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HER2-positive breast cancer: trastuzumab, lapatinib and emerging therapies
Drug Discovery Today: Therapeutic Strategies
Vol. 9, No. 2–3 2012
Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Genetics, drug discovery and clinical developments
HER2-positive breast cancer: trastuzumab, lapatinib and emerging therapies Roger Y. Tsang, Richard S. Finn* Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA
The discovery of the HER2 alteration in 20–25% of breast cancers has ushered in an era of molecularly targeted therapies. Targeting HER2 with antibody-
Section editor: Richard Wooster – GlaxoSmithKline, Cancer Metabolism DPU, Oncology R&D, Collegeville, PA, USA
based approaches, such as trastuzumab, or tyrosine kinase inhibitors, such as lapatinib, has yielded improvements in clinical outcomes. Nevertheless, mechanisms of actions underlying anti-HER2 therapies are incompletely understood, and drug resistance is frequently encountered in the clinic. In this review, standard-of-care and emerging therapies in HER2-positive breast cancer will be discussed, with a focus on strategies in late-phase clinical development.
Introduction The discovery of the HER2 alteration, specifically gene amplification and subsequent protein overexpression, in 20–25% of breast cancers, and its associated poor prognosis, has since revolutionized treatment of this clinical entity [1,2]. HER2/ neu/ErbB2 belongs to the ErbB/HER family of receptor tyrosine kinases which include EGFR/HER1, HER3 and HER4, HER2 (human epidermal growth factor receptor 2) and numerous ligands. Amplification results in increased homoand hetero-dimerization with its family members, resulting in enhanced signaling of cell proliferation and differentiation, survival and angiogenic pathways. Uniquely, a ligand has not been identified for HER2, and HER3, its preferred *Corresponding author.: R.S. Finn ([email protected]) 1740-6773/$ ß 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2011.04.004
dimerization partner, has ligands but a ‘dead’ kinase [3]. Currently there are several agents approved and in development for HER2-positive breast cancer. In this mini-review, currently US Food and Drug Administration (FDA) approved and investigational anti-HER2 therapies will be discussed, with a focus on promising strategies in late-phase clinical development (Table 1).
Trastuzumab Trastuzumab (Herceptin), a humanized monoclonal antibody targeting the extracellular domain (ECD) of HER2 and the first anti-HER2 therapy approved by the US FDA in 1998, has revolutionalized treatment of HER2-positive breast cancer. Although preclinical studies of trastuzumab have characterized its antitumor activity via inhibition of cell growth and signal transduction, its mechanisms of action remain incompletely elucidated [4]. Antibody-dependent cellular cytotoxicity (ADCC), decreased DNA repair, effects on angiogenesis and inhibition of cleavage of its ECD are all proposed mechanisms resulting in its antiproliferative and cytotoxic effects. Additionally, additive or synergistic interactions between trastuzumab and various chemotherapeutic agents were also demonstrated preclinically, highlighting the biological rationale for trastuzumab-based combination strategies [5]. e55
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Table 1. Summary of FDA approved and promising therapeutic strategies in HER2-positive breast cancer Therapy
Pros
Cons
Latest developments
Company
Refs
1. Trastuzumab
Established role and FDA approved in both metastatic and adjuvant settings. Robust survival advantages consistently demonstrated
Primary and secondary drug resistance are not uncommon. Cardiotoxicity when used with chemotherapy (especially anthracyclines)
Common backbone for novel anti-HER2 combination strategies
Genentech
[6–11, 14–18]
2. Lapatinib
FDA approved in MBC (with capecitabine or letrozole). Demonstrates activity in trastuzumab-refractory states
OS advantage not yet shown in MBC. Diarrhea and rash may be troublesome. Clinical drug resistance is also an important issue
Role in adjuvant setting under evaluation in comparison with trastuzumab alone or trastuzumab/lapatinib combinations in large global Phase III trial (ALTTO)
GlaxoSmithKline
[22–30]
3. Neratinib
Irreversible TKI inhibition of EGFR/HER2/HER4 inhibition may provide additional benefits. Encouraging activity observed in Phase I and II trials
Phase III study in progress. Like lapatinib, diarrhea is also common
Multiple Phase I and II trials are evaluating neratinib both as a single agent and in combination with chemotherapy or trastuzumab. Large Phase III MBC trial of neratinib plus paclitaxel versus trastuzumab plus paclitaxel is in progress
Pfizer
[35,36]
4. Afatinib
Irreversible TKI inhibition of EGFR/HER2/HER4 inhibition may provide additional benefits. Promising activity reported in Phase I and II trials
Phase III study in progress. Diarrhea and rash, similar to lapatinib, are also common
A global Phase III trial of afatinib plus vinorelbine versus trastuzumab plus vinorelbine in MBC is currently underway (LUX-Breast1)
Boehringer Ingelheim
[37,38]
5. Pertuzumab
Synergism with trastuzumab resulting from binding to different HER2 ECD epitope. Promising Phase II data (response rates, tolerability) with trastuzumab + pertuzumab combination
Phase III trials are in progress. Cardiotoxicity unclear
Under evaluation in combinations with trastuzumab, T-DM1, taxanes and other chemotherapeutic regimens, including the Phase III trial of Pertuzumab/ Trastuzumab/Docetaxel versus Trastuzumab/Docetaxel in first-line MBC (CLEOPATRA)
Genentech
[41–44]
6. T-DM1
Represents a novel drug developmental approach. Phase II data demonstrated robust activity and tolerability in heavily pretreated population
Phase III trials are in progress. Thrombocytopenia may limit dose delivery
Phase III trials of T-DM1 versus T-DM1/pertuzumab versus trastuzumab/taxane in first-line MBC (MARIANNE), and of T-DM1 verus lapatinib/capecitabine in trastuzumab-refractory MBC (EMILIA)
Genentech
[47–49]
