|1.||Use of lower limit of 95% CI versus point estimate|
|2.||Crediting 2- and 3-year survival advantage <10%|
|3.||Unscorable randomised studies because of scale deficiencies|
|4.||No mechanism to credit plateauing in PFS curve (when median PFS gain is small)|
|5.||Toxicity penalties: differential or not, which adverse effects|
|6.||Validity of QoL credit|
|7.||Crediting of single symptom improvements|
|8.||Inability to score FDA and EMA approved neoadjuvant therapies based on pCR|
|9.||PFS studies with early termination (based on planned interim survival analysis)|
|10.||Inability to score medications approved based on single-arm studies|
|11.||No recognition that some patients treated with non-curable intent, may be cured|
|12.||PFS penalty for no improvement in OS and QoL did not explicitly refer to mature survival data|
|Drug||Trial name||Disease||Setting||Primary outcome||PFS control||PFS gain||PFS HR||OS control||OS gain||OS HR||pCR||QoL||Toxicity||ESM0- MCBS V1.0||ESM0- MCBS V1.1||Ref.|
|Dacarbazine± ipilimumab||Melanoma||1st line metastatic||OS (crossover allowed)||5-year survival 8.8%||9.40% 2-year gain 11%||4||A/4||[|
|9.1 months||2.1 months||0.33 (0.24–0.53)|
|Pembrolizumab 2 or 10 mg/kg versus docetaxel||KEYNOTE- 010||Lung||2nd line after platinum based therapy OR TKI (for EGFR/ALK mutated) advanced NSCLC >1% tumour cell PD-L1||OS All >1%||8.5 months (all)||1.9 months (2)||0.71 (0.58–0.88)||Reduced grade 3/4 adverse events||No score||3||[|
|4.2 months (10)||0.61 (0.49–0.75)||5||5|
|PD-L1 >50%||8.2 months||6.7 months (2)||0.54 (0.38–0.77)||5||5|
|9.1 months (10)||0.50 (0.36–0.70)||5||5|
|Olaparib versus placebo||Ovarian cancer||BRCA ovarian in remission||PFS||4.3 months||6.9 months||0·18 (0·10–0·31)||27.8 months||2 months||0.73 (0.55–0.96)||No benefit||2a||3a||[|
|Trastuzumab and docetaxel± pertuzumab||NeoSphere||Breast||Neo-adjuvant HER2 overexpressed invasive ductal breast||pCR||NS||29% versus 46%||No score||Ca||[|
|Imiquimod 5% cream (5 or 7 days) versus placebo||Basal Cell||Superficial basal cell carcinoma in adults with normal immune systems when surgical methods are less appropriate||pCR (histologic clearance rates)||3% versus 79% (5 days)– 82% (7 days)||No score||C||[|
|Combination versus nivolumab versus ipilimumab||Melanoma||1st line advanced or metastatic melanoma||PFS||All 2.9 months||Combination 8.6 months||0.42 (0.31–0.57) Plateau with >10% gain at 1 year||Gr 3+ 55% versus 27%||2||3||[|
|Nivolumab 4 months||0.57 (0.43–0.76)||Gr 3+ 16% versus 29%||4||4|
|PD-L1+: 3.9 months||Combination 10.1 months|
|Nivolumab 10.1 months|
|PD-L1−: 2.8 months||Combination 8.4 months||Plateau with >10% gain at 1 year||2||3|
|Nivolumab 2.3 months|
|Pembrolizumab (2 versus 10 mg/kg) versus investigator-choice||KEYNOTE- 002||Melanoma||2nd line metastatic after failure of ipilimumab BRAF or MEK inhibitor||PFS||2.6 months||1.6 months (2 mg/kg)||0.45 (0.35–0..57) Plateau PFS gain >10% gain at 1 year||3a||4a||[|
|2 months (10 mg/kg)||0.39 (0.30–0.51) Plateau with >10% gain at 1 year||3a||4a|
|Drug||Trial name||Disease||Setting||Primary outcome||PFS control||PFS gain||PFS HR||OS control||OS gain||OS HR||pCR||QoL||Toxicity||ESM0- MCBS V1.0||ESM0- MCBS V1.1||Ref|
|T-DM1 versus lapatinib+ capecitabine||EMILIA||Breast||2nd line metastatic after trastuzumab failure||PFS and OS||6.4 months||3.2 months||0.65 (0.55– 0.77)||25.1 months||5.8 months||0.68 (0.55–0.85)||Delayed deterioration||5||4||[|
|Paclitaxel and carboplatin (5 or 6 cycles)± bevacizumab till 18 cycles or progression||ICON7||Ovarian||High-risk, early stage post-resection or advanced ovarian or primary peritoneal||PFS stratified for stage and risk of progression||(All) 17.4 months||2.4 months||0.87 (0.77–0.99)||(0.77–0.99)||NS||Minor deterioration||1||1||[|
|10.5 months||5.5 months||0.73(0.60– 0.93)||28.8 months||7.8 months||0.64 (0.48–0.85)||4||3|
|FOLFIRI± ramucirumab||RAISE||Colorectal||2nd line metastatic after bevacizumab, oxaliplatin, fluoropyrimidine||OS||11.7 months||1.6 months, 2-year survival gain 5%–10%||0.84 (0.73–0.97)||3||1||[|
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.
