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Breast Cancer
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Safety and Efficacy of Neratinib in Combination With Capecitabine in Patients With Metastatic Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer
Abstract
Neratinib is a potent irreversible pan-tyrosine kinase inhibitor with antitumor activity and acceptable tolerability in patients with human epidermal growth factor receptor 2 (HER2) –positive breast cancer. A multinational, open-label, phase I/II trial was conducted to determine the maximum-tolerated dose (MTD) of neratinib plus capecitabine in patients with solid tumors (part one) and to evaluate the safety and efficacy of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer (part two).
Part one was a 3 + 3 dose-escalation study in which patients with advanced solid tumors received oral neratinib once per day continuously plus capecitabine twice per day on days 1 to 14 of a 21-day cycle at predefined dose levels. In part two, patients with trastuzumab-pretreated HER2-positive metastatic breast cancer received neratinib plus capecitabine at the MTD. The primary end point in part two was objective response rate (ORR).
In part one (n = 33), the combination of neratinib 240 mg per day plus capecitabine 1,500 mg/m2 per day was defined as the MTD, which was further evaluated in part 2 (n = 72). The most common drug-related adverse events were diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%). In part two, the ORR was 64% (n = 39 of 61) in patients with no prior lapatinib exposure and 57% (n = 4 of 7) in patients previously treated with lapatinib. Median progression-free survival was 40.3 and 35.9 weeks, respectively.
Approximately 20% of women with breast cancer have human epidermal growth factor receptor 2 (HER2) –positive tumors,1 which are associated with aggressive disease and poor prognosis.2 The introduction of anti-HER2–directed therapies, such as trastuzumab,3–6 lapatinib,7,8 pertuzumab,9 and ado-trastuzumab emtansine,10 has been a major advance in the treatment of this type of breast cancer in the adjuvant and metastatic settings. However, some patients do not respond to HER2-directed therapy, and most patients who respond initially to trastuzumab acquire resistance within 1 year.5,6,9 Elucidating the mechanisms of resistance and the pathways by which these tumors escape trastuzumab-mediated cytotoxicity may improve patient outcomes.11 Thus, continued development of new HER2-directed strategies is needed, particularly for patients whose disease has progressed during prior regimens.
Neratinib (HKI-272) is a potent, low–molecular weight, irreversible pan-tyrosine kinase inhibitor with activity against HER1, HER2, and HER4.12,13 Neratinib demonstrated antitumor activity in a phase II study of patients with advanced HER2-positive breast cancer; in patients with prior trastuzumab exposure, the objective response rate (ORR) was 24%, and median progression-free survival (PFS) was 22 weeks, whereas in trastuzumab-naive patients, the ORR and PFS were higher (56% and 40 weeks, respectively).14 The most common adverse events with neratinib monotherapy were diarrhea, nausea, fatigue, and vomiting.14,15 In a randomized phase II study comparing neratinib with lapatinib plus capecitabine, neratinib demonstrated good antitumor activity (ORR, 29%; median PFS, 4.5 months) in patients with pretreated advanced HER2-positive breast cancer, although it was not as effective as the combination arm (ORR, 41%; median PFS, 6.8 months).16
Lapatinib, a reversible dual HER1/HER2 kinase inhibitor, has demonstrated efficacy and tolerability in combination with capecitabine in patients with advanced HER2-positive breast cancer. In a phase III study, lapatinib plus capecitabine improved time to progression (8.4 months) compared with capecitabine alone (4.4 months; P < .001).7 The updated efficacy results of this trial were supportive of the initial analysis and showed an increased time to progression from 4.3 to 6.2 months (P < .001) with the addition of lapatinib to capecitabine.8 A global expanded access program has since confirmed the favorable antitumor activity and tolerability of this regimen in patients with pretreated HER2-positive metastatic breast cancer.17,18
Our phase I/II trial evaluated the combination of neratinib and capecitabine in patients with solid tumors (part one) to determine the maximum-tolerated dose (MTD) of the combination and in patients with advanced HER2-positive breast cancer (part two) to test the antitumor efficacy of the regimen at the MTD. We hypothesized that neratinib would have strong activity in combination with capecitabine.
This was a multinational phase I/II, open-label, two-part study. Part one was a modified 3 + 3 dose-escalation study conducted to define the MTD of neratinib plus capecitabine in patients with advanced solid tumors. Part two was conducted to confirm the safety of the MTD and to evaluate the efficacy of neratinib plus capecitabine in patients with advanced HER2-positive breast cancer. The study was conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by the institutional review board or independent ethics committee of each participating center. All patients provided written informed consent before enrollment.