The pivotal trial evaluating the use of trastuzumab in combination with chemotherapy in the first-line setting of metastatic breast cancer (MBC) was reported by Slamon et al. [6] This multicenter, Phase III trial randomized 469 patients to receive paclitaxel trastuzumab (n = 188), or doxorubicin/ cyclophosphamide (AC) or epirubicin/cyclophosphamide (EC) trastuzumab (n = 281) depending upon whether they had received prior adjuvant anthracyclines. The addition of trastuzumab to chemotherapy resulted in an 18% higher response rate (50% versus 32%), a 2.8-month improvement in median TTP (7.4 versus 4.6 months) and a five-month improvement in median OS (25 versus 20 months). Notably, a 27% rate of symptomatic cardiac dysfunction (NYHA III/IV) was observed in the AC/trastuzumab arm, raising concerns of unacceptable cardiotoxicity with the concurrent use of e56
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anthracyclines and trastuzumab. In addition, multiple Phase II trials in the first-line, MBC setting have also demonstrated comparable efficacy with weekly trastuzumab plus weekly or three-weekly docetaxel in terms of response rates, TTP and OS, as well as patient tolerability [7–11]. The efficacy and safety of single-agent trastuzumab in the first-line setting for HER2-positive MBC demonstrated an overall response rate (ORR) of 35% in patients with tumors expressing 3+ IHC staining [12]. Trastuzumab monotherapy was well-tolerated, with fever (22%), chills (25%) and asthenia (23%) being the most common adverse events (AEs). The Phase III TAnDEM study evaluated a chemotherapy-free regimen in patients with both hormone and HER2 receptor-positive MBC, and reported a 2.4-month PFS improvement with the combination of trastuzumab plus anastrozole compared with anastro-
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zole alone (4.8 versus 2.4 months; HR = 0.63, P = 0.0016) in the overall intent-to-treat population. However, no overall survival advantage was demonstrated, and a higher incidence of grade 3 and 4 AEs was also observed in the trastuzumab plus anastrozole arm [13]. In the adjuvant setting, five key Phase III trials (NCCTG N9831, NSABP B-31, BCIRG 006, HERA and FinHER) evaluating the use of trastuzumab in HER2-positive breast cancer have reported significant clinical benefit [14–17]. A metaanalysis of the five trials published in 2008, which encompassed a total of 13,493 patients, identified survival advantages in terms of both DFS (RR 0.62, 95% CI 0.56–0.68) and OS (RR 0.66, 95% CI 0.57–0.77) when trastuzumab was added to adjuvant chemotherapy [18]. Additionally, rates of locoregional recurrence (RR 0.58, 95% CI 0.43–0.77) and distant recurrence (RR 0.60, 95% CI 0.52–0.68) favored the addition of adjuvant trastuzumab. Notably however, a higher incidence of congestive heart failure (RR 7.60, 95% CI 4.07– 14.18) and declines in LVEF (RR 2.09, 95% CI 1.84–2.37) were observed for patients receiving chemotherapy plus trastuzumab, which point to the importance of serial cardiac monitoring in this population. This will be especially important in the ongoing Phase III BETH trial, which is evaluating chemotherapy and trastuzumab with or without the antiVEGF monoclonal antibody bevacizumab in the adjuvant HER2-positive breast cancer setting. Still, de novo and acquired resistance to trastuzumab therapy is not uncommon and alternate therapeutic strategies in HER2-positive breast cancer are needed.
Lapatinib Lapatinib (Tykerb) is a reversible small molecule tyrosine kinase inhibitor of EGFR/HER1 and HER2. Current evidence, however, points to HER2 inhibition as the most likely primary driver of antitumor efficacy, rather than EGFR inhibition [19,20]. Preclinical studies of single-agent lapatinib in HER2-overexpressing cell lines demonstrated potent cell growth inhibition, apoptosis and decreased Akt and Erk pathway signal transduction [19,21]. Furthermore, lapatinib sensitivity was maintained in preclinical models of trastuzumab resistance [20]. In one of the initial Phase I clinical trials of lapatinib in patients with advanced solid malignancies and IHC-positive EGFR and/or HER2 expression, encouraging activity was demonstrated [22]. Of a total of 67 patients, all four partial responders had a breast cancer primary, IHC scores of 3+ for HER2 and previous exposure to trastuzumab. Stable disease was also seen in ten additional patients with breast cancer. At an average dose received of 1200 mg daily, lapatinib was overall well-tolerated, with diarrhea (42%), rash (31%) and fatigue (10%) being the most common AEs. Subsequent Phase II trials of single-agent lapatinib (1500 mg daily) in trastuzumab or chemotherapy-refractory advanced or MBC patients reported good tolerance and activity in
HER2-positive patients, with response rates of 4.3–7.7% by investigator assessment [23,24]. In 2007, US FDA first granted approval of lapatinib in combination with capecitabine based on results from a pivotal Phase III trial reported by Geyer et al. [25]. This study evaluated the combination of lapatinib and capecitabine versus capecitabine alone in patients with HER2-positive locally advanced or MBC who were refractory to treatment with an anthracycline, taxane and trastuzumab. A dose of lapatinib at 1250 mg daily continuously and capecitabine at 2000 mg/m2/day on days 1–14 of a 21-day cycle was utilized based upon earlier Phase I data [26]. Three hundred and twenty-five patients were randomized 1:1 and a four-month improvement in median TTP was reported (8.4 versus 4.4 months), with a HR of 0.49 (P < 0.001). Although the ORRs were higher in the combination arm at 22% (versus 14% for monotherapy arm), this was not statistically significant. Adverse effects attributable to lapatinib were consistent with those previously reported, including diarrhea, rash, fatigue and nausea/vomiting. Notably, an increased incidence of diarrhea and rash was seen in the combination arm. An updated efficacy analysis in 2008 confirmed the median TTP improvement, although the results were less modest (6.2 versus 4.3 months; HR 0.57, P = 0.00013) [27]. Recently, a final efficacy analysis reported no statistically significant differences in OS, but only a