Although a number of aspects concerning TIL therapy are uncertain, our results show that TIL therapy remains a promising addition to the treatment landscape of advanced melanoma as most of the “likely” scenarios resulted in TIL therapy being cost-effective. One should, however, keep in mind that these results were based on the safety and efficacy results that are currently available (phase I/II trials) [4,5,6,7]. The ongoing RCT conducted at NKI and Herlev Hospital (NCT02278887) is expected to bring the evidence needed to decide on its therapeutic position and adopt TIL therapy as a standard treatment option in advanced melanoma.
Implications for clinical practice
The results of the cost-effectiveness analysis showed in most of the preferred scenarios a high probability for TIL therapy to become cost-effective (55–99%) and they identify aspects that could facilitate the wide adoption of TIL therapy. For example, as the scenario “Automatic TIL production” showed the highest probability for TIL therapy to become cost-effective (99%), Research and Development should focus on optimizing the production process to facilitate potential upscaling and adoption of TIL therapy. In contrast, the scenarios showing a reduced chance for TIL therapy to become cost-effective, identify crucial contextual factors that should be considered when deciding to adopt TIL therapy. For example, outsourcing of the production of TILs may at first be expected to overcome known ATMP barriers as (i) inadequate financial support for the required investments, and manufacturing costs; (ii) a lack of regulatory knowledge, and (iii) challenging to upscale the production and (iiii) to comply with Good Manufacturing Practices [9, 23,24,25,26]. However, as a result of commercial pricing levels, assuming that the costs will be at least 3 times as high, this scenario resulted in a 0% probability for TIL therapy to become cost-effective. Following our analysis, assuming a WTP threshold of €80,000, the production costs of TIL may only increase 1.5 times (~€53,000) to be cost-effective compared to ipilimumab. Within this scenario, it should be kept in mind that the estimation of the commercial costs is uncertain. Especially because our assumption was based on the manufacturing costs in an academic setting and literature showed that commercial prices are mostly linked to what society would pay instead of its expected added value or of the actual manufacturing costs [27]. However, although the estimation is uncertain, the conclusion related to commercialization remains the same: Outsourcing could facilitate the implementation of TIL therapy, however, pricing agreements should be made with the commercial party to ensure cost levels that remain within the willingness to pay range of cost-effectiveness. In the US setting, TIL can be expected to be licensed and filed for FDA approval within the coming years, these insights are especially of interest to guide reimbursement decisions by insurance companies. An interesting scenario is the “Combination therapy” which showed a 12% probability of being cost-effective (ICER of €151,520), revealing that in this case either the treatment costs should decrease or the efficacy has to improve considerably. By automatizing the production of TILs, the probability of being cost-effective increased only to 28%. Therefore, when a combination of TIL therapy and for instance a certain checkpoint inhibitor seems promising, agreements on pricing with pharmaceutical companies for the combination therapy are necessary to remain within cost-effectiveness ranges.
The results on the questions related to future developments suggest that the adoption of TIL therapy may be hampered by the attitude of patients and clinicians. First of all, clinicians nowadays seem unconvinced to apply TIL therapy because of its perceived complexity and treatment intensity unless the therapy shows a 1-year survival rate of at least 61.3% (CI:55.2–67.5). Secondly, only a small proportion of the eligible patients seemed to be aware of TIL therapy as a treatment option. As the attitude of stakeholders and especially clinicians, is a known barrier for implementation of ATMPs, a pro-active information strategy in anticipation of this attitude is crucial when deciding to diffuse TIL therapy [24].
Comparison of our findings with current literature in the context of an ATMP
Another barrier that ATMPs face in the translational pathway is the rapidly evolving field of immunotherapy [8, 9]. We therefore compared our results with the most recent developments described in the literature and most of the “likely” scenarios still seem to be in line. For example, several trials investigate a combination of TIL therapy and other targeted therapies: pretreatment with ipilimumab followed by TIL and IL-2 (NCT01701674) [19] or pretreatment with vemurafenib followed by TIL and IL-2 and followed by vemurafenib (NCT01659151) [28]. Besides, several trials investigate or investigated the effectiveness of a lower dose of IL-2 treatment [17, 29] (NCT02354690), and finally, research groups evaluate the optimal process of producing TILs, aiming to improve the efficacy of TIL therapy e.g. by enriching T cell products with neo-antigens [17, 30].
