Application of the ESMO Magnitude of Clinical Benefit Scale to assess the clinical benefit of antibody drug conjugates in solid cancer: a systematic descriptive analysis of phase III and pivotal phase II trials

Introduction

Cancer is one of the leading causes of the death worldwide and ranks second in mortality below heart disease in the USA.1 2 Considering the off-target toxicities of chemotherapeutic drugs, novel anticancer agents which can selectively target cancer cells and attenuate side effects are urgent. Antibody drug conjugates (ADCs) are the emerging next generation therapeutics after monoclonal antibodies, attributing to the superior anticancer activity over traditional chemotherapy.3 4 In 2000, the US Food and Drug Administration (FDA) approved the first ADC, gemtuzumab ozogamicin (Mylotarg), for the treatment of patients with acute myeloid leukaemia.5 To date, a total of 15 ADCs have been approved worldwide and more than 100 ADCs are currently being evaluated in clinical trials.6

The paradigm of cancer therapy has shifted from the disease-centred strategy to a patient-centred strategy, emphasising the comprehensive value of the therapeutic regimen, including quality of life (QoL) and cost. However, it is always hard to objectively evaluate therapy value and clinical benefit. Both the American Society of Clinical Oncology Value Framework7 8 and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS)9 10 aimed to evaluate the clinical benefit of novel anticancer treatments. Besides, the ESMO-MCBS seems to be very reliable in advanced or metastatic diseases across all therapeutic settings in daily practice.11

Randomised controlled trials are regarded as the ‘gold standard’ in evaluating medicinal products.12 Considering an unmet medical need, single-arm trials can also support approvals, although uncommon. Here, we overview the landscape of ADCs approved by the FDA, the European Medicines Agency (EMA), the China National Medical Products Administration (NMPA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) for solid cancer, and describe the clinical benefit of these ADCs and further explore whether clinical benefit is related to high-quality cancer care.

Methods

Results

Discussion

To the best of our knowledge, this is the first review to apply ESMO-MCBS V.1.1 exclusively to approved ADCs. In this study, we used the ESMO-MCBS tool to gauge the magnitude of clinical benefit derived from phases II and III trials on ADC therapy for solid tumours. Our cohort of 16 clinical trials encompassed multiple therapeutic options with ADCs from 2000 to 2023.

Despite the preferred trials for the application of marketing approval, randomised controlled trials are not always likely to perform. In recent years, various drugs have been approved based on the single-arm trials. These approvals were instituted to fulfil an unmet medical necessity, with less comprehensive data compared with those for standard approval processes. However, the evidence level that the investigational drugs provide clinical benefits may be insufficient when solely based on single-arm trials. In our study, to evaluate whether the authorised drugs based on single-arm trials provided substantial benefit, we included these pivotal phase II single-arm trials leading to the approval.

The application of ESMO-MCBS forms on the basis of OS and/or PFS was less than those based on ORR (38% vs 56%). In five trials with the primary endpoint of PFS, four (80%) trials were assessed using form 2a instead of form 2b due to the OS advantage. However, a previous study revealed that conclusions based on PFS outcomes in these clinical trials might be overestimated by this scoring system, due to the statistical power to only detect significant differences in PFS, rather than OS.14 ORR is not a direct measure of clinical benefit; however, it is a measure of anticancer activity.36 A study found that 38% and 34% of anticancer drugs were approved by FDA based on ORR and PFS, shortening the development durations by 19 months and 11 months, respectively.37 Nevertheless, among 93 anticancer drugs with accelerated approvals, only 20% demonstrated an improvement in OS in confirmatory trials.38 As previously revealed, the definition of clinical value is different between stakeholders, causing different conclusions.39 For instance, the ESMO considers benefit as ‘living longer and/or living better’, which resonates in the ESMO-MCBS form for single-arm trials.9 10 This is confirmed in our findings that the benefit of the majority of ADCs was ‘modest’ according to ESMO-MCBS Scores. A high ESMO-MCBS Score for single-arm trials was related to favourable efficacy in combination with an improved QoL.40 Yet, delayed publications or publication bias for QoL is overlooked by ESMO-MCBS.41 Therefore, QoL appears of lesser importance in regulatory decision making on single-arm trials.