trend toward improved OS in the combination arm on exploratory analyses due to patient crossover and inadequate study power [28]. The second US FDA approved use of lapatinib is in combination with letrozole for first-line treatment in postmenopausal women with both hormone receptor positive and HER2-positive MBC. The EGF30008 Phase III trial randomized 1286 treatment-naı¨ve, locally advanced or MBC patients to receive either letrozole plus lapatinib (n = 642) or letrozole plus placebo (n = 644) [29]. In 219 patients with HER2-positive breast cancer, a five-month improvement in median PFS, the primary endpoint, was demonstrated for the combination arm (8.1 versus 3.0 months; HR 0.71, P = 0.019). Mature data for OS are not currently available. Similar to previous trials, diarrhea, rash, nausea and fatigue were the most commonly reported AEs. More recently, building on preclinical observations of synergism with lapatinib and trastuzumab in HER2-positive breast cancer [20] a Phase III trial evaluating lapatinib plus trastuzumab versus lapatinib alone was conducted in patients with MBC, whom had received a median of three prior trastuzumab-containing regimens [30]. Statistically significant improvements in PFS (12.0 versus 8.1 weeks; HR 0.73, P = 0.008) and clinical benefit rate (CBR) (24.7% versus 12.4%, P = 0.01) were observed for the combination arm. Thus far, only a trend in OS improvement was observed (51.6 versus 39.0 weeks, HR = 0.75, P = 0.106), although these data are not yet mature. In the adjuvant setting, the ALTTO trial (Adjuvant Lapatinib and/or www.drugdiscoverytoday.com
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Trastuzumab Treatment Optimization) is currently evaluating the combination of trastuzumab plus lapatinib in patients receiving chemotherapy in one of its four arms, and it is eagerly awaited with interest how this combination compares with the trastuzumab-only, lapatinib-only and sequential trastuzumab-lapatinib arms. Finally, in a subset analysis of lapatinib plus paclitaxel versus paclitaxel alone as first-line treatment of MBC in the EGF30001 Phase III trial, a median TTP improvement of 11.3 weeks was observed in the HER2positive population (36.4 versus 25.1 weeks; HR 0.53) [31,32]. However, neither this regimen nor the lapatinib plus trastuzumab combination is currently US FDA approved for use. Although lapatinib has consistently demonstrated modest efficacy in trastuzumab-refractory states in MBC, clinical resistance to lapatinib in HER2-positive disease remains a clinical challenge.
Other HER-targeted TKIs Unlike lapatinib, neratinib (HKI-272) [33] and afatinib (BIBW 2992) [34] represent two irreversible small molecule TKIs of EGFR/HER1, HER2, and HER4 (pan-HER) currently in clinical development, having shown evidence of activity in preclinical HER2 models. An initial Phase I study of neratinib in advanced solid tumors demonstrated a 32% partial response rate in 8 of 25 HER2-positive breast cancer patients previously treated with trastuzumab, anthracyclines and taxanes, with diarrhea as the dose-limiting toxicity [35]. A multicenter, Phase II study of single-agent neratinib in patients with advanced HER2-positive breast cancer also demonstrated modest clinical activity with an ORR of 24% and a median PFS of 22.3 weeks in the trastuzumab-refractory group (n = 66), and an ORR of 56% and median PFS of 39.6 weeks in the trastuzumab-naive group (n = 70 [36]). Diarrhea (up to 30%) was the most common grade 3/4 AE, and no cases of grade 3 or 4 cardiotoxicity were seen. A large Phase III trial of neratinib plus paclitaxel versus trastuzumab plus paclitaxel is currently underway in HER2-positive MBC (NCT00915018). Phase I and II trials of afatinib in trastuzumab-refractory, HER2-positive MBC have also demonstrated promising antitumor activity [37,38]. A Phase I trial of 53 patients with advanced solid tumors highlighted a case of prolonged SD for six months in a breast cancer patient given once-daily continuous dosing of afatinib [38]. The most common toxicities included diarrhea, nausea/vomiting, fatigue, rash and dry skin. An open-label, single-arm Phase II trial of afatinib in patients with trastuzumab-refractory HER2-positive MBC yielded partial responses in 4/41 and stable disease in 8/41 patients, maintained for four cycles or greater [37]. Again, diarrhea (22%) and grade 3 rash (9.8%) were the most common adverse effects with an afatinib dose of 50 mg daily. Given these encouraging results, an international Phase III trial (LUX-Breast1) of afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with trastuzumab-refrace58
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tory, HER2-positive MBC is currently under investigation (NCT01125566).
Pertuzumab Similar to trastuzumab, pertuzumab (Omnitarg, 2C4) is a humanized monoclonal antibody which targets a different epitope of the HER2 ECD [39,40]. In preclinical models, single-agent pertuzumab inhibited HER2 dimerization, resulting in decreased Akt and MAPK pathway activation, especially in the presence of heregulin (HRG) [39]. Importantly, the dual HER2 antibody approach of trastuzumab and pertuzumab demonstrated synergistic or enhanced in vitro and in vivo antitumor effects in breast cancer [41,42]. In a recently reported open-label, single-arm Phase II trial, the combination of trastuzumab (qweekly or q3w) plus pertuzumab (q3w) in 66 trastuzumab-refractory, HER2-positive MBC patients demonstrated a promising objective response rate of 24.2%, with five complete responders (7.6%) and 11 partial responders (16.7%) [43]. Stable disease of six months was seen in 17 patients (25.8%), yielding a CBR of 50%. Median PFS was 5.5 months, and the combination regimen appeared well-tolerated with no patient withdrawal secondary to cardiac-related events. By contrast, grade 2 and 3 left ventricular systolic dysfunction were reported in an earlier Phase II study [44]. Currently, multiple studies are evaluating the potential role of pertuzumab in combinations with trastuzumab, TDM1 (discussed below), taxanes and other chemotherapeutic regimens in early-stage and advanced breast cancer.
