New Medicines

NerlynxAdvanced HER-2-positive breast cancer - 3rd-line in combination with capecitabine


Licence extension / variation
Pierre Fabre

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Sep 20EU regulatory submission is on hold and will not be revisited until late 2022 at the earliest [23].
Mar 20The US FDA have approved a supplemental New Drug Application (sNDA) for neratinib in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting [21].
Nov 18Puma expects to report data from the PIII NALA trial in third-line metastatic breast cancer patients in Q4 18 or H1 19 [19].
Jul 09In PIII studies [3]


Irreversible dual inhibitor of the HER-2 and EGFR kinases
The incidence of BC in the UK is about 80 per 100,000 people. About 40% develop metastatic disease; 25% of these are HER2-positive which has a worse prognosis.
Advanced HER-2-positive breast cancer - 3rd-line in combination with capecitabine

Further information


Trial or other data

Jul 20PIII NALA RCT (n=621) reported neratinib plus capecitabine significantly improved PFS (HR 0.76; 95% CI, 0.63 to 0.93; P = 0.0059) and OS (HR 0.88; 95% CI, 0.72 to 1.07; P = 0.2098) vs lapatinib plus capecitabine with fewer interventions for CNS disease (22.8% v 29.2%; P = 0.043) [22].
Feb 20NALA trial (n=621) demonstrates a survival advantage with neratinib and capecitabine vs lapatinib and capecitabine (PFS at 6 and 12 months were 47% and 38%, and 29% and 15%, respectively). Puma plan to file a sNDA with the FDA this summer [20].
Jan 18PIII NCT01808573 study has completed recruitment. Estimated primary and study completion date delayed until Feb 19 [18].
Jan 17NCT01808573 still recruiting, estimated primary completion date: May 2017
Nov 15PIII NALA study (NCT01808573) is currently recruiting pts; timescales unchanged [17].
Nov 14In a PII study of 479 patients with HER2- positive breast cancer, median PFS with neratinib and paclitaxel was 16.6 months vs. 16.7 months with Herceptin and paclitaxel; overall response rates were 74.8% & 75.1%, respectively. In another secondary endpoint neratinib produced a 52.6% reduction in the incidence of CNS metastases vs. the Herceptin arm, a statistically significant result that Puma believes could help differentiate neratinib on the market for breast cancer therapies [15].
Apr 14Positive PII data announced by Puma Biotechnology. Neratinib plus chemo achieved a pathological complete response rate in 39% of patients vs. 23% of patients taking Herceptin and chemo. In a subset of high-risk patients, the pCR rate was 45% vs. 29% for standard care. Puma is now designing a PIII program for the HER2-positive patient group as well as the high-risk patients identified through genetic profiling [14].
Mar 14PIII NCT01808573 trial is recruiting pts. The study is expected to complete in May 18, with collection of primary outcome data complete in May 17 [13].
Dec 13Top line results reported from the PII trial I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2) in women with newly diagnosed Stage 2 or higher (tumour size ≥2.5cm) breast cancer. The study explored whether adding investigational drugs to standard chemotherapy in the neoadjuvant setting is better than standard chemotherapy. The primary endpoint is pathological complete response (pCR) in the breast and the lymph nodes at the time of surgery. The goal is to match investigational regimens with patient subsets on the basis of molecular characteristics and involves an adaptive trial design based on Bayesian predictive probability. In a set of 116 women (65 of whom were HER2 positive), pCR outcomes indicate that there is a 78.1% chance of neratinib + standard chemotherapy establishing superiority over trastuzumab + standard chemotherapy in a PIII study involving 300 patients who are HER2-positive/HR-negative. In HER2-positive patients only, the odds are 72.5%. As a result, the company plan to start a PIII I-SPY 3 study comparing neratinib vs. trastuzumab regimens [12]
Mar 13PIII study (NCT01808573) registered on The study is due to complete May 18, with primary outcome data collected by May 17 [11].
