1. Holmes, Frankie Ann MD

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Getting a cancer drug from the lab through approval from the FDA is often a long and winding road, fraught with many obstacles. Such was the case for the breast cancer drug neratinib, a promising new treatment option for early-stage HER2+ breast cancer patients who remain at risk for recurrence after trastuzumab-based therapy in the adjuvant setting.

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U.S. Oncology Research, the pioneering research arm of The U.S. Oncology Network, played a pivotal role in the drug's FDA approval in July 2017, supporting the drug's manufacturer through the ExteNET clinical trial that led to approval, as well as helping the manufacturer overcome challenges along the way.


New Development in HER2+ Treatment

Much progress has been made in treating HER2+ early-stage breast cancer, and neratinib represents a significant invasive disease free survival (iDFS) improvement upon standard of care, giving patients another highly effective oral treatment that can reduce the risk of HER2+ breast cancer returning. While trastuzumab has improved outcomes, there is still a 16 percent risk of death and 26 percent risk of tumor recurrence (J Clin Oncol 2014;32:3744-3752). Backdoor escape pathways exist for HER2+ cancer cells, even when chemotherapy and trastuzumab are used, resulting in recurrence.


Neratinib was developed to improve upon the standard of care and provide patients with early-stage HER2+ disease their best chance for survival. This treatment addresses these escape pathways by giving patients at risk the drug for 1 year after completion of HER2+ standard therapy. HER2+ breast cancer cells have 100 times the usual number of HER2 receptors (like cell phone towers) than normal breast cells, and they are located on the outside of the cell. These receptors allow the cancer cell to grow faster and spread more quickly.


Trastuzumab blocks these receptors outside the cell, preventing the growth signal. Neratinib works inside the cell, irreversibly binding to the HER2 receptor if the signal escapes despite the trastuzumab.


The ExteNET trial demonstrated that after 2 years of follow-up, patients treated with neratinib had a 34 percent reduction in the risk of recurrence compared to placebo. Invasive disease-free survival was 94.2 percent in patients treated with neratinib compared to 91.9 percent for the placebo (Lancet Oncol 2016;17:367-377). Additionally, an exploratory analysis after 5 years showed a consistent 27 percent risk reduction with neratinib versus a placebo (Lancet Oncol 2017;


FDA approval of neratinib was based on the global phase III ExteNET trial, a randomized, double-blind, placebo-controlled study utilizing neratinib following adjuvant trastuzumab treatment. Women (n=2,840) with early-stage HER2+ breast cancer were randomized to receive either neratinib (n=1,420) or placebo (n=1,420) for 1 year administered within 2 years of completing adjuvant trastuzumab.


U.S. Oncology Research played a leading role in the trial and FDA approval of the drug, contributing in a variety of ways.


Developing Trial Protocol

U.S. Oncology Research's involvement in the ExteNET trial began during the planning stages of the study. Trial information was presented to The U.S. Oncology Network's Breast Cancer Research Committee, which is comprised of senior leaders and individuals who accrue trials. We learned how neratinib was different from existing drugs and further reduced the risk of recurrence for early stage HER2+ patients with an irreversible PAN-HER inhibitor, unlike extracellular monoclonal antibodies. It sounded extremely promising and very applicable to our patients, and we voted to accept the trial.


I was nominated to be U.S. Oncology Research's Principal Investigator for the trial, so I became part of the ExteNET Trial Steering Committee (TSC) responsible for planning the details of the study and developing the protocol. The TSC, which included the National Principal Investigator and other researchers from the U.S. and around the world, gathered during the ASCO Annual Meeting, enabling us to discuss key aspects of the trial face-to-face. Discussions focused on the logistics of the global study, recruitment, and other important details such as defining appropriate endpoints. Once the protocol was completed, the trial was officially launched.


Driving Accruals

Ten U.S. Oncology Research-affiliated sites bid on the study. These sites were carefully vetted by the organization to ensure each had the necessary experience in clinical research, as well as sufficient support staff and resources to meet the trial criteria. The U.S. Oncology Network then assisted the practices with budgeting and contracting, ensuring adequate reimbursement for the practices, as well as funding for the cardiac aspects of the trial. Once vetting, budgeting, and contracting were completed, the 10 sites were accepted by the drug manufacturer, and the trial was launched within The U.S. Oncology Network.


