A Pooled Analysis of 2618 Patients Treated With Trastuzumab Beyond Progression for Advanced Breast Cancer

Review

A Pooled Analysis of 2618 Patients Treated With Trastuzumab Beyond Progression for Advanced Breast Cancer Fausto Petrelli, Sandro Barni Abstract Background: In HER2⫹ MBC, continuing trastuzumab (T) after the progression during a first-line T-based regimen, represents 1 of the possible strategies, even if few data from randomized trials exist in this setting. Materials and Methods: The authors have performed a systematic review through PubMed, including all prospective and retrospective publications exploring the efficacy of a T-based second-line therapy in HER2⫹ MBC patients treated beyond progression with a first-line T-containing treatment. Pooled estimates of the RR, TTP, and OS were calculated. Results: A total of 29 studies (4 randomized controlled phase III trials, 2 observational studies, 8 prospective nonrandomized trials, and 15 retrospective case series) were retrieved for a total of 2618 patients. All were treated with a second-line, T-based treatment beyond progression with a first-line T-based chemotherapy. Overall, the median RR, TTP, and OS obtained from the selected articles were 28.7%, 7, and 24 months. Conclusions: This pooled analysis confirms that continuing T beyond the first progression continues to be 1 of the effective and preferred choices in HER2⫹ MBC, failing a (T-based) first-line regimen. Clinical Breast Cancer, Vol. 13, No. 2, 81-7 © 2013 Elsevier Inc. All rights reserved. Keywords: HER2-positive, Metastatic breast cancer, Second-line

Introduction The standard treatment of HER2-positive (HER2⫹) metastatic breast cancer (MBC), a poor prognosis subgroup that accounts for approximately 25% of all breast cancer (BC) subtypes,1 is the association of chemotherapy plus trastuzumab (T). T, a humanized monoclonal antibody against HER2, improves the outcome when added to cytotoxic drugs (either anthracyclines- or taxanes-based chemotherapy) and represents the (first-line) treatment of choice in stage IV HER2⫹ disease.2 When the disease becomes resistant to T and progresses, the conduct of choice is more doubtful. In fact, the only other agent approved in this setting is lapatinib, an oral HER2-epidermal growth factor receptor tyrosine kinases inhibitor, that improved time to progression (TTP) with a hazard ratio (HR) of 0.57 and provided a trend toward improved overall survival (OS) (HR, 0.78) when added to capecitabine versus capecitabine alone in women with HER2⫹, locally advanced or metastatic BC previously treated with anthracyAzienda Ospedaliera di Treviglio, UO Oncologia medica, Treviglio, Italia Submitted: Jul 23, 2012; Revised: Nov 8, 2012; Accepted: Nov 13, 2012; Epub: Dec 29, 2012 Address for correspondence: Fausto Petrelli, MD, Azienda Ospedaliera Treviglio; Piazzale Ospedale 1, 24047, Treviglio, BG Italy E-mail contact: [email protected]

1526-8209/$ - see frontmatter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2012.11.008

cline, taxane, and T.3 Recently, however, T emtansine (T-DM1), a novel HER2 antibody drug conjugate in which T is bound to the highly potent antimicrotubule agent (DM1), which is derived from the toxic chemotherapy, maytansine, showed increased benefit compared with the lapatinib/capecitabine combination (in the same setting of patients) in the EMILIA study (An Open-Label Study of Trastuzumab Emtansine [T-DM1] vs Capecitabine⫹Lapatinib in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer).4 Median progression-free survival was longer in patients treated with T-DM1 than in those treated with the standard therapy. The median OS for those treated with standard therapy was 23.3 months and not yet reached for T-DM1. Another strategy to overcome T resistance, when the disease progress on T-based first-line treatment, is to associate another anti-HER2 agent with T (either pertuzumab or lapatinib). However, these agents are still not approved for this indication.5,6 In the pre-lapatinib era, the conventional treatment of HER2positive (⫹) MBC after progression during a first-line (T-based) chemotherapy was to switch to another cytotoxic drug maintaining T even beyond progression. The aim is to continue the HER2 pathway blockade. However, even if various institutional case series have been published demonstrating a high level of activity in continuing T beyond progression, only 1 randomized trial has been presented. In this trial (German Breast cancer Group [GBG]-26 trial), patients

