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Weighing the Options for Human Epidermal Growth Factor Receptor 2–Directed Therapy in Metastatic Breast Cancer Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA See accompanying articles on pages 1564 and 1574
Since the introduction of trastuzumab in the late 1990s, the treatment landscape for patients with metastatic human epidermal growth factor receptor 2 (HER2) –positive breast cancer has changed dramatically. In addition to trastuzumab, a series of novel HER2directed therapies has gained regulatory approval, including lapatinib, pertuzumab, and ado-trastuzumab-emtansine (T-DM1). The result is that for many patients, the disease has been transformed from a rapidly lethal illness to one in which episodes of disease progression are punctuated by long periods of tumor control.1 Despite these advances, HER2-positive metastatic breast cancer is still not generally curable, and the vast majority of patients will eventually succumb to their disease. Furthermore, over time, up to half of patients will develop CNS metastases, and these can be a source of both substantial morbidity and mortality.1,2 The two articles that accompany this editorial3,4 directly address several related questions. First, is there a preferred anti-HER2 therapy for use in the first-line setting? Second, does the choice of anti-HER2 therapy affect the incidence of brain metastases? In addition, these studies raise important considerations regarding trial design moving forward. In the NCIC Clinical Trials Group MA.31 trial, Gelmon et al3 directly compared first-line trastuzumab versus lapatinib, each paired with a taxane, in patients with HER2-positive metastatic breast cancer. Among the 652 patients in the intent-to-treat population, although the objective response rates were similar, progression-free survival (PFS) was inferior in the lapatinib arm (median, 9.0 v 11.3 months; hazard ratio [HR], 1.37; P ⫽ .001), and there was a trend for overall survival (OS) in favor of trastuzumab, which reached significance in the centrally confirmed HER2-positive subset (n ⫽ 537; HR, 1.47; P ⫽ .03). Patient-reported global quality of life, as assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (QLQ-C30), was similar between arms, although expected differences were seen that favored trastuzumab for outcomes such as diarrhea and rash. Rates of therapy discontinuation for reasons other than progression or death were similar between arms. The CEREBEL trial, as reported by Pivot et al,4 also compared trastuzumab versus lapatinib, this time with a capecitabine backbone. In contrast with MA.31, patients could be enrolled either in the first1530
© 2015 by American Society of Clinical Oncology
line setting or in a subsequent line of therapy. Just under half of patients who were included in CEREBEL had not received any previous therapy for metastatic breast cancer. As with MA.31, although objective response rates were similar between arms, patients who were randomly assigned to the trastuzumab-containing arm experienced longer PFS and OS compared with patients who were randomly assigned to the lapatinib-containing arm (median PFS, 6.6 v 8.1 months; HR, 1.30; 95% CI, 1.04 to 1.64; median OS, 22.7 v 27.3 months; HR, 1.34, 95% CI, 0.95 to 1.90). In placing these data into context, at least two issues come to mind: the patient populations enrolled, and data regarding other anti-HER2 agents that have been developed since these trials were initiated. The patient populations in both studies were notable: in MA.31, less than 20% of patients had received previous adjuvant or neoadjuvant trastuzumab, and 43% of patients presented with de novo metastatic disease. In CEREBEL, the patient population included 18% with de novo disease; only 28% of patients had received adjuvant trastuzumab, and only 35% had previously received trastuzumab for metastatic disease. Results of the studies are generally consistent with preoperative data from several studies, including CALGB (Cancer and Leukemia Group B) study 40601, in which lapatinibtaxane was inferior to trastuzumab-taxane with respect to the primary end point of pathologic complete response in newly diagnosed, trastuzumab-naïve patients with clinical stage II to III, HER2positive breast cancer.4a,5 To what extent MA.31 and CEREBEL can be generalized to a population of first-line patients with metastatic disease who have relapsed despite adjuvant trastuzumab is somewhat unclear. Indeed, in a hypothesis-generating subset analysis of CEREBEL, the benefit of trastuzumab-capecitabine compared with lapatinib-capecitabine was restricted to patients without previous exposure to trastuzumab or chemotherapy. PFS did not differ by arm among patients with previous trastuzumab exposure or those treated in the second-line setting or beyond. Since these trials were initiated, two new agents have gained regulatory approval for HER2-positive metastatic breast cancer: pertuzumab and T-DM1. Given the superiority of trastuzumab-taxane compared with lapatinib-taxane in MA.31, and the superiority of pertuzumab-trastuzumab-taxane compared with trastuzumab-taxane in CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), Journal of Clinical Oncology, Vol 33, No 14 (May 10), 2015: pp 1530-1533
