The development of immuno-oncology (IO) drugs has represented a significant breakthrough in the treatment of cancer. Currently, single-agent and combination immunotherapy regimens have been approved by the Food and Drug Administration (FDA) and European Medicines Agency for at least 20 indications.1

IOs differ from conventional chemotherapies as they target the patient's immune system rather than directly attacking the tumor. This immune activation can lead to durable responses and prolonged survival in some, but not all, treated patients. Long-term follow-up in patients with metastatic melanoma who received treatment with ipilimumab, for example, has shown 3-year survival rates ranging from 20% to 26%, and up to 10 years in some patients,2 whereas only 1%–2% of patients with metastatic melanoma achieve a durable long-term response to chemotherapy.3 Durable responses have also been observed in multiple other tumor types. For patients treated with nivolumab, overall survival (OS) curves have been seen to flatten at around 3 years, with estimated 5-year survival rates of approximately 30% for renal cell carcinoma, and 16% for non-small cell lung cancer (NSCLC).4 Even higher long-term survival rates (ie, plateaus) appear to be likely in patients receiving IO-combination therapy for these tumor types.5–7

Assessing the value of a new oncology drug is a key goal of health technology assessment (HTA) and pricing and reimbursement negotiations. While HTA agencies worldwide differ in terms of their assessment criteria and methods, the gold standard efficacy criterion in oncology is OS. The outcome is clear and measurable, and the benefit of longer survival is irrefutable. However, providing robust OS evidence requires large trial sample sizes and often many years of trial follow-up, which can potentially deny or delay critically ill patients access to life-extending therapies. Manufacturers are therefore faced with the challenge of demonstrating the potential long-term benefit of their IO therapies with short-term survival data.

The aim of this article is to report insights from multi-stakeholder interviews and expert panels, as well as the scientific literature, on the challenges regulators, HTA agencies, and payers commonly encounter when assessing the long-term benefits of IOs across a range of tumor types.

A pragmatic review of published literature in PubMed was conducted in September 2017 with the aim of gaining a deeper understanding of the topic to be addressed. Articles on IO or cancer immunotherapy were identified which contained data on long-term survival outcomes. Since IO therapies and their long-term benefits are relevant to multiple therapeutic areas, the searches and subsequent discussions were not focused on a single tumor type. A total of 27 published papers were identified for the topics extrapolation, long-term survival, survival modeling/analysis, alternative metrics/end points, surrogates, non-proportional hazards, and cure modeling. In addition, 86 reimbursement submissions were considered for ipilimumab, nivolumab, and pembrolizumab from agencies in Australia, Canada, Germany, Sweden, and the UK.

Multi-stakeholder interviews to develop this document were conducted between July 2017 and February 2018 (figure 1). A steering committee (SC) was convened which comprised nine payers, economists, and clinicians from the US, UK, France, Italy, and Sweden. They were tasked with developing a summary of the challenges that were specific to demonstrating the long-term benefit of IOs. Once the summary had been developed, it was reviewed and refined by conducting double-blind multi-stakeholder expert panels from the US, UK, France, Germany, and Sweden.

These five expert panels were asked to evaluate themes from the summary of challenges in terms of how they applied to each country’s assessment criteria. In line with the search criteria, participants were not asked to focus on a single tumor type. The panel sessions were run over 1 day, lasting around 6 hours each. The themes were either confirmed, amended, or replaced, and additions were also allowed. Recommendations to manufacturers for how best to meet and overcome the challenges in future submissions were reviewed. The SC then finalized the summary of challenges and a corresponding list of questions for manufacturers to consider at HTA submission.

The SC meetings and face-to-face expert panels were moderated by PRMA Consulting. Purposeful sampling approaches were used to identify potential participants for this research, based on the existing research networks and online searches. Panelists were recruited via email; six were recruited from each of the US, UK, and France, five from Germany, and four from Sweden.