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Trastuzumab Beyond Progression in HER2ⴙ Advanced BC with HER2⫹ BC that progressed during treatment with T were randomly assigned to receive capecitabine alone or associated with T.7 The study met its primary end point TTP, which was 5.6 months in the capecitabine group versus 8.2 months in the capecitabine plus T group, with an unadjusted hazard ratio of 0.69 (95% confidence interval [CI], 0.48 – 0.97; 2-sided log-rank P ⫽ .0338). Overall response rates (RR) were 27.0% with capecitabine and 48.1% with capecitabine plus T (odds ratio, 2.50; P ⫽ .0115). However the OS was not significantly different. That study, published in early 2009, was closed early because of poor accrual, after recruiting only 156 of 482 planned patients. Perhaps this was a result of diminished interest in the question after the release of data showing the benefit of lapatinib among patients who had progressed after taking T.7 Reflecting the current state of the art in this group of patients, the National Comprehensive Cancer Network (NCCN) guidelines state: ‘The panel recommends continuation of HER2 blockade for patients with HER2⫹ MBC which progresses on first-line T-containing regimens.’8 To quantify and expand the data about this setting of patients, even after the results of the Emilia study, and according to NCCN statement, the authors performed a systematic review and pooled analysis to cumulate existing evidence about the use of T beyond progression on a first-line T-based chemotherapy.

Methods Search Strategy and Selection of Trials A search of PubMed and EMBASE until September 17, 2012 was conducted. Keywords included in the search were ‘trastuzumab or herceptin’, ‘beyond progression or after progression or progressing or second line’, and ‘advanced breast cancer or metastatic breast cancer’. The search was limited to retrospective case series, prospective studies, or randomized controlled trials and articles published in English. Abstracts presented at American Society of Clinical Oncology Meetings, San Antonio Breast Cancer Symposium, European Society of Medical Oncology, European CanCer Organisation and other major cancer conferences included in EMBASE search results were considered too. To find any additional trials, the reference lists of included trials and large systematic reviews were searched. Trials were included that provided data for OS and/or either progression-free survival or TTP and/or RR (complete and partial responses) with T prescribed as second-line therapy after progression during a first-line T-based regimen. Inclusion criteria were (1) patients with HER2⫹ MBC who were exposed to a second-line, including a T-based regimen, either alone or combined with other treatment modalities, (2) clinical randomized controlled phase III trials, 1-arm prospective studies, or retrospective case series, (3) inclusion of patients progressing during a first-line T-based regimen, and (4) trial reporting OS and/or TTP and/or RR from the start of second-line therapy. Trials were excluded if they included patients pretreated with more than 2 lines of T-based chemotherapy and if they did not report results for OS and/or TTP and/or RR with a (T-based) second-line therapy. For series published from the same institution in different years, only the more recent publication was included in the analysis to exclude possible overlapping patients.

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The end points of this pooled analysis were to cumulate and summarize the median RR, TTP, and OS, retrieving these data from the published literature.

Data Abstraction and Statistical Analysis Two investigators independently extracted data from each article using a structured sheet and entered them into an Excel database. Median OS, median TTP (or progression-free survival), and RR (or number of events per number of patients) were extracted from all trials if available. Median TTP was defined as the time to the start of second-line therapy to progression of disease (second TTP); median OS was defined as the time to the start of second T-based therapy to death. If the OS was calculated from the start of first-line therapy, the median OS of interest was calculated as OS ⫺ TTP with first-line treatment (first TTP). The following information was also obtained from each report: year of publication, type of study, number of patients treated with T beyond progression, and type of schedules. Finally, the authors summarized the outcome data (range, weighted median, mean, standard deviation [SD], standard error [SE] of the mean and variance for both TTP and OS) for all trials through a descriptive statistical analysis. The results were graphically presented as box-and-whisker plots. For the graphs the MedCalc software version 12.3.0.0 was used. One-way analysis of variance (ANOVA) was also performed. For the RR end points a formal pooled analysis was performed with Forest plots. A formal heterogeneity test was performed. Pooled estimates of proportions with corresponding 95% CIs were calculated within a random effect model framework. Heterogeneity of combined study results was assessed by inconsistency statistic (I2) and its connected ␹2 test for heterogeneity, and I2 and the corresponding 95% CIs were calculated. No formal test was conducted for purpose of subgroup comparisons and results were solely displayed in a comparative descriptive manner. For the pooled analysis of RR and the respective Forest plot, the Comprehensive Meta Analysis version 2.2.06 4 July 27, 2011 software was used.