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Editorial
results of MA.31 are supportive of the choice of trastuzumab (as opposed to lapatinib) in CLEOPATRA, and for the use of first-line pertuzumab-trastuzumab-taxane in HER2-positive metastatic breast cancer, as per the current American Society of Clinical Oncology (ASCO) and European School of Oncology–European Society for Medical Oncology clinical practice guidelines.6-8 In the second-line setting, the EMILIA study, which directly compared T-DM1 versus lapatinib-capecitabine in patients pretreated with trastuzumab, indicated benefits for the former, both for PFS and OS.9 Thus, in countries in which pertuzumab and T-DM1 are available, lapatinib-based regimens have now moved to the thirdline and beyond. That said, it is important to note that several studies have demonstrated a clear benefit of lapatinib plus chemotherapy compared with chemotherapy alone in the first- and second-line settings; thus, lapatinib still has a role in earlier lines when other anti-HER2 agents are not available.10,11 A question left unanswered by all of the trials mentioned is this: what accounts for the difference in efficacy between trastuzumab and lapatinib when both ostensibly hit the same target? Sadly, despite years of experience with both agents, we still do not have a clear biologic explanation that has been adequately validated in human breast cancer, although many hypotheses have been put forward. In large part, this stems from historical limitations in collection of tumor and other biologic samples at the time of recurrence and subsequent progression and speaks to the importance of ongoing efforts to collect such samples for molecular characterization. Turning to the issue of CNS metastases, CEREBEL was the first breast cancer study that was designed specifically with a primary end point of CNS relapse. CNS events were also collected prospectively in MA.31 and provide another means to evaluate whether the choice of lapatinib or trastuzumab may affect CNS outcomes. In both trials, brain imaging was required as part of screening procedures, and patients with brain metastases were excluded. Unfortunately, despite several studies that demonstrated that lapatinib has CNS activity in patients with active brain metastases, lapatinib did not seem to prevent brain metastases in either CEREBEL or MA.31.12,13 There are several notable differences between these two studies that are worth highlighting. The first relates to the higher rate of detection of brain metastases on baseline screening in CEREBEL compared with MA.31. Indeed, in MA.31, screen failure as a result
of detection of asymptomatic brain metastases occurred in only four patients overall, whereas such events comprised 20% of screen failures in CEREBEL. To what extent this was because of the patient population (all first-line in MA.31, including a high proportion of patients with de novo metastatic disease v a mix of lines in CEREBEL), the type of baseline testing (either brain computed tomography [CT] or magnetic resonance imaging [MRI] in MA.31 v required MRI in CEREBEL), or simply random chance is difficult to know for certain. The proportion of patients who developed brain metastases while participating in the studies was also different between the two trials. In MA.31, 18% of patients in the lapatinib arm and 24% in the trastuzumab arm developed brain metastases, whereas in CEREBEL, the rates were much lower: 3% in the lapatinib arm and 5% in the trastuzumab arm. Similarly low rates were observed for patients without CNS metastases at baseline in the second-line EMILIA study (Table 1).14 None of the studies detected a statistically significant difference in the incidence of CNS metastasis by type of HER2 therapy. What, then, could account for the differences between the studies? One factor may be the requirement for baseline MRI in CEREBEL (v choice of CT or MRI in MA.31), given the higher sensitivity of MRI compared with CT for the detection of brain metastases. Thus, it is possible that more patients with occult brain metastases were allowed to enroll onto MA.31 as a result of an inferior screening modality. It is also possible that the timing of when patients were enrolled relative to their metastatic diagnosis could explain the differences between trials. In the observational registHER study, median time to development of first brain metastases from time of initial metastatic diagnosis was 13.3 months.2 MA.31 enrolled a somewhat more homogeneous (first-line only) patient population, and perhaps the timing of study entry and duration of protocol therapy simply coincided more fully with a period of higher CNS relapse risk. In an exploratory analysis of the first-line CLEOPATRA trial, the incidence of CNS metastases was approximately 13% across both arms. Although this rate is lower than that reported in MA.31, a major limitation of the analysis is that neither baseline nor subsequent CNS imaging studies were required in the absence of suggestive clinical symptoms, and thus the incidence of CNS metastasis was likely underestimated. At the same time, this rate is numerically higher than what has been reported in trials that included later-line patients, such as CEREBEL and EMILIA, and is