In part one, eligible patients had a confirmed diagnosis of a solid tumor not curable with available therapies. In part two, women with confirmed HER2-amplified metastatic or locally advanced breast cancer were eligible. HER2 status was documented locally by fluorescent (FISH) or chromogenic in situ hybridization (CISH), immunohistochemistry (IHC) 3+, or IHC 2+ confirmed by FISH or CISH. Patients were required to have experienced disease progression during or after ≥ one prior trastuzumab-containing regimen administered for ≥ 6 weeks for metastatic or locally advanced disease and received prior taxane treatment. Patients were excluded if they had received prior treatment with capecitabine, lapatinib (excluding preplanned patients enrolled with prior lapatinib treatment), any other HER2-targeted agent, or anthracyclines (cumulative dose of doxorubicin > 400 mg/m2 or epirubicin 800 mg/m2 or equivalent dose for other anthracyclines). All patients were required to be age ≥ 18 years, with an Eastern Cooperative Oncology Group performance status ≤ 2, and to have adequate hematologic, renal, and hepatic function.
In part one, patients received oral neratinib 160, 200, or 240 mg once daily continuously in combination with oral capecitabine 1,500 or 2,000 mg/m2 per day on days 1 to 14 of a 21-day cycle; the capecitabine dose was split into two equal doses and administered every 12 hours. Each patient received one dose level only. The dose levels were as follows: level one, neratinib 160 mg plus capecitabine 1,500 mg/m2 per day; level two, neratinib 240 mg plus capecitabine 1,500 mg/m2 per day; level three, neratinib 240 mg plus capecitabine 2,000 mg/m2 per day; level four, neratinib 200 mg plus capecitabine 2,000 mg/m2 per day; and level five, neratinib 160 mg plus capecitabine 2,000 mg/m2 per day. If dose level one, but not two, was tolerated, an intermediate dose level of neratinib 200 mg plus capecitabine 1,500 mg/m2 per day was considered.
If one of three patients experienced a dose-limiting toxicity (DLT), the cohort was expanded up to nine evaluable patients. The MTD was the highest dose at which ≤ one of six patients or two of nine patients experienced a DLT. If ≥ 33% of evaluable patients in a cohort experienced a DLT, dose escalation was stopped, and the prior dose level was considered the MTD. DLTs are defined in the Appendix (online only). In part two, all patients received neratinib plus capecitabine at the MTD defined in part one.
Adverse events were graded for severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). Tumor assessments were performed by computed tomography or magnetic resonance imaging at screening and then every 6 weeks (ie, two cycles). The ORR was assessed by the investigator based on modified RECIST (version 1.0).19 Partial and complete responses (CRs) were confirmed by repeat assessments ≥ 4 weeks after the criteria for response were first met. Patients were observed for up to 1 year or until disease progression, death, or initiation of new anticancer therapy, whichever occurred first.
In part one, the sample size was determined following pre-established rules for a dose-escalation study of a modified 3 + 3 design20; no formal statistical analysis was performed in part one. In part two, patients were divided into two groups (patients ± prior lapatinib exposure) and were analyzed separately. Sample size depended on MTD dose level. If the MTD equaled the maximum dose level, 20 to 30 patients were enrolled. If the MTD was lower than the maximum dose level, up to 80 patients were enrolled. The number of lapatinib-naive patients required was 54 evaluable patients based on a comparison of ORRs for historical controls, assuming an ORR for lapatinib plus capecitabine of 24%8 and for neratinib plus capecitabine of 40%, with a one-sided z test (type one error [alpha] = 0.05; 80% power). To compensate for an expected nonevaluable rate of 10%, approximately 60 lapatinib-naive patients were to be enrolled. In addition, up to 20 patients with prior lapatinib exposure were enrolled so that an exploratory analysis of this patient subset could be performed.
All patients who received ≥ one dose of neratinib were included in the safety analysis. Patients evaluable for efficacy must have received ≥ 2 weeks of neratinib plus capecitabine and completed a follow-up tumor assessment approximately two cycles after starting treatment.
The primary end point for part two was ORR, which was presented with 95% CIs. Secondary efficacy end points included clinical benefit (ORR or stable disease ≥ 24 weeks), PFS, and duration of response. PFS was calculated from the first dose of study drug until first documentation of recurrence or progression or death resulting from any cause; patients were otherwise censored at the last evaluation. Duration of response was calculated from the date of response until disease progression. Time-to-event end points were analyzed using the Kaplan-Meier method and presented as median values with 95% CIs (Brookmeyer and Crowley method).