T-DM1 The first-in-class antibody-cytotoxic drug conjugate trastuzumab-DM1 (T-DM1), is characterized by linking trastuzumab to the microtubule-depolymerizing agent emtansine (a maytansine derivative) via a nonreducible thioether linkage (SMCC) [45]. T-DM1 demonstrated selectivity for HER2-overexpressing tumor cell lines with potent in vitro and in vivo antitumor effects. Additionally, activity of T-DM1 was observed in HER2-overexpressing, trastuzumab-refractory tumors [45]. Likewise, activity of T-DM1 in lapatinib resistant preclinical models was also recently reported [46]. In the initial Phase I study of T-DM1 in HER2-positive MBC, significant clinical activity was observed in a heavily pretreated population (median of four prior chemotherapeutic agents), with a confirmed response rate of 44% in patients with measurable disease at the maximum-tolerated dose (MTD) of 3.6 mg/kg administered q3weekly [47]. T-DM1 was welltolerated overall, with only mild drug-related AEs including thrombocytopenia, transaminitis, fatigue, nausea and anemia. Of note, no cardiac toxicities requiring dose adjustments were reported in this trial. In an open-label, single-arm Phase II study of 112 patients with pretreated HER2-positive MBC (median of 3 prior chemotherapy agents), an ORR of 25.9% was reported [48]. In patients previously treated with both
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trastuzumab and lapatinib, the ORR was similar but slightly less at 24.2%. Single-agent T-DM1 was well-tolerated, with hypokalemia (8.9%) and thrombocytopenia (8%) being the most common grade 3 or 4 AEs. In a second Phase II study of T-DM1, which enrolled 110 heavily pretreated HER2-positive MBC patients who had all received prior anthracycline, taxane, capecitabine, trastuzumab and lapatinib (median of 7 prior systemic agents for metastatic disease), the reported ORR and CBR were 32.7% and 44.5% by independent review, respectively [49]. Similarly, T-DM1 was well-tolerated with no dose-limiting cardiotoxicities, with fatigue, nausea and thrombocytopenia being the most common AEs. Taken together, studies of single-agent T-DM1 to date have demonstrated robust activity and tolerability in the heavily pretreated HER2-positive MBC population. The results of ongoing Phase III trials of T-DM1, including a global trial (EMILIA) evaluating T-DM1 versus lapatinib plus capecitabine in this population previously treated with a taxane and trastuzumab are eagerly awaited.
Conclusion Breast cancer biology is complex, as represented by its heterogeneity and diverse molecular subtypes. With the discovery of HER2 amplification and overexpression in 20–25% of breast cancers and advent of trastuzumab, patients with HER2-positive breast cancer now experience improved survival. However, de novo and acquired drug resistance remains an important issue, and newer HER2-targeted agents are warranted. The dual EGFR/HER2 tyrosine kinase inhibitor lapatinib has demonstrated modest activity in both trastuzumab-naı¨ve (with letrozole or paclitaxel) and trastuzumabrefractory HER2-positive MBC, and its potential role in the adjuvant setting is under evaluation. Late-phase novel investigational agents in HER2-positive breast cancer, including neratinib, afatinib, pertuzumab and T-DM1, utilize rational combinations with chemotherapy, trastuzumab and/or lapatinib in attempts to optimize clinical efficacy and minimize untoward toxicities. Although promising Phase II efficacy data with these targeted agents have emerged, gastrointestinal toxicity (diarrhea) with neratinib and afatinib, cardiac toxicities with pertuzumab, and marrow toxicity (thrombocytopenia) with T-DM1 remain challenging clinical issues and may limit their therapeutic ratios and potential clinical utility. Results of ongoing Phase III studies with these agents, therefore, are eagerly awaited. Although beyond the scope of the present mini-review, other agents in clinical development including heat shock protein 90 (hsp90) inhibitors (e.g. tanespimycin), anti-VEGF agents (e.g. bevacizumab, sunitinib, sorafenib and pazopanib) and mTOR inhibitors (e.g. everolimus) represent alternative approaches and signify promising avenues in the management of HER2-positive breast cancer. Finally, further characterization and development of biomarkers may allow for patient enrichment in
efforts to optimize clinical efficacy and minimize toxicities in the anti-HER2 therapeutic space.
Acknowledgement RYT is a Research Fellow of The Terry Fox Foundation (award #020017), Canada.