Table 1. CNS Assessments and Incidence of Brain Metastases Across Selected Clinical Trials Line of Therapy
Trial MA.313
First line only
CLEOPATRA15
CEREBEL4 EMILIA14
Baseline CT or MRI required
Subsequent
Incidence of CNS Metastases: Patients Without CNS Metastases at Baseline
Required at time of systemic 18% (lapatinib-taxane); 24% progression or if clinical (trastuzumab-taxane) suspicion First line only Only required if Only if clinical suspicion 12.6% (trastuzumab-taxane); clinical 13.7% (trastuzumab-taxanesuspicion pertuzumab) Any line (44% MRI required Required every 12 weeks 3% (lapatinib-capecitabine); 5% first line) (trastuzumab-capecitabine) Second line CT or MRI Only if clinical suspicion 2% (T-DM1); 0.7% (lapatinibrequired capecitabine)
Incidence of CNS Metastases: Patients With Stable, Treated CNS Metastases at Baseline Excluded
Excluded
Excluded 22% (T-DM1); 16% (lapatinib-capecitabine)
Abbreviations: CLEOPATRA, Clinical Evaluation of Pertuzumab and Trastuzumab; CT, computed tomography; MA.31, NCIC Clinical Trials Group study MA.31; MRI, magnetic resonance imaging.
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supportive of a possible time-dependent risk of CNS metastases (Table 1).15 A final possibility is an effect of the systemic therapy itself on the incidence of CNS metastases. The chemotherapy backbone in CEREBEL consisted of capecitabine, which is known to have some CNS activity, even in the absence of concurrent HER2-directed therapy.16 The trial design does not allow us to determine whether the incidence of CNS metastases would have been higher by arm with a different chemotherapy backbone. In the EMILIA trial, the incidence of new CNS metastasis was low (2% or less) in both the lapatinibcapecitabine and T-DM1 arms.14 Notably, data are emerging that suggest potential CNS efficacy of T-DM1 in patients with active brain metastases.17 Could the low rates of CNS events in EMILIA be a result of a CNS-protective effect of systemic therapy in both arms? From a practical perspective, the collective data do not support the choice of a lapatinib-containing regimen for primary prevention of CNS metastasis and are consistent with current ASCO clinical practice guidelines for choice of systemic therapy for HER2-positive metastatic breast cancer.7 Notably, none of the studies mentioned here included patients with active (progressive) brain metastases, and for those patients, a systemic regimen such as lapatinib-capecitabine remains a valid option to be considered in the context of other modalities that may be available to patients, such as surgical resection and radiotherapy.18 From a clinical trials perspective, the data raise important questions regarding future trial design. An important clinical and research goal has been to identify strategies not only to treat established brain metastases but to prevent CNS relapse in the first place. CEREBEL was powered to detect a difference in CNS event rate of 20% versus 12%, on the basis of data from the pivotal trial of lapatinib-capecitabine versus capecitabine alone.10 In actuality, the CNS event rate in CEREBEL was only approximately 4% overall, leading to a significant underpowering for the primary end point. It is likely that one major contributor to the low event rate was the large proportion of patients with asymptomatic brain metastases who were screened out by baseline MRI testing (which was not required in the pivotal trial). The experience of both CEREBEL and EMILIA suggest that in the second-line setting and beyond, the event rate for new CNS events (after screening out patients with asymptomatic metastases) is low within the time frame of active protocol therapy and disease follow-up, and that primary prevention trials in this setting are unlikely to be successful in the absence of improved patient selection tools. Even if both CEREBEL and EMILIA had been large studies, and the actual numeric difference in CNS incidence that was observed between arms was not only preserved but became statistically significant, would it change practice to demonstrate an absolute 1.3% to 2% difference in CNS metastasis incidence favoring lapatinib, especially in light of PFS (CEREBEL) or OS (EMILIA) differences favoring the nonlapatinib-containing arms? To answer the question of CNS disease prevention in the second-line setting and beyond, it may be more fruitful and clinically relevant to test so-called secondary prevention approaches: that is, to enroll patients with a limited number of CNS metastases treated with stereotactic radiosurgery and then immediately randomly assign them to one of several systemic approaches to prevent and/or delay the time to subsequent CNS events. Here, the event rate is high over a relatively short time interval, and there is a strong desire among patients and physicians to delay salvage treatments such as whole-brain radiotherapy for as long as possi1532