A total of 105 patients were enrolled at 40 centers in 11 countries worldwide. In part one, six patients received neratinib 160 mg plus capecitabine 1,500 mg/m2 per day, nine patients received neratinib 160 mg plus capecitabine 2,000 mg/m2 per day, eight patients received neratinib 240 mg plus capecitabine 1,500 mg/m2 per day, and four patients received neratinib 240 mg plus capecitabine 2,000 mg/m2 per day. An additional six patients received an intermediate dose of neratinib 200 mg plus capecitabine 2,000 mg/m2 per day as a result of DLTs observed in the neratinib 240 mg cohort. Across dose-escalation cohorts, the most common primary cancers were breast (n = 16) and colorectal cancers (n = 9). In part two, 72 patients (68 evaluable for efficacy) with HER2-positive advanced breast cancer received neratinib plus capecitabine at the MTD; 65 patients were lapatinib naive, and seven patients had received prior lapatinib therapy. Baseline demographic and disease characteristics for all patients are listed in Table 1.
|
| Characteristic | Part One (advanced solid tumors) | Part Two (metastatic HER2-positive breast cancer) | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Neratinib 160 mg + Capecitabine 1,500 mg/m2 (n = 6) | Neratinib 160 mg + Capecitabine 2,000 mg/m2 (n = 9) | Neratinib 200 mg + Capecitabine 2,000 mg/m2 (n = 6) | Neratinib 240 mg + Capecitabine 1,500 mg/m2 (n = 8) | Neratinib 240 mg + Capecitabine 2,000 mg/m2 (n = 4) | No Prior Lapatinib (n = 65) | Prior Lapatinib (n = 7) | All Part-Two Patients (n = 72) | |||||||||
| No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | |
| Age, years | ||||||||||||||||
| Mean | 50 | 56 | 59 | 53 | 56 | 52 | 51 | 51 | ||||||||
| Range | 37-69 | 41-70 | 39-69 | 38-69 | 39-80 | 33-79 | 38-61 | 33-79 | ||||||||
| Sex | ||||||||||||||||
| Female | 4 | 67 | 6 | 67 | 3 | 50 | 5 | 63 | 3 | 75 | 65 | 100 | 7 | 100 | 72 | 100 |
| Male | 2 | 33 | 3 | 33 | 3 | 50 | 3 | 37 | 1 | 25 | 0 | 0 | 0 | 0 | 0 | 0 |
| Race | ||||||||||||||||
| White | 5 | 83 | 9 | 100 | 6 | 100 | 8 | 100 | 4 | 100 | 38 | 58 | 4 | 57 | 42 | 58 |
| Asian | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 25 | 39 | 3 | 43 | 28 | 39 |
| Black | 1 | 17 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 3 | 0 | 0 | 2 | 3 |
| ECOG PS | ||||||||||||||||
| 0/1 | 5 | 84 | 8 | 89 | 6 | 100 | 7 | 88 | 3 | 75* | 63 | 97 | 6 | 86 | 69 | 96 |
| 2 | 1 | 17 | 1 | 11 | 0 | 0 | 1 | 13 | 0 | 0 | 2 | 3 | 1 | 14 | 3 | 4 |
| HR-positive disease | 2 | 33 | 2 | 22 | 2 | 33 | 2 | 25 | 2 | 50 | 23 | 35 | 5 | 71 | 28 | 39 |
| Prior hormonal therapy | 3 | 50 | 3 | 33 | 2 | 33 | 2 | 25 | 2 | 50 | 24 | 37 | 3 | 43 | 27 | 38 |
| No. of prior lapatinib-containing regimens | ||||||||||||||||
| 0 | 3 | 50 | 7 | 78 | 5 | 83 | 8 | 100 | 4 | 100 | 64 | 99 | 1 | 14† | 65 | 90 |
| 1 | 2 | 33‡ | 2 | 22 | 1 | 17 | 0 | 0 | 0 | 0 | 1 | 2§ | 6 | 86 | 7 | 10 |
| No. of prior trastuzumab-containing regimens | ||||||||||||||||
| 0 | 3 | 50 | 6 | 67 | 3 | 50 | 5 | 63 | 1 | 25 | 0 | 0 | 0 | 0 | 0 | 0 |
| 1 | 1 | 17 | 0 | 0 | 0 | 0 | 2 | 25 | 0 | 0 | 47 | 72 | 4 | 57 | 51 | 71 |
| 2 | 0 | 0 | 0 | 0 | 1 | 17 | 0 | 0 | 1 | 25 | 14 | 22 | 2 | 29 | 16 | 22 |
| ≥ 3 | 2 | 33 | 3 | 33 | 2 | 34 | 1 | 13 | 2 | 50 | 4 | 6 | 1 | 14 | 5 | 7 |
| No. of prior taxane-containing regimens | ||||||||||||||||
| 0 | 3 | 50 | 4 | 44 | 3 | 50 | 5 | 63 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| ≥ 1 | 3 | 50 | 5 | 55 | 3 | 51 | 3 | 38 | 4 | 100 | 65 | 100 | 7 | 100 | 72 | 100 |
| No. of prior anthracycline-containing regimens | ||||||||||||||||
| 0 | 4 | 67 | 5 | 56 | 2 | 33 | 4 | 50 | 1 | 25 | 20 | 31 | 3 | 43 | 23 | 32 |
| ≥ 1 | 2 | 34 | 4 | 44 | 4 | 67 | 4 | 50 | 3 | 75 | 45 | 69 | 1 | 57 | 49 | 67 |
NOTE. Percentages for subcategories may not add to 100% because of rounding.
