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A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS)

      ABSTRACT

      The value of any new therapeutic strategy or treatment is determined by the magnitude of its clinical benefit balanced against its cost. Evidence for clinical benefit from new treatment options is derived from clinical research, in particular phase III randomised trials, which generate unbiased data regarding the efficacy, benefit and safety of new therapeutic approaches. To date, there is no standard tool for grading the magnitude of clinical benefit of cancer therapies, which may range from trivial (median progression-free survival advantage of only a few weeks) to substantial (improved long-term survival). Indeed, in the absence of a standardised approach for grading the magnitude of clinical benefit, conclusions and recommendations derived from studies are often hotly disputed and very modest incremental advances have often been presented, discussed and promoted as major advances or ‘breakthroughs’. Recognising the importance of presenting clear and unbiased statements regarding the magnitude of the clinical benefit from new therapeutic approaches derived from high-quality clinical trials, the European Society for Medical Oncology (ESMO) has developed a validated and reproducible tool to assess the magnitude of clinical benefit for cancer medicines, the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). This tool uses a rational, structured and consistent approach to derive a relative ranking of the magnitude of clinically meaningful benefit that can be expected from a new anti-cancer treatment. The ESMO-MCBS is an important first step to the critical public policy issue of value in cancer care, helping to frame the appropriate use of limited public and personal resources to deliver cost-effective and affordable cancer care. The ESMO-MCBS will be a dynamic tool and its criteria will be revised on a regular basis.

      Key words

      introduction

      The value of any new therapeutic strategy or treatment is determined by the magnitude of its clinical benefit balanced against its cost [
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      ]. Value considerations have become increasingly important in an era of rapid expansion of new, expensive cancer medicines and other technologies such as advanced radiotherapy techniques or robotic surgery which provide small incremental benefits [
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      ] within the context of cost-constrained health care systems [
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      Whereas costs of procurement and out of pocket expenditures vary from country to country, the magnitude of clinical benefit, as derived from well-designed clinical trials, is a relative constant. Consequently, meaningful discussion of value and relative value are predicated on an understanding of the magnitude of clinical benefit [
      • Porter M.E.
      What is value in health care?.
      ]. Clinical benefit in this context refers to the added benefit compared with a control which, in most cases, is the best current standard care.
      Evidence for clinical benefit from new treatment approaches is derived from comparative outcome studies, most commonly phase III randomised clinical trials, which generate ostensibly unbiased data regarding the efficacy, benefit and safety of new therapeutic approaches. The potential benefits of a new treatment can be summarised as either living longer and/or living better, evaluated in clinical studies through the treatment effect on overall survival (OS) and/or quality of life (QoL), and their surrogates (Table 1). In studies of interventions with curative intent in which mature survival data are not yet available disease-free survival (DFS), recurrence-free survival (RFS), event-free survival (EFS), distant disease-free survival and time to recurrence (TTR), are used as surrogate measures. The validity of this approach, though not uncontroversial [
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      • Tannock I.F.
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      ], is relatively well supported by data derived from a wide range of solid tumour settings including in colon [
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      • Haller D.G.
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      Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials.
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      Disease-free survival as a surrogate for overall survival in adjuvant trials of gastric cancer: a meta-analysis.
      ], lung [
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      End points for adjuvant therapy trials: has the time come to accept disease-free survival as a surrogate end point for overall survival?.
      ] cancers. In studies evaluating therapies in non-curative settings, progression-free survival (PFS), and time to progression (TTP) provide information about biological activity and may indicate benefit for some patients [
      • Saad E.D.
      • Katz A.
      • Hoff P.M.
      • Buyse M.
      Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature.
      ,
      • Shi Q.
      • Sargent D.J.
      Meta-analysis for the evaluation of surrogate endpoints in cancer clinical trials.
      ]; however, they are not reliable surrogates for improved survival [
      • Saad E.D.
      • Katz A.
      • Hoff P.M.
      • Buyse M.
      Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature.
      ,
      • Booth C.M.
      • Eisenhauer E.A.
      Progression-free survival: meaningful or simply measurable?.
      ,
      • Saad E.D.
      • Katz A.
      • Buyse M.
      Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical trials.
      ,
      • Wilkerson J.
      • Fojo T.
      Progression-free survival is simply a measure of a drug's effect while administered and is not a surrogate for overall survival.
      ,
      • Amir E.
      • Seruga B.
      • Kwong R.
      • et al.
      Poor correlation between progression-free and overall survival in modern clinical trials: are composite endpoints the answer?.
      ] or QoL [
      • Amir E.
      • Seruga B.
      • Kwong R.
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      Poor correlation between progression-free and overall survival in modern clinical trials: are composite endpoints the answer?.
      ,
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      Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer.
      ].
      Table 1Potential benefits of a new treatment
      Living longer
       Improved OS
       Improved surrogate of OS
        DFS (when OS data are immature in adjuvant setting)
        Improved PFS
      Living better
       Improved quality of life
       Improved surrogate of quality of life
        Improved PFS
       Reduced toxicity
      To date, there is no standard tool for grading the magnitude of clinical benefit of cancer therapies [
      • Ocana A.
      • Tannock I.F.
      When are ‘positive’ clinical trials in oncology truly positive?.
      ,
      • Vera-Badillo F.E.
      • Al-Mubarak M.
      • Templeton A.J.
      • Amir E.
      Benefit and harms of new anti-cancer drugs.
      ], which may range from trivial (median PFS advantage of only a few weeks) to substantial (improved long-term survival). Indeed, in the absence of a standardised approach for grading, the magnitude of clinical benefit, conclusions and recommendations derived from studies are often hotly disputed [
      • Ocana A.
      • Tannock I.F.
      When are ‘positive’ clinical trials in oncology truly positive?.
      ] and very modest incremental advances have often been presented, discussed and promoted as major advances or ‘breakthroughs’ [
      • Davis C.
      Drugs, cancer and end-of-life care: a case study of pharmaceuticalization?.
      ,
      • Ocana A.
      • Tannock I.F.
      When are ‘positive’ clinical trials in oncology truly positive?.
      ,
      • Vera-Badillo F.E.
      • Al-Mubarak M.
      • Templeton A.J.
      • Amir E.
      Benefit and harms of new anti-cancer drugs.
      ,
      • Saltz L.B.
      Progress in cancer care: the hope, the hype, and the gap between reality and perception.
      ,
      • Smith T.J.
      • Hillner B.E.
      Concrete options and ideas for increasing value in oncology care: the view from one trench.
      ,
      • Fojo T.
      • Grady C.
      How much is life worth: cetuximab, non–small cell lung cancer, and the $440 billion question.
      ]. Overestimating or overstating the benefits from new intervention can cause harm: it confounds public policy decision making [
      • Fojo T.
      • Grady C.
      How much is life worth: cetuximab, non–small cell lung cancer, and the $440 billion question.
      ], undermines the credibility of oncology research reporting [
      • Vera-Badillo F.E.
      • Al-Mubarak M.
      • Templeton A.J.
      • Amir E.
      Benefit and harms of new anti-cancer drugs.
      ,
      • Fojo T.
      • Grady C.
      How much is life worth: cetuximab, non–small cell lung cancer, and the $440 billion question.
      ,
      • Vera-Badillo F.
      • Shapiro R.
      • Ocana A.
      • et al.
      Bias in reporting of end points of efficacy and toxicity in randomized, clinical trials for women with breast cancer.
      ], harms patients who choose to undertake treatments based on exaggerated expectations that may subject them to either risk of adverse effects, inconvenience or substantial personal costs [
      • Vera-Badillo F.E.
      • Al-Mubarak M.
      • Templeton A.J.
      • Amir E.
      Benefit and harms of new anti-cancer drugs.
      ,
      • Smith T.J.
      • Hillner B.E.
      Concrete options and ideas for increasing value in oncology care: the view from one trench.
      ] and, in the public domain, they fuel sometimes inappropriate hype or disproportionate expectations about novel treatments [
      • Lewison G.
      • Tootell S.
      • Roe P.
      • Sullivan R.
      How do the media report cancer research? A study of the UK's BBC website.
      ,
      • Ooi E.S.
      • Chapman S.
      An analysis of newspaper reports of cancer breakthroughs: hope or hype?.
      ] and the need to allocate public or personal funds to provide them.
      It is important for the Oncology Community to present clear and unbiased statements regarding the magnitude of clinical benefit from new therapeutic approaches supported by credible research. ESMO aims to emphasize those treatments which bring substantial improvements to the duration of survival and/or the QoL of cancer patients which need to be distinguished from those whose benefits are more modest, limited or even marginal. To this end, ESMO has undertaken the development of a validated and reproducible tool to assess the magnitude of clinical benefit of anti-cancer interventions, the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). ESMO intends to apply this scale prospectively to each new anti-cancer drug/intervention that will be European Medicines Agency (EMA) approved. Drugs or treatment interventions that obtain the highest scores on the scale will be emphasized in the ESMO guidelines, with the hope that they will be rapidly endorsed by health authorities across the European Union.