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ble, given the potential for long-term cognitive toxicities.19 In contrast, given that the incidence of CNS events was relatively high in both MA.31 and CLEOPATRA, the first-line setting may still offer a potential patient population in whom to test novel primary prevention approaches. In conclusion, results of MA.31 and CEREBEL, taken together with the results of other trials in HER2-positive breast cancer, support the use of a trastuzumab-containing regimen in the first-line metastatic setting and do not support the selective use of lapatinib for brain metastasis prevention. The studies raise important questions about the feasibility of CNS prevention trials and offer lessons about how to conduct such trials moving forward. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at www.jco.org. REFERENCES 1. Olson EM, Najita JS, Sohl J, et al: Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the posttrastuzumab era. Breast 22:525-531, 2013 2. Brufsky AM, Mayer M, Rugo HS, et al: Central nervous system metastases in patients with HER2-positive metastatic breast cancer: Incidence, treatment, and survival in patients from registHER. Clin Cancer Res 17:4834-4843, 2011 3. Gelmon KA, Boyle FM, Kaufman B, et al: Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2–positive advanced breast cancer: Final results of NCIC CTG MA.31. J Clin Oncol 33:1574-1583, 2015 4. Pivot X, Manikhas A, Z˙urawski B, et al: CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer. J Clin Oncol 33:1564-1573, 2015 4a. Bonnefoi H, Jacot W, Saghatchian M, et al: Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: Results of the randomised phase II EORTC 10054 study. Ann Oncol 26:325-332, 2015 5. Carey LA, Berry DA, Olilia D, et al: Clinical and translational results of CALGB 40601: A neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer. J Clin Oncol 31:7s, 2013 (suppl; abstr 500) 6. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012 7. Giordano SH, Temin S, Kirshner JJ, et al: Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 32:2078-2099, 2014 8. Cardoso F, Costa A, Norton L, et al: ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Breast 23:489-502, 2014 9. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012 10. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006 11. Di Leo A, Gomez HL, Aziz Z, et al: Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol 26:5544-5552, 2008 12. Lin NU, Diéras V, Paul D, et al: Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 15:1452-1459, 2009 13. Bachelot T, Romieu G, Campone M, et al: Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): A single-group phase 2 study. Lancet Oncol 14:64-71, 2013 14. Krop IE, Lin NU, Blackwell K, et al: Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: A retrospective, exploratory analysis in EMILIA. Ann Oncol 26:113-119, 2015 15. Swain SM, Baselga J, Miles D, et al: Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: Results from the randomized phase III study CLEOPATRA. Ann Oncol 25:1116-1121, 2014 JOURNAL OF CLINICAL ONCOLOGY
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16. Rivera E, Meyers C, Groves M, et al: Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma. Cancer 107:1348-1354, 2006 17. Bartsch R, Berghoff AS, Preusser M: Breast cancer brain metastases responding to primary systemic therapy with T-DM1. J Neurooncol 116:205-206, 2014 18. Ramakrishna N, Temin S, Chandarlapaty S, et al: Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American
Society of Clinical Oncology clinical practice guideline. J Clin Oncol 32:21002108, 2014 19. Yang TJ, Oh JH, Folkert MR, et al: Outcomes and prognostic factors in women with 1 to 3 breast cancer brain metastases treated with definitive stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 90:518-525, 2014
DOI: 10.1200/JCO.2014.60.1427; published online ahead of print at www.jco.org on April 6, 2015
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AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Weighing the Options for Human Epidermal Growth Factor Receptor 2–Directed Therapy in Metastatic Breast Cancer The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Nancy U. Lin Consulting or Advisory Role: Novartis, GlaxoSmithKline, Genentech Research Funding: GlaxoSmithKline, Genentech, Array Biopharma, Kadmon, Novartis