Many different strategies were used to drive accruals. U.S. Oncology Research hosted a national initiation webinar where the drug manufacturer presented detailed information about the study. U.S. Oncology Research also held many other meetings to support the trial, often occurring in conjunction with national meetings where physicians and the drug manufacturer were already present, enabling easy access to the principals involved in the study. Clinical research nurses were also encouraged to attend these meetings, since they played a crucial role in screening and providing ongoing care to trial participants.


The Network Breast Cancer Research Committee used its own intranet to heavily promote the trial. Monthly teleconferences, study reminders, and emails to breast physicians and clinical research associates were utilized to remind them about the study. Monthly updates with graphs depicting planned versus actual accruals were also sent out to demonstrate progress.


This aggressive promotion created a high level of awareness among the physicians and research nurses treating patients, driving a large number of accruals across The U.S. Oncology Network. During the course of the trial, the 10 U.S. Oncology Research affiliated sites enrolled 230 patients the largest number of patients from any network representing approximately 10 percent of the 2,840 trial participants across the globe from North and South America, Europe, Australia, New Zealand, and Japan.


Partnering to Overcome Challenges

Several major obstacles were surmounted during neratinib's journey to FDA approval. The drug company that initially developed the therapy was bought by another pharmaceutical company that then subsequently wanted to divest itself of oncologic products. Consequently, the company changed the trial protocol to a 2-year follow-up rather than 5 years to allow it to terminate the trial quickly. Essentially, this was a death sentence for the drug. The FDA requires follow-up of at least 5 years for breast cancer trials, since patients remain at risk for 5 years, or longer in some cases.


Luckily, another company was able to acquire the drug in 2011; they strongly believed in its potential and championed its development, proceeding with a herculean effort to overcome the many challenges created by the ownership transitions. As expected, the FDA questioned the integrity of the trial data, but a well-respected statistician was brought in to certify the data was reliable. However, they still faced the problem caused by the trial ending at 2 years rather than 5, as breast cancer drugs are not approved with 2-year data. Consequently, protocol was opened again so patients who had completed the trial could be reconsented to allow for longer follow-up.


U.S. Oncology Research and I were anxious to help provide the long-term data, and I met several times with the company, reviewing trial data and developing strategies to accomplish the task. The protocol amendment had to be approved by each investigational review board and all trial sites. To drive the amendment through U.S. Oncology Research and implement the needed follow-up across The U.S. Oncology Network, I spearheaded the effort by calling and emailing my fellow researchers, asking them to find patients who had completed the trial and reconsent them for longer follow-up. U.S. Oncology Research staff provided invaluable support to accomplish the task, visiting each site and assisting in submitting the required documentation.


The final hurdle to overcome was FDA approval, and Joyce O'Shaughnessy, MD, with Texas Oncology-Baylor Charles A. Sammons Cancer Center in Dallas, a practice in The U.S. Oncology Network, played a key role. As an expert not only in breast cancer research, but also oncology drug development, she testified to the Oncologic Drugs Advisory Committee during the approval hearing, providing background information, describing the trial results, and explaining where the drug fit in the current treatment landscape.


Data With a Real-World View

Neratinib marks the 69th of 71 FDA approvals for a cancer therapy in which U.S. Oncology Research has played a role-approximately one-third of all cancer therapies approved by the FDA to date. As the largest accruing group in the neratinib trial, U.S. Oncology Research provided 10 percent of the study participants distributed across the U.S. This nationwide distribution was critical to the study, as it provided a representative sampling of cancer patients in local communities where the majority of patients are treated. Community data is especially valuable, as results can be different than when patients are treated at academic centers away from home.


While there were many challenges in the neratinib trial, getting a promising new drug into the hands of patients made it all worthwhile. Those of us who are privileged to play a role in research know that research cures cancer, and clinical trials turn data into medicines. The next groundbreaking drug could be right around the corner, but we will never know unless we have the funding and patient participation we need to conduct the clinical trials that unlock the mysteries of cancer.


FRANKIE ANN HOLMES, MD, is an oncologist with Texas Oncology and a member of The U.S. Oncology Network Breast Cancer Research Committee.

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