Roundtable on ImmunoOncology Federal Parliament Brussels July 02
Roundtable on Immuno-Oncology Federal Parliament – Brussels, July 02 nd 2015 ESMO Magnitude of Clinical Benefit Scale for new anticancer drugs Martine Piccart on behalf of ESMO Magnitude of Clinical Benefit Scale task force Institut Jules Bordet, Université Libre de Bruxelles Cette présentation est la propriété de l’ESMO www. esmo. org
New anticancer drugs hit the market at very high costs ! • The average cost of recently approved anticancer drugs is ≈ 9. 000 €/month • The cost to gain one year of life – In 1995 ≈ 50. 000 € – Today ≈ 200. 000€ L. Salz – ASCO 2015
Value ≠ Benefit
Possible scenarios in outcome of pivotal, randomized phase III clinical trials Survival results No difference Small, statistically significant difference possible EMA registration of new treatment Large, statistically significant difference very likely EMA registration of new treatment Standard treatment New treatment
Different impacts of new drugs on patient outcome Standard treat A New treat A B C B The new treatment controls the disease better initially, but the life of the pt is not extended. C What about Qo. L ? New treat A B C The new treatment controls the disease better and the pt lives longer Is this extension measured in days, weeks or months ?
Why an ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) ? ESMO • Committed Ø to promote high-quality, rational, responsible & affordable cancer care • Recognizes Ø the need for clear and unbiased statements regarding the magnitude of clinical benefit from new therapeutic approaches • Wants to Ø highlight treatments which bring substantial improvements to the duration of survival and/or the Qo. L of cancer patients • Hopes Ø The scale will facilitate access to important anticancer drugs all over Europe
Factors taken into account for ESMO-MCBS Overall survival, Progression free survival Prognosis of the condition Quality of Life Magnitude of Clinically Benefit Costs Toxicity Not analyzed in view of significant “Heterogeneity” across Europe
ESMO-MCBS substantial improvements • Curative setting A & B or non-curative setting 5 & 4 Curative A These drugs should ideally be accessible to all European citizens Non-curative 5 4 B 3 C 2 1
Evaluation form 1: for adjuvant and other treatments with curative intent Grade A >5% improved survival at ≥ 3 years follow-up Improvement in DFS alone (primary endpoint) (HR < 0. 65) in studies without mature survival data Grade B ≥ 3% but ≤ 5% improvement at ≥ 3 years follow-up Improvement in DFS alone (primary endpoint) (HR 0. 65 - 0. 8) without mature survival data Non inferior OS or DFS with reduced treatment toxicity or improved Qo. L (with validated scales) Non inferior OS or DFS with reduced treatment cost as reported study outcome (with equivalent outcomes and risks) Grade C < 3% improvement at ≥ 3 years follow-up Improvements in DFS alone (primary endpoint) (HR > 0. 8) in studies without mature survival data Mark with X if relevant
Evaluation form 1: for adjuvant and other treatments with curative intent Grade A >5% improved survival at ≥ 3 years follow-up Improvement in DFS alone (primary endpoint) (HR < 0. 65) in studies without mature survival data Grade B ≥ 3% but ≤ 5% improvement at ≥ 3 years follow-up Improvement in DFS alone (primary endpoint) (HR 0. 65 - 0. 8) without mature survival data Non inferior OS or DFS with reduced treatment toxicity or improved Qo. L (with validated scales) Non inferior OS or DFS with reduced treatment cost as reported study outcome (with equivalent outcomes and risks) Grade C < 3% improvement at ≥ 3 years follow-up Improvements in DFS alone (primary endpoint) (HR > 0. 8) in studies without mature survival data Mark with X if relevant