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Weighing the Options for Human Epidermal Growth Factor Receptor 2–Directed Therapy in Metastatic Breast Cancer Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA See accompanying articles on pages 1564 and 1574
Since the introduction of trastuzumab in the late 1990s, the treatment landscape for patients with metastatic human epidermal growth factor receptor 2 (HER2) –positive breast cancer has changed dramatically. In addition to trastuzumab, a series of novel HER2directed therapies has gained regulatory approval, including lapatinib, pertuzumab, and ado-trastuzumab-emtansine (T-DM1). The result is that for many patients, the disease has been transformed from a rapidly lethal illness to one in which episodes of disease progression are punctuated by long periods of tumor control.1 Despite these advances, HER2-positive metastatic breast cancer is still not generally curable, and the vast majority of patients will eventually succumb to their disease. Furthermore, over time, up to half of patients will develop CNS metastases, and these can be a source of both substantial morbidity and mortality.1,2 The two articles that accompany this editorial3,4 directly address several related questions. First, is there a preferred anti-HER2 therapy for use in the first-line setting? Second, does the choice of anti-HER2 therapy affect the incidence of brain metastases? In addition, these studies raise important considerations regarding trial design moving forward. In the NCIC Clinical Trials Group MA.31 trial, Gelmon et al3 directly compared first-line trastuzumab versus lapatinib, each paired with a taxane, in patients with HER2-positive metastatic breast cancer. Among the 652 patients in the intent-to-treat population, although the objective response rates were similar, progression-free survival (PFS) was inferior in the lapatinib arm (median, 9.0 v 11.3 months; hazard ratio [HR], 1.37; P ⫽ .001), and there was a trend for overall survival (OS) in favor of trastuzumab, which reached significance in the centrally confirmed HER2-positive subset (n ⫽ 537; HR, 1.47; P ⫽ .03). Patient-reported global quality of life, as assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (QLQ-C30), was similar between arms, although expected differences were seen that favored trastuzumab for outcomes such as diarrhea and rash. Rates of therapy discontinuation for reasons other than progression or death were similar between arms. The CEREBEL trial, as reported by Pivot et al,4 also compared trastuzumab versus lapatinib, this time with a capecitabine backbone. In contrast with MA.31, patients could be enrolled either in the first1530
© 2015 by American Society of Clinical Oncology
line setting or in a subsequent line of therapy. Just under half of patients who were included in CEREBEL had not received any previous therapy for metastatic breast cancer. As with MA.31, although objective response rates were similar between arms, patients who were randomly assigned to the trastuzumab-containing arm experienced longer PFS and OS compared with patients who were randomly assigned to the lapatinib-containing arm (median PFS, 6.6 v 8.1 months; HR, 1.30; 95% CI, 1.04 to 1.64; median OS, 22.7 v 27.3 months; HR, 1.34, 95% CI, 0.95 to 1.90). In placing these data into context, at least two issues come to mind: the patient populations enrolled, and data regarding other anti-HER2 agents that have been developed since these trials were initiated. The patient populations in both studies were notable: in MA.31, less than 20% of patients had received previous adjuvant or neoadjuvant trastuzumab, and 43% of patients presented with de novo metastatic disease. In CEREBEL, the patient population included 18% with de novo disease; only 28% of patients had received adjuvant trastuzumab, and only 35% had previously received trastuzumab for metastatic disease. Results of the studies are generally consistent with preoperative data from several studies, including CALGB (Cancer and Leukemia Group B) study 40601, in which lapatinibtaxane was inferior to trastuzumab-taxane with respect to the primary end point of pathologic complete response in newly diagnosed, trastuzumab-naïve patients with clinical stage II to III, HER2positive breast cancer.4a,5 To what extent MA.31 and CEREBEL can be generalized to a population of first-line patients with metastatic disease who have relapsed despite adjuvant trastuzumab is somewhat unclear. Indeed, in a hypothesis-generating subset analysis of CEREBEL, the benefit of trastuzumab-capecitabine compared with lapatinib-capecitabine was restricted to patients without previous exposure to trastuzumab or chemotherapy. PFS did not differ by arm among patients with previous trastuzumab exposure or those treated in the second-line setting or beyond. Since these trials were initiated, two new agents have gained regulatory approval for HER2-positive metastatic breast cancer: pertuzumab and T-DM1. Given the superiority of trastuzumab-taxane compared with lapatinib-taxane in MA.31, and the superiority of pertuzumab-trastuzumab-taxane compared with trastuzumab-taxane in CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), Journal of Clinical Oncology, Vol 33, No 14 (May 10), 2015: pp 1530-1533