Despite a minor number of inconsistencies between our final scores and the relevant ESMO scorecards, the final scores varied significantly due to these disparities. The reassessment of the ESMO-MCBS Score is important when results from confirmatory trials are published, which may affect the ESMO-MCBS Score. Furthermore, extended follow-up may also affect the EMSO-MCBS Score. For example, we previously assigned an ESMO-MCBS Score of ‘3’ for sacituzumab govitecan (ASCENT Trial) due to the increased toxicity; however, we finally assigned a score of ‘4’ due to a recent publication on health-related QoL.27 On the contrary, the score was found to decrease as OS data were mature and showed benefit while the value of OS HR was increased in the EMILIA16 17 and TROPiCS Trials.28 29 ESMO-MCBS can develop a specialised form for re-evaluation of the updated OS data. Additionally, adjustments sometimes might be confusing. For example, we assigned an ESMO-MCBS Score of ‘3’ for trastuzumab deruxtecan (DESTINY-Breast03 Trial) based on form 2a due to the improved OS; however, the ESMO-MCBS scorecard showed ‘4’ due to the long-term plateau in the PFS curve based on form 2b. Although grades ≥3 adverse events may be different between the treatment arms, it was not always statistically significant in publications. Besides, adverse events that can affect the daily well-being of patients may not be consistently published. Clearer definitions or quantifications of toxicity profiles in future ESMO-MCBS versions are highly desirable. Furthermore, several trials had no published scorecard, because they are approved by jurisdictions other than the EMA and FDA. We suggest that ESMO-MCBS scorecards can also publish the drugs that are approved by other agencies other than FDA and EMA.

Almost half of positive clinical trials are unable to demonstrate a substantial clinical benefit based on the ESMO framework, and this has drawn criticism in light of market approvals for anticancer drugs in recent periods.42–44 In our study, only 4/16 (25%) of the clinical trials can meet the ESMO-MCBS threshold for clinical benefit. Notably, all single-arm trials cannot meet the ESMO-MCBS threshold for clinical benefit. Form 3 is used to assess single-arm trials, but it should also be noted that by using this form, only grades from 1 to 4 can be attained. As a result, the threshold can only be met if the study demonstrates HRQoL improvements, or additionally, if confirmatory phase IV trials are accessible.

Furthermore, in a head-to-head trial (DESTINY-Breast03) to compare the efficacy and safety of trastuzumab deruxtecan with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, trastuzumab deruxtecan showed a superior OS over trastuzumab emtansine.21 22 Thus, we are also confused that whether the OS gain in the ESMO-MCBS tool can evaluate the benefits of different drugs in the same indication or the same drug in different indications. The thresholds for the OS gain appear a bit lenient.

This study has several implications. First, this study showed clinical benefits for limited ADCs in solid tumours, suggesting that subsequent clinical trials on the treatment of solid tumours with ADCs should follow the cases with meaningful clinical benefit. Second, value frameworks can help not only identify drugs with low or uncertain clinical benefit that should be targeted for price negotiations, but also therapies with evidence of higher clinical benefit to improve access to benefit drugs, thereby contributing to patient-centred cancer treatment goals. Finally, the ADCs with HRQoL improvement showed clinical benefit, suggesting that HRQoL should be paid sufficient attention in clinical trials and clinical treatment strategies.

There are several limitations in our study. First, we limited our analysis to solid tumours and excluded drugs approved to treat haematological malignancies. When this study was completed in June 2023, the haematology-specific version has yet to be published. We will further access the clinical benefits of ADCs for haematological malignancies according to the currently published ESMO-MCBS:H V.1.0.45 Another main limitation is publication selection bias. However, we implemented a rigorous search strategy to mitigate it. Publications were selected by two investigators independently based on predefined inclusion and exclusion criteria. We specifically excluded phase I and non-pivotal phase II trials to evaluate novel therapies with sufficient efficacy and toxicity data, thereby primarily including authorised regimens applied in routine clinical practice. Furthermore, the limited toxicity data accessible within published clinical trials hindered our ability to accurately adjust preliminary grades. Additionally, our study was also limited by the lack of drug costs, which may help clinicians to select the optimal therapeutic drugs developed for the same clinical entity.23

In conclusion, this is the first study that used the ESMO-MCBS tool to assess the clinical benefit of ADCs across several solid cancers. ESMO-MCBS are important tools for assessing the clinical benefit of cancer drugs, but not all drugs met the meaningful benefit threshold. Those therapeutic regimens with improved HRQoL showed clinical value, suggesting that clinical trials and clinical treatment strategies should pay more attention to HRQoL. Furthermore, a more exhaustive rule for toxicity penalties due to adverse event is required, as well as the approach to an adjusted scoring for the trials with HRQoL data.