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Pertuzumab Monotherapy After Trastuzumab-Based Treatment and Subsequent Reintroduction of Trastuzumab: Activity and Tolerability in Patients With Advanced Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer
Abstract
The combination of pertuzumab and trastuzumab resulted in a clinical benefit rate (CBR) of 50% in patients with human epidermal growth factor receptor 2 (HER2) –positive breast cancer whose disease progressed during prior trastuzumab-based therapy. To define whether this previously observed encouraging activity was a result of the combination of pertuzumab and trastuzumab or of pertuzumab alone, we recruited a third cohort of patients who received pertuzumab without trastuzumab. We then investigated the impact of reintroducing trastuzumab to patients whose disease progressed on pertuzumab monotherapy.
Twenty-nine patients with HER2-positive breast cancer whose disease progressed during prior trastuzumab-based therapy received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) until progressive disease or unacceptable toxicity. Seventeen patients with disease progression continued to receive pertuzumab (at the same dose), with the addition of trastuzumab (4 mg/kg loading dose and then 2 mg/kg weekly or 8 mg/kg loading dose and then 6 mg/kg every 3 weeks).
All 29 patients enrolled for pertuzumab monotherapy experienced disease progression. The objective response rate (ORR) and CBR were 3.4% and 10.3%, respectively, during pertuzumab monotherapy. With the addition of trastuzumab, the ORR and CBR were 17.6% and 41.2%, respectively. Progression-free survival was longer with combination therapy than pertuzumab monotherapy (17.4 v 7.1 weeks, respectively). Treatment was well tolerated with minimal cardiac dysfunction.
Overexpression of the human epidermal growth factor receptor 2 (HER2) is found in 15% to 25% of patients with breast cancer and has been shown to be a negative prognostic factor if specific therapy is not given.1–3 The HER2-targeted humanized monoclonal antibody, trastuzumab, improves survival in HER2-positive metastatic breast cancer (MBC) and early breast cancer.4–8 Trastuzumab binds to the juxtamembrane extracellular subdomain IV of HER2 and exerts its antitumor activity in a number of ways, including inhibition of signal transduction and the triggering of antibody-dependent cellular cytotoxicity (ADCC).9,10 Although trastuzumab has transformed the course of HER2-positive disease,11 alternative treatment options are needed for patients who experience disease progression while receiving trastuzumab or other HER2-targeted therapies.
Pertuzumab is also a humanized monoclonal antibody that targets the HER2 receptor and, like trastuzumab, activates ADCC.12 However, unlike trastuzumab, pertuzumab binds to the dimerization domain of HER2, blocking dimer formation with other members of the HER family.13 Of the HER family dimers, HER2:HER3 dimers are particularly potent for tumorigenic downstream signaling.14 Blocking dimerization prevents downstream signaling mediated by multiple HER family members and, therefore, potentially provides a more comprehensive blockade than inhibiting only HER2 signaling.15
Because pertuzumab and trastuzumab bind to different epitopes of HER2, it was hypothesized that the complementary mechanisms of action of the two agents could lead to synergistic antitumor effects when given in combination.16 Evidence from preclinical studies supported this hypothesis.12,17
In the phase II study BO17929, the activity of combination therapy with pertuzumab and trastuzumab was investigated in patients with HER2-positive MBC that had progressed during prior trastuzumab-based therapy.18 Two cohorts of patients received combination therapy until progressive disease or unacceptable toxicity. Combination therapy was well tolerated, with no additional cardiac dysfunction.19 Efficacy results from the first two cohorts of the study showed a clinical benefit rate (CBR) of 50%. Of the 66 patients enrolled, complete response (CR) was observed in four patients (6.06%), partial response (PR) in 12 patients (18.18%), and stable disease (SD) for over 6 months in 17 patients (25.8%).18
To address whether the encouraging activity of pertuzumab observed in BO17929 was a result of its combination with trastuzumab or of pertuzumab alone, we recruited a third cohort (cohort 3) of patients who had experienced progression on trastuzumab-based therapy and assigned them to pertuzumab monotherapy. Within this cohort, we also investigated the impact of reintroducing trastuzumab therapy to patients who experienced progression on pertuzumab monotherapy.