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Editorial
results of MA.31 are supportive of the choice of trastuzumab (as opposed to lapatinib) in CLEOPATRA, and for the use of first-line pertuzumab-trastuzumab-taxane in HER2-positive metastatic breast cancer, as per the current American Society of Clinical Oncology (ASCO) and European School of Oncology–European Society for Medical Oncology clinical practice guidelines.6-8 In the second-line setting, the EMILIA study, which directly compared T-DM1 versus lapatinib-capecitabine in patients pretreated with trastuzumab, indicated benefits for the former, both for PFS and OS.9 Thus, in countries in which pertuzumab and T-DM1 are available, lapatinib-based regimens have now moved to the thirdline and beyond. That said, it is important to note that several studies have demonstrated a clear benefit of lapatinib plus chemotherapy compared with chemotherapy alone in the first- and second-line settings; thus, lapatinib still has a role in earlier lines when other anti-HER2 agents are not available.10,11 A question left unanswered by all of the trials mentioned is this: what accounts for the difference in efficacy between trastuzumab and lapatinib when both ostensibly hit the same target? Sadly, despite years of experience with both agents, we still do not have a clear biologic explanation that has been adequately validated in human breast cancer, although many hypotheses have been put forward. In large part, this stems from historical limitations in collection of tumor and other biologic samples at the time of recurrence and subsequent progression and speaks to the importance of ongoing efforts to collect such samples for molecular characterization. Turning to the issue of CNS metastases, CEREBEL was the first breast cancer study that was designed specifically with a primary end point of CNS relapse. CNS events were also collected prospectively in MA.31 and provide another means to evaluate whether the choice of lapatinib or trastuzumab may affect CNS outcomes. In both trials, brain imaging was required as part of screening procedures, and patients with brain metastases were excluded. Unfortunately, despite several studies that demonstrated that lapatinib has CNS activity in patients with active brain metastases, lapatinib did not seem to prevent brain metastases in either CEREBEL or MA.31.12,13 There are several notable differences between these two studies that are worth highlighting. The first relates to the higher rate of detection of brain metastases on baseline screening in CEREBEL compared with MA.31. Indeed, in MA.31, screen failure as a result
of detection of asymptomatic brain metastases occurred in only four patients overall, whereas such events comprised 20% of screen failures in CEREBEL. To what extent this was because of the patient population (all first-line in MA.31, including a high proportion of patients with de novo metastatic disease v a mix of lines in CEREBEL), the type of baseline testing (either brain computed tomography [CT] or magnetic resonance imaging [MRI] in MA.31 v required MRI in CEREBEL), or simply random chance is difficult to know for certain. The proportion of patients who developed brain metastases while participating in the studies was also different between the two trials. In MA.31, 18% of patients in the lapatinib arm and 24% in the trastuzumab arm developed brain metastases, whereas in CEREBEL, the rates were much lower: 3% in the lapatinib arm and 5% in the trastuzumab arm. Similarly low rates were observed for patients without CNS metastases at baseline in the second-line EMILIA study (Table 1).14 None of the studies detected a statistically significant difference in the incidence of CNS metastasis by type of HER2 therapy. What, then, could account for the differences between the studies? One factor may be the requirement for baseline MRI in CEREBEL (v choice of CT or MRI in MA.31), given the higher sensitivity of MRI compared with CT for the detection of brain metastases. Thus, it is possible that more patients with occult brain metastases were allowed to enroll onto MA.31 as a result of an inferior screening modality. It is also possible that the timing of when patients were enrolled relative to their metastatic diagnosis could explain the differences between trials. In the observational registHER study, median time to development of first brain metastases from time of initial metastatic diagnosis was 13.3 months.2 MA.31 enrolled a somewhat more homogeneous (first-line only) patient population, and perhaps the timing of study entry and duration of protocol therapy simply coincided more fully with a period of higher CNS relapse risk. In an exploratory analysis of the first-line CLEOPATRA trial, the incidence of CNS metastases was approximately 13% across both arms. Although this rate is lower than that reported in MA.31, a major limitation of the analysis is that neither baseline nor subsequent CNS imaging studies were required in the absence of suggestive clinical symptoms, and thus the incidence of CNS metastasis was likely underestimated. At the same time, this rate is numerically higher than what has been reported in trials that included later-line patients, such as CEREBEL and EMILIA, and is