Results Of the 357 articles retrieved including 69 abstracts from major conferences, 53 were eligible after abstract selection (Figure 1). After reading the full texts, only 29 studies, including 30 publications,4,7,9 –35 were finally considered eligible for this systematic review (Table 1).4,6,7,9 –35 In fact, because of data overlap between the previous studies or more recent updated reports, 4 of them were excluded from the final analysis. Another 19 publications were excluded because they did not present the outcome needed. Four randomized controlled phase III trials, 2 observational studies, 8 prospective nonrandomized trials, and 15 retrospective case series were included in this analysis, for a total of 2618 treated with a second-line T-based treatment beyond progression on a first-line T-based chemotherapy. The number of patients per trial ranged from 7 to 500.

Pooled Analysis of RR, TTP, and OS Response rate, TTP/progression-free survival and OS were available from 22, 21, and 16 studies. Overall RR was 28.7% (95% CI, 23.6%–34.4%; range, 11.8%– 48.1%) (Figure 2). The results for the RR pooled analysis showed a high heterogeneity (I2, 71.8%; P ⬍

Fausto Petrelli, Sandro Barni Figure 1 Selection of Publications Included in the Pooled-analysis

Records identified through PubMed and EMBASE searching (including conferences abstracts) (n = 357) Records excluded (n =314) 87 review, letters, commentaries 147 not 2nd line breast cancer studies 18 publications not in English language 52 studies not including trastuzumab Publications assessed for eligibility (n = 53)

Studies included in qualitative synthesis (n =30)

Publications excluded (n=23) 18 did not reported data of interest 5 older updates of the trials

Studies included in quantitative synthesis (meta-analysis) (n =29)

.0001). This is likely because of the retrospective nature of the included articles. For this reason a random effect model was used. The relative weight of each trial ranged from 1.82% to 7.82%. For TTP the mean is 7.6 months and the weighted median TTP was 7 months (range, 3–12.4); SD, SE, and variance are, respectively 2.38, 0.546, and 5.67. The study of Tripathy13 was excluded because did not report a precise value (Figure 3 for the weighted median TTP box-and-whisker plot). For OS the mean is and the weighted median OS were 25.7 and 24 months (range, 11.2-46.65); SD, SE, and variances are, respectively 8.08, 2.16, and 65.39 (Figure 4 for the weighted median OS boxand-whisker plot). These plots graphically synthesize the overall range, median, and interquartile range (25%–75%) of the median values for both TTP and OS reported in the trials. One-way ANOVA was performed for RR and both TTP and OS analysis. The results were P ⫽ .36, .46, and .43, respectively, that is the hypothesis of similar median is accepted. This confirms that data are similar and not statistically different even if a high grade of heterogeneity is evident among trials.

Discussion The results of this pooled analysis of 29 studies, including 2618 HER2⫹ MBC patients treated with T beyond the failure of a

previous first-line therapy containing the same agent, substantially confirms the activity of the present strategy in this setting of patients. The choice of treatment after progression on T-based chemotherapy is generally the continuous HER2 blockade with an anti-HER2 agent (lapatinib or T) associated with another chemotherapy partner (generally capecitabine, the most used agent in published phase III trials). A previous similar analysis of 12 studies published by Mannocci in 201036 found similar figures regarding TTP (26 weeks), with different results for the combination of vinorelbine/T and capecitabine/T (19.5 and 30.3 weeks, respectively). However, this review did not include data about RR and OS. These data are also similar to the systematic review of Fabi et al, which calculated a TTP of 6 months and an RR of 21% from 9 trials in 2008.37 This is the first pooled analysis that evaluates responses and survival other than TTP in more than double the number of patients. The pooled analysis of this study included patients treated with T alone, with radiotherapy or endocrine therapy, which might explain the lower RR and TTP results compared with the von Minckwitz trial.7,34 In fact, the combination of anastrozole plus T is associated with 4.8 months of TTP and an RR of 20% in randomized phase III trials.38 In addition, T mono-