Abbreviations: HER2, human epidermal growth factor receptor 2; HR, hormone receptor; ECOG PS, Eastern Cooperative Oncology Group performance status.
*ECOG PS missing for one patient.
†This patient was protocol violator for this cohort (did not receive prior lapatinib).
‡One patient received two prior lapatinib-containing regimens.
§This patient was protocol violator for this cohort (received prior lapatinib).
At the time of this analysis (September 2011), 20 patients in part two remained on study, and 52 patients (72%) had discontinued study treatment, most commonly because of disease progression (n = 41); other reasons included adverse events (n = 5), patient request (n = 3), discontinuation by study sponsor (n = 1), investigator request (n = 1), and other (n = 1). Median treatment duration, dose delays, and reductions are summarized in Table 2. Just more than half of patients required at least one capecitabine dose delay (53%) or dose reduction (56%).
|
| Parameter | Part One | Part Two | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Neratinib 160 mg + Capecitabine 1,500 mg/m2 (n = 6) | Neratinib 160 mg + Capecitabine 2,000 mg/m2 (n = 9) | Neratinib 200 mg + Capecitabine 2,000 mg/m2 (n = 6) | Neratinib 240 mg + Capecitabine 1,500 mg/m2 (n = 8) | Neratinib 240 mg + Capecitabine 2,000 mg/m2 (n = 4) | No Prior Lapatinib (n = 65) | Prior Lapatinib (n = 7) | All Part-Two Patients (n = 72) | |||||||||
| No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | |
| Treatment duration, weeks* | ||||||||||||||||
| Median | 14.4 | 11.9 | 12.0 | 9.6 | 37.9 | 36.1 | 29.9 | 36.0 | ||||||||
| Range | 3.0-30.7 | 1.1-30.9 | 4.9-82.9 | 0.1-73.1 | 5.3-89.0 | 1.1-99.0 | 7.7-70.9 | 1.1-99.0 | ||||||||
| Relative dose-intensity | ||||||||||||||||
| Capecitabine | ||||||||||||||||
| Median | 0.903 | 0.870 | 0.897 | 0.896 | 0.714 | 0.855 | 0.775 | 0.851 | ||||||||
| Range | 0.57-1.00 | 0.61-1.00 | 0.51-0.97 | 0.50-1.03 | 0.53-0.83 | 0.47-1.14 | 0.49-1.03 | 0.47-1.14 | ||||||||
| Neratinib | ||||||||||||||||
| Median | 0.992 | 0.991 | 0.926 | 0.991 | 0.711 | 1.00 | 0.986 | 1.00 | ||||||||
| Range | 0.94-1.00 | 0.59-1.00 | 0.55-1.00 | 0.96-1.00 | 0.27-0.97 | 0.49-1.01 | 0.67-1.01 | 0.49-1.01 | ||||||||
| ≥ One dose reduction | ||||||||||||||||
| Capecitabine | 1 | 17 | 5 | 56 | 4 | 67 | 3 | 38 | 4 | 100 | 37 | 57 | 3 | 43 | 40 | 56 |
| Neratinib | 0 | 0 | 1 | 11 | 3 | 50 | 0 | 0 | 4 | 100 | 13 | 20 | 1 | 14 | 14 | 19 |
| ≥ One dose delay | ||||||||||||||||
| Capecitabine | 4 | 67 | 6 | 67 | 3 | 50 | 3 | 38 | 4 | 100 | 34 | 52 | 4 | 57 | 38 | 53 |
| Neratinib | 3 | 50 | 5 | 56 | 4 | 67 | 6 | 75 | 4 | 100 | 29 | 45 | 5 | 71 | 34 | 47 |
*Duration of treatment is based on duration of neratinib administration; data for duration of capecitabine were similar.
No patient in the neratinib 160 mg plus capecitabine 1,500 mg/m2 per day or neratinib 240 mg plus capecitabine 1,500 mg/m2 per day cohorts experienced a DLT. Two of nine patients in the neratinib 160 mg plus capecitabine 2,000 mg/m2 per day cohort experienced a DLT (grade 3 fatigue, n = 2; grade 3 ataxia, n = 1; grade 3 diarrhea, n = 1). Therefore, the dose was escalated to neratinib 240 mg plus capecitabine 2,000 mg/m2 per day; two of four patients in this cohort experienced a DLT (grade 4 diarrhea, n = 1; grade 3 AST and ALT increases, n = 1). Because of DLTs observed in this cohort, six additional patients received an intermediate dose of neratinib 200 mg plus capecitabine 2,000 mg/m2 per day; two of six patients experienced a DLT in this cohort (grade 3 asthenia and decreased appetite, n = 1; grade 3 diarrhea, n = 1). Thus, the MTD was determined to be neratinib 240 mg and capecitabine 1,500 mg/m2 per day and was further evaluated in part two.