Some developments found in literature, however, were not incorporated. For instance, several studies evaluate different lymphodepleting preparative regimens such as total body irradiation (TBI) in combination with chemotherapy [17, 31]. It is currently unclear whether such a regimen would be applied soon, but this scenario could influence the cost-effectiveness as TBI (requiring autologous PSC support) would significantly increase the costs. Besides, a very likely scenario that is not incorporated in this analysis, is the use of TIL therapy in other tumors such as renal cell cancer, ovarian cancer, and colorectal cancer [32,33,34,35] (NCT01174121). This scenario should be kept in mind as it may facilitate the adoption of TIL by positively influence the clinicians’ attitude as clinical experience and exposure increases, and production costs may decrease. Furthermore, a recent literature review highlighted several potential agents (e.g. TIM3, GITR, OX40) that could be promising in treating advanced melanoma in the future [36]. Those agents are currently subject to the first phase I and II studies to evaluate their safety and efficacy [36]. Therefore, our study might have underestimated the likelihood of the competition scenario. However, available data on the efficacy and possible costs of those alternatives is too preliminary to incorporate these results in the cost-effectiveness analysis. When these agents are proven to be safe, effective, and more effective compared to TIL therapy, those new treatments could hamper the adoption of TIL therapy.
Observations from the scenario method and future directions
A wide range in the expected likelihood of the scenarios was identified (Fig. 2), which challenged the labeling process for likely and unlikely scenarios. This may be explained by several factors. First, when a respondent is not (yet) involved in the TIL therapy process, it is harder to have an opinion on the likelihood of these scenarios as theoretical models describe that some extent of experience is needed to evaluate the future adoption process [37]. Second, faced with uncertainty, respondents could be hesitant in choosing extreme options such as 0 and 100% likelihood. Finally, it is likely that the expected timing of these scenarios, if they are likely, differ across countries and hospitals as the adoption process and attitude towards TIL differs per site. The respondents originated from 12 different countries which could thus explain some of the wide ranges, as in one country a scenario may be likely in the coming 5 years (e.g. commercialization in the US) and in another country not at all.
Furthermore, we are aware that the scenarios labeled as “unlikely” and therefore not incorporated in the cost-effectiveness analysis, could still play a role in the adoption process of TIL therapy (e.g. biomarker development, possible dominance of T-cell receptor (TCR) gene therapy over TIL therapy, influence by companies and competition). These factors should not be neglected and it would be valuable to incorporate these in future decision-making processes.
Additionally, as the chance on the development of other types of cancer by using TIL therapy was thought to be 6.4% (CI:4.5–8.3%; Supplement 6) on average, clinical studies having a longer follow-up time than the current observational studies should evaluate the actual risk. When the risk is shown to be evident, it should be ethically discussed whether TIL treatment may still be preferred over ipilimumab. Finally, based on the currently available clinical evidence, data are lacking for one of the most likely scenarios, “third-line treatment”, to evaluate the relative cost-effectiveness of TIL therapy. When estimating the expected costs of palliative chemotherapy we can estimate the incremental QALYs needed to become cost-effective at a certain willingness to pay threshold. When estimating the costs of on average 3.5 doses of chemotherapy (dacarbazine) [38] at €17.102 based on a three-weekly dosage of 200 mg/m2 for 5 days [20, 39] compared to the costs of TIL therapy, the difference in QALY’s should be at least 0.561. This means that TIL therapy has to show a substantial gain in survival and/or quality of life or a reduction in follow-up costs to become cost-effective in the third line. Such a calculation is informative but to inform decision-makers on the effects of this likely scenario, clinical outcomes after progression on both PD-1 inhibitors and CTL-4 antibodies based on e.g. clinical registries should be obtained. Next, we should compare these to clinical outcomes of TIL therapy in patients that progressed on multiple treatment strategies, such as reported in the study of Sarnaik and colleagues [40].
Strengths and limitations
The main strength of the present study is that we systematically drafted future scenarios (qualitatively) with internal and external experts, using a Constructive Technology Assessment framework [11, 41] and using multiple Delphi rounds. This provides a comprehensive insight into the potential future developments that could influence TIL adoption and provides research and development teams with valuable information to anticipate possible future developments. Since the landscape of immunotherapy for melanoma is continuously developing, the expectations of the experts were compared to the most recent literature reviews and ongoing clinical trials to select the “likely” scenarios and discuss our results. The main limitation is obviously, that the scenarios may not even keep up with actual developments. Other limitations are related to the early nature of this analysis. For example, to simulate the combination therapy, the input for the model was based on a first observational study in which only 13 patients were enrolled that received the combination of TIL therapy and ipilimumab [19]. Additionally, the chosen cut-off value of ≥55% to evaluate scenarios as “likely” could be questioned due to the high uncertainty surrounding the likelihood scores. However, since the expert opinions and recent literature verified that the “likely” scenarios based on the cut-off value were “likely”, a different cut-off value is not expected to have altered our conclusions. Furthermore, the cost-effectiveness analyses were conducted from a Dutch perspective similar to the original model by Retèl et al. 2018. The costs for both TIL therapy and ipilimumab are expected to differ between countries [42] which limits the generalizability of the cost-effectiveness results in different settings. The generalizability may also be limited by the fact that mainly experts from European countries completed the questionnaire. However, by verifying the likelihood results with the most recent literature, the identified crucial contextual factors are expected to hold also in other countries because similar (financial) challenges are expected regarding e.g. outsourcing and providing a combination of therapies.