The methods used in BO17929 have been elaborated previously and, therefore, will only be described briefly here.18
Key inclusion criteria were as follows: women age ≥ 18 years; histologically confirmed HER2-positive MBC that had previously progressed on trastuzumab-based therapy; up to three prior chemotherapy regimens; at least one measurable lesion according to RECIST20; Eastern Cooperative Oncology Group performance status ≤ 2; and signed, informed consent. Main exclusion criteria included the following: prior targeted therapy (other than trastuzumab); history of cardiac disease or cardiac adverse events (AEs) related to trastuzumab treatment; and CNS metastases. Patients were only included if they had received their last dose of trastuzumab ≥ 4 weeks before the first study day.
The study was a nonrandomized, Simon-type, two-stage design, as described previously.18 Given the encouraging findings in the original BO17929 study, the trial protocol was amended to recruit a further cohort of patients who would receive pertuzumab monotherapy. The inclusion criteria were kept the same except that, in this part of the study, patients were included only if they had received their last dose of trastuzumab ≥ 4 weeks before the first day of study. Pertuzumab monotherapy was continued until documented progressive disease or unacceptable toxicity. For patients who tolerated pertuzumab but whose disease progressed during pertuzumab therapy, trastuzumab could be reintroduced and given in combination with pertuzumab, at the investigator's discretion. Alternatively, the patient would be withdrawn from study and offered whatever therapy was clinically indicated.
On study day 1, a loading dose of pertuzumab 840 mg was administered as an intravenous infusion. On day 22 and every 3 weeks thereafter, pertuzumab was given at a fixed dose of 420 mg. For patients who experienced disease progression and went on to have trastuzumab therapy reintroduced, intravenous infusion of trastuzumab was given either weekly or every 3 weeks according to local requirements. Weekly trastuzumab was administered at a loading dose of 4 mg/kg followed by 2 mg/kg weekly thereafter. If trastuzumab was given every 3 weeks, patients received an 8 mg/kg loading dose on day 1 followed by 6 mg/kg on day 22 and every 3 weeks thereafter. When receiving combination therapy, trastuzumab was administered first, followed by pertuzumab.
The primary end points of the study were the objective response rate (ORR; defined as CR + PR) and CBR (defined as ORR + SD > 24 weeks) of therapy. Secondary end points included duration of response, time to response, time to tumor progression (TTP), progression-free survival (PFS), and overall survival.
The safety population included all patients who received pertuzumab and had at least one postbaseline safety analysis. AEs were assessed throughout the duration of the study and for 28 days after cessation of study medication. Incidence of AEs was reported and graded according to Common Terminology Criteria for Adverse Events (version 3.0).
Left ventricular ejection fraction (LVEF) was measured by echocardiography or multiple-gated acquisition scan. All echocardiography scans underwent central review, but patient management was based on local readings. If LVEF decreased by ≥ 10 percentage points to less than 50% absolute value and had not increased by more than 5 percentage points and to ≥ 50% by the final visit, cardiac monitoring was repeated after 6 and 18 weeks or until LVEF had increased to above these thresholds. For patients with an asymptomatic decrease in LVEF (≤ 45%), the decision to continue or stop study medication was based on the measured LVEF and changes in LVEF from baseline. Study medication was withdrawn from any patients with symptomatic cardiac dysfunction.
Tumor response was evaluated according to RECIST.20 Tumors were assessed by computed tomography or magnetic resonance imaging of thorax, abdomen, and pelvis at screening and after every second cycle of therapy for eight cycles. During the follow-up period, tumor response was evaluated every four cycles. For each patient, the same scanning technique was used to evaluate the tumor throughout the study. The best overall response end point (defined as CR, PR, SD lasting through at least eight cycles of therapy, or progressive disease) was assigned for each patient.