      background and methodology

      An ESMO Task Force to guide the development of the grading scale was established in March 2013. The members of the Task Force co-chaired by Elisabeth de Vries and Martine Piccart are Richard Sullivan, Nathan Cherny, Urania Dafni, Martijn Kerst, Alberto Sobrero and Christoph Zielinski. A first-generation draft scale was developed and adapted through a ‘snowball’ method based upon previous work of Task Force members who had independently developed preliminary models of clinical benefit grading. The first-generation scale was sent for review by 276 members of the ESMO faculty and a team of 51 expert biostatisticians.
      The second-generation draft was formulated based on the feedback from faculty and biostatisticians and the conceptual work of Alberto Sobrero regarding the integration of both hazard ratio (HR), prognosis and absolute differences in data interpretation [
      • Sobrero A.
      • Bruzzi P.
      Incremental advance or seismic shift? The need to raise the bar of efficacy for drug approval.
      ,
      • Sobrero A.F.
      • Pastorino A.
      • Sargent D.J.
      • Bruzzi P.
      Raising the bar for antineoplastic agents: how to choose threshold values for superiority trials in advanced solid tumors.
      ]. The second-generation draft was applied in a wide range of contemporary and historical disease settings by members of the ESMO-MCBS Task Force, the ESMO Guidelines Committee and a range of invited experts. Results were scrutinised for face validity, coherence and consistency. Where deficiencies were observed or reported, targeted modifications were implemented and the process of field testing and review was repeated. This process was repeated through 13 redrafts of the scale preceding the current one (ESMO-MCBS v1.0). The final version and fielded testing results were reviewed by selected members of the ESMO faculty and the ESMO Executive Board.
      The goal of the ESMO-MCBS evaluation was to assign the highest grade to trials having adequate power for a relevant magnitude of benefit, and to make appropriate grade adjustment to reflect the observed magnitude of benefit. To achieve this goal, a dual rule was implemented; first, taking into account the variability of the estimated HR from a study, the lower limit of the 95% confidence interval (CI) for the HR is compared with specified threshold values; and secondly the observed absolute difference in treatment outcomes is compared with the minimum absolute gain considered as beneficial. Different candidate threshold values for HR and absolute gains for survival, DFS and PFS, adjusted to represent as accurately as possible the expert opinion of the oncology community, have been explored through extensive simulations. The finally implemented combined thresholds for the HR and the minimum observed benefit that could be considered as deserving the highest grade in both the curative and non-curative setting are outlined in Table 2.
      Table 2Maximal preliminary scores
      Treatments with curative intent (form 1)
      >5% improvement of survival at ≥3-year follow-up
       Improvements in DFS alone HR <0.60 (primary end point) in studies without mature survival data
      Treatments with non-curative intent (form 2)
      Primary outcome OS (form 2a)
       Control ≤12 months
         HR ≤0.65 AND gain ≥3 months OR
         Increase in 2-year survival alone ≥10%
       Control >12 months
         HR ≤0.70 AND gain ≥5 months OR
         Increase in 3-year survival alone ≥10%
      Primary outcome PFS (form 2b)
       Control ≤6 months
         HR ≤0.65 AND gain ≥1.5 months
       Control >6 months
         HR ≤0.65 AND gain ≥3 months
      In all forms, HR thresholds refer to the lower extreme of the 95% CI (Figure 1). The performance of the evaluation rule based on the lower limit of the 95% CI of HR, was compared with the simpler rule of using a cut-off for the point estimate of HR, in conjunction with the additional rule on the minimum absolute gain in treatment outcome. The simulation results under different HR values and corresponding power, favoured the proposed approach to use the lower limit of the 95% CI which takes into account the variability of the estimate. The correspondence between an HR value and the minimum absolute gain considered as beneficial according to the ESMO-MCBS, is presented by median survival (OS or PFS) for standard treatment, in Figure 2. For example, for a standard treatment median survival of 6 months, an absolute gain of 3 months corresponds to an HR = 0.67, while a gain of 1.5 months corresponds to an HR = 0.8.
      Figure 1
      Figure 1Use of threshold HR in the ESMO-MCBS exemplified for HR threshold of 0.65.
      Figure 2
      Figure 2The correspondence between an HR value and the minimum absolute gain in months considered as beneficial according to the ESMO-MCBS by median survival (OS or PFS) for control.

       the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS v1.0)

      The ESMO Magnitude of Clinical Benefit Scale version 1 (ESMO-MCBS v1.0) (Appendix 1) has been developed only for solid cancers. Given the profound differences between the curative and palliative settings, the tool is presented in two parts. Form 1 is used to evaluate adjuvant and other treatments with curative intent. Form 2 (a, b or c) is used to evaluate non-curative interventions, with form 2a for studies with OS as the primary outcome, form 2b for studies with PFS or TTP as primary outcomes, 2c for studies with QoL, toxicity or response rate (RR) as primary outcomes and for non-inferiority studies. Form 2a is prognostically sub-stratified for studies where the control arm produced OS greater or less than or equal to 1 year and form 2b for studies where the control arm produced PFS greater or less than or equal to 6 months.

       eligibility for application of the ESMO-MCBS

      The ESMO-MCBS can be applied to comparative outcome studies evaluating the relative benefit of treatments using outcomes of survival, QoL, surrogate outcomes for survival or QoL (DFI, EFS, TTR, PFS and TTP) or treatment toxicity in solid cancers. Eligible studies can have either a randomised or comparative cohort design [
      • Concato J.
      • Shah N.
      • Horwitz R.I.
      Randomized, controlled trials, observational studies, and the hierarchy of research designs.
      ,
      • Berger M.L.
      • Dreyer N.
      • Anderson F.
      • et al.
      Prospective observational studies to assess comparative effectiveness: the ISPOR good research practices task force report.
      ] or a meta-analysis which report statistically significant benefit from any one, or more of the evaluated outcomes. When more than one study has evaluated a single clinical question, results derived from well-powered registration trials should be given priority.
      Studies with pre-planned subgroup analyses with a maximum of three subgroups can be scored. When statistically significant results are reported for more than one subgroup, then each of these should be evaluated separately. Subgroups not showing statistically significant results are not graded. Except for studies that incorporate collection of tissue samples to enable re-stratification based on new genetic or other biomarkers, findings from un-planned (post hoc) subgroup analysis cannot be graded and they can only be used as foundation for hypothesis generation.

       form 1

      This form is used for adjuvant and neoadjuvant therapies and for localised or metastatic diseases being treated with curative intent. This scale is graded A, B or C. Grades A and B represent a high level of clinical benefit (Figure 3). The scale makes allowance for early data demonstrating high DFS without mature survival data. Studies initially evaluated based on DFS criteria alone will need to be revaluated when mature survival data is available. Hyper-mature data from studies that were un-blinded after compelling early results with subsequent access to the superior arm are contaminated, subsequently late intention-to-treat (ITT) follow-up data are not evaluable [
      • Joensuu H.
      HERA crosses over.
      ,
      • Gianni L.
      • Dafni U.
      • Gelber R.D.
      • et al.
      Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial.
      ]. Pathological complete remission from neoadjuvant therapies is not included as a criteria for clinical benefit because of lack of consistent evidence that it is a valid surrogate for survival in clinical studies [
      • Bianchini G.
      • Gianni L.
      Surrogate markers for targeted therapy-based treatment activity and efficacy.
      ,
      • Burki T.K.
      Pathological complete response is no surrogate for survival.
      ,
      • Glynne-Jones R.
      • Mawdsley S.
      • Pearce T.
      • Buyse M.
      Alternative clinical end points in rectal cancer—are we getting closer?.
      ,
      • Cortazar P.
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      Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
      ].
      Figure 3
      Figure 3Visualisation of ESMO-MCB scores for curative and non-curative setting. A & B and 5 and 4 represent the grades with substantial improvement.

       forms 2

      These forms are used for studies of new agents or approaches in the management of cancers without curative intent. This scale is graded 5, 4, 3, 2, 1, where grades 5 and 4 represent a high level of proven clinical benefit (Figure 3).

       form 2a

      This version is used for therapies evaluated using a primary outcome of OS. The form is stratified by median OS of the control arm ≤12 and >12 months. Preliminary grading takes into consideration HR and median survival gain as well as late survival advantage and is reported on a 4-point scale. When there is differential grading between the median and late survival gain, the higher score prevails. Preliminary scores can be upgraded by 1 point when the experimental arm demonstrates improved QoL or delayed deterioration in QoL using a validated scale or substantial reduction in grade 3 or 4 toxicity. A score of 5 can only be achieved when optimal survival outcomes are further enhanced by data indicating reduced toxicity or improved QoL.

