Comparative and combined effectiveness of innovative therapies in cancer: a literature review

In the past decade, emerging knowledge on the complexity and behavior of cancer cells has resulted in large investments in clinical research, fostering a new era of novel and expensive medicines, which include targeted and immune therapies [1,2]. These medicines shift the ‘one-size-fits-all’ approach of conventional cytostatics to a targeted cancer- and immune-cell approach, which therefore classifies them as innovative medicines [3]. Today, many novel medicines are entering clinical trials, quickly increasing the number of available, but often unaffordable, treatment options in oncology [1,2]. With this evolution, the relative efficacy of these products has become an important issue for healthcare decision-making.

However, while developing innovative therapies is difficult, achieving therapeutic innovation, that is, providing favorable and clinically significant benefits, preferably in an area of unmet need, is even more complicated [3]. Accordingly, the need to concomitantly combine various drugs with complementary mechanisms of action has become apparent, which aggravates the affordability problem [4,5]. For example, significant benefits for HER2-overexpressing metastatic breast cancer patients have been demonstrated using concomitant pertuzumab and trastuzumab, two recombinant humanized monoclonal antibodies, as compared with using trastuzumab alone. The combination represented a substantial improvement of 6.3 and 16.3 months in progression-free survival (PFS) and overall survival (OS), respectively [6], however, it comes with a cost of $713,219 per quality-adjusted life-years gained, and is under no circumstance likely to be cost-effective [7].

Consequently, comparisons are also highly necessary for concomitant treatments, because nonadditive differences in the costs and benefits mean that separate regulatory decisions are needed [8]. This is important for both noncompeting and (in)directly competing products, the latter being defined as those medicines that target the same therapeutic indication and patient (sub)population with similar or dissimilar active substances from different manufacturers.

Unfortunately, the comparative and/or combined effects of these novel treatments are often unassessed, creating considerable concerns regarding the exorbitant and unbalanced nature of novel cancer therapy prices [9,10]. This causes regulatory agencies to demand for additional randomized controlled trials (RCTs). However, in turn, clinical trials performing head-to-head comparisons and/or assessing plausible concomitant treatments are highly time-consuming and expensive [11], with the resulting treatment pathways driving the cost of cancer care ever higher [12]. This is especially true for novel cancer therapies and even more so for forthcoming gene therapies. Presumably, such hurdles withhold manufacturers from conducting multiproduct assessments of novel products in the competitive pharmaceutical environment, especially if they have already obtained market access [11,12].

The objective of this review is to examine those clinical studies that have investigated the efficacy and effectiveness of (competing) innovative therapies in comparison and/or in combination with each other to gain better understanding of the phenomenon. Innovative therapies are defined here as products that enable a personalized treatment approach, such as targeted and immune therapies. First, the methodology used to perform the literature review is described. Subsequently, its results are described for both pre- and postmarket investigations and analyzed in terms of the included products’ marketing authorization holders. Following this, the implications of these studies are discussed, together with the importance of real-world investigations for facilitating such assessments.

In total, 1404 articles were found through the search strategy. After duplicate removal and application of the inclusion and exclusion criteria, 48 relevant articles reporting comparative and combined effectiveness studies of innovative cancer treatments were retained (Figure 1). Of these, 35 and 13 were pre- and post-marketing studies, respectively. A detailed overview of these studies, including summarized information on study designs and conclusions, is presented in the Appendix. After grouping those assessing the same compared and/or combined treatments per indication and combining studies per product assessed, 34 unique comparisons and combinations were found (28 premarket and seven postmarket; Table 1). Below is given a description of these studies for four cancer indications: breast, colorectal, non-small-cell lung and melanoma. In addition, a nonexhaustive overview of 57 ongoing studies is presented in the Appendix.

In total, 48 studies were found that assessed comparative and/or combined effects of targeted or immune therapies in breast cancer, colorectal cancer, NSCLC and melanoma. To evaluate efficacy and/or effectiveness, such comparative studies should conduct head-to-head comparisons of the novel product with equivalent products, which may be the current standard treatment [66]. Likewise, combination studies should compare the concomitant treatment with the single treatment with one of these products [66]. These combinations should be based on specific rationales supported by research data and should not be restricted by competition, that is, by enabling comparative studies across drug manufacturers. Ultimately, when their outcomes show further therapeutic benefits, for example when the resultant OS, PFS, QoL and cost–effectiveness data are favorable, such investigations may greatly assist regulatory and reimbursement processes [67].

The first published comparative analysis (2012) assessed the differences between trastuzumab-emtansine and lapatinib through a Phase III trial in breast cancer patients [16]. Since then, 12 more comparative RCT studies have followed. Presumably, these were imitated when additional evidence was required for marketing or subsequent reimbursement approval. As a consequence, these studies were found to be industry funded, that is, by the manufacturer applying for marketing authorization. Thus, as the responsibility for conducting such multiproduct assessments lies in the hands of the manufacturer, high RCT costs and intense market competition can prevent such comparative research, despite the promising insights and benefits it can provide for healthcare decision-making. This is especially true for marketed and reimbursed medicinal products.