To achieve 24 evaluable patients, a minimum sample size of 27 patients was estimated to be required. The sample size was originally developed based on Simon's two-stage design for objective response only. The decision was made to continue with these numbers for the first and final stage of the trial. An optimum design was selected, with a null hypothesis for ORR ≤ 7%, a one-sided α = .10, and power of 60% to detect a clinically meaningful ORR of ≥ 13%. Specifically, the trial could be stopped for lack of activity if ≤ one response out of 24 patients was observed at the first stage, when the 24th patient had completed at least two cycles of therapy and an efficacy assessment at the end of cycle 2. The probability of early termination given that the true response rate was ≤ 7% was 49.2%. The null hypothesis could be rejected after the second stage if there were ≥ seven responses out of 58 patients.
ORR and CBR were reported. Time to response, TTP, PFS, and overall survival were analyzed, with estimates for the median time to event (if reached) and the corresponding two-sided 80% CIs given.
Baseline patient and disease characteristics are listed in Table 1. All patients had previously received trastuzumab; the mean duration of prior trastuzumab treatment was 87.2 weeks (standard deviation, 69.0 weeks). All patients had also received prior chemotherapy, with 25 patients (86%) being treated for metastatic disease (range, one to five prior lines). Two patients did not meet the inclusion criteria because they had received more than three lines of previous cytotoxic therapy in the metastatic setting, but they were allowed to continue in the trial.
|
| Demographic or Disease Characteristic | Pertuzumab Monotherapy (N = 29) | Pertuzumab + Trastuzumab (n = 17) | ||
|---|---|---|---|---|
| No. of Patients | % | No. of Patients | % | |
| Age, years | ||||
| Median | 55 | 54 | ||
| Range | 38-65 | 40-63 | ||
| Received anthracyclines in previous treatment | 21 | 72 | 13 | 76.5 |
| ECOG performance status | ||||
| 0 | 19 | 10 | ||
| 1 | 9 | 7 | ||
| 2 | 1 | 0 | ||
| Organ site of target lesions | ||||
| Visceral | 16 | 55.2 | 10 | 58.8 |
| Lung | 8 | 27.6 | 5 | 29.4 |
| Liver | 9 | 31.0 | 5 | 29.4 |
| Adrenal | 0 | 0 | 0 | 0 |
| Pleura | 1 | 3.4 | 0 | 0 |
| Peritoneum | 0 | 0 | 0 | 0 |
| Lymph | 15 | 51.7 | 3 | 17.6 |
| Bone | 0 | 0 | 9 | 52.9 |
| Soft tissue | 3 | 10.3 | 1 | 5.9 |
| Other | 5 | 17.2 | 2 | 11.8 |
| Estrogen receptor status | ||||
| Positive | 45 | 53 | ||
| Negative | 55 | 47 | ||
| No. of metastatic sites involved | ||||
| Median | 4 | 4 | ||
| Range | 1-11 | 1-7 | ||
Abbreviation: ECOG, Eastern Cooperative Oncology Group.
Patients received a median of three cycles (range, one to 24 cycles) of pertuzumab monotherapy. The 17 patients who went on to receive dual therapy had also received a median of three cycles of pertuzumab monotherapy and went on to receive a median of six cycles (range, one to 37 cycles) in the dual-agent phase. The flow of patients through the study is shown in Figure 1.
Fig 1. Study design: flowchart of treatment received and numbers of patients remaining on study in cohort 3. HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; PD, progressive disease.
All patients who received pertuzumab were assessed for safety. Overall treatment was well tolerated, with serious AEs being experienced by only one patient. Twenty-seven patients (93%) on pertuzumab monotherapy experienced at least one AE; however, these AEs were mainly grade 1 or 2 (Table 2). Fifteen patients (88%) on combination therapy experienced at least one AE, but all AEs except six were grade 1 or 2 (Table 2).