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Li, D. et al. (2008) BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27, 4702–4711 Wong, K-K. et al. (2009) A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin. Cancer Res. 15, 2552–2558 Burstein, H.J. et al. (2010) Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J. Clin. Oncol. 28, 1301–1307 Hicklish, T. et al. (2009) Use of BIBW 2992, a novel irreversible EGFR/HER1 and HER2 tyrosine kinase inhibitor to treat patients with HER2-positive metastatic breast cancer after failure of treatment with trastuzumab (abstract 5060). Cancer Res. 69 Yap, T.A. et al. (2010) Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J. Clin. Oncol. 28, 3965–3972 Agus, D.B. et al. (2002) Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2, 127–137 Franklin, M.C. et al. (2004) Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5, 317–328 Nahta, R. et al. (2004) The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res. 64, 2343–2346 Scheuer, W. et al. (2009) Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 69, 9330–9336 Baselga, J. et al. (2010) 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. 28, 1138–1144 Portera, C.C. et al. (2008) 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. 14, 2710–2716 Lewis Phillips, G.D. et al. (2008) Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 68, 9280–9290 Junttila, T.T. et al. (2010) Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res. Treat. e pub ahead of print Krop, I.E. et al. (2010) Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2positive metastatic breast cancer. J. Clin. Oncol. 28, 2698–2704 Burris, H.A. et al. (2011) Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2) – positive breast cancer after prior HER2-directed therapy. J. Clin. Oncol. 29, 388–405 Krop, I.E. et al. (2009) A phase II study of trastuzumab-DM1 (T-DM1), a novel HER2 antibody–drug conjugate, in HER2+ metastatic breast cancer (MBC) patients previously treated with conventional chemotherapy, lapatinib and trastuzumab (abstract 710). Cancer Res. 69
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Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Genetics, drug discovery and clinical developments
HER2-positive breast cancer: trastuzumab, lapatinib and emerging therapies Roger Y. Tsang, Richard S. Finn* Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA
The discovery of the HER2 alteration in 20–25% of breast cancers has ushered in an era of molecularly targeted therapies. Targeting HER2 with antibody-
Section editor: Richard Wooster – GlaxoSmithKline, Cancer Metabolism DPU, Oncology R&D, Collegeville, PA, USA
based approaches, such as trastuzumab, or tyrosine kinase inhibitors, such as lapatinib, has yielded improvements in clinical outcomes. Nevertheless, mechanisms of actions underlying anti-HER2 therapies are incompletely understood, and drug resistance is frequently encountered in the clinic. In this review, standard-of-care and emerging therapies in HER2-positive breast cancer will be discussed, with a focus on strategies in late-phase clinical development.
Introduction The discovery of the HER2 alteration, specifically gene amplification and subsequent protein overexpression, in 20–25% of breast cancers, and its associated poor prognosis, has since revolutionized treatment of this clinical entity [1,2]. HER2/ neu/ErbB2 belongs to the ErbB/HER family of receptor tyrosine kinases which include EGFR/HER1, HER3 and HER4, HER2 (human epidermal growth factor receptor 2) and numerous ligands. Amplification results in increased homoand hetero-dimerization with its family members, resulting in enhanced signaling of cell proliferation and differentiation, survival and angiogenic pathways. Uniquely, a ligand has not been identified for HER2, and HER3, its preferred *Corresponding author.: R.S. Finn ([email protected]) 1740-6773/$ ß 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2011.04.004
dimerization partner, has ligands but a ‘dead’ kinase [3]. Currently there are several agents approved and in development for HER2-positive breast cancer. In this mini-review, currently US Food and Drug Administration (FDA) approved and investigational anti-HER2 therapies will be discussed, with a focus on promising strategies in late-phase clinical development (Table 1).
Trastuzumab Trastuzumab (Herceptin), a humanized monoclonal antibody targeting the extracellular domain (ECD) of HER2 and the first anti-HER2 therapy approved by the US FDA in 1998, has revolutionalized treatment of HER2-positive breast cancer. Although preclinical studies of trastuzumab have characterized its antitumor activity via inhibition of cell growth and signal transduction, its mechanisms of action remain incompletely elucidated [4]. Antibody-dependent cellular cytotoxicity (ADCC), decreased DNA repair, effects on angiogenesis and inhibition of cleavage of its ECD are all proposed mechanisms resulting in its antiproliferative and cytotoxic effects. Additionally, additive or synergistic interactions between trastuzumab and various chemotherapeutic agents were also demonstrated preclinically, highlighting the biological rationale for trastuzumab-based combination strategies [5]. e55
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Table 1. Summary of FDA approved and promising therapeutic strategies in HER2-positive breast cancer Therapy
Pros
Cons
Latest developments
Company
Refs
1. Trastuzumab
Established role and FDA approved in both metastatic and adjuvant settings. Robust survival advantages consistently demonstrated
Primary and secondary drug resistance are not uncommon. Cardiotoxicity when used with chemotherapy (especially anthracyclines)
Common backbone for novel anti-HER2 combination strategies