       form 2b

      This version is used for therapies evaluated using a primary end point of PFS or TTP. The form is stratified by median duration of PFS of the control arm ≤6 and >6 months. The maximal preliminary score is discounted to 3 because PFS and TTP are surrogate outcomes with a less reliable relationship to improved survival or QoL [
      • Saad E.D.
      • Katz A.
      • Hoff P.M.
      • Buyse M.
      Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature.
      ,
      • Booth C.M.
      • Eisenhauer E.A.
      Progression-free survival: meaningful or simply measurable?.
      ,
      • Saad E.D.
      • Katz A.
      • Buyse M.
      Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical trials.
      ,
      • Wilkerson J.
      • Fojo T.
      Progression-free survival is simply a measure of a drug's effect while administered and is not a surrogate for overall survival.
      ,
      • Amir E.
      • Seruga B.
      • Kwong R.
      • et al.
      Poor correlation between progression-free and overall survival in modern clinical trials: are composite endpoints the answer?.
      ]. In studies that allow crossover on subsequent therapy, this may be the best available evidence of activity since subsequent therapies may reduce the likelihood of observing survival benefit.
      Preliminary scores derived from PFS studies can be upgraded or downgraded depending on secondary outcomes such as toxicity data, improvement in OS or data derived from QoL evaluation. This form incorporates an adverse effect criterion for down-grading in cases of severe toxicity compared with the control arm. If an OS advantage is observed as a secondary outcome, scores are upgraded using the scale on form 2a. In PFS studies that evaluate global QoL, positive findings (as evidenced by statistically significant improvement in global QoL or delayed deterioration in QoL) will upgrade the evaluation by 1 point and, in the absence of survival advantage, the absence of QoL advantage will result in a down-grading by 1 point.

       form 2c

      This form is used for therapies evaluated in non-inferiority (equivalence) studies and for studies in which the primary outcomes are QoL, toxicity or RR.

       field testing of ESMO-MCBS

      ESMO-MCBS has been applied in a wide range of solid tumours by members of the ESMO-MCBS Task Force, the ESMO Guidelines Committee and a range of invited experts (Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, Table 12).
      Table 3Field testing ESMO-MCBS v1.0: lung cancer
      Lung cancer

      Medication (new versus control)Trial nameSettingPrimary outcomePFS controlPFS gainPFS HROS controlOS gainOS HRQoLToxicityESM0-MCBSRef.
      Erlotinib versus carboplatin gemcitabineOPTIMAL,

      CTONG-0802
      First-line stage IIIb or IV non-squamous, with EGFR mutationPFS4.6 months8.5 months0.16 (0.10–0.26) 12% less serious

       adverse events
      4[
      • Zhou C.
      • Wu Y.-L.
      • Chen G.
      • et al.
      Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study.
      ]
      Erlotinib versus

      platinum-based

      chemotherapy doublet
      EURTACFirst-line stage IIIb or IV non-squamous, with EGFR mutationPFS (crossover allowed)5.2 months4.5 months0.37 (0.25-0.54)19.5 monthsNS 15% less severe

       adverse

       reactions
      4[
      • Rosell R.
      • Carcereny E.
      • Gervais R.
      • et al.
      Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
      ]
      Gefitinib versus carboplatin + paclitaxelIPASSFirst-line stage IIIb or IV adenocarcinoma, with EGFR

       mutation
      PFS (crossover allowed)6.3 months3.3 months0.48 (0.34–0.67)Improved Reduced toxicity4[
      • Fukuoka M.
      • Wu Y.-L.
      • Thongprasert S.
      • et al.
      Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS).
      ,
      • Mok T.S.
      • Wu Y.-L.
      • Thongprasert S.
      • et al.
      Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma.
      ]
      Afatinib versus Cisplatin + pemetrexedLUX—Lung 3First-line stage IIIb or IV adenocarcinoma with EGFR mutation (Del19/L858R)PFS (crossover allowed)6.9 months







      6.9 months
      4.2 months







      6.7 months
      0.58 (0.43–0.78)







      0.47 (0.34–0.65)
      Improved







      Improved
      4[
      • Sequist L.V.
      • Yang J.C.-H.
      • Yamamoto N.
      • et al.
      Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
      ,
      • Yang J.C.-H.
      • Hirsh V.
      • Schuler M.
      • et al.
      Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations.
      ]
      Crizotinib versus chemotherapyFirst-line stage IIIb or IV non-squamous, with ALK mutationPFS (crossover allowed)3.0 months4.7 months0.49 (0.37–0.64)Improved 1% increased

       toxic death
      4[
      • Shaw A.T.
      • Kim D.-W.
      • Nakagawa K.
      • et al.
      Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
      ]
      Crizotinib versus cisplatin + pemetrexedFirst-line stage IIIb or IV non-squamous, with ALK mutationPFS7.0 months3.9 months0.45 (0.35–0.60)Improved4[
      • Solomon B.J.
      • Mok T.
      • Kim D.W.
      • et al.
      First-line crizotinib versus chemotherapy in ALK-positive lung cancer.
      ]
      Pemetrexed versus placeboStage IIIb or IV disease maintenance after responding to four cycles platinum doubletPFS stratified

      for histology

      (non-squamous)
      2.6 months1.9 months0.47 (0.37–0.60)10.3 months5.2 months0.70 (0.56–0.88)4[
      • Ciuleanu T.
      • Brodowicz T.
      • Zielinski C.
      • et al.
      Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.
      ]
      Cisplatin pemetrexed versus cisplatin gemcitabineFirst-line stage IIIb or IV (non-squamous)OS (non-inferiority)10.4 months1.4 months0.81 (0.70–0.94)Less grade 3 +

      toxicity

      neutropenia

      anaemia

      thrombocytopenia
      4[
      • Scagliotti G.V.
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      • von Pawel J.
      • et al.
      Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non–small-cell lung cancer.
      ]
      Chemotherapy ±

       palliative care
      Stage IV

       non-small-cell

       ECOG <2
      QoL8.9 months2.7 monthsHR for death in

      control

      arm 1.7 (1.14–2.54)
      Improved4[
      • Temel J.S.
      • Greer J.A.
      • Muzikansky A.
      • et al.
      Early palliative care for patients with metastatic non-small-cell lung cancer.
      ]
      Paclitaxel/carboplatin ± bevacizumabFirst-line stage IIIb or IV, non-squamousOS10.3 months2.0 months0.79 (0.67–0.92)2[
      • Sandler A.
      • Gray R.
      • Perry M.C.
      • et al.
      Paclitaxel–carboplatin alone or with bevacizumab for non–small-cell lung cancer.
      ]
      Erlotinib versus placeboSATURNStage IIIb or IV disease maintenance after responding to four to six cycles platinum doubletPFS11.1 weeks1.2 weeks0.71 (0.62–0.82)11.0 months1.0 months0.81 (0.70–0.95)1[
      • Cappuzzo F.
      • Ciuleanu T.
      • Stelmakh L.
      • et al.
      Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study.
      ]
      Table 4Field testing ESMO-MCBS v1.0: breast cancer
      Breast cancer

      MedicationTrial nameSettingPrimary outcomePFS controlPFS gainPFS HROS controlOS gainOS HRQoLToxicityESM0-MCBSRef.
      Chemotherapy ± trastuzumabHERA(Neo)adjuvant HER-2-positive tumoursDFS2-year DFS 77.4%8.40%0.54 (0.43–0.67)A[
      • Piccart-Gebhart M.J.
      • Procter M.
      • Leyland-Jones B.
      • et al.
      Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.
      ]
      T-DM1 versus lapatinib +

      capecitabine
      EMILIASecond-line metastatic after trastuzumab failurePFS and OS6.4 months3.2 months0.65 (0.55–0.77)25 months6.8 months0.68 (0.55–0.85)Delayed deterioration5[
      • Verma S.
      • Miles D.
      • Gianni L.
      • et al.
      Trastuzumab emtansine for HER2-positive advanced breast cancer.
      ,
      • Welslau M.
      • Dieras V.
      • Sohn J.H.
      • et al.
      Patient-reported outcomes from EMILIA, a randomized phase 3 study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer.
      ]
      Trastuzumab + chemotherapy ±