Likewise, the first Phase III study evaluating the combined effect of innovative products was published in 2009 (the bevacizumab plus panitumumab Phase III RCT for colorectal cancer) [36]. Since then, 21 more combinatory RCTs have been carried out on the specified cancer indications and many more, including concomitant treatments consisting of more than three novel products, could be investigated. Again, most of these studies were industry funded. However, the majority of the combination RCTs (16 out of 22) involved medicinal products from the same manufacturer. Hence, such assessments are predominantly performed for in-house medicines as they can broaden their targeted patient populations in existing indications and/or provide new opportunities to new cancer indications (also referred to as drug repurposing) by use ‘in combination with’ as opposed to ‘as an alternative to’. Consequently, this finding may imply that the most promising concomitant treatments are not always being tested. Among other reasons, this is caused by the intense market competition for innovative therapies in oncology.

Last, only 13 postmarketing studies were found, of which six specifically investigated the trastuzumab plus pertuzumab combination. Hence, we can acknowledge that much more work could be done on comparative and combined treatment effectiveness. Since it is difficult to test all comparisons of novel (competitive) products during RCTs, we believe that multiproduct assessments in real-life clinical practice are absolutely necessary. This is especially so as real-world data (RWD), when registered, are often the only existing source of evidence on long-term cost–effectiveness [68], essential for innovative therapies and required by regulatory agencies [69]. Additionally, regulatory approval of new indications and new concomitant therapies for marketed products can be supported by RWD in situations in which the (combined) treatments’ efficacy has already been demonstrated by off-label usage [70]. The need for real-world assessments is reinforced by the emergence of outcome-based managed entry agreements, which provide patients with early access to the most effective but highly expensive (concomitant) treatments by balancing affordability to therapeutic value [69]. Accordingly, we believe that such RWD-based projects could greatly facilitate multiproduct effectiveness and cost–effectiveness assessments of (early) marketed targeted and immune therapies, within and across different manufactures, and should therefore be encouraged.

Furthermore, there is an urgent need to collect evidence on the best treatment strategies in translational research and to invest in the development of models that can help in predicting therapy response. Such translational data could allow investment in the most meaningful studies and pave the way for sequential therapies by early treatment intervention, thereby optimizing patient care and reducing exorbitant treatment costs. Therefore, the collection of samples during pre- and post-market studies for translational research by an independent research institution should be encouraged in order to obtain maximum information from clinical trials. Hence, performing such RWD-based studies could initiate new RCTs if necessary and ultimately guide clinical treatment guidelines to optimize individual patient treatment pathways.

However, our study does not come without limitations. Specifically, this review focused on published studies only (a nonexhaustive overview of ongoing Phase III/IV studies is included in the appendix). In light of the increasing availability and emerging pipeline of targeted and immune therapies in oncology, a future update of this literature review would be well advised. On top of that, this review focused on direct comparison studies only. Indirect comparisons or meta-analyses may also have potential value to inform healthcare decision-making, although currently they are not routinely accepted by regulatory agencies except when they demonstrate noninferiority [71].

While comparative studies on (concomitant) innovative cancer therapies have been studied far too little across different manufacturers, they are extremely important for healthcare decision-makers to manage therapeutic innovation at an acceptable cost [8,67]. In this scenario, RWD are starting to be recognized as a powerful repository of evidence, because regulatory agencies might utilize evidence derived from real-world outcomes to support regulatory decisions [69,70], and because practitioners might employ such evidence on therapeutic cost–effectiveness in single and concomitant therapies to optimize treatment pathways. Furthermore, such assessments could be a way to gather translational data for use in predicting therapy response, that is, to identify mechanisms of (non)response and new therapeutic targets of action. This can initiate new small proof of concept studies, which could fasten innovative treatment development, and guide therapeutic treatment practices.

Unfortunately, the absence of an appropriate regulatory framework enforcing postmarketing comparative studies and concomitant therapy pilot projects, together with related high costs and intensive market competition, currently prevents cross-border multiproduct assessment studies. Therefore, we encourage the initiation and conduct of real-world studies by trusted third parties. To enable this, oncologists should have access to appropriate data through disease registries and should have incentives to conduct translational research using RWD.

With the growing importance of real-world evidence and translational research on medicinal products [66–70] together with the development of good procedural practices for observational and/or comparative studies by the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and International Society for Pharmacoepidemiology (ISPE) special taskforce [68], we expect that future comparative assessments will include more real-world research and will follow these procedural practice guidelines to increase study credibility. Moreover, we expect more involvement of independent research institutions during these future RWD studies.

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/full/10.2217/cer-2018-0131

This literature review benefitted from the review of L Brochez, dermato-oncologist in the Department of Dermatology, Ghent University Hospital, Belgium and steering member of the Immuno-Oncology Network Ghent (ION) and the Cancer Research Institute Ghent (CRIG).

Financial support for this study was provided entirely by a grant from the Vlerick Business School. The funding agreement ensured the authors’ independence in designing the study, interpreting its results and publishing the report. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.