Treatment-related adverse events of any grade observed in ≥ 15% of patients in study parts one and two (N = 105) included diarrhea (88%), palmar-plantar erythrodysesthesia syndrome (PPE; 48%), nausea (37%), vomiting (29%), decreased appetite (26%), asthenia (19%), and fatigue (18%). The most common grade 3/4 treatment-related adverse events across the study were diarrhea (23%), PPE (12%), and vomiting, asthenia, and decreased appetite (5% each). In part two, the incidence of grade 3/4 diarrhea was 26%; PPE, 14%; asthenia, 4%; and vomiting, 4% (Table 3). Treatment-related serious adverse events were reported in 10 patients (10%); the most common events were diarrhea (n = 4), vomiting (n = 2) and hypokalemia (n = 2).
|
| Event* | Part One | Part Two | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Neratinib 160 mg + Capecitabine 1,500 mg/m2 (n = 6) | Neratinib 160 mg + Capecitabine 2,000 mg/m2 (n = 9) | Neratinib 200 mg + Capecitabine 2,000 mg/m2 (n = 6) | Neratinib 240 mg + Capecitabine 1,500 mg/m2 (n = 8) | Neratinib 240 mg + Capecitabine 2,000 mg/m2 (n = 4) | No Prior Lapatinib (n = 65) | Prior Lapatinib (n = 7) | All Part-Two Patients (n = 72) | |||||||||
| No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | |
| Any grade 3/4 AE | 4 | 67 | 6 | 67 | 5 | 83 | 4 | 50† | 4 | 100 | 39 | 60 | 4 | 57 | 43 | 60 |
| Diarrhea | 0 | 0 | 2 | 22 | 1 | 17 | 0 | 0 | 2 | 50 | 17 | 26 | 2 | 29 | 19 | 26 |
| PPE | 0 | 0 | 2 | 22 | 0 | 0 | 0 | 0 | 1 | 25 | 10 | 15 | 0 | 0 | 10 | 14 |
| Asthenia | 0 | 0 | 0 | 0 | 2 | 33 | 0 | 0 | 1 | 25 | 3 | 5 | 0 | 0 | 3 | 4 |
| Decreased appetite | 0 | 0 | 0 | 0 | 2 | 33 | 0 | 0 | 1 | 25 | 2 | 3 | 0 | 0 | 2 | 3 |
| Vomiting | 0 | 0 | 0 | 0 | 1 | 17 | 0 | 0 | 1 | 25 | 3 | 5 | 0 | 0 | 3 | 4 |
| Fatigue | 0 | 0 | 2 | 22 | 0 | 0 | 0 | 0 | 1 | 25 | 0 | 0 | 0 | 0 | 0 | 0 |
| Hypokalemia | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 | 3 | 43 | 4 | 6 |
| Elevated AST | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 25 | 2 | 3 | 0 | 0 | 2 | 3 |
Abbreviations: AE, adverse event; PPE, palmar-plantar erythrodysesthesia syndrome.
*According to National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0).
†AEs were as follows (one event each): anemia, abdominal pain, ascites, nausea, small intestinal obstruction, disease progression, general physical health deterioration, prolonged activated partial thromboplastin time, dehydration, and hypoglycemia.
The incidence and characteristics of diarrheal events are summarized in Table 4. In part two, diarrhea typically occurred early (median time to onset, 2 days after start of treatment) and was transient (median duration, 2 days). Of the 65 patients from parts one and two who experienced diarrhea, 11 (15%) and eight patients (11%) were managed by dose interruptions and dose reductions, respectively, whereas four patients (6%) withdrew from the study.