      pertuzumab
      CLEOPATRAFirst-line metastaticPFS12.4 months6 months0.62 (0.52–0.84)40.8 months15.7 months0.68 (0.56-0.84)No improvement4[
      • Swain S.M.
      • Kim S.-B.
      • Cortés J.
      • et al.
      Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study.
      ,
      • Baselga J.
      • Cortés J.
      • Kim S.-B.
      • et al.
      Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.
      ,
      • Swain S.M.
      • Baselga J.
      • Kim S.-B.
      • et al.
      Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer.
      ,
      • Cortes J.
      • Baselga J.
      • Im Y.H.
      • et al.
      Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer.
      ]
      Lapatinib ± trastuzumabEGF104900Third-line metastaticPFS2 months1 months0.73 (0.57–0.93)9.5 months4.5 months0.74 (0.57–0.97)4[
      • Blackwell K.L.
      • Burstein H.J.
      • Storniolo A.M.
      • et al.
      Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 study.
      ,
      • Blackwell K.L.
      • Burstein H.J.
      • Storniolo A.M.
      • et al.
      Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer.
      ]
      Capecitabine ± lapatinibSecond-line metastatic after trastuzumab failurePFS4.4 months4 months0.49 (0.34–0.71)NS3[
      • Geyer C.E.
      • Forster J.
      • Lindquist D.
      • et al.
      Lapatinib plus capecitabine for HER2-positive advanced breast cancer.
      ]
      Eribulin versus other

      chemotherapy
      EMBRACEThird-line metastatic after anthracycline and taxaneOS10.6 months2.5 months0.81 (0.66–0.99)2[
      • Cortes J.
      • O'Shaughnessy J.
      • Loesch D.
      • et al.
      Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study.
      ]
      Paclitaxel ± bevacizumabFirst-line metastaticPFS5.9 months5.8 months0.60 (0.51–0.70)NSNo improvement2[
      • Miller K.
      • Wang M.
      • Gralow J.
      • et al.
      Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer.
      ]
      Exemestane ± everolimusBOLERO-2Metastatic after failure of aromatase inhibitor (with PFS >6 months)PFS4.1 months6.5 months0.43 (0.35–0.54)NSNo improvement2[
      • Baselga J.
      • Campone M.
      • Piccart M.
      • et al.
      Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.
      ]
      Table 5Field testing ESMO-MCBS v1.0: prostate cancer
      Prostate cancer

      MedicationTrial nameSettingPrimary outcomePFS controlPFS gainPFS HROS controlOS gainOS HRQoLToxicityESM0-MCBSRef.
      Best standard non-chemotherapy or radiotherapy treatment ± radium-223ALSYMPCACastration refractory and bone painOS11.3 months3.6 months0.70 (0.55–0.88)Improved5[
      • Parker C.
      • Nilsson S.
      • Heinrich D.
      • et al.
      Alpha emitter radium-223 and survival in metastatic prostate cancer.
      ]
      Prednisone ± abirateroneCastration refractory after docetaxelOS10.9 months3.9 months0.65 (0.54–0.77)4[
      • De Bono J.S.
      • Logothetis C.J.
      • Molina A.
      • et al.
      Abiraterone and increased survival in metastatic prostate cancer.
      ]
      Enzalutamide versus placeboAFFIRMCastration refractory after docetaxelOS13.6 months4.8 months0.63 (0.53–0.75)Improved4[
      • Cabot R.C.
      • Harris N.L.
      • Rosenberg E.S.
      • et al.
      Increased survival with enzalutamide in prostate cancer after chemotherapy.
      ]
      Enzalutamide versus placeboPREVAILCastration refractory pre-docetaxelPFS and OS3.2 months>12 months0.19 (0.15–0.23)30.2 months2.2 months0.71 (0.60–0.84)Improved3[
      • Beer T.M.
      • Armstrong A.J.
      • Rathkopf D.E.
      • et al.
      Enzalutamide in metastatic prostate cancer before chemotherapy.
      ]
      Docetaxel(Q7 or Q21) prednisone versus mitoxantrone + prednisoneCastration refractoryOS16.5 months2.4 months (Q21)

      0.9 months (Q7)
      0.76 (0.62–0.94)

      0.83 (0.70–0.99)
      Improved

      Improved
      3[
      • Tannock I.F.
      • de Wit R.
      • Berry W.R.
      • et al.
      Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.
      ]
      Cabazitaxel + prednisone versus mitoxantrone + prednisoneTROPICCastration refractory after docetaxelOS12.7 months2.4 months0.70 (0.59–0.83)2[
      • de Bono J.S.
      • Oudard S.
      • Ozguroglu M.
      • et al.
      Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial.
      ]
      Table 6Field testing ESMO-MCBS v1.0: colorectal cancer
      Colorectal cancer

      MedicationTrial nameSettingPrimary outcomePFS controlPFS gainPFS HROS controlOS gainOS HRQoLToxicityESM0-MCBSRef.
      FOLFOX4 ± panitumumabPRIMEFirst-line metastatic (post hoc KRAS, NRAS BRAF WT)PFS7.9 months2.3 months0.72 (0.58–0.90)20.2 months5.8 months0.78 (0.62–0.99)4[
      • Douillard J.-Y.
      • Oliner K.S.
      • Siena S.
      • et al.
      Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal cancer.
      ]
      Panitumumab + mFOLFOX6 versus bevacizumab + mFOLFOX6PEAKFirst-line metastatic (KRAS-WT)PFSNS24.3 months9.9 months0.62 (0.44–0.89)4a[
      • Schwartzberg L.S.
      • Rivera F.
      • Karthaus M.
      • et al.
      PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer.
      ]
      FOLFIRI ± cetuximabCRYSTALFirst-line metastatic stratified for KRAS-WT (post hoc KRAS, NRAS WT)PFS8.4 months3.0 months0.56 (0.41–0.76)20.2 months8.2 months0.69 (0.54–0.88)4[
      • Van Cutsem E.
      • Lenz H.J.
      • Kohne C.H.
      • et al.
      Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer.
      ]
      Cetuximab versus best supportive careRefractory metastatic KRAS-WTOS1.9 months1.8 months0.4 (0.30–0.54)4.8 months4.7 months0.55 (0.41–0.7404[
      • Karapetis C.S.
      • Khambata-Ford S.
      • Jonker D.J.
      • et al.
      K-ras mutations and benefit from cetuximab in advanced colorectal cancer.
      ]
      FOLFOX4 ± panitumumabPRIMEFirst-line metastatic KRAS-WTPFS8 months1.6 months0.80 (0.66–0.97)19.4 months4.4 months0.83 (0.70–0.98)3[
      • Douillard J.-Y.
      • Siena S.
      • Cassidy J.
      • et al.
      Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.
      ,
      • Douillard J.
      • Siena S.
      • Cassidy J.
      • et al.
      Final results from PRIME: randomized phase 3 study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer.
      ]
      FOLFIRI ± cetuximabCRYSTALFirst-line metastatic stratified for KRAS-WTPFS8.4 months1.5 months0.70 (0.56–0.87)20 months3.5 months0.80 (0.67–0.95)3[
      • Van Cutsem E.
      • Köhne C.-H.
      • Hitre E.
      • et al.
      Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.
      ,
      • Van Cutsem E.
      • Köhne C.-H.
      • Láng I.
      • et al.
      Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status.
      ]
      ILF ± bevacizumabFirst-line metastaticOS15.6 months4.7 months0.66 (0.54–0.81)3[
      • Hurwitz H.
      • Fehrenbacher L.
      • Novotny W.
      • et al.
      Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.
      ]
      FOLFIRI ± panitumumabSecond-line metastatic KRAS-WTPFS3.9 months2 months0.73 (0.59–0.90)3[
      • Peeters M.
      • Price T.J.
      • Cervantes A.
      • et al.
      Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer.
      ]
      FOLFOX ± bevacizumab versus bevacizumab aloneE3200Second-line metastatic after FOLFIRIOS10.8 months2.1 months0.75 (0.63–0.89)2[
      • Giantonio B.J.
      • Catalano P.J.
      • Meropol N.J.
      • et al.
      Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200.
      ]
      Panitumumab, versus best supportive careThird-line metastatic stratified for KRASPFS7.3 weeks5 weeks0.45 (0.34–0.59)2[
      • Amado R.G.
      • Wolf M.
      • Peeters M.
      • et al.
      Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.
      ]
      FOLFIRI bevacizumab versus FOLFOXIRI bevacizumabFirst-line metastaticPFS9.7 months2.4 months0.75 (0.62–0.90)NS2[
      • Loupakis F.
      • Cremolini C.
      • Masi G.
      • et al.
      Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.
      ]
      TAS-102 versus placeboCONCOURSEThird-line or beyond metastaticOS5.3 months1.8 months0.68 (0.058–0.81)2[
      • Mayer R.J.
      • Van Cutsem E.
      • Falcone A.
      • et al.
      Randomized trial of TAS-102 for refractory metastatic colorectal cancer.
      ]
      Regorafenib versus placeboCORRECTThird-line metastaticOS5 months1.4 months077 (0.64–0.94)1[
      • Grothey A.
      • Cutsem E.V.
      • Sobrero A.
      • et al.
      Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
      ]
      Second-line chemotherapy ± bevacizumabML18147Second line beyond progression on bevacizumabOS9.6 months1.5 months0.81 (0.69–0.94)1[
      • Bennouna J.
      • Sastre J.
      • Arnold D.
      • et al.
      Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial.
      ]
      FOLFIRI ± afliberceptVELOURSecond line after oxaliplatin-based treatmentOS4.7 months2.2 months0.76 (0.66–0.87)12.1 months1.5 months0.82 (0.71–0.94)1[
      • Van Cutsem E.
      • Tabernero J.
      • Lakomy R.
      • et al.
      Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen.
      ]
      FOLFIRI ± RamucirumabRAISESecond-line metastatic after bevacizumab, oxaliplatin, fluoropyrimidineOS11.7 months1.6 months0.84 (0.73–0.97)1[
      • Tabernero J.
      • Yoshino T.
      • Cohn A.L.
      • et al.
      Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study.
      ]
      aUnbalanced crossover.
      Table 7Field testing ESMO-MCBS v1.0: ovarian cancer
      Ovarian cancer

