HEOR Articles

Delivering on Promises: Enhancing Patient Access to Neoadjuvant Cancer Treatments

Milayna Subar, MD, Global Medical & Scientific Affairs, Merck & Co, Kenilworth, NJ, USA; Ravinder Dhawan, PhD, Center for Observational and Real-World Evidence, Merck & Co, Kenilworth, NJ, USA; Ala’a Kutkut, MD, Global/EMEAC Oncology Policy, Merck & Co, Kriens, Switzerland; Michele Pistollato, PhD, Charles River Associates, London, England, UK


There is universal agreement on the objective of defeating cancer. Neoadjuvant treatment administered at early potential curative settings has the potential to achieve this objective. But developing neoadjuvant treatment has unique challenges. It may take years to reach efficacy conclusions from endpoints such as overall survival, from trials in patients with early-stage disease and consequently impacting the opportunity to provide effective, potentially curative therapeutic options to patients. Although standards are slowly evolving, there is a lack of alignment among stakeholders on the suitability and value of non-overall survival endpoints and a need to increase mutual understanding to overcome the access challenges for neoadjuvant treatment in oncology.


Delivering Innovation Through Intervention

Neoadjuvant treatments for patients with cancer is vitally important and has a great potential to be curative or delay relapse and lower the overall burden of disease. In addition to improving the prognosis for patients, interventions at earlier stages of the disease (eg, nonmetastatic settings) can reduce long-term direct and indirect costs for health systems. Some of the most recent scientific advances in treating cancers are immunotherapies. These are now being applied in early stage disease settings as neoadjuvant treatment.1 There are currently over 300 trials listed on ClinicalTrials.gov exploring the use of immunotherapy in early stage disease settings across several cancer types including breast, melanoma, renal cell cancer, esophageal cancer, and lung cancer.2

There is considerable hope that the use of immunotherapies in neoadjuvant settings will activate the immune response to eradicate micrometastases thereby preventing recurrence of disease and improving overall survival while preserving quality of life.


An Access Challenge for Neoadjuvant Treatments in Oncology

There is a barrier that can affect the commercialization and fast uptake of these medicines: the lack of alignment between different stakeholders on the acceptance of endpoints other than overall survival used to demonstrate their clinical effectiveness. Market access and coverage policies for medicines have been based traditionally on randomized controlled trials that assess final outcomes such as overall survival, morbidity, and health-related quality of life.3 Given the medical need in many oncology indications and the promising benefits of immunotherapies, regulatory agencies have approved treatments increasingly based on evidence of their efficacy on biomarkers or intermediate endpoints (sometimes termed “surrogate endpoints” where there is a clear relationship with another endpoint of interest) to accelerate patient access.

“Market access and coverage policies for medicines have traditionally been based on randomized controlled trials that assess final outcomes such as overall survival, morbidity, and health-related quality of life.”


However, reimbursement decision bodies and health technology assessment agencies in general have been less willing to accept these endpoints.4 There have been some exceptions. In some circumstances, they have also made recommendations that relied entirely on treatment effects derived from trials that assessed surrogate endpoints. To date, a disease-free survival benefit has been reported in several neoadjuvant studies and adjuvant immunotherapy has been approved in melanoma based on this endpoint, though access challenges persist in some regions.5 Similarly, event-free survival has been accepted to show the benefit of treatments in high-risk, early stage triple-negative breast cancer.6 Despite their appeal, the use of non-overall survival endpoints for reimbursement recommendations remains difficult, as payers often express concerns that these endpoints may not capture the combined risk-benefit profile of a technology, or that superiority using these endpoints may not translate into long-term benefits for patients or, if it did, the healthcare system may not judge the benefits to be good value for money.


The Debate on the Use of Non-Overall Survival Endpoints

From an industry perspective, the analysis of overall survival (the “gold standard” for a treatment’s approval) becomes less efficient in certain disease states where years may be needed in order for sufficient survival events to occur in order to demonstrate statistical benefit. Even then, the analysis of non-overall survival endpoints may be confounded by the effect of other subsequent therapies used over the duration.7 For this reason, the analysis of alternative endpoints (such as pathological complete response, disease-free survival, or event-free survival) is frequently incorporated in clinical trials of neoadjuvant treatments because they allow saving valuable time in the development process. Given the global scope of clinical trials, choices need to be made on which endpoints to measure and the impact that the consequent trial design can have on time to patient access. The difficulties to accept non-overall survival endpoints for reimbursement could lead to a lack of access to treatments, or to significant delays.


“Given the global scope of clinical trials, choices need to be made on which endpoints to measure and the impact that the consequent trial design can have on time to patient access.”