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Trastuzumab Beyond Progression in HER2ⴙ Advanced BC Table 1 Characteristics of Included Trials TTP/PFS Second-Line (Median Months)

OS Second Line (Median Months)

Schedule of Treatment

First Author/Year

Type of Study

Christodoulou/20039

Retrospective case series

26

NA

NA

23

H with weekly paclitaxel (n ⫽ 26)

Fountzilas/200310

Retrospective case series

80

23.7

5.2

22.2

H with paclitaxel or vinorelbine (n ⫽ NA)

Suzuki/200311

Prospective study

24

42a

3a

NA

H with vinorelbine (n ⫽ 24)

Gelmon/200412

Retrospective case series

105

32.3b

6.5

23.1

NA

Prospective extension trial (H0659g)

93

11.8

⬎6

NA

H alone (n ⫽ 22); H with paclitaxel (n ⫽ 30); H with vinorelbine (n ⫽ 20); H with docetaxel (n ⫽ 17); H with 5FU (n ⫽ 11); H with other CT (n ⫽ 28); H with OT (n ⫽ 15); H with RT (n ⫽ 40)

García-Sáenz/200514

Retrospective case series

31

25.8

3

NA

H with taxanes (n ⫽ 14); H with vinorelbine (n ⫽ 10); H with other agents (n ⫽ 7)

Stemmler/200515

Retrospective case series

23

39.1

NA

NA

NA

Morabito/200616

Prospective study

7

28.5

NA

NA

H with gemcitabine and vinorelbine (n ⫽ 7)

Tripathy/200413

Bartsch/200617

Retrospective case series

54

25.9

6

Not reached

H with vinorelbine (n ⫽ 15); H with capecitabine (n ⫽ 11); H with gemcitabine (n ⫽ 9); H with docetaxel (n ⫽ 11); H with platinum derivatives (n ⫽ 0); H with other agents (n ⫽ 8)

Furukawa/200618

Prospective singleinstitution case series

15

15.4

NA

NA

H with paclitaxel (n ⫽ 15 after previous single agent H)

Adamo/200719

Retrospective case series

26

23

9

11.2

H alone (n ⫽ 14) or H with CT (n ⫽ 12)

Bartsch/200720

Prospective study

21

19

7

NA for secondline treated patients only

H with capecitabine (n ⫽ 21)

Bartsch/200821

Prospective study

8

37.5

6

NA for secondline treated patients only

H with gemcitabine (n ⫽ 8)

Montemurro/200822

Retrospective case series

83

28

8.4

20.6

H with CT (n ⫽ 83)

46.65

Most pts received H in combination with a single CT agent (mainly taxanes and vinorelbine)

23

Cancello/2008

Retrospective case series

59

16

5.25

Bartsch/2009

Retrospective case series

97

30.9

7

35

H with capecitabine (n ⫽ 23); H with vinorelbine (n ⫽ 30); H with taxanes (n ⫽ 21); H with gemcitabine (n ⫽ 12); H with anthracyclines or others (n ⫽ 11)

Rugo/200925

Retrospective case series

500

NA

NA

21.2

NA

Phase II trial

15c

27

4

NA

Gemcitabine with H (n ⫽ 15 treated as second-line)

Randomized phase III

78

48.1 (vs. 27)

8.2 (vs. 5.6)

24.9

Capecitabine with H (n ⫽ 78) vs. capecitabine (n ⫽ 78)

24

Yardley/200926 von Minckwitz/2009 and 20117,34

84

RR SecondLine (%)

Number of Patients

Reference

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Fausto Petrelli, Sandro Barni Table 1 Continued

Type of Study

Number of Patients

RR SecondLine (%)

TTP/PFS Second-Line (Median Months)

OS Second Line (Median Months)

Schedule of Treatment

Extra/201027

Observational Hermine study

107

NA

10.2

Not reached

NA

Metro/201028

Retrospective case series

69

27.5

6.5

25.7

H with vinorelbine (n ⫽ 10); H with taxanes (n ⫽ 11); H with other agents (n ⫽ 16)

29

Randomized phase III (JO17360 Trial Group)