      MedicationTrial nameSettingPrimary outcomePFS controlPFS gainPFS HROS controlOS gainOS HRQoLToxicityESM0-MCBSRef.
      Paclitaxel or topotecanor liposomal doxorubicin ± bevacizumabAURELIARecurrent platinum resistantPFS (crossover allowed)3.4 months3.3 months0.48 (0.38–0.60)Improved4[
      • Naumann R.W.
      • Coleman R.L.
      Management strategies for recurrent platinum-resistant ovarian cancer.
      ,
      • Stockler M.R.
      • Hilpert F.
      • Friedlander M.
      • et al.
      Patient-reported outcome results from the open-label phase III AURELIA trial evaluating bevacizumab-containing therapy for platinum-resistant ovarian cancer.
      ]
      Paclitaxel and carboplatin (five or six cycles) ± bevacizumab till 18 cycles or progressionICON7High-risk, early-stage post-resection or advanced ovarian or primary peritonealPFS stratified for stage and risk of progression(All) 22.4 months

      (high risk)

      14.5 months
      1.7 months



      3.6 months
      0.81 (0.70–0.94)



      0.73 (0.60–0.90)
      28.8 months7.8 monthsNS



      0.64 (0.48–0.85)
      1



      4
      [
      • Perren T.J.
      • Swart A.M.
      • Pfisterer J.
      • et al.
      A phase 3 trial of bevacizumab in ovarian cancer.
      ]
      Gemcitabine and carboplatin ± bevacizumabOCEANSRecurrent platinum sensitivePFS (crossover allowed)8.4 months4 months0.48 (0.39–0.61)3[
      • Aghajanian C.
      • Blank S.V.
      • Goff B.A.
      • et al.
      OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or Fallopian tube cancer.
      ]
      Paclitaxel and carboplatin (6 cycles) ± bevacizumab continual till 10 months or progressionGOG 218Incompletely resected stage III and stage IVPFS (crossover allowed)10.3 monthsBevacizumab

       continual

      3.9 months
      0.72 (0.63–0.82)NS3[
      • Burger R.A.
      • Brady M.F.
      • Bookman M.A.
      • et al.
      Incorporation of bevacizumab in the primary treatment of ovarian cancer.
      ]
      Liposomal doxorubicin ± trabectedinOVA-301Second-line metastaticPFS stratified for platinum sensitivity/ resistance(sensitive) 7.5 months

      (resistant)

      5.8 months
      1.7 months



      1.5 months
      0.73 (0.56–0.95)



      0.79 (0.65–0.96)
      2[
      • Monk B.J.
      • Herzog T.J.
      • Kaye S.B.
      • et al.
      Trabectedin plus pegylated liposomal doxorubicin in recurrent ovarian cancer.
      ]
      Olaparib versus placeboBRCA ovarian cancer in remissionPFS4.3 months6.9 months0.18 (0.10–0.31)NSNot improved2[
      • Ledermann J.
      • Harter P.
      • Gourley C.
      • et al.
      Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial.
      ]
      Table 8Field testing ESMO-MCBS v1.0: renal cell cancer
      Renal cell cancer

      MedicationTrial nameSettingPrimary outcomePFS controlPFS gainPFS HROS controlOS gainOS HRQoLToxicityESM0-MCBSRef.
      Pazopanib versus sunitinibCOMPARZFirst-line metastatic RCC with clear-cell componentPFS non-inferiority9.5 monthsNSReduced4[
      • Motzer R.J.
      • Hutson T.E.
      • Cella D.
      • et al.
      Pazopanib versus sunitinib in metastatic renal-cell carcinoma.
      ]
      Temsirolimus versus interferon versus combinedFirst-line poor-prognosis metastatic RCCOS7.3 months(TEM alone) 3.3 months0.73 (0.58–0.92)4[
      • Hudes G.
      • Carducci M.
      • Tomczak P.
      • et al.
      Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.
      ]
      Sunitinib versus interferonFirst-line metastaticPFS crossover allowed5 months6 months0.42 (0.32–0.054)21.8 months4.6 monthsNSImproved4[
      • Motzer R.J.
      • Hutson T.E.
      • Tomczak P.
      • et al.
      Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.
      ,
      • Motzer R.J.
      • Hutson T.E.
      • Tomczak P.
      • et al.
      Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma.
      ]
      Axitinib versus sorafenibAXISPreviously treated metastatic RCCPFS4.7 months2.0 months0.66 (0.55–0.81)3[
      • Rini B.
      • Escudier B.
      • Tomczak P.
      • et al.
      Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.
      ]
      Sorafenib versus placeboTARGETSecond line locally advanced or metastaticOS2.8 months2.7 months0.44 (0.35–0.55)15.9 months3.4 months0.77 (0.63–0.95)3[
      • Escudier B.
      • Eisen T.
      • Stadler W.M.
      • et al.
      Sorafenib in advanced clear-cell renal-cell carcinoma.
      ]
      Everolimus versus placeboRECORD1Second or third line after TKI metastatic RCCPFS crossover allowed1.9 months2.1 months0.30 (0.22–0.40)3[
      • Motzer R.J.
      • Escudier B.
      • Oudard S.
      • et al.
      Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial.
      ]
      Pazopanib versus placeboSecond line locally advanced or metastaticPFS crossover allowed4.2 months5 months0.46 (0.34–0.62)3[
      • Sternberg C.N.
      • Davis I.D.
      • Mardiak J.
      • et al.
      Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial.
      ]
      Interferon ± bevacizumabAVORENFirst-line metastatic RCC with clear cellPFS5.4 months4.6 months0.63 (0.52–0.75)3[
      • Escudier B.
      • Pluzanska A.
      • Koralewski P.
      • et al.
      Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial.
      ]
      Interferon ± bevacizumabCALGB 90206First-line metastatic RCC with clear cellOS amended to PFS5.2 months3.3 months0.71 (0.66–0.83)1[
      • Rini B.I.
      • Halabi S.
      • Rosenberg J.E.
      • et al.
      Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206.
      ]
      Table 9Field testing ESMO-MCBS v1.0: Sarcoma
      Sarcoma

      MedicationTrial nameSettingPrimary outcomePFS controlPFS gainPFS HROS controlOS gainOS HRQoLToxicityESM0-MCBSRef.
      Imatinib 1 year versus placeboACOSOG Z9001Adjuvant for GISTRFS stratified for risk1-year RFS 83%13%0.35 (0.22–0.53)A[
      • DeMatteo R.P.
      • Ballman K.V.
      • Antonescu C.R.
      • et al.
      Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial.
      ]
      3 versus 1 year imatinibSSG XVIIIAdjuvant for high-risk GIST5-year RFS48%18%0.46 (0.32–0.65)A[
      • Joensuu H.
      • Eriksson M.
      • Hall K.S.
      • et al.
      One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial.
      ]
      Sunitinib versus placeboAdvanced GIST second line after imatinibTTP crossover allowed6.4 weeks16.9 weeks0.33 (0.23–0.47)3[
      • Demetri G.D.
      • van Oosterom A.T.
      • Garrett C.R.
      • et al.
      Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial.
      ]
      Regorafenib versus placeboGRIDThird line after imatinib and sunitinibPFS crossover allowed0.9 months3.7 months0.27 (0.19–0.39)3[
      • Demetri G.D.
      • Reichardt P.
      • Kang Y.-K.
      • et al.
      Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
      ]
      Pazopanib versus placeboPALETTEPreviously treated non-GIST metastatic soft tissue sarcomaPFS1.6 months3 months0.31 (0.24–0.40)3[
      • van der Graaf W.T.
      • Blay J.-Y.
      • Chawla S.P.
      • et al.
      Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial.
      ]
      Ridaforolimus versus placeboSUCCEEDSarcoma after response or stable disease with first-line treatmentPFS14.6 weeks3.1 weeks0.72 (0.61–0.85)1[
      • Demetri G.D.
      • Chawla S.P.
      • Ray-Coquard I.
      • et al.
      Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy.
      ]
      Table 10Field testing ESMO-MCBS v1.0: melanoma
      Melanoma