Clinicians may find alternative, non-overall survival endpoints such as a biomarker or disease response relevant in a neoadjuvant setting as they can provide early evidence of the tumor sensitivity to treatment, may enable more efficient surgical excision, and increase the opportunity to cure early stage tumors. In breast cancer, clinical response can influence the extent of surgery and nodal dissection which, from a patient perspective, also has significant aesthetic and psychological implications. Pathological complete response (absence of invasive cancer in the breast) demonstrated at the time of resection is associated with improved prognosis and decreased risk of recurrence, and has been accepted by some as a surrogate endpoint for overall survival for nonimmunologic therapies.8 However, the applicability of specific endpoints to assess benefits can vary considerably across different types (and subtypes) of tumors. If the treatment goal is eradication of cancer, in general, prescribers are looking for a long-term outcome benefit (overall survival, event-free survival, disease-free survival, or invasive disease-free survival).9 In some instances, involvement of multidisciplinary teams can refine research protocols to better support relevant patient outcomes throughout the continuum of the neoadjuvant treatment.

“In breast cancer, clinical response can influence the extent of surgery and nodal dissection which, from a patient perspective, also has significant aesthetic and psychological implications.”


In general, especially in Europe, payers argue that they want to maintain the high standard of randomized clinical trials based on overall survival and long-term safety data. They are willing to use a different endpoint only if there is a clear relationship between the endpoint and overall survival from clinical studies in relevant disease settings and target populations. Their argument is that “accelerated” regulatory approvals without overall survival data add uncertainty to their decision-making process. However, there are also calls within some payer groups to step away from the “traditional paradigm of overall survival” and take a more holistic approach to consider the value of neoadjuvant treatment can deliver in a physician’s treatment strategy. In this case, the argument is that physicians are ready to prescribe neoadjuvant treatments to patients, but the healthcare systems (and the payers) are not ready yet.

From a policy perspective, there exist different tools to deal with uncertainty (ranging from horizon scanning to anticipate system readiness to pipeline products, to generation and use of real-world data to better address information gaps). As payers and HTA bodies are more receptive to treatments used in early stage disease settings if uncertainty is reduced, there should be more consideration of these tools. However, some of these mechanisms, such as managed entry agreements, can be particularly complex to implement, even face legal barriers, and add to the challenges for neoadjuvant treatment. Options to address these complexities include efforts to improve data quality and analytic methods and increased clarity and infrastructure for the collection and use of real-world data.


“There is a need to develop a shared understanding of the challenges and discuss the different solutions that could advance the debate on access to neoadjuvant treatment in oncology.”


A Fine Line to Travel for Faster Patient Access

Overall, the demands from healthcare decision makers to have more certainty about the value of a medicine needs to be balanced with the desire from patients for faster access to effective treatments, especially in areas of great unmet need. In the oncology space there are numerous endpoints widely accepted to provide patients with novel therapies to treat cancers at later stages (eg, progression-free survival in stage III and IV tumors).10 However, this willingness has not consistently translated into treatment for earlier stages of disease. The complexity of the access challenges requires particular alignment between the stakeholders (patient, payers, physicians, regulators, and industry), especially on the consideration of endpoints. To ensure that no opportunity is missed because of the lack of mutual understanding, there should be a joint effort to identify and implement solutions that would enable the development of novel effective medicines and patient access in
neoadjuvant oncology settings.



1. Krishnamoorthy M, Lenehan JG, Maleki Vareki S. Neoadjuvant immunotherapy for high-risk, resectable malignancies: Scientific rationale and clinical challenges. J Natl Cancer Inst. 2021;113(7):823-832.
2. Helwick C, Mittendorf EA. What’s the Current Status of Neoadjuvant Immunotherapy? Published April 25, 2020. Accessed July 31, 2021.
3. Fitzpatrick R, Davey C, Buxton MJ, Jones DR. Evaluating patient-based outcome measures for use in clinical trials. Health Technol Assess. 1998;2(14):i-iv,1-74.
4. Harbeck N, Schneeweiss A, Thuss-Patience P, et al. Neoadjuvant and adjuvant end-points in health technology assessment in oncology. Eur J Cancer. 2021;147:40-50.
5. US Food and Drug Administration. FDA Approves Pembrolizumab for Adjuvant Treatment of Melanoma. Published December 6, 2021. Accessed July 31, 2021.
6. US Food and Drug Administration. FDA Approves Pembrolizumab for High-Risk Early-Stage Triple-Negative Breast Cancer. Published July 27, 2021. Accessed July 31, 2021.
7. Topalian SL, Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science. 2020;367(6477).
8. Huang M, O’Shaughnessy J, Zhao J, et al. Evaluation of pathologic complete response as a surrogate for long-term survival outcomes in triple-negative breast cancer. J Natl Compr Canc Netw. 2020:18(8):1096-1104.
9. Tolaney S, Garrett-Mayer E, White J, et al. Updated standardized definitions for efficacy end points (STEEP) in adjuvant breast cancer clinical trials: STEEP Version 2.0J Clin Oncol. 2021; 39(24):2720-2731.

10. Gyawali B, Hey SP, Kesselheim AS. Evaluating the evidence behind the surrogate measures included in the FDA’s table of surrogate endpoints as supporting approval of cancer drugs. EClinicalMedicine 2020;21:100332.

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