|
| Parameter | Part One | Part Two | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Neratinib 160 mg + Capecitabine 1,500 mg/m2 (n = 6) | Neratinib 160 mg + Capecitabine 2,000 mg/m2 (n = 9) | Neratinib 200 mg + Capecitabine 2,000 mg/m2 (n = 6) | Neratinib 240 mg + Capecitabine 1,500 mg/m2 (n = 8) | Neratinib 240 mg + Capecitabine 2,000 mg/m2 (n = 4) | No Prior Lapatinib (n = 65) | Prior Lapatinib (n = 7) | All Part-Two Patients (n = 72) | |||||||||
| No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | |
| Patients with ≥ one diarrhea event | 4 | 67 | 8 | 89 | 6 | 100 | 6 | 75 | 4 | 100 | 59 | 91 | 6 | 86 | 65 | 90 |
| Drug-related event | 4 | 67 | 8 | 89 | 6 | 100 | 6 | 75 | 4 | 100 | 58 | 89 | 6 | 86 | 64 | 89 |
| Serious event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 25 | 1 | 2 | 2 | 29 | 3 | 4 |
| Time to event, days | ||||||||||||||||
| Median | 7.0 | 6.5 | 7.5 | 10.5 | 3.0 | 2.0 | 6.5 | 2.0 | ||||||||
| Range | 5-63 | 2-14 | 4-22 | 7-69 | 1-8 | 1-164 | 3-23 | 1-164 | ||||||||
| Duration of event, days | ||||||||||||||||
| Median | 2.0 | 15.0 | 6.5 | 21.0 | 8.0 | 2.0 | 4.0 | 2.0 | ||||||||
| Range | 1-13 | 2-77 | 1-36 | 1-85 | 1-63 | 1-418 | 1-309 | 1-418 | ||||||||
| Management* | ||||||||||||||||
| Dose reduction | 0 | 0 | 2 | 22 | 1 | 17 | 0 | 0 | 0 | 0 | 6 | 9 | 1 | 14 | 7 | 10 |
| Dose delay | 1 | 17 | 1 | 11 | 1 | 17 | 0 | 0 | 2 | 50 | 10 | 15 | 1 | 14 | 11 | 15 |
| Led to withdrawal | 0 | 0 | 0 | 0 | 1 | 17 | 0 | 0 | 0 | 0 | 3 | 5 | 1 | 14 | 4 | 6 |
*It was recommended that diarrhea be managed with antidiarrheal agents (eg, loperamide); those unresponsive to medical treatment may also have required interruption and/or reduction of study medication; dose reduction and delay data relate to neratinib.
The following cardiovascular adverse events were reported: pericardial effusion (n = 2) and tachycardia (n = 1) in part one, and angina, myocardial ischemia, pericarditis, sinus tachycardia, and tachycardia (n = 1 each) in part two, none of which were considered treatment related by the investigator. A reduction in left ventricular ejection fraction of ≥ 10% was observed in two patients, including one patient in the neratinib 160 mg plus capecitabine 2,000 mg/m2 per day cohort (13% reduction) and one patient in part two (12% reduction). No congestive heart failure was reported.
Elevated liver function tests considered to be of potential clinical importance included elevated AST in four (4%) of 104 evaluable patients and elevated ALT in three (3%) of 104 patients during treatment; at the final visit, elevated AST and ALT levels were present in none and in two (3%) of 62 patients, respectively. No cases of elevated alkaline phosphatase of potential clinical importance were observed. No patient cases met Hy's law criteria (ie, total bilirubin > 2× upper limit of normal [ULN], AST or ALT ≥ 3× ULN, and alkaline phosphatase < 2× ULN) at any time during the study.
During parts one and two, a total of 14 patients (13%) experienced adverse events requiring treatment discontinuation; the most common reasons for treatment discontinuation were diarrhea (n = 5) and abnormal liver function tests (n = 2).
Thirteen patients died during the study, including 11 patients who died as a result of progressive disease (six within 28 days of final dose), one patient (neratinib 200 mg plus capecitabine 2,000 mg/m2 per day cohort) who died as a result of unrelated hemorrhagic shock, and one patient whose cause of death was unclear, although it was noted to be likely related to disease.
Best ORRs and their durations based on investigator review are summarized in Table 5. The ORR was 64% (95% CI, 51% to 76%) for lapatinib-naive patients, including 12% of patients achieving a CR. The ORR was 57% (95% CI, 18% to 90%) in patients who had previously received lapatinib, including one patient (14%) with a CR. An additional 8% and 14% of patients in each cohort, respectively, achieved stable disease for ≥ 24 weeks. Median PFS was 40.3 weeks (95% CI, 30.3 to 66.0 weeks) for patients with no prior lapatinib (Table 6; Fig 1) and 35.9 weeks (95% CI, 18.9 to 60.1 weeks) for those who had received prior lapatinib.
|
| Response | No Prior Lapatinib (n = 61) | Prior Lapatinib (n = 7) | ||
|---|---|---|---|---|
| No. | % | No. | % | |
| ORR* | 39 | 64 | 4 | 57 |
| 95% CI | 51 to 76 | 18 to 90 | ||
| CR | 7 | 12 | 1 | 14 |
| PR | 32 | 53 | 3 | 43 |
| Duration of response, weeks | ||||
| Median | 46.3 | 48.3 | ||
| Range | 11.1-90.1 | 18.0-61.0 | ||
| 95% CI | 30.1 to NE | 30.0 to 61.0 | ||
| SD, weeks | ||||
| < 24 | 12 | 20 | 2 | 29 |
| ≥ 24 | 5 | 8 | 1 | 14 |
| Median | 24.1 | 23.8 | ||
| Range | 6.4-83.3 | 6.1-29.6 | ||
| 95% CI | 12.1 to 72.0 | 18.0 to 29.6 | ||
| CBR† | 44 | 72 | 5 | 71 |
| 95% CI | 59 to 83 | 29 to 96 | ||
| PD | 5 | 8 | 0 | 0 |
Abbreviations: CBR, clinical benefit rate; CR, complete response; NE, not estimable; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.