|
| Adverse Event | Pertuzumab Monotherapy (N = 29) | Trastuzumab + Pertuzumab (n = 17) | ||||||
|---|---|---|---|---|---|---|---|---|
| All Grades | Grade 3/4 | All Grades | Grade 3/4 | |||||
| No. | % | No. | % | No. | % | No. | % | |
| Diarrhea | 14 | 48.3 | 1 | 3 | 5 | 29 | 1 | 6 |
| Nausea | 10 | 34.5 | 0 | 0 | 5 | 29 | 0 | 0 |
| Vomiting | 7 | 24 | 0 | 0 | 4 | 24 | 0 | 0 |
| Fatigue | 5 | 17 | 1 | 3 | 4 | 24 | 1 | 6 |
| Asthenia | 5 | 17 | 0 | 0 | 2 | 12 | 0 | 0 |
| Back pain | 5 | 17 | 0 | 0 | 2 | 12 | 1 | 6 |
| Musculoskeletal chest pain | 3 | 10 | 0 | 0 | 0 | 0 | 0 | 0 |
| Abdominal distension | 3 | 10 | 0 | 0 | 0 | 0 | 0 | 0 |
| Abdominal pain upper | 3 | 10 | 0 | 0 | 1 | 6 | 0 | 0 |
| Decreased appetite | 3 | 10 | 0 | 0 | 2 | 12 | 0 | 0 |
| Arthralgia | 3 | 10 | 0 | 0 | 1 | 6 | 0 | 0 |
| Dyspnea | 3 | 10 | 0 | 0 | 0 | 0 | 0 | 0 |
| Pruritus | 3 | 10 | 0 | 0 | 2 | 12 | 0 | 0 |
| Rash | 3 | 10 | 0 | 0 | 3 | 18 | 0 | 0 |
| Headache | 2 | 7 | 0 | 0 | 2 | 12 | 0 | 0 |
| Chills | 0 | 0 | 0 | 0 | 3 | 18 | 0 | 0 |
| Weight decrease | 0 | 0 | 0 | 0 | 3 | 18 | 0 | 0 |
| Constipation | 1 | 3 | 0 | 0 | 2 | 12 | 0 | 0 |
| Dizziness | 0 | 0 | 0 | 0 | 2 | 12 | 0 | 0 |
| Influenza-like illness | 0 | 0 | 0 | 0 | 2 | 12 | 0 | 0 |
| Left ventricular dysfunction | 0 | 0 | 0 | 0 | 2 | 12 | 0 | 0 |
| Pain in extremity | 1 | 3 | 0 | 0 | 2 | 12 | 0 | 0 |
| Oropharyngeal pain | 2 | 7 | 1 | 3 | 1 | 6 | 0 | 0 |
| Upper respiratory tract infection | 0 | 0 | 0 | 0 | 3 | 18 | 0 | 0 |
| Grade 3/4 adverse events that did not occur in ≥ 10% of patients | ||||||||
| Abdominal pain | 2 | 7 | 1 | 3 | 0 | 0 | 0 | 0 |
| Femur fracture* | 1 | 3 | 1 | 3 | 0 | 0 | 0 | 0 |
| Ocular icterus | 1 | 3 | 1 | 3 | 0 | 0 | 0 | 0 |
| Syncope | 1 | 3 | 1 | 3 | 0 | 0 | 0 | 0 |
| Pain | 0 | 0 | 0 | 0 | 1 | 6 | 1 | 6 |
| Depression | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 6 |
| Osmotic demyelination syndrome* | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 6 |
*Considered a serious adverse event.
The most common AEs were diarrhea and nausea, which were manageable and usually resolved without sequelae. While on trial treatment, one patient died of hepatorenal failure as a result of progressive disease on study day 70. This patient was a 63-year-old white woman with ductal breast cancer with metastatic disease in the liver and lymph nodes and a medical history of hypertension, peripheral edema, and obesity. After showing her first disease progression, she had received vinorelbine plus trastuzumab for approximately 10 weeks. After the diagnosis of her second disease progression, she subsequently received two cycles of pertuzumab and then one cycle of pertuzumab plus trastuzumab on study day 43. The patient died before the scheduled tumor assessment was carried out. The investigator considered her death to be unrelated to study medication and recorded the underlying cause of death as MBC.