Feb 13Puma has reached agreement with the FDA under a Special Protocol Assessment (SPA) for the planned PIII trial of neratinib (PB272) in patients with HER2-positive metastatic breast cancer who have failed two or more prior treatments (third-line disease). The EMA has also provided follow-on scientific advice (SA). The trial will compare neratinib + capecitabine vs lapatinib plus capecitabine in ~ 600 patients at 150 sites in North America, Europe and Asia-Pacific. The co-primary endpoints progression-free survival and overall survival. The Company plans to use the progression-free survival data as the basis for submission in the US and EU for Accelerated/Conditional Approval for neratinib. Patient enrollment will begin March or April 2013 [10].
Dec 12Results from an ongoing PII trial were presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium. The study enrolled patients with HER2+ metastatic breast cancer and disease progression on trastuzumab. Patients received a median of 3 prior cytotoxic regimens (range 1-12) before entering the trial. Of the 27 patients enrolled, 14 (52%) had either estrogen receptor+ disease or progesterone receptor+ disease; 20 patients (74%) had visceral metastases and 3 (11%) brain metastases. The combination of PB272 and temsirolimus had acceptable tolerability. The most frequently observed severe AEs were grade 3 diarrhoea (22%), grade 3 mucositis (15%), grade 3 hyperglycaemia (4%), grade 3 leukopenia (4%), and grade 3 fatigue (4%). 12 patients (44%) experienced a partial response (PR) and 1 patient (4%) experienced prolonged stable disease (SD) for > 6 months, which translates to a clinical benefit rate of 48%. Patients who experienced a PR demonstrated a maximum change in the size of their target lesions of between 33% and 83%. Clinical benefit (PR and SD) was seen in patients previously treated with trastuzumab, lapatinib, T-DM1 and pertuzumab. Median PFS was 4.2 months. Tumour biopsies were taken to assess expression or mutational changes in phosphatase and tensin homolog (PTEN) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and to correlate them with response to the combination of PB272 and temsirolimus. Of the 9 patients whose tumours were analysed for PIK3CA, 2 had mutated PIK3CA. Treatment with the combination of PB272 and temsirolimus resulted in clinical benefit in both patients. Of the 17 patients whose tumours were analyzed for PTEN status, 8 had reduced PTEN expression and 7 had absent PTEN expression. Treatment resulted in clinical benefit in 7 (88%) of the 8 patients with reduced PTEN expression and in 6 (86%) of the 7 patients with absent PTEN expression. Enrollment in this trial is continuing and is anticipated to reach a total of 34 patients [9].
Apr 12NCT00878709 (ExteNET) is an ongoing PIII placebo-controlled trial of neratinib after trastuzumab in 2800+ women with early-stage HER-2/Neu overexpressed/amplified breast cancer. Primary outcome data (disease free survival) are expected Nov 12 and the study is due to complete Oct 13. The company are focussing on use in patients with HER-2-positive locally advanced or metastatic breast cancer who have received prior treatment with trastuzumab and have stopped a number of studies in populations different to this [8].
Dec 11Results of a PII RCT reported at the 2011 San Antonio Breast Cancer Symposium. The study compared PB272 as monotherapy (240mg daily) vs lapatinib plus capecitabine in patients with confirmed HER2+ metastatic or locally advanced breast cancer and disease progression following prior treatment with trastuzumab and a taxane. 2% of 117 patients on neratinib had a complete response, 27% a partial response and 15% stable disease for > 6 months (overall response rate 29% and a clinical benefit rate 44%). For the 116 patients on lapatinib and capecitabine, 4% had a complete response, 36% a partial response and 23% stable disease (overall response rate 40% and a clinical benefit rate 63%). The median PFS was 4.5 months vs 6.8 months, respectively. The most frequent severe AEs were diarrhea (28% and 10% respectively had grade 3/4 diarrhea) and palmar-plantar erythrodysesthesia (hand-foot syndrome - 0% and 14% with grade 3/4 PPE) [7].
Dec 11Puma report positive PI/II data for neratinib. The study involved 61 BC pts previously treated with trastuzumab & chemotherapy, given neratinib in combination with capecitabine. Results showed 7 (11%) pts experienced a complete response, 32 (52%) pts experienced a partial response & 5 (8%) pts experienced stable disease for greater than 6 mths - an overall response rate of 64% & a clinical benefit rate of 72%. The company plan to continue development [6].
