PharmaShots Interview: Pierre Fabre’ Roberta Valenti Shares Insights on Nerlynx (neratinib) for the Treatment of HER2 Early Breast Cancer

In an interview with PharmaShots, Roberta Valenti, Global Medical Director at Pierre Fabre shared her views on Nerlynx (neratinib) in P-II (CONTROL) study & showed improved tolerability with all the investigated diarrhoea prophylaxis strategies, presented at SABCS 2021

Shots:

The P-II (CONTROL) study evaluates 6 preventive antidiarrheal prophylaxis options with loperamide for the prevention of neratinib-associated diarrhoea. Patients will receive neratinib (240 mg/day) for 1yr. who had completed trastuzumab-based adjuvant therapy for stage I–IIIc HER2+ breast cancer
The results showed a reduction in incidence, severity & duration of neratinib-associated grade 3 diarrhoea in patients with prophylactic anti-diarrhoea or dose escalation schedule of neratinib associated with loperamide @2wks., improved tolerability in HER2+ eBC patients
The study was based on the (ExteNET) study results, grade ≥3 diarrhoea was observed in 40% of patients & 17% discontinued the study

Tuba: Discuss the study design of the CONTROL study.

Roberta Valenti: The CONTROL study was an international, multi-cohort, open-label, phase 2 study designed to investigate six prophylaxis options for the prevention of neratinib (NERLYNX) associated diarrhoea. Previously reported interim data suggested that the two-week (DE1) cohort of neratinib dose escalation in association with loperamide (as necessary) resulted in the best diarrhoea profile.

Adult patients (n=563) with stage I–IIIc HER2+ breast cancer who had completed trastuzumab-based adjuvant therapy within one year prior to study entry received oral neratinib (240 mg/day) for one year and were enrolled sequentially into six separate cohorts.

1. Loperamide prophylaxis.

2. Budesonide + loperamide prophylaxis.

3. Colestipol + loperamide prophylaxis.

4. Colestipol prophylaxis + loperamide pro re nata (PRN), as necessary.

5. Neratinib DE1 (2-week escalation) + loperamide (PRN, as necessary).

6. Neratinib DE2 (4-week escalation) + loperamide (PRN, as necessary).

Previously reported interim data suggested that the two-week (DE1) cohort of neratinib dose escalation in association with loperamide (as necessary) resulted in the best anti-diarrhoea approach compared to the other bi-weekly dose escalation regimen (DE2 cohort).

Tuba: What are the key takeaways of the data presented at SABCS?

Roberta Valenti: The key takeaways from both the CONTROL clinical study and ELEANOR real-world evidence (RWE) studies presented at the 2021 San Antonio Breast Cancer Symposium (SABCS) were that associated diarrhoea adverse events reported following treatment with neratinib in the ExteNET study are manageable with proactive management strategies.

Indeed, the final findings included data from DE2 (four-week dose-escalation cohort) which assessed patients taking neratinib + loperamide PRN with a 4-week escalation.

At least 75% of patients received neratinib for longer than 11.06 months in DE1 (two-week cohort), compared with 7.46 months in the DE2 cohort.

The DE1 cohort also had the lowest rate of diarrhoea-related discontinuations (3.3%) and dose hold (11.7%).

Overall, the data demonstrated improved tolerability of neratinib with all diarrhoea prophylaxis strategies and reconfirmed that neratinib two-week dose escalation with loperamide PRN allows patients to stay on treatment longer, thus having the potential to receive the full benefit of neratinib therapy.

These results provide reassurance to clinicians that neratinib is a reliable treatment option that can be well tolerated and are an important milestone for patients with early HER2+/HR+ breast cancer as, despite the advances offered by trastuzumab, up to 33% of HER2+ patients will still experience a recurrence of the disease.

Tuba: Tell us more about Nerlynx. Discuss its MOA, ROA, and therapeutic efficacy.

Roberta Valenti: Neratinib (NERLYNX) is a type of targeted therapy for breast cancer called tyrosine kinase inhibitor - an irreversible pan-HER inhibitor (it inhibits HER1, HER2 & HER4).

Neratinib (NERLYNX) is indicated for the extended adjuvant treatment of adult patients with early-stage hormone receptor-positive HER2-overexpressed/amplified breast cancer and who completed adjuvant trastuzumab-based therapy less than one year ago.

Neratinib (NERLYNX) is a once-daily oral tablet treatment (6 tablets of 40mg) to be taken continuously for one year.

Tuba: How can you say that Nerlynx would be new hope for early-stage HER2+/HR+ breast cancer?

Roberta Valenti: HER2+ breast cancer is a highly aggressive form of cancer for which an unmet medical need remains as patients still recur from their cancer. Over the last 20 years, treatment of patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer has considerably improved. The development and addition of (neo)adjuvant trastuzumab to chemotherapy in patients with early HER2+ breast cancer (EHBC) has been shown to provide improvements in both invasive disease-free survival (iDFS) and overall survival. However, despite such promising clinical outcomes, about 30% of patients still recur at 10 years from diagnosis calling for the development of new preventive approaches.