Table 1. CNS Assessments and Incidence of Brain Metastases Across Selected Clinical Trials Line of Therapy
Trial MA.313
First line only
CLEOPATRA15
CEREBEL4 EMILIA14
Baseline CT or MRI required
Subsequent
Incidence of CNS Metastases: Patients Without CNS Metastases at Baseline
Required at time of systemic 18% (lapatinib-taxane); 24% progression or if clinical (trastuzumab-taxane) suspicion First line only Only required if Only if clinical suspicion 12.6% (trastuzumab-taxane); clinical 13.7% (trastuzumab-taxanesuspicion pertuzumab) Any line (44% MRI required Required every 12 weeks 3% (lapatinib-capecitabine); 5% first line) (trastuzumab-capecitabine) Second line CT or MRI Only if clinical suspicion 2% (T-DM1); 0.7% (lapatinibrequired capecitabine)
Incidence of CNS Metastases: Patients With Stable, Treated CNS Metastases at Baseline Excluded
Excluded
Excluded 22% (T-DM1); 16% (lapatinib-capecitabine)
Abbreviations: CLEOPATRA, Clinical Evaluation of Pertuzumab and Trastuzumab; CT, computed tomography; MA.31, NCIC Clinical Trials Group study MA.31; MRI, magnetic resonance imaging.
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supportive of a possible time-dependent risk of CNS metastases (Table 1).15 A final possibility is an effect of the systemic therapy itself on the incidence of CNS metastases. The chemotherapy backbone in CEREBEL consisted of capecitabine, which is known to have some CNS activity, even in the absence of concurrent HER2-directed therapy.16 The trial design does not allow us to determine whether the incidence of CNS metastases would have been higher by arm with a different chemotherapy backbone. In the EMILIA trial, the incidence of new CNS metastasis was low (2% or less) in both the lapatinibcapecitabine and T-DM1 arms.14 Notably, data are emerging that suggest potential CNS efficacy of T-DM1 in patients with active brain metastases.17 Could the low rates of CNS events in EMILIA be a result of a CNS-protective effect of systemic therapy in both arms? From a practical perspective, the collective data do not support the choice of a lapatinib-containing regimen for primary prevention of CNS metastasis and are consistent with current ASCO clinical practice guidelines for choice of systemic therapy for HER2-positive metastatic breast cancer.7 Notably, none of the studies mentioned here included patients with active (progressive) brain metastases, and for those patients, a systemic regimen such as lapatinib-capecitabine remains a valid option to be considered in the context of other modalities that may be available to patients, such as surgical resection and radiotherapy.18 From a clinical trials perspective, the data raise important questions regarding future trial design. An important clinical and research goal has been to identify strategies not only to treat established brain metastases but to prevent CNS relapse in the first place. CEREBEL was powered to detect a difference in CNS event rate of 20% versus 12%, on the basis of data from the pivotal trial of lapatinib-capecitabine versus capecitabine alone.10 In actuality, the CNS event rate in CEREBEL was only approximately 4% overall, leading to a significant underpowering for the primary end point. It is likely that one major contributor to the low event rate was the large proportion of patients with asymptomatic brain metastases who were screened out by baseline MRI testing (which was not required in the pivotal trial). The experience of both CEREBEL and EMILIA suggest that in the second-line setting and beyond, the event rate for new CNS events (after screening out patients with asymptomatic metastases) is low within the time frame of active protocol therapy and disease follow-up, and that primary prevention trials in this setting are unlikely to be successful in the absence of improved patient selection tools. Even if both CEREBEL and EMILIA had been large studies, and the actual numeric difference in CNS incidence that was observed between arms was not only preserved but became statistically significant, would it change practice to demonstrate an absolute 1.3% to 2% difference in CNS metastasis incidence favoring lapatinib, especially in light of PFS (CEREBEL) or OS (EMILIA) differences favoring the nonlapatinib-containing arms? To answer the question of CNS disease prevention in the second-line setting and beyond, it may be more fruitful and clinically relevant to test so-called secondary prevention approaches: that is, to enroll patients with a limited number of CNS metastases treated with stereotactic radiosurgery and then immediately randomly assign them to one of several systemic approaches to prevent and/or delay the time to subsequent CNS events. Here, the event rate is high over a relatively short time interval, and there is a strong desire among patients and physicians to delay salvage treatments such as whole-brain radiotherapy for as long as possi1532