*ORR includes CR and PR.
†CBR includes CR, PR, and SD ≥ 24 weeks.
|
| Cohort (study part) | No. of Patients | Median PFS (weeks) | 95% CI |
|---|---|---|---|
| Two | 61 | 40.3 | 30.3 to 66.0 |
| One and two | 63 | 42.0 | 35.0 to 72.0 |
Abbreviation: PFS, progression-free survival.
*Receiving neratinib 240 mg plus capecitabine 1,500 mg/m2.
Fig 1. Progression-free survival (PFS) in patients receiving neratinib 240 mg plus capecitabine 1,500 mg/m2 with no prior lapatinib treatment from study part two (n = 61) and parts one and two (n = 63; evaluable population). Kaplan-Meier median PFS was based on investigator assessment of radiographic and clinical data. Thirty-seven patients (61%) with no prior lapatinib treatment from part two and 38 patients (60%) with no prior lapatinib treatment from parts one (maximum-tolerated dose [MTD] level) and two experienced progressive disease or death as of this analysis; 24 and 25 patients, respectively, were censored in this analysis.
This phase I/II study investigating the combination of neratinib plus capecitabine established the MTD of neratinib as 240 mg (same as recommended phase II dose for neratinib monotherapy14) plus capecitabine 1,500 mg/m2 per day in patients with solid tumors. Subsequent investigation of this dose regimen in patients with HER2-positive advanced breast cancer demonstrated that this schedule has a manageable toxicity profile, diarrhea and PPE being the most common grade 3/4 toxicities, and that the regimen is clinically active. Overall, the combination of neratinib plus capecitabine was associated with an acceptable safety and tolerability profile and considerable clinical activity.
The most common grade 3/4 treatment-related adverse events were diarrhea (23%) and PPE (12%). The most frequent toxicities reported with capecitabine monotherapy are PPE and GI events.21–23 Although the incidence of grade 3 PPE in this study was consistent with rates reported with capecitabine monotherapy (12% v 13% to 24%21–23), the incidence of grade 3/4 diarrhea was higher (23% v 8% to 11%21–23), as expected from the combination of two drugs associated with GI effects. In this study, diarrhea typically occurred within a few days of neratinib initiation (median, 2 days) and could generally be managed based on severity with dose adjustments or antidiarrheal medication; primary prophylaxis for diarrhea was not permitted in the study protocol. Only five patients (5%) discontinued treatment because of diarrhea, as in previous neratinib monotherapy studies.14,15 Because trastuzumab has been associated with type II cardiotoxicity,24 cardiac safety was monitored during this study. However, there was little evidence of clinically significant events. Overall, no unexpected toxicity was observed in patients receiving neratinib plus capecitabine, with few patients discontinuing treatment as a result of toxicity.
In this study, clinical responses at the MTD were observed in 63% of patients (64% of lapatinib-naive patients and 57% of patients previously treated with lapatinib), and median durations of response were 46 and 48 weeks, respectively. This is a slightly higher response rate than and similar duration of response to those observed in previous neratinib monotherapy studies (but in populations previously treated with trastuzumab).14,15 An ORR of 40% with neratinib monotherapy was recently reported.16 In our trial, all patients included in part two had experienced progression during previous trastuzumab-based therapy, and median PFS with neratinib plus capecitabine was 40 weeks in the lapatinib-naive cohort and 36 weeks in the prior lapatinib cohort. These results compare favorably with those previously observed in the monotherapy study for patients who received prior trastuzumab (22 weeks).14 The results of our study also compare favorably with the combination of lapatinib plus capecitabine as an indirect comparison. In a phase III study, both ORR (24%) and clinical benefit rate (29%) with lapatinib plus capecitabine were lower than the rates seen with neratinib plus capecitabine in our study.8
The experience acquired in this trial has led to the initiation of a phase III registration trial (NALA; EUDRACT No. 2012-004492-38) to compare the activity of neratinib plus capecitabine with that of lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer who have received two HER2-directed regimens in the metastatic setting. Pertuzumab and ado-trastuzumab emtansine are allowed as previous anti-HER2 treatments. In the NALA trial, primary prophylaxis with antidiarrheal treatment will be implemented from cycle one in an attempt to reduce the frequency and severity of these events. If the trial is positive, neratinib could become a new standard in the third-line setting for HER2-positive patients.
Studies investigating other neratinib-based combinations are under way, including a trial investigating neratinib plus paclitaxel compared with trastuzumab plus paclitaxel in the first-line treatment of HER2-positive breast cancer and trials assessing the activity of neratinib in combination with trastuzumab,25 paclitaxel,26 temsirolimus,27 and vinorelbine28 in HER2-positive breast cancer or other solid tumors, as well as monotherapy in non–HER2-amplified populations expressing HER2 driver mutations.
