Getting medicines to people with breast cancer sooner
In recent years, there has been major progress in cancer care – from prevention and screening to treatment – with the result that more people with cancer are living better and longer lives than ever before.1,2
Outcomes for people with advanced cancers have improved overall;2and when the disease is caught early, before it has spread to other parts of the body, people may now be offered treatments that increase their chance of cure.3
In HER2-positive breast cancer, which represents approximately one in five of all cases of breast cancer,4 development of HER2-targeted therapies has transformed the treatment landscape to the extent that people with this particularly aggressive type of the disease today typically have better outcomes than those with less aggressive HER2-negative breast cancer.5 However, with approximately 330,000 people diagnosed with HER2-positive breast cancer worldwide every year and 100,000 people still dying from the disease annually,4,6 there is still work to be done.
"Despite significant improvements in the treatment of HER2-positive breast cancer, there is still a clear need to continue to bring efficacious and innovative medicines to patients who may benefit from these treatments," said Eleonora Restuccia, Senior International Medical Director. "As treatments get better and clinical trials get longer, more complex and costly, there is a great opportunity for us to challenge our approach to research and reflect the growing need to make innovative medicines available to patients as quickly as possible."
Learn more about clinical trials and why we do them in this Roche video here
Overall survival is the ultimate treatment goal but as a trial endpoint it presents specific challenges
When it comes to clinical study endpoints, overall survival (OS) or the length of time someone with cancer survives from the point at which they began treatment has historically been the "gold standard" of measuring a medicine’s efficacy. Despite being used for years in clinical trials, particularly in trials for some types of advanced tumours (e.g. breast cancer), using OS is becoming increasingly challenging.
As people with cancer live longer, it can take more time and resources to demonstrate whether a new medicine makes a significant difference to their survival compared to an older treatment. To adapt to this, progression-free survival (PFS) was proposed as an alternative measure to OS that would provide an earlier indication of a treatment’s benefit over time. PFS is measured as the length of time people live from the point of randomisation into a study until disease recurrence, worsening or death. PFS is now widely used in many clinical trials in the advanced breast cancer (aBC) as the primary endpoint.
Unsure about the differences between early and advanced breast cancer and how they are treated? Visit this infographic here to learn more
It takes a long time to show differences between treatments in early-stage breast cancer
When trying to apply the same measure to clinical trials in the early breast cancer (eBC) setting, where there is the potential to cure or to achieve long periods of remission, the situation is even more complex.7 Showing a significant difference in OS between treatments can take many years. In addition, a large number of patients are required to be involved in the trial.
Similarly to the aBC setting, alternative endpoints have been introduced in the eBC setting to address this challenge. Using endpoints such as event-free survival (EFS; the length of time people live from randomisation into the study until disease recurrence, worsening or death) and disease-free survival (DFS; the length of time people live from the removal of the tumour [i.e. from the time of surgery] until disease recurrence or death) has provided intermediate measures of a treatment’s efficacy. However, even with these endpoints it can take years to demonstrate a drug’s effectiveness.
Approximately two in three people are diagnosed with breast cancer at an early stage.8 Treatment for breast cancer has the greatest impact in the early stage, where it can potentially prevent the disease from returning and spreading. Therefore, every year that passes without new and potentially more effective treatments, while they are still being investigated in clinical trials, may translate into many thousands of patients potentially missing out on the opportunity of an improved chance of cure.
"At Roche, we recognised this need and asked ourselves: what can we do to bring those new treatments to patients with eBC faster? We challenged our approach to clinical trials and adopted pathological complete response (pCR), an innovative endpoint which allows us to demonstrate a drug’s efficacy quicker than was ever possible before," explained Eleonora Restuccia.
pCR is an accepted endpoint in neoadjuvant eBC studies
In eBC, a patient can receive a neoadjuvant (i.e. before surgery) treatment with the aim of shrinking the tumour as much as possible, and thus enable an easier surgical procedure with a better outcome. As an effect of the neoadjuvant treatment, the patient can achieve a pCR which means there are no cancer cells detectable anymore at the time of surgery in the affected breast and lymph nodes. Even when pCR is achieved, however, it does not always mean the cancer is completely gone, and that is why adjuvant treatment given after surgery is a key step in removing remaining cancer cells, preventing the cancer from returning and increasing the chance of cure.