Lancet Oncol. 2015; 16: 499-508
|Gemcitabine± nab-paclitaxel||Pancreatic||1st line advanced or metastatic. Good performance status (KPS>70%)||OS||6.7 months 2-year survival 4%||1.8 months 2-year survival gain 5%||0.72 (0.62–0.83)||3||2||[|
|Docetaxel± ramucirumab||REVEL||Lung||2nd line after platinum based therapy NSCLC||OS||9.1 months||1.4 months 2-year survival gain 3–5%||0.86 (0.75–0.98)||2||1||[|
Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.
Lancet. 2014; 384: 665-673
|Drug||Disease||Setting||Stratification||ORR||CR||DoR||PFS||Survival||QoL||Toxicity||ESMO- MCBS 1.0||ESM0- MCBS 1.1||Ref.|
|AZD9291 (Osimertib)||Lung||EGFR Inhibitor–Resistant NSCLC phase 2, RR, stratified for EGFR T790M mutation||MUT||61%||6+ months||9.6 months||No score||3||[|
|WT||21%||2.8 months||No score||1|
|Ceritinib||Lung||ALK mutated NSCLC stratified for prior/no-prior crizotinib||Prior crizotinib||56%||8.2+ months||6.9 months||No score||3||[|
|No prior crizotinib||62%||10.2 months||No score||3|
|Crizotinib||Lung||2nd line metastatic NSCLC whose tumours are ROS1 positive.||72%||7%||17.6 months||19.2 months||No score||3||[|
|Crizotinib||Lung||NSCLC whose tumours are ALK mutated||61.8%||10 months||9.7 months||No score||3||[|
|Nivolumab||Hodgkin’s||Classical Hodgkin lymphoma that has relapsed or progressed after autologous haematological stem cell transplantation and post-transplantation brentuximab vedotin||87%||17%||8.7 months||24+ months||No score||3||[|
|Olaparib||Ovarian||After three lines therapy BRCA mutated (germline OR somatic)||31%||3%||7 months||7 months||16 months||No score||3||[|
|Atezolizumab||Urothelial||Platinum resistant locally advanced or metastatic transitional cell cancer stratified by PD-L1 immunohistochemistry score (IC 2/3)||26%||11%||11.7 months||No score||3||[|
|Everolimus||Brain||Subependymal giant-cell astrocytomas in tuberous sclerosis||RR: tumour volume (vol.)||100% (decrease volume >30%)||24+ months||Improved||No score||4||[|
|Pembrolizumab||Head and Neck||PD-L1-positive squamous cell H+N carcinoma after 1st line||16%||5%||6+ months||No score||1||[|
|Pembrolizumab||Colorectal||2nd line+metastatic colorectal cancer (MMR-d) (MSI-high (microsatellite instability) who have received prior therapy||62%||5.9+ months||No score||3||[|
- Cherny N.I.
- Sullivan R.
- Dafni U.
- et al.
- Studies with pre-planned subgroup analyses with a maximum of three subgroups can be graded (provided there is adjustment for multiple comparisons).
- When statistically significant results are reported for any subgroup, then each of these should be graded 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 (posthoc) subgroup analysis cannot be graded and they can only be used as foundation for hypothesis generation.
- Paz-Ares L.
- Socinski M.
- Shahidi J.
- et al.
- Garon E.B.
- Ciuleanu T.E.
- Arrieta O.
- et al.
- Tabernero J.
- Yoshino T.
- Cohn A.L.
- et al.
- European Society for Medical Oncology
Figure 1. ESMO Magnitude of Clinical Benefit Scale v1.1.
- IF median OS with the standard treatment is ≤12 months
- IF median OS with the standard treatment >12 months, ≤24 months
- IF median OS with the standard treatment >24 months
- IF median PFS with standard treatment ≤6 months
- IF median PFS with standard treatment >6 months
- Adequately powered studies showing statistically significant improvement in the primary outcome (defined byP <0.050)
- Careful analyses ‘control arm’ and identification of end points.
- Check subgroup analysis.
- a. Studies with pre-planned subgroup analyses with a maximum of three subgroups can be graded (provided there is adjustment for multiple comparisons).
- b. When statistically significant results are reported for any subgroup, then each of these should be graded separately.
- c. Subgroups not showing statistically significant results are not graded.
- d. 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.