One patient withdrew from dual-agent therapy as a result of the serious AE of central pontine myelinolysis that was considered by the investigator as possibly related to study treatment. After completing 11 cycles of pertuzumab alone, the patient developed brain metastases. She was treated with whole-brain radiotherapy and then started treatment with pertuzumab in combination with trastuzumab (in violation of the protocol). After receiving a total of 11 cycles of combination therapy, the patient was noted to have slurred speech and incoordination, and subsequently, central pontine myelinolysis (investigator-reported term) was diagnosed. The event resolved with sequelae after 234 days, and the patient was still alive 6 months later. It is pertinent to note that, apart from cerebral and cerebellar metastases and recent radiotherapy to the brain, the patient had decreased appetite at the time of onset of the syndrome and was diabetic (receiving insulin and metformin). This patient also experienced the only other serious AE reported in cohort 3 of this study (unrelated femur fracture at cycle 4 of single-agent pertuzumab therapy).
Cardiac function was carefully monitored during the study, and changes in LVEF from baseline during both monotherapy and combination therapy are shown in Figure 2. Statistical analysis of LVEF change was not powered for significance because of low patient numbers and was descriptive only. Three patients experienced asymptomatic grade 2 reductions in LVEF (by ≥ 10% and to < 50% in absolute value), two of which were during pertuzumab monotherapy and one during combination therapy. Two of these LVEF decreases were detected only by local readings, and neither required treatment; one patient had a dose interruption, and one patient stopped study treatment as a result of progressive disease. The other LVEF decrease was detected only by central assessment at cycle 1 and had recovered to more than 50% at cycle 4; at all stages, local LVEF readings were ≥ 55%.
Fig 2. Mean change in left ventricular ejection fraction (LVEF) from baseline over time during pertuzumab monotherapy and pertuzumab and trastuzumab combination therapy (local echocardiogram reading) in cohort 3.
The efficacy analysis was based on the entire treated population, which included all 29 patients. Of the 29 patients enrolled on pertuzumab monotherapy, all experienced disease progression; 17 of these patients went on to receive combination therapy with pertuzumab and trastuzumab.
While receiving pertuzumab monotherapy, one (3.4%) of 29 patients achieved a PR lasting 24 weeks (168 days), and two patients (6.9%) had SD lasting for at least eight treatment cycles, leading to ORR and CBR of 3.4% and 10.3%, respectively (Table 3). The median duration of CBR during pertuzumab monotherapy was 35.3 weeks (range, 23 to 36 weeks). During pertuzumab monotherapy, three patients had SD lasting for less than eight treatment cycles (two patients for four cycles and one patient for six cycles).
|
| Response | Cohorts 1 and 2: Pertuzumab + Trastuzumab (n = 66) | Cohort 3: Pertuzumab Only (n = 29) | Cohort 3: Pertuzumab + Trastuzumab (n = 17) | |||
|---|---|---|---|---|---|---|
| No. of Patients | % | No. of Patients | % | No. of Patients | % | |
| CR | 4 | 6.06 | 0 | 0.0 | 0 | 0.0 |
| PR | 12 | 18.18 | 1 | 3.4 | 3 | 17.6 |
| Objective response rate (CR + PR) | 16 | 24.24 | 1 | 3.4 | 3 | 17.6 |
| SD ≥ 6 months | 17 | 25.8 | 2 | 6.9 | 4* | 23.5 |
| Clinical benefit rate (CR + PR + SD ≥ 6 months) | 33 | 50.0 | 3 | 10.3 | 7 | 41.2 |
| Progressive disease | 33 | 50.0 | 26 | 89.7 | 10† | 58.8 |
Abbreviations: CR, complete response; PR, partial response; SD, stable disease.
*One patient's disease was reported as not assessable, but this patient remains well on trastuzumab and pertuzumab after more than 20 cycles of therapy.
†The patient who died of hepatorenal failure (underlying cause was metastatic breast cancer) did not have a tumor assessment performed in dual phase.
Among the 17 patients who received combination therapy, 13 (76.5%) withdrew as a result of progression, one withdrew as a result of toxicity (central pontine myelinolysis), one died as a result of hepatorenal toxicity (underlying cause was MBC), and two (12%) did not progress and remained on treatment.
