppl 15):41s (abstract 1003). 36. Montemurro F, Faggiuolo R, Redana S, et al. Continuation of trastuzumab beyond disease progression. J Clin Oncol 2005; 23:2866-8; discussion 2868-9. 37. Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 2010; 28:1138-44. 38. Antoine E-C, Extra J-M, Vincent-Salomon A, et al. Favourable multiple lines of trastuzumab (Herceptin®) may provide a survival benefit for women with HER2positive metastatic breast cancer: data from the Hermine Cohort study. Proc Breast Symp 2007: 173 (abstract 230). 39. Extra JM, Antoine EC, Vincent-Salomon A, et al. Efficacy of trastuzumab in routine clinical practice and after progression for metastatic breast cancer patients: The Observational Hermine Study. Oncologist 2010; 15:799-809. 40. Rugo HS, Kaufman PA, Ulcickas Wood M, et al. registHER: an observational cohort study of survival of patients with HER2-positive metastatic breast cancer and use of trastuzumab following progression. Cancer Res 2009; 69(suppl 2):250s (abstract 3142).

18

Clinical Breast Cancer February 2012

41. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2–positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol 2009; 27:1999-2006. 42. von Minckwitz G, Schwedler K, Schmidt M, et al. Final overall survival analysis of the TBP phase III study (GBG 26 / BIG 3-05): capecitabine vs capecitabine ⫹ trastuzumab in patients with HER2-positive metastatic breast cancer progressing during trastuzumab treatment. Cancer Res 2010; 70(suppl 24):459s (abstract P614-05). 43. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2positive advanced breast cancer. N Engl J Med 2006; 355:2733-43. 44. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 2010; 28:1124-30. 45. Blackwell KL, Burstein HJ, Sledge G, et al. Updated survival analysis of a randomized study of lapatinib alone or in combination with trastuzumab in women with HER2-positive metastatic breast cancer progressing on trastuzumab therapy. Cancer Res 2009; 69(24 suppl):499s (abstract 61). 46. Lang I, Bell R, Feng F, et al. Trastuzumab use at relapse after adjuvant trastuzumab therapy in HER2-positive breast cancer. J Clin Oncol 2011; 29(15s);63s (abstr 575). 47. Munoz-Mateu M, Urruticoechea A, Separovic R, et al. Trastuzumab plus capecitabine with or without pertuzumab in patients with HER2-positive MBC whose disease has progressed during or following trastuzumab-based therapy for first-line metastatic disease: a multicenter, randomized, two-arm, phase II study (PHEREXA). J Clin Oncol 2011; 29(suppl 15):11s (abstr TPS118). 48. Pegram M, Hsu S, Lewis G, et al. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 1999; 18:2241-51. 49. Pegram MD, Lopez A, Konecny G, et al. Trastuzumab and chemotherapeutics: drug interactions and synergies. Semin Oncol 2000; 27(Suppl 11):21-5. 50. Mannocci A, De Feo E, de Waure C, et al. Use of trastuzumab in HER2-positive metastatic breast cancer beyond disease progression: a systematic review of published studies. Tumori 2010; 96:385-91. 51. Bartsch R, De Vries C, Pluschnig U, et al. Predicting for activity of second-line trastuzumab-based therapy in her2-positive advanced breast cancer. BMC Cancer 2009; 9:367. 52. Portera C, Walshe J, Rosing D, et al. Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with [corrected] human epidermal growth factor receptor 2-positive metastatic breast cancer. Clin Cancer Res 2008; 14:2710-16. 53. Baselga J, Imadalou K, Paton V, et al. Efficacy, safety and tolerability of dual monoclonal antibody therapy with pertuzumab ⫹ trastuzumab in HER2⫹ metastatic breast cancer patients previously treated with trastuzumab. Cancer Res 2009; 69(suppl 2):249s (abstract 3138).