- Survival gain >10% at 2, 3 or 5 years on Kaplan Meyer plots
- Long term survival with plateau in Kaplan Meyer plots at 5 or 7 years
- Reduced toxicity
- Improvement in quality of life
- Report final adjusted grade taken into account toxicity, and QoL when relevant
- Indicators of toxicity
- Survival data also available
- Early termination with crossover based on planned interim survival analysis
- Greater than 10% gain in PFA at 2 or 3 years (tail of curve)
- Global QoL advantage using validated scale if applicable
- Report final adjusted grade taken into account toxicity, survival advantage and QoL when applicable
|First name||Last name||Country||First name||Last name||Country|
|Dirk||Arnold||Germany and Portugal||Alan||Horwich||UK|
|Michele||Ghielmini||Switzerland||Martin||Van den Bent||Netherlands|
- Supplementary Tables
- 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).Ann Oncol. 2015; 26: 1547-1573
- Process is the point: justice and human rights: priority setting and fair deliberative process.Am J Public Health. 2008; 98: 1573-1577
- Accountability for reasonableness.BMJ. 2000; 321: 1300-1301
- Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial.Lancet Oncol. 2015; 16: 763-774
- Correlation of EGFR-expression with safety and efficacy outcomes in SQUIRE: a randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin plus necitumumab versus gemcitabine-cisplatin alone in the first-line treatment of patients with stage IV squamous non-small cell lung cancer.Ann Oncol. 2016; 27: 1573-1579
- Perils of the pathologic complete response.J Clin Oncol. 2016; 34: 3959-3962
- Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.Lancet Oncol. 2012; 13: 25-32
- Trastuzumab emtansine for HER2-positive advanced breast cancer.N Engl J Med. 2012; 367: 1783-1791
- 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.Cancer. 2014; 120: 642-651
- 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.Lancet Oncol. 2013; 14: 461-471
- Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.N Engl J Med. 2012; 366: 109-119
- Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer.N Engl J Med. 2015; 372: 724-734
- Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer.Ann Oncol. 2013; 24: 2630-2635
- Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104.J Clin Oncol. 2002; 20: 3054-3060
- Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.N Engl J Med. 2011; 364: 2517-2526
- Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial.J Clin Oncol. 2015; 33: 1191-1196
- Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.Lancet. 2016; 387: 1540-1550
- Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.Lancet. 2014; 384: 665-673
- 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.Lancet Oncol. 2015; 16: 499-508
- Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.N Engl J Med. 2013; 369: 1691-1703
- Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.N Engl J Med. 2015; 373: 1627-1639
- Nivolumab vs docetaxel in patients with advanced NSCLC: CheckMate 017/057 2-y update and exploratory cytokine profile analyses.J Clin Oncol. 2016; 34 (suppl abstr 9025)
- Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34
- Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.Lancet Oncol. 2015; 16: 908-918
- Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.N Engl J Med. 2012; 366: 1382-1392
- 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.Lancet Oncol. 2014; 15: 852-861
- Quality of life during olaparib maintenance therapy in platinum-sensitive relapsed serous ovarian cancer.Br J Cancer. 2016; 115: 1313-1320
- Utilisation of the ESMO-MCBS in practice of HTA.Ann Oncol. 2016; 27: 2134-2136
- The Esmo magnitude of clinical benefit scale for novel cancer medicines – correspondence with prioritization decisions in updating the Israeli National List of Health Services.Value Health. 2015; 18: A336
- ESMO Clinical Practice Guidelines News.in: ESMO, Lugano2016
- The European Society for Medical Oncology Magnitude of Clinical Benefit Scale in daily practice: a single institution, real-life experience at the Medical University of Vienna.ESMO Open. 2016; 1: e000066
- Do contemporary randomized controlled trials meet ESMO thresholds for meaningful clinical benefit?.Ann Oncol. 2017; 28: 157-162
- 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial.Lancet Oncol. 2016; 17: 791-800
- Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies.J Am Acad Dermatol. 2004; 50: 722-733
- Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised trial.Lancet Oncol. 2013; 14: 236-243
- A phase 3 trial of bevacizumab in ovarian cancer.N Engl J Med. 2011; 365: 2484-2496
- AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.N Engl J Med. 2015; 372: 1689-1699
- Ceritinib in ALK-rearranged non-small-cell lung cancer.N Engl J Med. 2014; 370: 1189-1197
- Crizotinib in ROS1-rearranged non-small-cell lung cancer.N Engl J Med. 2014; 371: 1963-1971
- Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703
- Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.Lancet Oncol. 2012; 13: 1011-1019
- PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma.N Engl J Med. 2015; 372: 311-319
- Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.J Clin Oncol. 2015; 33: 244-250
- MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.Nature. 2014; 515: 558-562
- Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial.Lancet. 2016; 387: 1909-1920
- Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis.N Engl J Med. 2010; 363: 1801-1811
- Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial.Lancet Oncol. 2016; 17: 956-965
- PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med. 2015; 372: 2509-2520
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