For the best overall response end point, three patients (17.6%) achieved a PR (Fig 3), four patients (13.5%) had SD for at least eight cycles of treatment, and 10 patients (58.8%) experienced progressive disease. This led to an ORR and a CBR of 17.6% and 41.2%, respectively. The median duration of ORR during dual therapy was 44.3 weeks (range, 30 to 101 weeks). In total, two patients remained on combination therapy at the time of writing this article.
Fig 3. Series of computed tomography scans from one patient illustrating the response to the reintroduction of trastuzumab after pertuzumab monotherapy. PD, progressive disease; PR, partial response.
PFS and TTP were both longer during combination therapy than during pertuzumab monotherapy, but this comparison was not statistically analyzed. Median PFS and TTP were both 7.1 weeks (80% CI, 6 to 10 weeks) during monotherapy and were 17.4 weeks (80% CI, 6 to 29 weeks) and 17.4 weeks (80% CI, 6 to 36 weeks), respectively, during combination therapy. Overall survival data have not yet reached maturity.
After the observation of encouraging activity with pertuzumab and trastuzumab combination therapy in patients with HER2-positive MBC who had experienced progression on trastuzumab-based therapy,18 the recruitment of a third cohort of patients, who received pertuzumab without trastuzumab, enabled the safety and efficacy of pertuzumab as monotherapy to be investigated. Because these patients had previously received trastuzumab, it was also possible to investigate the impact of reintroducing trastuzumab to patients whose disease had progressed on pertuzumab monotherapy.
Pertuzumab monotherapy showed modest efficacy in patients with HER2-positive MBC who had experienced progression during prior trastuzumab-based therapy, with only one patient responding and a CBR of 10%. In comparison, after reintroduction of trastuzumab, the combination of pertuzumab and trastuzumab showed much greater activity than pertuzumab alone, with ORR and CBR of 17.6% and 41.2%, respectively. This is comparable to the CBR reported for combination therapy in cohorts 1 and 2 of this study (ORR, 24%; CBR, 50%).18 This high response rate was particularly impressive given that the patients had previously experienced disease progression while receiving each of the two therapies alone and were not receiving concomitant cytotoxic chemotherapy.
To our knowledge, this is the first report of clinical responses to combined targeted therapies in patients who had experienced disease progression after exposure to the same therapies given individually. These responses underscore the primary role that HER2 plays in driving the growth of these tumors, even after multiple lines of treatment with anti-HER2 therapies. The clinical responses observed during combination trastuzumab and pertuzumab therapy also support the concept that antireceptor agents with complementary mechanisms may be more active when given together than when given alone. Activation of HER2 can occur in a ligand-dependent manner, where HER2 functions as a coreceptor with other HER/ErbB family members, most notably HER3.21 Binding of pertuzumab sterically blocks this association.22 Preclinical studies using a combination of trastuzumab and pertuzumab demonstrate strongly enhanced activity with combination treatment, suggesting that blockade of both ligand-dependent and ligand-independent signaling is necessary for optimal response.12,17
Another possibility is that the changes in geometry caused by the interaction of trastuzumab and pertuzumab with the HER2 receptor could also result in an increase in the recruitment of immune effector cells to the tumor site.9 Recently, it was reported that the therapeutic effect of anti-HER2 antibodies not only relies on innate immunity (ADCC) but also requires an adaptive immune response.23 Tumor cell death induced by ADCC caused the release of danger signals that trigger activation of antigen-presenting cells and generate CD8α+-dependent adaptive antitumor immunity.23 Interestingly, taxane administration after antibody therapy abrogates this secondary immune response.23
We initially proposed the concept of dual receptor blockade by using combined antireceptor agents with nonoverlapping mechanisms of action over a decade ago,24,25 and this, to our knowledge, is the first demonstration of this concept in patients. The results observed with our antibody doublet may also be applicable to other receptor tyrosine kinases because combined antibodies against distinct epitopes of the same receptor tyrosine kinase were also reported in experimental models for insulin-like growth factor 1 receptor26 and epidermal growth factor receptor.27
In conclusion, our findings suggest that combining anti-HER receptor monoclonal antibodies may result in an improved receptor blockade and a better clinical outcome. Furthermore, despite the small sample size and single-arm design of BO17929, our results support the conclusion that, in patients with HER2-positive MBC who have experienced progression during prior trastuzumab-based therapy, combination therapy with pertuzumab and trastuzumab is more active than pertuzumab alone.