Based on more recent advances, therapeutic strategies for patients with HER2+ tumors are now incorporating the use of newer (neo)adjuvant treatments, such as pertuzumab and trastuzumab emtansine, which have shown to further improve the invasive DFS (iDFS) benefit gained with trastuzumab.

In this context, the tyrosine kinase inhibitor neratinib (NERLYNX) is the first and only product to be approved as extended adjuvant therapy for early-stage HER2+/HR+ breast cancer, offering the opportunity to further reduce the risk of recurrence. Clinical data have demonstrated that neratinib (NERLYNX) significantly improves iDFS at 2- and 5-years vs placebo, and also more specifically in the subgroup of patients who did not achieve a pathological complete response.

Tuba: How to reduce diarrhea so that patients would stay on treatment and benefit from Nerlynx?

Roberta Valenti: The CONTROL study has demonstrated that associated diarrhoea adverse events reported in ExteNET are manageable with proactive management strategies.

The data demonstrated improved tolerability of neratinib with all the investigated diarrhoea prophylaxis strategies and suggested that neratinib two-week dose escalation with loperamide PRN allows patients to stay on treatment longer, thus having the potential to receive the full benefit of neratinib therapy.

Preliminary results from ELEANOR prospective observational study confirm that these approaches are feasible in clinical practice.

Tuba: Highlight the key points of your collaboration with PUMA Biotechnology.

Roberta Valenti: Our partnership with PUMA Biotechnology involving the introduction of neratinib (NERLYNX) has been an exciting addition to our strong oncology portfolio. We are committed to ensuring more patients with HER2+/HR+ early breast cancer are able to access treatments that can improve their lives. Pierre Fabre has exclusive commercialization rights for neratinib (NERLYNX) in European countries (excluding Russia and Ukraine), along with francophone countries of North Africa, Turkey, Middle East, and the agreement was more recently extended to Greater China (which includes mainland China, Taiwan, Hong Kong, and Macau).

Tuba: What are your upcoming steps for patients with early-stage HER2+/HR+ breast cancer?

Roberta Valenti: Ongoing studies will support shaping better outcomes for neratinib (NERLYNX) patients.

Pierre Fabre is committed to pursuing investigation on the best diarrhoea management strategy HCPs can offer their neratinib (NERLYNX) patients:

The DIANER study evaluates the incidence of discontinuations due to diarrhoea at 3 cycles in patients with HER2+/HR+ breast cancer treated with neratinib and different anti-diarrhoeal strategies.

ELEANOR is the first Non-Interventional Study (NIS) to investigate the real-world use of neratinib and its treatment management in the EU label population in Germany, Austria, and Switzerland. NIS is to investigate the rate of patients being adherent (i.e., neratinib intake for more than 75% of treatment days) to neratinib treatment. The study plans to recruit 300 patients with HER2+/HR+ early breast cancer who were treated with neratinib as per the EU SmPC.

NERLYFE is a post-approval safety study (PASS) to investigate the real-world use of neratinib and its treatment management in the EU label population across Europe, monitoring for the rate of permanent discontinuations due to diarrhea and the impact of education of patients and treating physicians in its incidence and severity.

References:

Ruiz-Borrego M, et al. ‘Bringing diarrhea under CONTROL: dose escalation reduces neratinib-associated diarrhea and improves tolerability in HER2-positive early-stage breast cancer’ San Antonio Breast Cancer Symposium 2020 Poster #PS13-20
Chan A et al ‘Final findings from the CONTROL trial of diarrheal prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer’ San Antonio Breast Cancer Symposium 2021 Poster #P5-18-02
Lüftner D et al ‘First interim analysis from ELEANOR: a multi-national, prospective, non-interventional study (NIS) in patients with human epidermal growth factor receptor-positive (HER2+) early breast cancer (eBC) observing real-life extended adjuvant treatment with neratinib’ San Antonio Breast Cancer Symposium 2021 Poster #P2-13-30
Chan A et al ‘Final Efficacy Results of Neratinib in HER2-positive Hormone receptor-positive Early-stage Breast Cancer from the Phase III ExteNET Trial. Clin Breast Cancer. 2021 Feb;21(1):80-91.e7
NERLYNX (neratinib) Summary of Product Characteristics (SmPC) https://www.medicines.org.uk/emc/product/10477/smpc#gref
Chan A et al ‘Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer ExteNET) a multicentre, randomized, double-blind, placebo-controlled, phase 3 trial Lancet Oncol 2016; 17: 367-77
Untch M, et al. How to Optimise Extended Adjuvant Treatment with Neratinib for Patients with Early HER2+ Breast Cancer. Oncol Ther. 2021 Dec;9(2):297-309

Source: Canada Protection Plan

About Author:

Roberta Valenti is the Global Medical Director at Pierre Fabre Group. She holds a Bachelor’s degree from the Pharmaceutical Biotechnology, University of Milan