      MedicationTrial nameSettingPrimary outcomePFS controlPFS gainPFS HROS controlOS gainOS HRQoLToxicityESM0-MCBSRef.
      Ipilimumab ± glycoprotein 100 vaccine versus vaccine alonePreviously treated metastaticOS6.4 months3.7 months0.69 (0.56–0.85)4[
      • Hodi F.S.
      • O'Day S.J.
      • McDermott D.F.
      • et al.
      Improved survival with ipilimumab in patients with metastatic melanoma.
      ]
      Vemurafenib versus dacarbazineBRIM-3First line or second line after IL-2 metastatic with BRAF V600E mutationPFS and OS1.6 months4.7 months0.26 (0.20–0.33)9.7 months3.9 months0.70 (0.57–0.87)4[
      • Chapman P.B.
      • Hauschild A.
      • Robert C.
      • et al.
      Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
      ,
      • McArthur G.A.
      • Chapman P.B.
      • Robert C.
      • et al.
      Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study.
      ]
      Trametinib versus dacarbazine or paclitaxelMETRICUnresectable or metastatic with BRAF V600E mutationPFS (crossover allowed)1.5 months3.3 months0.45 (0.33–0.63)6 months: 67%14%Improved4a[
      • Flaherty K.T.
      • Robert C.
      • Hersey P.
      • et al.
      Improved survival with MEK inhibition in BRAF-mutated melanoma.
      ,
      • Schadendorf D.
      • Amonkar M.
      • Milhem M.
      • et al.
      Functional and symptom impact of trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-of-life analyses of the METRIC study.
      ]
      Dabrafenib ± trametinibFirst line unresectable or metastatic with BRAF V600E mutationToxicity, PFS5.8 months3.6 months0.30 (0.25–0.62)12% reduction skin cancer4[
      • Flaherty K.T.
      • Infante J.R.
      • Daud A.
      • et al.
      Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.
      ]
      Dabrafenib versus dacarbazineFirst line unresectable or metastatic with BRAF V600E mutationPFS (crossover allowed)2.7 months2.1 months0.30 (0.18–0.51)Improved4[
      • Hauschild A.
      • Grob J.-J.
      • Demidov L.V.
      • et al.
      Dabrafenib in BRAF mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.
      ,
      • Grob J.-J.
      • Amonkar M.
      • Martin-Algarra S.
      • et al.
      Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality of life analyses of the BREAK-3 study comparing dabrafenib with DTIC.
      ]
      Dabrafenib + trametinib versus vemurafenibFirst line unresectable or metastatic with BRAF V600E mutationOS7.3 months4.1 months0.69 (0.53–0.89)1 year: 65%7%0.69 (0.53–0.89)17% reduction skin cancer4*[
      • Robert C.
      • Karaszewska B.
      • Schachter J.
      • et al.
      Improved overall survival in melanoma with combined dabrafenib and trametinib.
      ]
      Vemurafenib ± cobimetinibFirst line unresectable or metastatic with BRAF V600E mutationPFS6.2 months3.7 months0.51 (0.39–0.68)9 months: 73%8%9% reduction skin cancer4*[
      • Larkin J.
      • Ascierto P.A.
      • Dreno B.
      • et al.
      Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.
      ]
      Dacarbazine ± nivolumabFirst line unresectable or metastatic BRAF V600-WTOS2.2 months2.9 months0.43 (0.34–0.56)10.8 months6+ months0.42 (0.25–0.73)4*[
      • Robert C.
      • Long G.V.
      • Brady B.
      • et al.
      Nivolumab in previously untreated melanoma without BRAF mutation.
      ]
      Dacarbazine ± ipilimumabFirst-line metastaticOS (crossover allowed)3-year survival

      12.2%

      9.1 months
      8.60%



      2.1 months
      0.33 (0.24–0.533[
      • Robert C.
      • Thomas L.
      • Bondarenko I.
      • et al.
      Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
      ,
      • Maio M.
      • Grob J.J.
      • Aamdal S.
      • et al.
      Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III Trial.
      ]
      aImmature survival data.
      Table 11Field testing ESMO-MCBS v1.0: pancreatic cancer
      Pancreatic cancer

      MedicationTrial nameSettingPrimary outcomePFS controlPFS gainPFS HROS controlOS gainOS HRQoLToxicityESM0-MCBSRef.
      FOLFIRINOX versus gemcitabineFirst line advanced or metastatic,good PSOS (crossover allowed)6.8 months4.4 months0.57 (0.45–0.73)Delayed deterioration5[
      • Conroy T.
      • Desseigne F.
      • Ychou M.
      • et al.
      FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
      ]
      Gemcitabine ± nab-paclitaxelFirst line advanced or metastatic,good PSOS6.7 months1.8 months0.72 (0.61–0.83)

       5% gain at 24 months
      3[
      • Von Hoff D.D.
      • Ervin T.
      • Arena F.P.
      • et al.
      Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
      ]
      Gemcitabine ± erlotinibFirst line advanced or metastaticOS5.9 months0.3 months0.82 (0.69–0.99)1[
      • Moore M.J.
      • Goldstein D.
      • Hamm J.
      • et al.
      Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group.
      ]
      Table 12Field testing ESMO-MCBS v1.0: gastro-oesophageal cancer
      Gastro-oesophageal cancer

      MedicationTrial nameSettingPrimary outcomePFS controlPFS gainPFS HROS controlOS gainOS HRQoLToxicityESM0-MCBSRef.
      Surgery ± perioperative epirubicin, cisplatin, 5-FUISRCTN

      93793971
      Gastric or distal oesophagus stage II–IIIOS5 years: 23%13%0.66 (0.53–0.81)A[
      • Cunningham D.
      • Allum W.H.
      • Stenning S.P.
      • et al.
      Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.
      ]
      Surgery ± perioperative cisplatin/5-FUGastric or distal oesophagus stage II–IIIOS5 years: 24%14%0.69 (0.50–0.95)A[
      • Ychou M.
      • Boige V.
      • Pignon J.-P.
      • et al.
      Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial.
      ]
      Ramucirumab versus placeboREGARDSecond-line gastro-oesophageal or gastric cancer after cisplatin/5-FUOS3.2 months2 months0.78 (0.60–0.99)2[
      • Fuchs C.S.
      • Tomasek J.
      • Yong C.J.
      • et al.
      Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial.
      ]
      When discrepancies between graders were observed, this was generally related to either inaccurate data extraction, variable interpretation of the significance and severity of toxicity data, or errors in applying the data to the correct grading criteria.

      discussion

       inherent challenges in developing standard Clinical Benefit Scale

      The substantial variability of study designs (crossover, non-crossover and partial crossover), planned outcomes and reported outcomes inherently challenge the process of developing a unified scale of clinical benefit. This challenge is all the greater in an era in which both researchers and regulatory authorities are employing surrogate outcome indicators as primary end points for both research and registration criteria [
      • Davis C.
      Drugs, cancer and end-of-life care: a case study of pharmaceuticalization?.
      ]. A unified scaling approach requires a process of relative weighting of evidence that demands conceptual rigor, careful reviews of the validity and strength of surrogate end points and clinical nuance.