A randomized, phase II trial (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation [NEOSPHERE]) has recently demonstrated increased activity with the combination of pertuzumab and trastuzumab compared with pertuzumab or trastuzumab monotherapy in patients with early-stage breast cancer in the neoadjuvant setting.28 Dual anti-HER2 blockade, achieved by using a combination of an antibody (trastuzumab) and a tyrosine kinase inhibitor (lapatinib), has also recently been shown to improve PFS and CBR compared with lapatinib alone in patients with HER2-positive MBC who experienced progression on prior trastuzumab-containing regimens29 and to increase the pathologic CR rate compared with lapatinib alone when administered to HER2-positive patients in the neoadjuvant setting.30 The role of combination therapy is being further addressed in the ongoing Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trial, a phase III study investigating trastuzumab and docetaxel with or without pertuzumab as a first-line treatment for patients with HER2-positive MBC.31
See accompanying editorial on page 1574 and article on page 1712
Supported by F. Hoffmann-La Roche, Basel, Switzerland.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Clinical trial information can be found for the following: NCT00301899.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Graham A. Ross, Roche (C); Joanna Dixon, Roche (C); Tania Szado, Roche (C) Consultant or Advisory Role: Javier Cortés, Roche (C), Novartis (C); Pierre Fumoleau, sanofi-aventis (C), Roche (C), Johnson & Johnson (C); Teresa M. Petrella, Roche (C); Karen Gelmon, Roche (C); Xavier Pivot, Roche (C), GlaxoSmithKline Beecham (C); Shailendra Verma, Roche (U); Joan Albanell, Roche (C); Pierfranco Conte, Roche (C), GlaxoSmithKline (C); Luca Gianni, Roche (C), Genentech (C), GlaxoSmithKline (C), Wyeth (C), Novartis (C), Pfizer (C), Eisai (C), Morphotek (C), Celgene (C); José Baselga, Roche (C) Stock Ownership: Graham A. Ross, Roche; Tania Szado, Roche Honoraria: Javier Cortés, Roche, GlaxoSmithKline , Cephalon, Celgene, Amgen; Teresa M. Petrella, Roche; Karen Gelmon, Roche; Xavier Pivot, sanofi-aventis; Pierfranco Conte, Roche, GlaxoSmithKline Research Funding: Karen Gelmon, Roche; Pierfranco Conte, GlaxoSmithKline Expert Testimony: None Other Remuneration: None
Conception and design: Javier Cortés, Joan Albanell, Graham A. Ross, José Baselga
Financial support: Graham A. Ross
Administrative support: Graham A. Ross
Provision of study materials or patients: Javier Cortés, Giulia Valeria Bianchi, Teresa M. Petrella, Graham A. Ross, Tania Szado
Collection and assembly of data: Javier Cortés, Pierre Fumoleau, Giulia Valeria Bianchi, Karen Gelmon, Shailendra Verma, Joan Albanell, Pierfranco Conte, Ana Lluch, Stefania Salvagni, Veronique Servent, Luca Gianni, Graham A. Ross, Tania Szado, José Baselga
Data analysis and interpretation: Javier Cortés, Pierre Fumoleau, Teresa M. Petrella, Karen Gelmon, Xavier Pivot, Shailendra Verma, Pierfranco Conte, Luca Gianni, Maurizio Scaltriti, Graham A. Ross, Joanna Dixon, Tania Szado, José Baselga
Manuscript writing: All authors
Final approval of manuscript: All authors
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Acknowledgment
Presented in part at the 32nd Annual San Antonio Breast Cancer Symposium, December 9-13, 2009, San Antonio, TX, and the 45th Annual Meeting of the American Society of Clinical Oncology, May 29-June 2, 2009, Orlando, FL.
Support for third-party writing assistance for this article was provided by F. Hoffmann-La Roche.
