In 2018, more than four million people across Europe were diagnosed with some form of cancer. Scientific advances have delivered new medicines that have contributed to improved cancer survival, with US cancer mortality rates reducing by 12% as a result of better therapies, compared to a reduction of around 5% attributable to advances in early detection. As more treatments are developed for earlier stages of the disease, where there is greater potential for a cure, new challenges arise in establishing evidence that satisfies both healthcare regulators and payers.
In early disease and other settings where patients have a relatively good prognosis, it is more difficult to gather evidence on the impact of a treatment on overall survival (OS) for both ethical and time reasons. A broader range of clinical endpoints is needed to better describe the benefits patients with earlier-stage disease can expect. There may also be a need to evolve payment models to manage any uncertainties from payers regarding the long-term benefits of the treatment.
The payer-regulator evidence gap
Overall survival is the time a patient lives after diagnosis or from the start of treatment and is seen as the most objective and clinically relevant endpoint. It can be challenging to measure however, particularly in earlier-stage disease, as any subsequent therapies may influence the duration of survival, and it may be hard to isolate the benefit due specifically to the drug under investigation.
Regulatory bodies worldwide have implemented processes to ensure swift approval of medicines in areas of high unmet need, provided data demonstrates a favourable benefit:risk profile. Reimbursement bodies that need to evaluate effectiveness and value frequently request additional data to make their decisions. As trial designs and endpoints in early disease settings are evolving, payers may be faced with challenges in determining value based on the evidence presented to them derived from their traditional assessment frameworks.
Challenges of demonstrating overall survival benefit in early disease settings
Many new cancer therapies are first developed in metastatic, later-stage, cancer where the impact of a new therapy on OS can be more easily measured. However, measuring OS in patients with earlier-stage disease can be challenging for several reasons:
- Baseline survival times are longer in early-stage disease, and other measures of clinical benefit become relevant such as avoidance of recurrence and quality of life
- Patients with earlier-stage disease may receive several different lines of therapy after the study treatment, meaning the OS data reflects the impact of all these therapies rather than the single treatment being tested.
For therapies trialled in earlier disease, the payers’ preferred endpoint of mature OS may not be available at the time of evaluation, therefore posing challenges for patients waiting for new medicines to be made available, unless data using other, non-OS, endpoints can be considered.
Which alternative endpoints can assess clinical benefit in early-stage disease?
Alternative endpoints to measure the clinical benefit a treatment brings to patients may include avoidance of recurrence, relapse or other complications of disease whether measured symptomatically, radiographically, and increasingly with novel measurement techniques. These endpoints characterise patient-relevant benefit that can be more easily attributed to the intervention being studied.
Regulatory bodies have already demonstrated willingness to consider such endpoints in their assessment of new oncology therapies.
Payers may be more uncertain in the use of these endpoints to assign value to new oncology therapies. In December 2018, IQVIA and AstraZeneca conducted a blinded survey of 65 payers in eight countries (Australia, Canada, France, Germany, Italy, Spain, UK, USA) which found a lower awareness of non-OS endpoints beyond progression-free survival (PFS), and an associated lower level of confidence/trust in those endpoints.
The survey also demonstrated that payers familiar with endpoints beyond OS may be willing to accept some in certain scenarios such as areas of high unmet need, early lines of therapy, and long survival indications. However, they remain generally sceptical about non-OS endpoints and do not anticipate major changes in the next three to five years.
What can be done to bridge this evidence gap?
Given the challenges in delivering data that satisfies all stakeholders within a reasonable timeframe, it’s imperative that researchers continue to define endpoints that can better characterise the benefit of new drugs for early disease.
As part of the Lung Ambition Alliance, a partnership with the International Association for the Study of Lung Cancer (IASLC), Guardant Health and the Global Lung Cancer Coalition (GLCC), AstraZeneca is working to validate relevant endpoints to accelerate drug approval in earlystage lung cancer through the Major Pathologic Response (MPR) Project.
The Alliance is exploring whether MPR and other relevant endpoints can be validated in the adjuvant and neoadjuvant settings, by pooling data from cooperative groups and pharmaceutical industry trials.
Endpoints in early-stage oncology trials
| Endpoints | Definition |
| Relapse-free survival (RFS) | The length of time after primary treatment for a cancer ends that the patient survives without any signs or symptoms of that cancer |
| Event-free survival (EFS) | The length of time after primary treatment for a cancer ends that the patient remains free of certain complications or events that the treatment was intended to prevent or delay. These events may include the return of the cancer or the onset of certain symptoms, such as bone pain from cancer that has spread to the bone. |
| Pathologic complete response (PCR) | The lack of all signs of cancer in tissue samples removed during surgery or biopsy after treatment with radiation or chemotherapy. |
| Major pathologic response (MPR) | 10% or less residual viable tumour cells detected in tumour samples removed during surgery or biopsy after treatment with radiation or chemotherapy. |
| Circulating tumour DNA (ctDNA) | Tumour-derived fragmented DNA in the bloodstream. Blood biopsies may be taken at various time points to monitor tumour progression through a treatment regimen and detect residual disease. |
Is there a way to accelerate patient access to medicines for earlystage cancers in the interim?
A more flexible approach may be needed where payer uncertainty on the quantity and value of benefit remains. This need is particularly acute as treatments move into earlier lines of therapy, where benefit may be defined by endpoints beyond overall survival. On the industry side, there also needs to be flexibility in exploring novel payment methods that address payers’ concerns about evidence uncertainty.
Industry, regulators and healthcare payers need to engage in a constructive dialogue and collaborate where needed to validate and use new endpoints. Only by doing this can we satisfy payer needs to understand the value a medicine brings in different settings, while fulfilling our ultimate goal of bringing an effective treatment to patients with earlier stages of disease as quickly as possible.