For more information on the differences between, as well as the aims of, neoadjuvant and adjuvant treatment, see this short slideshow here
One of the main advantages of using pCR as an endpoint for eBC trials is that it allows the assessment of whether a medicine is working to be made immediately after the surgery - much faster than was possible before - i.e. within a matter of weeks versus potentially years. In this way, pCR provides an early indication of a treatment’s efficacy in the pre-surgery setting and is now a commonly accepted measure in breast cancer trials for neoadjuvant treatments.
Adapting clinical trials is only half the equation
Ensuring we have endpoints in place for clinical trials that allow assessment of efficacy earlier than before is only one part of getting medicines to patients faster. Another important part is ensuring that health authorities accept these endpoints as a valid basis for the approval of a medicine, which requires robust clinical evidence.
Health authorities have also recognised the need to bring new medicines to patients with eBC as quickly as possible. This recognition lead to our close collaboration with both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to evaluate the scientific rationale and evidence for the use of pCR as an endpoint in eBC trials.
Creating a new regulatory pathway
In October 2015, the EMA issued final guidance (here) which states that the approval of a new medicine for high-risk eBC may be acceptable based on pCR, provided that the medicine’s mechanism of action is well-characterised and that supporting data show a major increase in pCR with only minor changes in toxicity.9 A year earlier, the U.S. FDA also issued guidance supporting the accelerated approval of eBC medicines based on pCR data.10 This means that there is now a regulatory pathway in place to ensure patients with eBC may start benefitting from treatments sooner than was ever possible before, in the pre-surgery setting, while large clinical trials to demonstrate clinical benefit of these treatments in the adjuvant setting are still ongoing.
pCR is an example of how recognition of an evolving landscape of clinical development, clear understanding of the unmet need, innovative thinking and close collaboration with health authorities came together to bring about a significant change to the way in which we evaluate treatments. "Pushing the boundaries of science and creating opportunities to bring medicines to patients sooner is part of our commitment to better meet the needs of patients," said Eleonora Restuccia. "That is why we will continue to lead the science and challenge ourselves every step of the way for the benefit of patients."
1. CancerProgress.Net [Online]. Progress & Timeline. Available from: http://cancerprogress.net/timeline/quality-life [Accessed November 2015].
2. National Cancer Institute [Online]. SEER Cancer Statistics Review, 1975 – 2012. Available from: http://seer.cancer.gov/csr/1975_2012/results_merged/topic_survival.pdf [Accessed November 2015].
3. Cancer Research UK [Online]. Why is early diagnosis important? Available from: http://www.cancerresearchuk.org/about-cancer/cancer-symptoms/why-is-early-diagnosis-important [Accessed November 2015].
4. Wolff AC, et al. Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol 2013;31(31):3997-4013.
5. Dawood S, et al. Prognosis of Women With Metastatic Breast Cancer by HER2 Status and Trastuzumab Treatment: An Institutional-Based Review. J Clin Oncol 2010;28(1):92-8.
6. World Health Organization [Online]. Breast Cancer: Estimated Incidence, Mortality and Prevalence Worldwide in 2012. Available from: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx [Accessed November 2015].
7. Wolff AC and Davidson NE. Early Operable Breast Cancer. Curr Treat Options Oncol 2000; Aug;1(3):210-20.
8. National Cancer Institute [Online]. SEER Stat Fact Sheets: Female Breast Cancer. Available from: http://seer.cancer.gov/statfacts/html/breast.html [Accessed November 2015].
9. European Medicines Agency [Online]. Appendix 4 to the guideline on the evaluation of anticancer medicinal products in man. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/10/WC500195215.pdf[Accessed November 2015].
10. Food and Drug Administration [Online]. Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm305501.pdf [Accessed November 2015].