       validity of the ESMO-MCBS

      The ESMO-MCBS version 1 (ESMO-MCBS v1.0) provides an objective and reproducible approach that allows comparisons of the magnitude of benefit between studies that incorporate different primary outcomes (OS, PFS, QoL) and different designs through a process of variable weighting of primary outcomes and adjustments for significant secondary outcomes and toxicity.
      The development process has been compliant with the criteria for ‘accountability for reasonableness’ which represent the ethical gold-standard for a fair priority setting process in public policy [
      • Gruskin S.
      • Daniels N.
      Process is the point: justice and human rights: priority setting and fair deliberative process.
      ,
      • Daniels N.
      Accountability for reasonableness.
      ]. The validity of the ESMO-MCBS is derived from (i) clinically relevant and reasonable criteria for prioritisation of different types of benefit, i.e. that cure takes precedence over deferral of death, direct end points such as survival and QoL take precedence over less reliable surrogates such as PFS or RR and that the interpretation of the evidence for benefit derived from indirect primary outcomes (such as PFS or RR) may be influenced by secondary outcome data, (ii) coherence: procedural agreements regarding the evidence to be used/not used, how it will be analysed and evaluated, and precautions to minimising bias (including conflict of interest issues) based upon an understanding of the relative strengths and weaknesses of the usual measured outcomes OS and QoL, and their surrogates [
      • Seruga B.
      • Tannock I.F.
      Up-front use of aromatase inhibitors as adjuvant therapy for breast cancer: the emperor has no clothes.
      ,
      • Sargent D.J.
      • Wieand H.S.
      • Haller D.G.
      • et al.
      Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials.
      ,
      • Oba K.
      • Paoletti X.
      • Alberts S.
      • et al.
      Disease-free survival as a surrogate for overall survival in adjuvant trials of gastric cancer: a meta-analysis.
      ,
      • Mauguen A.
      • Pignon J.-P.
      • Burdett S.
      • et al.
      Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data.
      ,
      • Gill S.
      • Sargent D.
      End points for adjuvant therapy trials: has the time come to accept disease-free survival as a surrogate end point for overall survival?.
      ,
      • Saad E.D.
      • Katz A.
      • Hoff P.M.
      • Buyse M.
      Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature.
      ,
      • Shi Q.
      • Sargent D.J.
      Meta-analysis for the evaluation of surrogate endpoints in cancer clinical trials.
      ,
      • Booth C.M.
      • Eisenhauer E.A.
      Progression-free survival: meaningful or simply measurable?.
      ,
      • Saad E.D.
      • Katz A.
      • Buyse M.
      Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical trials.
      ,
      • Wilkerson J.
      • Fojo T.
      Progression-free survival is simply a measure of a drug's effect while administered and is not a surrogate for overall survival.
      ,
      • Amir E.
      • Seruga B.
      • Kwong R.
      • et al.
      Poor correlation between progression-free and overall survival in modern clinical trials: are composite endpoints the answer?.
      ,
      • Berruti A.
      • Amoroso V.
      • Gallo F.
      • et al.
      Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies.
      ] and rigorous bio statistical review, (iii) wide applicability over a range of solid cancers and a range of prognoses that have been rigorously tested (iv) statistical validity and (v) a transparent process of development with scope for peer review, appeal and revision.
      ESMO-MCBS scores for a specific therapy are not generalisable to indications outside the confines of the context in which they have been evaluated. Consequently, the ESMO-MCBS score for a particular medication or therapeutic approach may vary depending on the specifics of the indication and may vary between studies.

       limitations of the ESMO-MCBS v1.0

      The ESMO-MCBS can only be applied to comparative research outcomes; it is therefore not applicable when evidence of benefit derives from single-arm studies. This limits its utility in the uncommon situation in which registration is granted on the basis of outcomes reported from single-arm studies.
      The process of relative weighting of evidence and the thresholds for HR and absolute gains involves judgements and subjective considerations which are amenable to dispute and challenge and indeed, this is invited as part of the dynamic process of peer review and further development.

       factors that may skew or alter ESMO-MCBS scores

       control arm evaluation

      The ESMO-MCBS evaluates data derived from comparative research, either randomised phase II [
      • Gan H.K.
      • Grothey A.
      • Pond G.R.
      • et al.
      Randomized phase II trials: inevitable or inadvisable?.
      ] or phase III studies or cohort studies. The validity of the results may be influenced by the quality and design of the study. Design issues are critical insofar as studies that incorporate a relatively weak control arm may generate the impression of exaggerated benefit. This was manifest in studies evaluating treatment options for hormone refractory prostate cancer where one study used mitoxantrone/prednisone as the control arm [
      • de Bono J.S.
      • Oudard S.
      • Ozguroglu M.
      • et al.
      Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial.
      ] based on the findings of a phase III study comparing prednisone versus the combination of prednisone and mitoxantrone which demonstrated improved QoL but no survival advantage for the combination therapy [
      • Tannock I.F.
      • Osoba D.
      • Stockler M.R.
      • et al.
      Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points.
      ] and others used prednisone alone [
      • De Bono J.S.
      • Logothetis C.J.
      • Molina A.
      • et al.
      Abiraterone and increased survival in metastatic prostate cancer.
      ] or placebo [
      • Cabot R.C.
      • Harris N.L.
      • Rosenberg E.S.
      • et al.
      Increased survival with enzalutamide in prostate cancer after chemotherapy.
      ].

       crossover

      Crossover, or subsequent treatment of control arm patients with biologically similar agent, severely compromises the ability to derive reliable data regarding the survival advantage of treatments in phase III studies. This factor may impact on OS results as illustrated by the study of dacarbazine versus ipilimumab in metastatic melanoma [
      • Robert C.
      • Thomas L.
      • Bondarenko I.
      • et al.
      Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
      ] in which the evidence for survival advantage was diluted by the crossover provision in the study. In some instances in which strong PFS advantage is seen, crossover of this type will obscure the potential survival benefit of the new treatment. Statistical approaches to estimate longer term clinical outcomes despite substantial treatment crossover have been developed [
      • Robins J.M.
      • Finkelstein D.M.
      Correcting for noncompliance and dependent censoring in an AIDS clinical trial with Inverse Probability of Censoring Weighted (IPCW) Log-Rank Tests.
      ,
      • Shao J.
      • Chang M.
      • Chow S.C.
      Statistical inference for cancer trials with treatment switching.
      ], and applied [
      • Jin H.
      • Tu D.
      • Zhao N.
      • et al.
      Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover.
      ,
      • Colleoni M.
      • Giobbie-Hurder A.
      • Regan M.M.
      • et al.
      Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1–98 study.
      ,
      • Finkelstein D.M.
      • Schoenfeld D.A.
      Correcting for discretionary treatment crossover in an analysis of survival in the Breast International Group BIG 1–98 trial by using the inverse probability of censoring weighted method.
      ,
      • Rimawi M.
      • Hilsenbeck S.G.
      Making sense of clinical trial data: is inverse probability of censoring weighted analysis the answer to crossover bias?.
      ]. While these approaches are encouraging, they incorporate a range of assumptions and are not universally accepted [
      • Prasad V.
      • Grady C.
      The misguided ethics of crossover trials.
      ].

       unbalanced crossover

      In other instances, unbalanced crossover may exaggerate differences in survival. For instance, in the PEAK study comparing FOLFOX6 with either bevacizumab or panitumumab among the patients with KRAS wild-type tumours, only 38% of those in the bevacizumab arm received any EGFR antibody in subsequent therapy [
      • Stintzing S.
      • Jung A.
      • Modest D.
      • et al.
      Analysis of KRAS/NRAS and BRAF mutations in FIRE- 3: a randomized phase III study of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS (exon 2) metastatic colorectal cancer patients.
      ]. Although this study showed a survival advantage of 9.9 months over a baseline of 24.3 months for patient initiated on treatment with panitumumab, it remains unclear as to whether this was affected by the sequence of treatments or if it was the result that more than half of the patients in the bevacizumab arm were never exposed to an EGFR antibody.

       follow-up reports

      In some studies, first reports are followed up with subsequent further relevant data analysis. This is particularly true when mature survival data were not available in studies with a primary outcome of PFS or DFS and in studies that have incorporated post hoc stratification based on refined appreciation of tumour biology that may impact on outcome evaluation.
      Both of these phenomena were observed in the three publications reporting the findings from the same study on FOLFOX4 ± panitumumab for the first-line treatment of KRAS wild-type colorectal cancer [
      • Douillard J.-Y.
      • Oliner K.S.
      • Siena S.
      • et al.
      Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal cancer.
      ,
      • Douillard J.-Y.
      • Siena S.
      • Cassidy J.
      • et al.
      Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.
      ,
      • Douillard J.
      • Siena S.
      • Cassidy J.
      • et al.
      Final results from PRIME: randomized phase 3 study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer.
      ]. The study, which did allow for crossover to other EGFR antibodies, had PFS as a primary end point. The initial publication demonstrated a modest PFS advantage with non-significant median OS gain [
      • Douillard J.-Y.
      • Siena S.
      • Cassidy J.
      • et al.
      Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.
      ]. The subsequent publication of mature data demonstrated a significant OS gain [
      • Douillard J.
      • Siena S.
      • Cassidy J.
      • et al.
      Final results from PRIME: randomized phase 3 study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer.
      ] with the greatest benefit restricted to patients with KRAS, NRAS, BRAF wild-type tumours [
      • Douillard J.-Y.
      • Oliner K.S.
      • Siena S.
      • et al.
      Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal cancer.
      ]. Almost identical data maturation was observed in the CRYSTAL study evaluating FOLFIRI± cetuxumab in the same clinical setting [
      • Van Cutsem E.
      • Lenz H.J.
      • Kohne C.H.
      • et al.
      Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer.
      ,
      • Van Cutsem E.
      • Köhne C.-H.
      • Hitre E.
      • et al.
      Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.
      ,
      • Van Cutsem E.
      • Köhne C.-H.
      • Láng I.
      • et al.
      Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status.
      ].
      Maturation of survival data also increased the ESMO-MCBS score of vemurafenib in the treatment of metastatic melanoma [
      • Chapman P.B.
      • Hauschild A.
      • Robert C.
      • et al.
      Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
      ,
      • McArthur G.A.
      • Chapman P.B.
      • Robert C.
      • et al.
      Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study.
      ] from ESMO-MCBS 3 based on PFS to 4, based on OS.

