Expert Insight Into: Open Label, Phase II Trial of an Irreversible ErbB Receptor Tyrosine Kinase Inhibitor in Patients with Advanced ErbB2-Positive Breast Cancer (Part 7 of Series)

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Aggregate Data
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General Policies
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Revision date: This policy was last updated on September 30, 2003.

Clinical Insights

Neratinib is an investigational, irreversible inhibitor of ErbB2 and other ErbB family receptor tyrosine kinases
A phase II trial found that neratinib treatment was associated with substantial activity in trastuzumab-naive patients with advanced breast cancer as well as patients who had received prior trastuzumab.

PLEASE NOTE: Each article is selected by faculty on the scientific merits of the new data. It is one part of a bundled series of articles that, as a group, provide a full and balanced perspective.

ErbB2 (Her2) is a member of the ErbB family of receptor tyrosine kinases (RTKs). Overexpression of ErbB2 in breast cancer tumors is associated with increased risk of recurrence and progression. Trastuzumab is currently in widespread use for treatment of ErbB2-overexpressing breast cancer, but recurrence and progression are common even in trastuzumab-treated patients. The orally available, small-molecule RTK inhibitor, lapatinib, also inhibits ErbB and ErbB2, and is approved for use in combination with capecitabine in patients with ErbB2-positive breast cancer who have received prior therapy.

Neratinib is an irreversible, small-molecule inhibitor of ErbB2 and other members of the ErbB family. Burstein and colleagues conducted an open-label, multicenter, phase II trial of neratinib in ErbB2-overexpressing patients with advanced breast cancer (stage IIIB, IIIC, or IV) not curable with available therapy.¹ The trial enrolled two groups of patients: patients who had progressed after receiving at least 6 weeks (median 14.3 months) of trastuzumab (n = 66) therapy in the adjuvant or advanced setting, and trastuzumab-naive patients (n = 70). All participants received oral neratinib (240 mg once daily). The primary endpoint was progression-free survival (PFS) at 16 weeks for the evaluable population. Tumor responses were assessed by independent reviewers and by investigators using modified RECIST criteria.

At 16 weeks, 37 of 63 (59%; 95% CI,45% to 71%) patients in the trastuzumab-exposed group and 50 of 64 (78%; 95% CI, 66% to 87%) patients in the trastuzumab-naive group satisfied PFS criteria based on independent radiologic assessment. Median PFS was 22.3 (95% CI, 15.9 to 31.6) and 39.6 (95% CI, 31.0 to 55.1) weeks for the two groups, respectively. Rates of complete and partial response and stable disease are shown in the table. The objective response rates were 24% (95% CI, 14% to 36%) and 56% (95% CI, 43% to 69%) in the prior trastuzumab and trastuzumab-naïve groups respectively. The median durations of objective response were 39.3 weeks (95% CI, 32.2 to 93.7 weeks) and 52.4 weeks (95% CI, 33.1 weeks to not estimable) in the two groups, respectively. Rates of clinical benefit rate were 33% (95% CI, 22% to 46%) and 69% (95% CI, 56% to 80%), respectively. The investigators also reported that tumor burdens declined in 74% and 88% of patients in the two groups, respectively.

Table. Tumor response rates in the evaluable population

	Prior trastuzumab (n = 63)	Trastuzumab-naive (n = 64)
Complete response, n	0	1
Partial response, n (%)	15 (24)	35 (55)
Stable disease ≥ 24 weeks	6 (10)	8 (13)

The most commonly reported adverse events were diarrhea (93% of patients), nausea (36%), vomiting (31%) and fatigue (24%), with diarrhea being the only grade 3 or 4 adverse event reported in more than 10% of patients (21%). Dose reductions for adverse events were required in 33% of prior trastuzumab patients and 13% of trastuzumab-naive patients.

Monitoring of left-ventricular ejection fraction found little change in median values during the study. One patient had grade 3 cardiotoxicity and one patient had grade 4 acute left ventricular failure, both of which were considered unrelated to neratinib therapy.

Overall, the results suggest that neratinib provides substantial clinical benefit in patients with advanced ErbB2-positive breast cancer, even in patients who progressed on prior trastuzumab therapy. The results are comparable to lapatinib monotherapy as first-line treatment in patients with ErbB2-overexpressing, advanced breast cancer, in which 63% of patients achieved progression-free survival at 16 weeks.² Lapatinib has also been shown to significantly improve objective response rates, and median time to progression when added to capecitabine in patients with prior anthracycline, taxane, and trastuzumab therapy.³ Indirect comparison to lapatinib suggests that neratinib is associated with fewer cutaneous adverse effects but more gastrointestinal adverse effects. Ongoing trials are studying combination and sequential therapies involving neratinib and other RTK inhibitors, as well as cytotoxic agents, as first-line or second-line therapy for advanced breast cancer.

Reference

Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, Tan AR, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol 2010;28:1301-1307.

Gomez HL, Doval DC, Chavez MA, Ang PC, Aziz Z, Nag S, et al. Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. J Clin Oncol 2008;20;26:2999-3005.

Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733-2743.

Privacy Policy

Expert Insight Into:
Open Label, Phase II Trial of an Irreversible ErbB Receptor Tyrosine Kinase Inhibitor in Patients with Advanced ErbB2-Positive Breast Cancer (Part 7 of Series)

Based on the Article:

Neratinib, an Irreversible ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Advanced ErbB2-Positive Breast Cancer. J Clin Oncol. 2010;28:1301-1307.

Medical Writer: Kenneth P. Scholz, PhD
Expert Faculty: Harold J. Burstein, MD, PhD

Available for CME/CE:

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Pharmacists

Estimated time for completion of this activity:

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CE Information: Pharmacists

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Available for CME/CE:

Physicians

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Privacy Policy

Expert Insight Into: Open Label, Phase II Trial of an Irreversible ErbB Receptor Tyrosine Kinase Inhibitor in Patients with Advanced ErbB2-Positive Breast Cancer (Part 7 of Series)

Based on the Article: Neratinib, an Irreversible ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Advanced ErbB2-Positive Breast Cancer. J Clin Oncol. 2010;28:1301-1307.

Medical Writer: Kenneth P. Scholz, PhD Expert Faculty: Harold J. Burstein, MD, PhD

Available for CME/CE:

Physicians

Nurses

Pharmacists

Estimated time for completion of this activity:

Target Audience

Activity Goal

Learning Objective (s)

CME Information: Physicians

Statement of Accreditation

Credit Designation

CE Information: Nurses

CE Information: Pharmacists

CME/CE Instructions

Available for CME/CE:

Physicians

Nurses

Pharmacists

Estimated time for completion of this activity:

Target Audience

Activity Goal

Learning Objective (s)

CME Information: Physicians

Statement of Accreditation

Credit Designation

CE Information: Nurses

CE Information: Pharmacists

CME/CE Instructions

Expert Insight Into:
Open Label, Phase II Trial of an Irreversible ErbB Receptor Tyrosine Kinase Inhibitor in Patients with Advanced ErbB2-Positive Breast Cancer (Part 7 of Series)

Based on the Article:

Neratinib, an Irreversible ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Advanced ErbB2-Positive Breast Cancer. J Clin Oncol. 2010;28:1301-1307.

Medical Writer: Kenneth P. Scholz, PhD
Expert Faculty: Harold J. Burstein, MD, PhD