In summary, neratinib 240 mg plus capecitabine 1,500 mg/m2 per day has encouraging antitumor activity in patients with pretreated advanced HER2-positive breast cancer. Treatment-related diarrhea requires clinical intervention before the use of this combination in future clinical trials. The phase III NALA registration trial testing this combination is ongoing worldwide, and results are expected in the near future.
Supported by Pfizer and Wyeth. Editorial and medical writing support provided by MedErgy HealthGroup (funded by Pfizer) and Miller Medical Communications (funded by Puma Biotechnology).
Clinical trial information: NCT00741260.
Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Although all authors completed the disclosure declaration, the following author(s) and/or an author's immediate family member(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: Kongming Wang, Pfizer (C) Consultant or Advisory Role: Cristina Saura, Puma Biotechnology (C); Javier Cortés, Roche, Novartis (C), Celgene (C); Miguel Martin, Pfizer (C), Novaris (C), AstraZeneca (C); Sung-Bae Kim, Novartis (U) Stock Ownership: Kongming Wang, Pfizer Honoraria: Javier Cortés, Roche, Novartis, Celgene, Eisai Research Funding: Wael Harb, Horizon Oncology Research; Sung-Bae Kim, Novartis, Ildong Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None
Conception and design: Cristina Saura, Javier Cortés, Caroline Germa, Kongming Wang, José Baselga
Provision of study materials or patients: Binghe Xu, Wael Harb, Rebecca Moroose, Javier Cortés
Collection and assembly of data: Cristina Saura, Jose A. Garcia-Saenz, Binghe Xu, Wael Harb, Rebecca Moroose, Timothy Pluard, Caroline Germa, Kongming Wang, Miguel Martin, Sung-Bae Kim
Data analysis and interpretation: Cristina Saura, Binghe Xu, Javier Cortés, Corrine Kiger, Kongming Wang, Miguel Martin, José Baselga, Sung-Bae Kim
Manuscript writing: All authors
Final approval of manuscript: All authors
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| chromogenic in situ hybridization (CISH): | a method to detect gene amplification and chromosomal translocations by hybridizing the complementary strand of a nucleotide probe to the sequence of interest. In contrast to fluorescent in situ hybridization, the DNA probe is detected using a simple enzymatic peroxidase reaction and visualized using a conventional microscope. |
| Eastern Cooperative Oncology Group performance status: | criteria used by doctors and researchers to define the progression of a patient's disease, assessing how the disease affects daily living habits, and to assist in the determination of the appropriate treatment and prognosis. |
| fluorescent in situ hybridization (FISH): | in situ hydridization is a sensitive method generally used to detect specific gene sequences in tissue sections or cell preparations by hybridizing the complementary strand of a nucleotide probe to the sequence of interest. FISH uses a fluorescent probe to increase the sensitivity of in situ hybridization. |
| HER2/neu (human epidermal growth factor receptor 2): | also called ErbB2. HER2/neu belongs to the epidermal growth factor receptor (EGFR) family and is overexpressed in several solid tumors. Like EGFR, it is a tyrosine kinase receptor whose activation leads to proliferative signals within the cells. On activation, the human epidermal growth factor family of receptors are known to form homodimers and heterodimers, each with a distinct signaling activity. Because HER2 is the preferred dimerization partner when heterodimers are formed, it is important for signaling through ligands specific for any members of the family. It is typically overexpressed in several epithelial tumors. |
| immunohistochemical analyses: | techniques used to evaluate the levels and patterns of expression of protein on cells or tissue specimens located on flat slides. |
| Response Evaluation Criteria in Solid Tumors (RECIST): | a model proposed by the Response Evaluation Criteria Group by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. |
| tyrosine kinase inhibitors: | molecules that inhibit the activity of tyrosine kinase receptors. Tyrosine kinase inhibitors are small molecules developed to inhibit the binding of ATP to the cytoplasmic region of the receptor (eg, gefitinib), thus further blocking the cascade of reactions that is activated by the pathway. |
Acknowledgment
Presented in part at the Cancer Therapy and Research Center–American Association for Cancer Research San Antonio Breast Cancer Symposium, San Antonio, TX, December 6-10, 2011.
We thank the participating patients and their families; the global network of investigators, research nurses, study coordinators, and operations staff; and Kimberly Brooks, PhD, for editorial and medical writing support.
Dose-limiting toxicity was defined as any of the following events: grade 3/4 nonhematologic toxicity (except grade 3 asthenia unless lasting ≥ 3 days, grade 3 nausea or vomiting, or grade 3/4 infection unless associated with grade 3/4 neutropenia); grade 3 diarrhea lasting > 2 days despite optimal medical therapy or associated with fever or dehydration; grade 4 neutropenia lasting ≥ 7 days or grade 4 febrile neutropenia; grade 4 thrombocytopenia lasting ≥ 3 days or complicated with bleeding; or delayed recovery from one of these toxicities delaying initiation of the next dose by > 3 weeks.