ESMO-MCBS distinctions: for treatment with non-curative intent Primary endpoint OS PFS or TTP Median with standard therapy Other than OS or PFS ≤ 6 months > 6 months ≤ 1 year > 1 year
A. Application of the scale to new drugs for poor prognosis diseases Non curative setting
Evaluation form 2 a: treatments with non-curative intent, primary endpoint OS IF median OS with the standard treatment is ≤ 1 year Grade 4 HR ≤ 0. 65 AND Gain ≥ 3 months Increase in 2 year survival alone ≥ 10% Grade 3 HR ≤ 0. 65 AND Gain 2. 5 -2. 9 months Increase in 2 year survival alone 5 - <10% Grade 2 HR > 0. 65 -0. 70 OR Gain 1. 5 -2. 4 months Increase in 2 year survival alone 3 - <5% Grade 1 HR > 0. 70 OR Gain < 1. 5 month Increase in 2 year survival alone < 3% Mark with X if relevant
B. Application of the scale for diseases with a medium prognosis Non curative setting
Evaluation form 2 a: treatments with non-curative intent, primary endpoint OS IF median OS with the standard treatment is > 1 year Grade 4 HR ≤ 0. 70 AND Gain ≥ 5 months Increase in 3 year survival alone ≥ 10% Grade 3 HR ≤ 0. 70 AND Gain 3 -4. 9 months Increase in 3 year survival alone 5 - <10% Grade 2 HR > 0. 70 -0. 75 OR Gain 1. 5 -2. 9 months Increase in 3 year survival alone 3 - <5% Grade 1 HR > 0. 75 OR Gain < 1. 5 month Increase in 3 year survival alone <3% Mark with X if relevant
Evaluation form 2 a: treatments with non-curative intent, primary endpoint OS Step 1 Preliminary magnitude of clinical benefit grade (highest grade scored) 4 Step 2 3 2 1 Assessment Qo. L & grade 3 -4 toxicities Does secondary endpoint Qo. L show improvement Are there statistically significantly fewer grade 3 -4 toxicities impacting daily well-being* *not including alopecia, myelosuppression, but rather chronic nausea, diarrhea, fatigue, etc. Adjustment: Upgrade 1 level if improved Qo. L or less toxicity or is shown Step 3 Final adjusted magnitude of clinical benefit grade 5 4 3 2 1
ESMO-MCBS distinctions: for treatment with non-curative intent Primary endpoint OS PFS or TTP Median with standard therapy Other than OS or PFS ≤ 6 months > 6 months ≤ 1 year > 1 year
Evaluation form 2 b: treatments with non-curative intent, primary endpoint PFS or TTP Studies with median PFS with standard treatment > 6 months Grade 3 HR ≤ 0. 65 AND Gain ≥ 3 months Grade 2 HR ≤ 0. 65 BUT Gain < 3 months Grade 1 HR > 0. 65 Mark with X if relevant
Evaluation form 2 b: treatments with non-curative intent, primary endpoint PFS or TTP Step 1 Preliminary magnitude of clinical benefit grade (highest grade scored) 3 Step 2 Look at OS : 2 1 if improved, go to the OS scale; if not improved, go to steps 2 and 3 Toxicity and Qo. L adjustment when only a PFS improvement
Evaluation form 2 b: treatments with non-curative intent, primary endpoint PFS or TTP Toxicity assessment (adverse effect criterion) Step 2 Is the new treatment associated with a statistically significant incremental rate of: «toxic» death > 2% cardiovascular ischemia > 2% hospitalization for «toxicity» > 10% excess rate of severe CHF > 4% grade 3 neurotoxicity > 10% severe other irreversible or longlasting toxicity > 2% please specify: Mark with X if relevant (Incremental rate refers to the comparison versus standard therapy in the control arm) Assessment Qo. L & grade 3 -4 toxicities Step 3 Was Qo. L measured as a secondary outcome Does secondary endpoint Qo. L show improvement Are there statistically significantly fewer grade 3 -4 toxicities impacting daily well-being* *not including alopecia, myelosuppression, but rather chronic nausea, diarrhea, fatigue, etc.