Genentech
[6–11, 14–18]
2. Lapatinib
FDA approved in MBC (with capecitabine or letrozole). Demonstrates activity in trastuzumab-refractory states
OS advantage not yet shown in MBC. Diarrhea and rash may be troublesome. Clinical drug resistance is also an important issue
Role in adjuvant setting under evaluation in comparison with trastuzumab alone or trastuzumab/lapatinib combinations in large global Phase III trial (ALTTO)
GlaxoSmithKline
[22–30]
3. Neratinib
Irreversible TKI inhibition of EGFR/HER2/HER4 inhibition may provide additional benefits. Encouraging activity observed in Phase I and II trials
Phase III study in progress. Like lapatinib, diarrhea is also common
Multiple Phase I and II trials are evaluating neratinib both as a single agent and in combination with chemotherapy or trastuzumab. Large Phase III MBC trial of neratinib plus paclitaxel versus trastuzumab plus paclitaxel is in progress
Pfizer
[35,36]
4. Afatinib
Irreversible TKI inhibition of EGFR/HER2/HER4 inhibition may provide additional benefits. Promising activity reported in Phase I and II trials
Phase III study in progress. Diarrhea and rash, similar to lapatinib, are also common
A global Phase III trial of afatinib plus vinorelbine versus trastuzumab plus vinorelbine in MBC is currently underway (LUX-Breast1)
Boehringer Ingelheim
[37,38]
5. Pertuzumab
Synergism with trastuzumab resulting from binding to different HER2 ECD epitope. Promising Phase II data (response rates, tolerability) with trastuzumab + pertuzumab combination
Phase III trials are in progress. Cardiotoxicity unclear
Under evaluation in combinations with trastuzumab, T-DM1, taxanes and other chemotherapeutic regimens, including the Phase III trial of Pertuzumab/ Trastuzumab/Docetaxel versus Trastuzumab/Docetaxel in first-line MBC (CLEOPATRA)
Genentech
[41–44]
6. T-DM1
Represents a novel drug developmental approach. Phase II data demonstrated robust activity and tolerability in heavily pretreated population
Phase III trials are in progress. Thrombocytopenia may limit dose delivery
Phase III trials of T-DM1 versus T-DM1/pertuzumab versus trastuzumab/taxane in first-line MBC (MARIANNE), and of T-DM1 verus lapatinib/capecitabine in trastuzumab-refractory MBC (EMILIA)
Genentech
[47–49]
The pivotal trial evaluating the use of trastuzumab in combination with chemotherapy in the first-line setting of metastatic breast cancer (MBC) was reported by Slamon et al. [6] This multicenter, Phase III trial randomized 469 patients to receive paclitaxel trastuzumab (n = 188), or doxorubicin/ cyclophosphamide (AC) or epirubicin/cyclophosphamide (EC) trastuzumab (n = 281) depending upon whether they had received prior adjuvant anthracyclines. The addition of trastuzumab to chemotherapy resulted in an 18% higher response rate (50% versus 32%), a 2.8-month improvement in median TTP (7.4 versus 4.6 months) and a five-month improvement in median OS (25 versus 20 months). Notably, a 27% rate of symptomatic cardiac dysfunction (NYHA III/IV) was observed in the AC/trastuzumab arm, raising concerns of unacceptable cardiotoxicity with the concurrent use of e56
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anthracyclines and trastuzumab. In addition, multiple Phase II trials in the first-line, MBC setting have also demonstrated comparable efficacy with weekly trastuzumab plus weekly or three-weekly docetaxel in terms of response rates, TTP and OS, as well as patient tolerability [7–11]. The efficacy and safety of single-agent trastuzumab in the first-line setting for HER2-positive MBC demonstrated an overall response rate (ORR) of 35% in patients with tumors expressing 3+ IHC staining [12]. Trastuzumab monotherapy was well-tolerated, with fever (22%), chills (25%) and asthenia (23%) being the most common adverse events (AEs). The Phase III TAnDEM study evaluated a chemotherapy-free regimen in patients with both hormone and HER2 receptor-positive MBC, and reported a 2.4-month PFS improvement with the combination of trastuzumab plus anastrozole compared with anastro-
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zole alone (4.8 versus 2.4 months; HR = 0.63, P = 0.0016) in the overall intent-to-treat population. However, no overall survival advantage was demonstrated, and a higher incidence of grade 3 and 4 AEs was also observed in the trastuzumab plus anastrozole arm [13]. In the adjuvant setting, five key Phase III trials (NCCTG N9831, NSABP B-31, BCIRG 006, HERA and FinHER) evaluating the use of trastuzumab in HER2-positive breast cancer have reported significant clinical benefit [14–17]. A metaanalysis of the five trials published in 2008, which encompassed a total of 13,493 patients, identified survival advantages in terms of both DFS (RR 0.62, 95% CI 0.56–0.68) and OS (RR 0.66, 95% CI 0.57–0.77) when trastuzumab was added to adjuvant chemotherapy [18]. Additionally, rates of locoregional recurrence (RR 0.58, 95% CI 0.43–0.77) and distant recurrence (RR 0.60, 95% CI 0.52–0.68) favored the addition of adjuvant trastuzumab. Notably however, a higher incidence of congestive heart failure (RR 7.60, 95% CI 4.07– 14.18) and declines in LVEF (RR 2.09, 95% CI 1.84–2.37) were observed for patients receiving chemotherapy plus trastuzumab, which point to the importance of serial cardiac monitoring in this population. This will be especially important in the ongoing Phase III BETH trial, which is evaluating chemotherapy and trastuzumab with or without the antiVEGF monoclonal antibody bevacizumab in the adjuvant HER2-positive breast cancer setting. Still, de novo and acquired resistance to trastuzumab therapy is not uncommon and alternate therapeutic strategies in HER2-positive breast cancer are needed.