Oct 11Pfizer and Puma Biotechnology have signed an agreement that gives Puma sole responsibility for global development and commercialization of neratinib. Pfizer will receive payments on development milestones and royalty payments for any sales of neratinib [5]. Puma intends to focus development on patients with HER2+ locally advanced or metastatic breast cancer who have received prior trastuzumab-based therapy. Puma intends to initiate trials in this patient population in the first half of 2012. Prior to the licensing agreement Pfizer had been sponsoring two trials of neratinib: 1) the NEfERTT trial, a PII trial of neratinib + paclitaxel vs trastuzumab + paclitaxel for treatment-naive patients with HER2+ metastatic breast cancer, and 2) the ExteNET trial, a PIII study of neratinib after adjuvant trastuzumab in patients with early stage breast cancer. Puma intends to stop enrollment of new patients and proceed with winding down both trials [5].
Dec 09PII trial assessed safety and efficacy of neratinib (240mg od orally) as monotherapy in pts with advanced HER2 +ve breast cancer assigned to 2 cohorts: prior treatment with trastuzumab (cohort 1) and no prior trastuzumab treatment (cohort 2). Focus was on GI and CV safety profiles. Diarrhoea that developed in patients receiving neratinib had early onset (median time to onset three days), but its frequency and severity decreased with time on neratinib. Neratinib-related diarrhoea was managed with standard supportive therapy and dose interruptions and/or reductions. Anti-diarrheal medications for supportive therapy were used by 85% of the study patients. Dose reductions to manage diarrhoea were applied in 30% of patients in cohort 1 and in 7% 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 III/IV diarrhoea event vs. patients with no diarrhoea or a maximum grade I/II diarrhoea event. Vomiting, of any grade, occurred in 29% of patients and was managed with the use of anti-emetic medications and dose modifications. In this study, neratinib was not linked with clinically significant cardiotoxicity; no patients had congestive heart failure. (4)
Jul 09Three PIII studies are registered, all with a primary outcome of progression free survival. NCT00878709 (ExteNET) is investigating whether neratinib vs placebo can reduce the risk of recurrence over 5 years in 3850 women with early stage HER-2 positive breast cancer after treatment with trastuzumab. Study Start Date: July 2009 Estimated Study Completion Date: June 2016. NCT00777101 is comparing neratinib vs lapatinib plus capecitabine in 1000 women who have erbB-2 (HER-2) positive metastatic or locally advanced breast cancer. Study Start Date: November 2008. Estimated Study Completion Date: November 2013. NCT00915018 is investigating neratinib plus paclitaxel vs trastuzumab + paclitaxel as first-line treatment in 1200 women with ErbB-2-positive locally recurrent or metastatic breast cancer. Study Start Date: June 2009. Estimated Study Completion Date: August 2012 [3].
May 09Preliminary data from two ongoing studies reported. One is an ongoing PI/II study of neratinib in combination with trastuzumab in patients with advanced ErbB-2 positive breast cancer that progressed following therapy with trastuzumab. 16-week PFS rate was 45% in the 28 evaluable patients, and median PFS was 16 weeks. The second PI/II open-label study evaluated a combination with paclitaxel. 102 patients were enrolled. The overall response rate at 16-weeks was 63% in 97 evaluable patients. Diarrhoea was most common adverse event in both studies (2).
Dec 08Phase II trial assessed the safety and efficacy of neratinib (240 mg oral daily) in 136 females diagnosed with ErbB-2-positive locally advanced or metastatic breast cancer (stage IIIB, IIIC or IV). The main outcome of the open-label, two-arm study was the 16-week progression-free survival (PFS) rate. Secondary outcomes included safety, objective response rate (complete and partial responses) and clinical benefit rate (objective response + stable disease). Results suggest that neratinib has antitumour activity in females with advanced breast cancer positive for the ErbB-2 receptor (also known as HER-2 or Neu). (1)

Evidence based evaluations