Evaluation form 2 b: treatments with non-curative intent, primary endpoint PFS or TTP Step 4 Final Adjustments a. Downgrade 1 level if ≥ 1 of above incremental toxicities b. Upgrade 1 level if > Qo. L or if <grade 3 -4 toxicities that bother patients c. When OS as 2 nd endpoint is improved, it prevails, score according to form 2 a d. Downgrade 1 level if the drug ONLY leads to improved PFS and Qo. L assessment does not demonstrate improved Qo. L Final, toxicity and Qo. L adjusted, magnitude of clinical benefit grade 4 3 2 1 Highest grade that can be achieved is grade 4
Field testing Breast Cancer Medication Trial Setting Chemo +/- HERA trastuzumab Primary PFS PFS HR OS OS outcome control gain (Neo)Adjuvant HER DFS 2 y DFS 8. 4% 0. 54 -2 positive tumors 77. 4% (0. 43 -0. 67) T-DM 1 vs EMILIA capecitabine + lapatinib 2 nd line metastatic PFS & OS 6. 4 m 3. 2 0. 65 25 m 6. 8 0. 68 Later after trastuzumab m (0. 55 -0. 77) m (0. 55 -0. 85) deterio failure ration Trastuzumab + CLEOPATR 1 st line metastatic PFS chemo +/- A pertuzumab Lapatinib +/- EGF 3 rd line metastatic PFS trastuzumab 104900 Capecitabine Geyer, +/- lapatinib 2006 2 nd line metastatic PFS after trastuzumab failure Eribulin vs EMBRACE 3 rd line metastatic OS other chemo after anthracycline & taxane Paclitaxel +/- Miller, 1 st line metastatic PFS bevacizumab 2007 Exemestane +/ BOLERO-2 Metastatic after PFS - everolimus failure aromatase inhibitor+PFS >6 m 12. 4 m 6 m OS HR Qo. L ESM 0 MCBS A 0. 62 40. 8 m 15. 7 0. 68 (0. 52 -0. 84) m (0. 56 -0. 84) ~ 5 4 0. 73 9. 5 m 4. 5 0. 74 (0. 57 m (0. 57 -0. 97) 0. 93) 4. 4 m 0. 49 NS (0. 34 -0. 71) 4 10. 6 m 2. 5 0. 81 m (0. 66 -0. 99) 2 2 m 1 m 5. 9 m 5. 8 0. 6 m (0. 51 -0. 70) 4. 1 m 6. 5 0. 43 m (0. 36 -0. 54) 3 NS ~ 2
Field testing Lung Cancer (1) Medication. Trial Setting Primary PFS outcome control gain PFS HR OS OS Qo. L Toxicity control HR ESM 0 MCBS 12% < serious adverse events 4 15% < severe adverse reactions 4 < toxicity 4 Erlotinib vs OPTIMEL, 1 st line stage 3 b/4 PFS carboplatin CTONG- non-squamous + gemcitabine 0802 EGFR mutation 4. 6 m 8. 5 m 0. 16 (0. 10 -0. 26) Erlotinib vs EURTAC 1 st line stage 3 b/4 PFS, Pt-based non-squamous + crossover chemo EGFR mutation allowed doublet 5. 2 m 4. 5 m 0. 37 19. 5 m (0. 25 -0. 54) Gefitinib vs IPASS carboplatin + paclitaxel 1 st line stage 3 b/4 PFS, non-squamous + crossover EGFR mutation allowed 6. 3 m 3. 3 m 0. 48 (0. 34 -0. 67) Afatinib vs LUX cisplatin + Lung 3 pemetrexed 1 st line stage 3 b/4 PFS, non-squamous + crossover EGFR mutation allowed Del 19/L 858 R 6. 9 m 4. 2 m 0. 58 (0. 43 -0. 78) 4 6. 9 m 6. 7 m 0. 47 (0. 34 -0. 65) 4 1 st line stage 3 b/4 PFS, non-squamous + crossover ALK mutation allowed 3. 0 m 4. 7 m 0. 49 (0. 37 -0. 64) 7. 0 m 3. 9 m 0. 45 (0. 35 -0. 60) Crizotinib vs Shaw chemo 2013 Crizotinib vs Solomon 1 st line stage 3 b/4 PFS cisplatin + 2014 non-squamous + pemetrexed ALK mutation NS 1% > toxic death 4 4
Conclusions and next steps Ø ESMO-MCBS offers an objective and reproducible approach to grade drugs and • To determine which drugs are immediately required for European citizens • Relevance clear based on ESMO Anti-neoplastic medicines survey • To include findings in guidelines • To support § clinical decision making § counseling patients § editorial decisions and commentaries Ø ESMO-MCBS v 1 will be published in Annals of Oncology, early release http: //annonc. oxfordjournals. org/lookup/doi/10. 1093/annonc/mdv 249 Ø Version 1 • A «lively» instrument needing regular updates by ESMO committee a) As more mature data of clinical trials become available, allowing fine tuning for efficacy and toxicity b) New drugs and new indications will become available c) Adaptations of the grading of the scale may be required