36

d

47.2

12.4 (PFS)

NA

H with docetaxel second-line (n ⫽ 36) after progression with H alone (n ⫽ 56) vs. H with docetaxel first-line (n ⫽ 56)

Baselga/20106

Phase II trial

28

17.8

NA

NA

H with pertuzumab (n ⫽ 28 patients treated after only 1 previous H-based treatment)

Waddell/201130

Retrospective case series

81

61 (DCR)

6.25

22

H alone (n ⫽ 11); H with CT (n ⫽ 44); H with OT (n ⫽ 2); H with RT (n ⫽ 24) H with taxanes (n ⫽ 106); H with gemcitabine (n ⫽ 22); H with aromatase inhibitors (n ⫽ 24); H with other agents (n ⫽ 15)

Reference

First Author/Year

Inoue/2010

Campiglio/201131

Retrospective case series

154

NA

NA

27 and 21 in responders and nonresponder in first-line (P ⬍ .001 vs. halting H)

Huober/201132

Retrospective case series

68

NA

7

24.3

H with CT (n ⫽ 51)

Hayashi/201133

Retrospective case series

76

NA

NA

19.85

H with CT (n ⫽ 50)

Verma/20124

Randomized phase III

495

43.6

9.6 (PFS)

30.9

T-DM1 (n ⫽ 495) vs. lapatinib with capecitabine (n ⫽ 496)

Pivot/201235

Randomized phase III

159 (pretreated with H)

NA

6.1

27.3

Capecitabine with lapatinib (n ⫽ 271) vs. capecitabine with trastuzumab (n ⫽ 269)

n ⫽ 2,618 (7–500)

Pooled overall RR, 28.7% (11.8–48.1)

Median, 7 (3–12.4)

Median, 24 (11.2–46.65)

Pooled Analysis (Range)

Abbreviations: 5FU ⫽ 5Fluorouracil; CT ⫽ chemotherapy; DCR ⫽ disease control rate; H ⫽ Herceptin; NA ⫽ not available; OS ⫽ overall survival; OT ⫽ hormonal therapy; PFS ⫽ progression-free survival; RR ⫽ response rate; RT ⫽ radiotherapy; T-DM1 ⫽ trastuzumab emtansine; TTP ⫽ time to progression. a Including 6 patients that received treatment as third-line therapy. b Only patients undergoing therapy with trastuzumab alone, trastuzumab with taxanes, trastuzumab with vinorelbine were considered for RR. c Fifteen out of 37 patients treated with previous trastuzumab as first-line therapy. d Refer to the 36 patients that were treated with H ⫹ docetaxel after progression on H alone.

therapy obtained approximately 15% of the responses in the multinational Cobleigh et al study of 1999.39 This analysis confirms that the median OS for this group of patients is approximately 2 years, a value similar to the results of the GBG-26 trial.34 The result is probably largely influenced by the postprogression therapies started when the patients progressed after second-line therapy. In fact, some patients are currently exposed to multiple lines of treatment after first-line therapy, and this could affect the final outcome of these patients. Shi et al demonstrated that among 128 patients who received at least 1 line of T-based therapy, for those who received more than 1 line of T, the median OS was 44 months, and for those receiving only 1 line, it was 27.6 months (P ⫽ .059).40 Extra et al and Fabi et al also showed that the median OS for patients who were exposed to T, even in second-line, was 38 months

and not reached compared with 16 and 16.8 months for those stopping T after first-line therapy.27,37 The present results have to be considered in light of the updated literature data in which the current choice of treatment for HER2⫹ MBC is the continuation of a HER2 blockade in combination with a different cytotoxic drug (usually capecitabine with lapatinib or T or the association of lapatinib plus T, as currently proposed by the 2012 NCCN guidelines). In an observational study, Wong et al showed that more than three-quarters of patients treated with T for HER2⫹ MBC at 8 NCCN centers until 2004 continued this agent even beyond progression.41 Recently, other agents have demonstrated activity as second-line therapy after T failure. Pertuzumab, a HER2-targeted monoclonal antibody that potently inhibits HER2 dimerization and HER2-me-

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Trastuzumab Beyond Progression in HER2ⴙ Advanced BC Figure 2 Forest Plot for Response Rate Meta-Analysis