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ble, given the potential for long-term cognitive toxicities.19 In contrast, given that the incidence of CNS events was relatively high in both MA.31 and CLEOPATRA, the first-line setting may still offer a potential patient population in whom to test novel primary prevention approaches. In conclusion, results of MA.31 and CEREBEL, taken together with the results of other trials in HER2-positive breast cancer, support the use of a trastuzumab-containing regimen in the first-line metastatic setting and do not support the selective use of lapatinib for brain metastasis prevention. The studies raise important questions about the feasibility of CNS prevention trials and offer lessons about how to conduct such trials moving forward. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at www.jco.org. REFERENCES 1. Olson EM, Najita JS, Sohl J, et al: Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the posttrastuzumab era. Breast 22:525-531, 2013 2. Brufsky AM, Mayer M, Rugo HS, et al: Central nervous system metastases in patients with HER2-positive metastatic breast cancer: Incidence, treatment, and survival in patients from registHER. Clin Cancer Res 17:4834-4843, 2011 3. Gelmon KA, Boyle FM, Kaufman B, et al: Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2–positive advanced breast cancer: Final results of NCIC CTG MA.31. J Clin Oncol 33:1574-1583, 2015 4. Pivot X, Manikhas A, Z˙urawski B, et al: CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer. J Clin Oncol 33:1564-1573, 2015 4a. Bonnefoi H, Jacot W, Saghatchian M, et al: Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: Results of the randomised phase II EORTC 10054 study. Ann Oncol 26:325-332, 2015 5. Carey LA, Berry DA, Olilia D, et al: Clinical and translational results of CALGB 40601: A neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer. J Clin Oncol 31:7s, 2013 (suppl; abstr 500) 6. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012 7. Giordano SH, Temin S, Kirshner JJ, et al: Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 32:2078-2099, 2014 8. Cardoso F, Costa A, Norton L, et al: ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Breast 23:489-502, 2014 9. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012 10. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006 11. Di Leo A, Gomez HL, Aziz Z, et al: Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol 26:5544-5552, 2008 12. Lin NU, Diéras V, Paul D, et al: Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 15:1452-1459, 2009 13. Bachelot T, Romieu G, Campone M, et al: Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): A single-group phase 2 study. Lancet Oncol 14:64-71, 2013 14. Krop IE, Lin NU, Blackwell K, et al: Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: A retrospective, exploratory analysis in EMILIA. Ann Oncol 26:113-119, 2015 15. Swain SM, Baselga J, Miles D, et al: Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: Results from the randomized phase III study CLEOPATRA. Ann Oncol 25:1116-1121, 2014 JOURNAL OF CLINICAL ONCOLOGY
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16. Rivera E, Meyers C, Groves M, et al: Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma. Cancer 107:1348-1354, 2006 17. Bartsch R, Berghoff AS, Preusser M: Breast cancer brain metastases responding to primary systemic therapy with T-DM1. J Neurooncol 116:205-206, 2014 18. Ramakrishna N, Temin S, Chandarlapaty S, et al: Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American
Society of Clinical Oncology clinical practice guideline. J Clin Oncol 32:21002108, 2014 19. Yang TJ, Oh JH, Folkert MR, et al: Outcomes and prognostic factors in women with 1 to 3 breast cancer brain metastases treated with definitive stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 90:518-525, 2014
DOI: 10.1200/JCO.2014.60.1427; published online ahead of print at www.jco.org on April 6, 2015
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AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Weighing the Options for Human Epidermal Growth Factor Receptor 2–Directed Therapy in Metastatic Breast Cancer The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Nancy U. Lin Consulting or Advisory Role: Novartis, GlaxoSmithKline, Genentech Research Funding: GlaxoSmithKline, Genentech, Array Biopharma, Kadmon, Novartis
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