Acknowledgments • Task Force members Martine Piccart, Co-chair Richard Sullivan Nathan Cherny Urania Dafni Martijn Kerst Alberto Sobrero Christoph Zielinski • ESMO ex Board • ESMO Staff: Keith Mc. Gregor and Nicola Latino • Numerous people who helped testing the scale
BACK-UPS
Differences in access to relevant new anticancer drugs in Europe • Differences between countries in: – drug related health care expenditures – drug prices – access time to drugs after approval by EMA • Sometimes lack of drug supply in “countries with cheaper drugs” due to parallel import to “countries where the drug is more expensive”. • Unequal access within some countries: – sometimes (co)-payment of the drug costs by patients required
ESMO-MCBS for solid tumors was developed with “Snowball” method
“Snowball” method Previous work of Task Force Members 1 st draft scale Biostatisticians 1 st ESMO faculty field testing Feedback + Integration work Sobrero on role HR, prognosis & absolute differences in data interpretation 2 nd draft scale 13 drafts scale Applied in wide range of settings by Task Force & invited experts Simulation scenarios 2 nd ESMO faculty field testing Final Scale Sobrero A et al. J Clin Oncol 2009 Sobrero A et al Clin Cancer Res 2015
Underlying Premises ESMO-MCBS 1. Cure takes precedence over deferral of death 2. Direct endpoints such as survival and Qo. L take precedence over surrogates such as PFS or RR 3. DFS in curative disease is a more valid surrogate than PFS or RR in non-curative disease 4. Interpretation of the evidence for benefit derived from surrogate outcomes (such as PFS) may be influenced by secondary outcome data
3 Rules, #1 ESMO-MCBS Data derived from comparative research: 1. Priority: Strong level of evidence from large phase III studies, > lesser level of evidence from comparative cohort studies or randomized phase II studies 2. Careful analyses “control arm” and identification of endpoints. 3. Subgroup analysis. – preplanned in ESMO-MCBS when ≤ 3 subgroups defined «a priori» : benefit in a subgroup for the primary endpoint can be «scaled» , provided adjusted for multiple comparisons – unplanned not in ESMO-MCBS considered hyposthesis generating
3 Rules, #2 ESMO-MCBS a. More than one outcome may be applicable b. For a required HR, not the point estimate but the lower limit of the 95% CI is used to take into account the variability of the estimate Example: for threshold set at HR ≤ 0. 70 it is the lower limit of the 95%CI which has to be ≤ 0. 70 0. 71 0. 78 0. 86 Trial X 0. 65 Trial Y 0. 58 Trial Z 0. 5 0. 76 0. 69 0. 7 0. 89 Trial X does not qualify Trials Y and Z do qualify 0. 82 1. 0 HR
3 Rules, #3 ESMO-MCBS 1. Ni 2. Ni Check for: • indicators of severe toxicity or reduced grade 3 -4 toxicity that bothers patients • global Qo. L advantage using validated scale quality of life toxicity Ø Report final adjusted grade taken into account toxicity and Qo. L when applicable
Forms ESMO-MCBS Curative Setting → Evaluation form 1 Non-curative setting → Evaluation form 2 a, b, c 2 a: primary endpount OS 2 b: primary endpoint PFS or TTP 2 c: other primary endpoint On top of each form
Field testing Melanoma (2) version light Medication Trial Setting Dabrafenib + trametinib Robert 2015 vs vemurafenib ESM 0 MCBS 1 st line unresectable or metastatic 4* + BRAF V 600 E mutation Vemurafenib +/cobimetinib Larkin 2014 1 st line unresectable or metastatic + BRAF V 600 E mutation 4* Dacarbazine +/- nevolumab Robert 2015 1 st line unresectable or metastatic + BRAF V 600 E mutation 4 Dacarbazine +/- ipilimimab Robert 2011 Maio 2015 1 st line metastatic 3 * immature survival data
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