Lapatinib Lapatinib (Tykerb) is a reversible small molecule tyrosine kinase inhibitor of EGFR/HER1 and HER2. Current evidence, however, points to HER2 inhibition as the most likely primary driver of antitumor efficacy, rather than EGFR inhibition [19,20]. Preclinical studies of single-agent lapatinib in HER2-overexpressing cell lines demonstrated potent cell growth inhibition, apoptosis and decreased Akt and Erk pathway signal transduction [19,21]. Furthermore, lapatinib sensitivity was maintained in preclinical models of trastuzumab resistance [20]. In one of the initial Phase I clinical trials of lapatinib in patients with advanced solid malignancies and IHC-positive EGFR and/or HER2 expression, encouraging activity was demonstrated [22]. Of a total of 67 patients, all four partial responders had a breast cancer primary, IHC scores of 3+ for HER2 and previous exposure to trastuzumab. Stable disease was also seen in ten additional patients with breast cancer. At an average dose received of 1200 mg daily, lapatinib was overall well-tolerated, with diarrhea (42%), rash (31%) and fatigue (10%) being the most common AEs. Subsequent Phase II trials of single-agent lapatinib (1500 mg daily) in trastuzumab or chemotherapy-refractory advanced or MBC patients reported good tolerance and activity in
HER2-positive patients, with response rates of 4.3–7.7% by investigator assessment [23,24]. In 2007, US FDA first granted approval of lapatinib in combination with capecitabine based on results from a pivotal Phase III trial reported by Geyer et al. [25]. This study evaluated the combination of lapatinib and capecitabine versus capecitabine alone in patients with HER2-positive locally advanced or MBC who were refractory to treatment with an anthracycline, taxane and trastuzumab. A dose of lapatinib at 1250 mg daily continuously and capecitabine at 2000 mg/m2/day on days 1–14 of a 21-day cycle was utilized based upon earlier Phase I data [26]. Three hundred and twenty-five patients were randomized 1:1 and a four-month improvement in median TTP was reported (8.4 versus 4.4 months), with a HR of 0.49 (P < 0.001). Although the ORRs were higher in the combination arm at 22% (versus 14% for monotherapy arm), this was not statistically significant. Adverse effects attributable to lapatinib were consistent with those previously reported, including diarrhea, rash, fatigue and nausea/vomiting. Notably, an increased incidence of diarrhea and rash was seen in the combination arm. An updated efficacy analysis in 2008 confirmed the median TTP improvement, although the results were less modest (6.2 versus 4.3 months; HR 0.57, P = 0.00013) [27]. Recently, a final efficacy analysis reported no statistically significant differences in OS, but only a trend toward improved OS in the combination arm on exploratory analyses due to patient crossover and inadequate study power [28]. The second US FDA approved use of lapatinib is in combination with letrozole for first-line treatment in postmenopausal women with both hormone receptor positive and HER2-positive MBC. The EGF30008 Phase III trial randomized 1286 treatment-naı¨ve, locally advanced or MBC patients to receive either letrozole plus lapatinib (n = 642) or letrozole plus placebo (n = 644) [29]. In 219 patients with HER2-positive breast cancer, a five-month improvement in median PFS, the primary endpoint, was demonstrated for the combination arm (8.1 versus 3.0 months; HR 0.71, P = 0.019). Mature data for OS are not currently available. Similar to previous trials, diarrhea, rash, nausea and fatigue were the most commonly reported AEs. More recently, building on preclinical observations of synergism with lapatinib and trastuzumab in HER2-positive breast cancer [20] a Phase III trial evaluating lapatinib plus trastuzumab versus lapatinib alone was conducted in patients with MBC, whom had received a median of three prior trastuzumab-containing regimens [30]. Statistically significant improvements in PFS (12.0 versus 8.1 weeks; HR 0.73, P = 0.008) and clinical benefit rate (CBR) (24.7% versus 12.4%, P = 0.01) were observed for the combination arm. Thus far, only a trend in OS improvement was observed (51.6 versus 39.0 weeks, HR = 0.75, P = 0.106), although these data are not yet mature. In the adjuvant setting, the ALTTO trial (Adjuvant Lapatinib and/or www.drugdiscoverytoday.com
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Trastuzumab Treatment Optimization) is currently evaluating the combination of trastuzumab plus lapatinib in patients receiving chemotherapy in one of its four arms, and it is eagerly awaited with interest how this combination compares with the trastuzumab-only, lapatinib-only and sequential trastuzumab-lapatinib arms. Finally, in a subset analysis of lapatinib plus paclitaxel versus paclitaxel alone as first-line treatment of MBC in the EGF30001 Phase III trial, a median TTP improvement of 11.3 weeks was observed in the HER2positive population (36.4 versus 25.1 weeks; HR 0.53) [31,32]. However, neither this regimen nor the lapatinib plus trastuzumab combination is currently US FDA approved for use. Although lapatinib has consistently demonstrated modest efficacy in trastuzumab-refractory states in MBC, clinical resistance to lapatinib in HER2-positive disease remains a clinical challenge.
Other HER-targeted TKIs Unlike lapatinib, neratinib (HKI-272) [33] and afatinib (BIBW 2992) [34] represent two irreversible small molecule TKIs of EGFR/HER1, HER2, and HER4 (pan-HER) currently in clinical development, having shown evidence of activity in preclinical HER2 models. An initial Phase I study of neratinib in advanced solid tumors demonstrated a 32% partial response rate in 8 of 25 HER2-positive breast cancer patients previously treated with trastuzumab, anthracyclines and taxanes, with diarrhea as the dose-limiting toxicity [35]. A multicenter, Phase II study of single-agent neratinib in patients with advanced HER2-positive breast cancer also demonstrated modest clinical activity with an ORR of 24% and a median PFS of 22.3 weeks in the trastuzumab-refractory group (n = 66), and an ORR of 56% and median PFS of 39.6 weeks in the trastuzumab-naive group (n = 70 [36]). Diarrhea (up to 30%) was the most common grade 3/4 AE, and no cases of grade 3 or 4 cardiotoxicity were seen. A large Phase III trial of neratinib plus paclitaxel versus trastuzumab plus paclitaxel is currently underway in HER2-positive MBC (NCT00915018). Phase I and II trials of afatinib in trastuzumab-refractory, HER2-positive MBC have also demonstrated promising antitumor activity [37,38]. A Phase I trial of 53 patients with advanced solid tumors highlighted a case of prolonged SD for six months in a breast cancer patient given once-daily continuous dosing of afatinib [38]. The most common toxicities included diarrhea, nausea/vomiting, fatigue, rash and dry skin. An open-label, single-arm Phase II trial of afatinib in patients with trastuzumab-refractory HER2-positive MBC yielded partial responses in 4/41 and stable disease in 8/41 patients, maintained for four cycles or greater [37]. Again, diarrhea (22%) and grade 3 rash (9.8%) were the most common adverse effects with an afatinib dose of 50 mg daily. Given these encouraging results, an international Phase III trial (LUX-Breast1) of afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with trastuzumab-refrace58
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tory, HER2-positive MBC is currently under investigation (NCT01125566).
