Pfizer Inc announced results from studies evaluating neratinib (HKI-272), an investigational, orally administered, pan-ErbB inhibitor, in patients with human epidermal growth factor receptor-2 (HER2, also known as ErbB2) positive breast cancer at the 2009 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS). Neratinib is now part of Pfizer’s expanded oncology portfolio, following the recent acquisition of Wyeth.

“Data gathered from ongoing clinical trials of neratinib, both as a monotherapy and in combination, continue to support its evaluation in HER2 positive metastatic breast cancer,” said Maria Koehler Women’s Cancers Strategy for Pfizer Oncology. “We look forward to studying neratinib further in an effort to help seek to provide HER2 targeted therapies for patients battling this aggressive disease.”

Breast cancer of the HER2 positive type accounts for 20 to 30 per cent of all breast cancers and is identified by the overexpression of the HER2 protein in tumour tissue. HER2 positive breast cancer is more aggressive than other breast cancers and has an increased likelihood of metastasizing.

Neratinib shows activity in phase 1/2 study
This ongoing, phase-1/2, open-label, two-part study evaluates the safety and efficacy of neratinib in combination with weekly paclitaxel in patients with solid tumours and HER2 positive metastatic breast cancer (Poster #5081). Part 1 of the study showed that a standard oral dose of 240 mg of neratinib daily can be given with 80 mg/m2 of paclitaxel weekly to patients with solid tumours. In part 2, only patients with HER2 positive metastatic breast cancer (newly diagnosed or following up to three recurrences) received therapy to evaluate the overall response rate (ORR) of this combination of neratinib and paclitaxel.

As of October 19, 2009, an ORR (including both complete and partial responses) of 69 per cent (n=68) was observed, from a total of 99 patients with HER2 positive breast cancer who were evaluable for efficacy analysis in part 2 of this ongoing study. In the first-line metastatic setting of 33 patients, the ORR was 70 percent (n=23). Overall response rates observed in patients with hormone-receptor positive tumours, prior exposure to endocrine therapy, and previous taxane therapy, were 84 per cent (n=46), 80 per cent (n=31) and 76 per cent (n=47), respectively. Median progression-free survival (PFS) for all patients with HER2 positive breast cancer was estimated at 52.1 weeks (95 per cent C.I. 47.7-NE).

In part 2 of the study, preliminary clinical data indicate the combination of neratinib 240 mg and paclitaxel 80 mg/m2 was tolerable, with a similar toxicity profile to each drug given as monotherapy. The most common treatment-emergent adverse events occurring in =20 per cent of patients included diarrhoea, neutropenia, alopecia, peripheral neuropathy, leucopenia, infection (any site), anaemia, rash, nausea, vomiting, fatigue, anorexia and pyrexia. Diarrhoea of any grade was the most common adverse event (in 91 per cent of patients), and presented as a grade 3/4 adverse event in 28 per cent of patients. Diarrhoea was generally observed early (median onset, three days after the first dose of neratinib; median duration, 30 days). Fifteen and 37 patients required dose reductions of neratinib and paclitaxel, respectively, because of adverse events, and a total of 49 patients discontinued the study. Most study discontinuations (39 patients) were secondary to disease progression. Three patients discontinued therapy due to adverse events (renal failure, left ventricular ejection fraction reduction, and mouth ulceration).

Phase 2 safety results of Neratinib Monotherapy in patients with HER2 positive breast cancer
A phase-2 study evaluated the safety and efficacy of oral neratinib (240 mg daily) as a monotherapy in patients with advanced HER2 positive breast cancer assigned to two cohorts: those with prior trastuzumab treatment (cohort 1) and those with no prior trastuzumab treatment (cohort 2)(Poster #5096). The new analysis presented at SABCS focused on the gastrointestinal and cardiovascular safety profiles of neratinib seen in this study.

Diarrhoea that developed in patients treated with single agent neratinib had early onset (median time to onset three days), but its frequency and severity decreased with time on neratinib. Neratinib-related diarrhea was managed with standard supportive therapy and dose interruptions and/or reductions. Anti-diarrheal medications for supportive therapy were used by 85 per cent of patients in the study. Dose reductions to manage diarrhea were applied in 30 per cent of patients in cohort one and in seven per cent of patients in cohort 2. One patient with prior trastuzumab therapy discontinued treatment as a result of diarrhoea.

There was no statistically significant difference in PFS for patients with a maximum grade 3/4 diarrhoea event versus patients with no diarrhoea or a maximum grade 1/2 diarrhoea event.

Vomiting, any grade, occurred in 29 per cent of patients and was managed with the use of anti-emetic medications and dose modifications.

In this study, neratinib was not associated with clinically significant cardiotoxicity; no patients had congestive heart failure.