       using data from the ESMO-MCBS

      The ESMO-MCBS incorporates a structured, rational and valid approach to data interpretation and analysis that reduces the tendency to have judgements affected by bias or uninformed and/or idiosyncratic data interpretation. Consequently, application of the scale reduces the likelihood that statements of clinical benefit will be distorted by either overestimation or overstatement on one extreme or, nihilism at the other. This structured and disciplined approach to deriving estimates of clinically meaningful benefit from published data can be used in a range of settings.

       public policy applications

      Grading derived from the ESMO-MCBS provides a backbone for value evaluations for cancer medicines. Medicines and therapies that fall into the ESMO-MCBS A + B for curative therapies and 4 + 5 for non-curative therapies should be emphasized for accelerated assessment of value and cost-effectiveness. While a high ESMO-MCBS score does not automatically imply high value (that depends on the price), the scale can be utilised by to frame such considerations [
      • Shih Y.C.
      • Ganz P.A.
      • Aberle D.
      • et al.
      Delivering high-quality and affordable care throughout the cancer care continuum.
      ] and can help public policy-makers advance ‘accountability for reasonableness’ in resource allocation deliberations [
      • Gruskin S.
      • Daniels N.
      Process is the point: justice and human rights: priority setting and fair deliberative process.
      ,
      • Daniels N.
      Accountability for reasonableness.
      ].

       formulation of clinical guidelines

      The prevailing current practice of the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), ESMO and the National Cancer Institute (NCI) in their guidelines is to grade the ‘level of evidence’ supporting the efficacy of therapeutic interventions; grading the evidence as very high when derived from meta-analyses of well-conducted phase III studies, or from large well-conducted phase III studies relative to lower levels such as that derived from non-randomised studies, anecdote or expert clinical opinion. A major shortcoming of this approach is that it may result in a high level of evidence irrespective of the actual magnitude of the benefit observed, even if the magnitude of the benefit is very limited [
      • Petticrew M.
      • Roberts H.
      Evidence, hierarchies, and typologies: horses for courses.
      ]. This discrepancy has been emphasized by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group which was formed in 2000 to improve the quality of guideline formulation. The GRADE working group emphasised that a particular quality of evidence does not necessarily imply a particular strength of recommendation [
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      ,
      • Balshem H.
      • Helfand M.
      • Schunemann H.J.
      • et al.
      GRADE guidelines: 3. rating the quality of evidence.
      ]. They have developed and championed a widely endorsed approach emphasising appropriate framing of research and guideline questions [
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • et al.
      GRADE guidelines: 2. framing the question and deciding on important outcomes.
      ], evaluation of the strength of recommendations that incorporates evaluation of the balance between desirable and undesirable outcomes (estimated effects), and the confidence in the magnitude effect of the interventions on important outcomes [
      • Andrews J.C.
      • Schunemann H.J.
      • Oxman A.D.
      • et al.
      GRADE guidelines: 15. going from evidence to recommendation-determinants of a recommendation's direction and strength.
      ].
      This recommendation can be accomplished by describing both the level of benefit and the level of evidence for recommended therapeutic interventions. For cancer therapies, the ESMO-MCBS scale provides a clear, well-structured and validated mechanism to indicate the magnitude of benefit in addition to the level of evidence that can inform both national and international (e.g. ESMO) guidelines.

       clinical decision making

      The data encapsulated in ESMO-MCBS scoring can help clinicians to weigh the relative merits of competing relevant therapeutic options in situations in which there is no direct comparative data comparing the available therapeutic options. The grading may also be of benefit in explaining the relative merit of therapeutic options to patients and their families. This information may be especially helpful when treatments incorporate substantial out of pocket costs and the real ‘value’ of the treatment needs to be candidly addressed to avoid over investment or sacrifice of limited financial resources to pay for treatments that have only limited magnitude of benefit.

       editorial decisions and commentaries

      The ESMO-MCBS may be of use to editors, peer reviewers and commentators in considering the clinical significance of research findings from randomised clinical studies, cohort studies and meta-analyses with statistically significant positive findings.

       relevance to the ASCO initiatives

      ASCO has undertaken two initiatives to help promote the value in cancer care. The first was a working group to propose new thresholds for the approval of cancer medications [
      • Ellis L.M.
      • Bernstein D.S.
      • Voest E.E.
      • et al.
      American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes.
      ]. For each of four conditions (metastatic colon cancer, metastatic breast cancer, non-small-cell lung cancer and pancreatic cancer), they have proposed thresholds for meaningful clinical benefit improvement defined in terms of minimal increases in OS (absolute and HR) and also thresholds for minimal increases in surrogate indicators including 1-year survival and PFS. Interestingly, in non-curative therapies, the ASCO recommended thresholds for survival benefit correlate very closely to the thresholds for ESMO-MCBS score of 4–5 (in form 2a) and the recommended thresholds for PFS correlate closely with the thresholds for ESMO-MCBS score of 3–4 which is the highest attainable when the primary outcome is PFS (in form 2b). Secondly, ASCO has developed a Value in Cancer Care Task Force that has been charged with the challenge of developing a framework for evaluating value in oncology. While concurring with ESMO that the evaluation of net clinical benefit is key element in the evaluation of value, ASCO has not yet described their proposed approach to evaluate the magnitude of clinical benefit. A key challenge for the future will be to establish whether there can be harmonisation between the different approaches to value in Europe and the United States.

      conclusion

      ESMO is committed to promoting rational, responsible and affordable cancer care, the importance of organisational integrity, and the promotion of best use of limited health care resources. The ESMO-MCBS v1.0 was born out of these considerations. It represents a first version of a well-validated tool to stratify the magnitude of clinical benefit for new anti-cancer treatments and is applicable over a full range of solid tumours. Based on the data derived from well-structured phase III clinical trials or meta-analyses, the tool uses a rational, structured and consistent approach to derive a relative ranking of the magnitude of benefit that can be anticipated from any new treatment. The ESMO-MCBS is an important first step to the major ongoing task of evaluating value in cancer care which is essential for appropriate uses of limited public and personal resources for affordable cancer care. The ESMO-MCBS will be a dynamic tool and its criteria will be revised on a regular basis pending peer reviewed feedback and developments in cancer research and therapies.

      funding

      This project was funded by ESMO .

      disclosure

      The authors have declared the following: UD: lecture fees—Amgen. EGEV: research grants from Roche/Genentech, Amgen, Novartis, Pieris and Servier to the institute, data monitoring committee Biomarin, advisory board Synthon. MJP: board member—PharmaMar; Consultant (honoraria)—Amgen, Astellas, AstraZeneca, Eli Lilly, GSK, Invivis, MSD, Novartis, Pfizer, Roche/Genentech, Sanofi Aventis, Symphogen, Synthon, Verastem; Research grants to Institute: most companies; Speakers bureau/stock ownership: none. AS: advisory Board and Symposia Satellite with; Amgen, Bayer, Celgene, Merck, Roche and Sanofi. CZ: advisory Boards—Roche, Celgene, Bristol Myers-Squibb; lecture fees—Amgen, Bristol Myers-Squibb. All remaining authors have declared no conflicts of interest.

      acknowledgements

      The authors wish to acknowledge the support and contribution of the ESMO Executive Board, the ESMO Faculty, Members of the ESMO Guidelines Committee, and the logistic and organisational support provided by ESMO Staff and in particular Nicola Latino. Appendix 2 lists biostatistics and oncology colleagues who provided feedback on earlier versions of the scale and the manuscript.

      appendix 1

       ESMO magnitude of Clinical Benefit Scale v1.0

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      appendix 2

      Fabrice Andre, France; Dirk Arnold, Germany; Paolo A. Ascierto, Italy; Stefan Bielack, Germany; Jean Yves Blay, France; Federico Cappuzzo, Italy; Fatima Cardoso, Portugal; Andrés Cervantes, Spain; Fortunato Ciardiello, Italy; Alan Stuart Coates, Australia; Karina Dahl Steffensen, Denmark; Theo M. De Reijke, The Netherlands; Jean Yves Douillard, France; Reinhard Dummer, Switzerland; Tim Eisen, UK; Enriqueta Felip, Spain; Constantine Gatsonis, USA; Heikki Joensuu, Finland; Ian Judson, UK; Vesa Kataja, Finland; Roberto Labianca, Italy; Jonathan A. Ledermann, UK; Sumithra J. Mandrekar, USA; Stefan Michiels, France; Mansoor Raza Mirza, Denmark; Mustafa Özgüroğlu, Turkey; Chris Parker, UK; Camillo Porta, Italy; Noemi Reguart, Spain; Daniel J. Sargent, USA; Elżbieta Senkus, Poland; Cristiana Sessa, Switzerland; Kirsten Sundby Hall, Norway; JosepTabernero, Spain; Dongsheng Tu, Canada; Johan Vansteenkiste, Belgium.

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