Study name

Fountzilas 2003 Suzuki 2003 Gelmon 2004 Tripathy 2004 Garcia-Saenz 2005 Stemmler 2005 Bartsch 2006 Morabito 2006 Furukawa 2006 Adamo 2007 Bartsch 2007 Cancello 2008 Montemurro 2008 Bartsch 2008 Von Minckwitz 2009 Yardley 2009 Bartsch 2009 Metro 2010 Inoue 2010 Baselga 2010 Verma 2012

Event rate

Statistics for each study Lower Upper Z-Value p-Value limit limit

0.237 0.420 0.323 0.118 0.258 0.391 0.190 0.285 0.154 0.230 0.190 0.160 0.280 0.375 0.481 0.270 0.309 0.275 0.472 0.178 0.436 0.287

0.156 0.244 0.241 0.067 0.135 0.217 0.073 0.072 0.043 0.107 0.073 0.087 0.194 0.125 0.373 0.106 0.225 0.183 0.317 0.076 0.393 0.236

0.342 0.620 0.418 0.201 0.437 0.597 0.411 0.673 0.425 0.427 0.411 0.276 0.386 0.715 0.591 0.536 0.408 0.392 0.632 0.363 0.480 0.344

–4.447 –0.780 –3.546 –6.258 –2.573 –1.037 –2.607 –1.099 –2.381 –2.593 –2.607 –4.669 –3.863 –0.699 –0.336 –1.710 –3.663 –3.596 –0.336 –3.097 –2.840 –6.761

Event rate and 95% CI

0.000 0.435 0.000 0.000 0.010 0.300 0.009 0.272 0.017 0.010 0.009 0.000 0.000 0.484 0.737 0.087 0.000 0.000 0.737 0.002 0.005 0.000 –0.50

0.25 Favours B

0.50

Figure 4 Box-and-Whisker Plot of Overall Survival (the Middle Line Represents the Median Overall Survival)

TTP: months

0 0

2

4

6

8

10

12

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5

10

15

20

25

30

35

40

45

50

14

diated signaling pathways, showed an objective RR of 24% and a median progression-free survival of 5.5 months when added to T in patients in whom disease progressed during previous T-based therapy.6 Furthermore, the recent EMILIA study, which compared T-DM1 with capecitabine/lapatinib combination, showed superiority for the first agent (9.6 vs. 6.4 months) for progression-free survival and OS. Thus, it will likely become the future standard of care after T failure.4 The safety of this strategy seems high with cardiac events of any grade in the T beyond progression group, similar to the control arm in the GBG-26 trial.7 In retrospective case series presented here, rare cardiac events are reported. Overall, the option to offer the continuation of T beyond progression has to be carefully evaluated after a complete cardiac monitoring at the start and during therapy.

86

0.00

OS: months

Figure 3 Box-and-Whisker Plot of Time to Progression (the Middle Line Represents the Median Time to Progression)

–0.25 Favours A

However, this pooled analysis suffers from some limitations. First, it is composed mainly of literature-based and retrospective series. Second, it is presently unknown from this review which is the preferred combination to adopt in this setting. Third, the characteristics of patients who received a second T regimen beyond progression are not homogeneous for site and extent of disease, and responsiveness to treatments. In addition, RR could have been underestimated because many patients received T alone as second-line therapy, and it is less active when used alone. Finally, TTP measurement timing might differ among studies, which could bias these data.

Conclusion This systematic review and pooled analysis of 2618 patients shows an RR of approximately 30%, a 7-month TTP, and a median OS of almost 2 years with the use of a second T-containing regimen in

Fausto Petrelli, Sandro Barni HER2⫹ MBC patients who have progressed on a T-based first-line therapy. However, the final results of ongoing phase III trials comparing T- versus lapatinib-based regimens are urgently needed, because only prospective studies can elucidate the dilemma about the efficacy of a second-line T-based therapy beyond progression. Meanwhile, other agents such as T-DM1 have demonstrated superiority over lapatinib/capecitabine, which represents 1 of the standards of care and is a current option according to the NCCN guidelines. Thus, continuing T even after an initial failure represents still now an accepted and effective choice in advanced HER2⫹ BC.

Disclosures All authors have no conflicts of interest.

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