Pertuzumab Similar to trastuzumab, pertuzumab (Omnitarg, 2C4) is a humanized monoclonal antibody which targets a different epitope of the HER2 ECD [39,40]. In preclinical models, single-agent pertuzumab inhibited HER2 dimerization, resulting in decreased Akt and MAPK pathway activation, especially in the presence of heregulin (HRG) [39]. Importantly, the dual HER2 antibody approach of trastuzumab and pertuzumab demonstrated synergistic or enhanced in vitro and in vivo antitumor effects in breast cancer [41,42]. In a recently reported open-label, single-arm Phase II trial, the combination of trastuzumab (qweekly or q3w) plus pertuzumab (q3w) in 66 trastuzumab-refractory, HER2-positive MBC patients demonstrated a promising objective response rate of 24.2%, with five complete responders (7.6%) and 11 partial responders (16.7%) [43]. Stable disease of six months was seen in 17 patients (25.8%), yielding a CBR of 50%. Median PFS was 5.5 months, and the combination regimen appeared well-tolerated with no patient withdrawal secondary to cardiac-related events. By contrast, grade 2 and 3 left ventricular systolic dysfunction were reported in an earlier Phase II study [44]. Currently, multiple studies are evaluating the potential role of pertuzumab in combinations with trastuzumab, TDM1 (discussed below), taxanes and other chemotherapeutic regimens in early-stage and advanced breast cancer.
T-DM1 The first-in-class antibody-cytotoxic drug conjugate trastuzumab-DM1 (T-DM1), is characterized by linking trastuzumab to the microtubule-depolymerizing agent emtansine (a maytansine derivative) via a nonreducible thioether linkage (SMCC) [45]. T-DM1 demonstrated selectivity for HER2-overexpressing tumor cell lines with potent in vitro and in vivo antitumor effects. Additionally, activity of T-DM1 was observed in HER2-overexpressing, trastuzumab-refractory tumors [45]. Likewise, activity of T-DM1 in lapatinib resistant preclinical models was also recently reported [46]. In the initial Phase I study of T-DM1 in HER2-positive MBC, significant clinical activity was observed in a heavily pretreated population (median of four prior chemotherapeutic agents), with a confirmed response rate of 44% in patients with measurable disease at the maximum-tolerated dose (MTD) of 3.6 mg/kg administered q3weekly [47]. T-DM1 was welltolerated overall, with only mild drug-related AEs including thrombocytopenia, transaminitis, fatigue, nausea and anemia. Of note, no cardiac toxicities requiring dose adjustments were reported in this trial. In an open-label, single-arm Phase II study of 112 patients with pretreated HER2-positive MBC (median of 3 prior chemotherapy agents), an ORR of 25.9% was reported [48]. In patients previously treated with both
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trastuzumab and lapatinib, the ORR was similar but slightly less at 24.2%. Single-agent T-DM1 was well-tolerated, with hypokalemia (8.9%) and thrombocytopenia (8%) being the most common grade 3 or 4 AEs. In a second Phase II study of T-DM1, which enrolled 110 heavily pretreated HER2-positive MBC patients who had all received prior anthracycline, taxane, capecitabine, trastuzumab and lapatinib (median of 7 prior systemic agents for metastatic disease), the reported ORR and CBR were 32.7% and 44.5% by independent review, respectively [49]. Similarly, T-DM1 was well-tolerated with no dose-limiting cardiotoxicities, with fatigue, nausea and thrombocytopenia being the most common AEs. Taken together, studies of single-agent T-DM1 to date have demonstrated robust activity and tolerability in the heavily pretreated HER2-positive MBC population. The results of ongoing Phase III trials of T-DM1, including a global trial (EMILIA) evaluating T-DM1 versus lapatinib plus capecitabine in this population previously treated with a taxane and trastuzumab are eagerly awaited.
Conclusion Breast cancer biology is complex, as represented by its heterogeneity and diverse molecular subtypes. With the discovery of HER2 amplification and overexpression in 20–25% of breast cancers and advent of trastuzumab, patients with HER2-positive breast cancer now experience improved survival. However, de novo and acquired drug resistance remains an important issue, and newer HER2-targeted agents are warranted. The dual EGFR/HER2 tyrosine kinase inhibitor lapatinib has demonstrated modest activity in both trastuzumab-naı¨ve (with letrozole or paclitaxel) and trastuzumabrefractory HER2-positive MBC, and its potential role in the adjuvant setting is under evaluation. Late-phase novel investigational agents in HER2-positive breast cancer, including neratinib, afatinib, pertuzumab and T-DM1, utilize rational combinations with chemotherapy, trastuzumab and/or lapatinib in attempts to optimize clinical efficacy and minimize untoward toxicities. Although promising Phase II efficacy data with these targeted agents have emerged, gastrointestinal toxicity (diarrhea) with neratinib and afatinib, cardiac toxicities with pertuzumab, and marrow toxicity (thrombocytopenia) with T-DM1 remain challenging clinical issues and may limit their therapeutic ratios and potential clinical utility. Results of ongoing Phase III studies with these agents, therefore, are eagerly awaited. Although beyond the scope of the present mini-review, other agents in clinical development including heat shock protein 90 (hsp90) inhibitors (e.g. tanespimycin), anti-VEGF agents (e.g. bevacizumab, sunitinib, sorafenib and pazopanib) and mTOR inhibitors (e.g. everolimus) represent alternative approaches and signify promising avenues in the management of HER2-positive breast cancer. Finally, further characterization and development of biomarkers may allow for patient enrichment in
efforts to optimize clinical efficacy and minimize toxicities in the anti-HER2 therapeutic space.
Acknowledgement RYT is a Research Fellow of The Terry Fox Foundation (award #020017), Canada.
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