The summary of challenges for evaluating and communicating the long-term benefits of IOs at HTA submission is presented in table 1. The challenges correspond with questions for manufacturers to consider and are grouped into key areas: how the mechanism of action of IO therapy may impact on longer-term survival; the estimation of the survival benefit; and limited data available at the time of HTA submission.

Our findings indicate that, despite over a decade of use, there remain significant challenges in how best to demonstrate the long-term benefit of IOs to HTA agencies, clinicians, and payers. We have presented a succinct summary of the key challenges facing manufacturers when submitting evidence at HTA in demonstrating the full value of IOs for a range of tumor types, and further questions for consideration, in table 1. Many of these are well known and have been discussed in published literature, but they currently remain largely unresolved.

In general, longer-term follow-up should be standard practice for IO clinical trials. Long-term response and OS data could alleviate many of the current challenges. Research on biomarkers or other predictors of response and durable survival should also continue, as a successful biomarker could help clinical trials management and still provide timely patient access—a key goal in all drug development. As IOs may potentially be used in earlier stages of disease in the near future, surrogate end points will become even more important and should be validated. Greater development and use of RWE spans all stakeholders and is a key part of overcoming the gap between RCT data with low external validity and properly measuring long-term survival benefit.

From the perspective of manufacturers, the recommendations primarily involve further analysis and communication. Analysis of survival data should continue to explore methods that are appropriate to the mechanism of action, as standard measures of survival benefit are not appropriate. Manufacturers should also continue to communicate the mechanism of action and its impact on long-term response, survival benefit, and how it changes outcomes data and methods of analysis.

We have attempted to synthesize in table 1 a structured way in which manufacturers should link the mechanism of action of IOs to subsequent expectations of the shape of the long-term survival curve such as the plateau effect. This links logically into the statistical and economic modeling of long-term survival, focusing on model structure and survival curve extrapolation methodology, but also accounting for the limited clinical trial data at HTA submission.

From the perspective of HTA agencies, there is an apparent need for more explicit consideration of the same issues around mechanism of action and survival analysis, including how it is incorporated into economic modeling. HTA agencies can help effect change in modeling by manufacturers by explicitly recommending modeling approaches that acknowledge and reflect the underlying biology and natural history of disease and treatment effect, rather than attempts at statistical curve fitting. HTA agencies can also increase communication with manufacturers prior to submission to align on appropriate methods of analysis.

Payers can also help these processes to evolve with formal reviews of past decisions. Retrospective reviews will help to improve the use of surrogates and the potential for long-term data to be used in the future to update decisions. As well as helping to better understand how past data, methods, and decisions appear today, this would support the use of conditional approvals and reimbursement based on surrogate end points with confirmatory real-world or long-term follow-up data.

Assessment processes and preferred methodology differ across countries, meaning that there is some limit to how much consistency in assessing IO survival benefit is achievable. However, an European Union-wide cooperation on HTA has been proposed recently by the European Commission, focusing on relative effectiveness assessment (REA) for pharmaceuticals and medical devices.95 In an editorial assessing this proposal, Kanavos et al highlighted that the HTA framework must be more explicit and realistic about clinical value definition, what constitutes quality of evidence, how RWE is handled, and how to ensure consistency in REA interpretation.96 They concluded that this initiative can deliver wider benefits, a key one being member states having more resources to assess performance of interventions in their healthcare systems.

We have presented here the key challenges faced when demonstrating long-term survival benefit from treating patients with IOs: challenges linked to the IO mechanism of action, the analysis and extrapolation of long-term survival data, and using data that may be immature at the time of HTA submission. We outlined ways in which manufacturers can meet or mitigate these challenges, with a focus on strengthening survival analysis methods to capture the underlying biology of disease and treatment, rather than just statistical curve fit, including the potential use of biomarkers, surrogate end points, and RWE in modeling.

It is crucial that patients have timely access to novel therapies and particularly breakthrough therapies such as IOs. Therefore, we outlined the steps that manufacturers are recommended to take to develop and submit evidence to HTA bodies in a structured and consistent way, and to drive wider education across all stakeholders—manufacturers, payers, and clinicians—in considering long-term survival benefits with IOs.