Appropriate e sostenibili Alberto Sobrero IRCCS San Martino IST Genova Alberto Sobrero IRCCS San Martino IST Genova

Clinical determinants of our choices PATIENT TUMOR TREATMENT Age PS Comorbid. Attitude Resectability Symptoms Bulk Clin. course Efficacy toxicity logistics (cost)

Factors taken into account for ESMO-MCBS HR Gains in median Long term effects OS PFS RR QOL Prognosis of the condition Toxicity Costs Magnitude clinically benefit Not analyzed in view of significant “Heterogeneity” across Europe

ESMO-MCBS substantial improvements Curative setting A & B or non-curative setting 5 & ABCABC Curative Non-curative Higher priority for rapid access across EU Cherney NI, et al. Ann Oncol. 2015;26(8): 1547–1573.

PFS or TTP Primary endpoint OS Median with standard therapy ≤ 1 year > 1 year Median with standard therapy ≤ 6 months> 6 months Other than OS or PFS No downgrading for gr 3-4 toxicities Upgrade possible if less gr 3-4 tox a/o better Q of life Downgrading for gr 3-4 toxicities Upgrade possible if less gr 3-4 tox a/o better Q of life ESMO-MCBS distinctions: for treatment with non-curative intent

Evaluation form 2a: treatments with non-curative intent, primary endpoint OS Mark with X if relevant ≤ 1 year IF median OS with the standard treatment is ≤ 1 year HR ≤ 0.65 AND Gain ≥ 3 months Increase in 2 year survival alone ≥ 10% Grade 3 Grade 2 HR ≤ 0.65 AND Gain months Increase in 2 year survival alone 5- <10% HR > OR Gain 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% Grade 4

Evaluation form 2a: treatments with non-curative intent, primary endpoint OS 4321 Preliminary magnitude of clinical benefit grade (highest grade scored) Does secondary endpoint QoL show improvement Are there statistically significantly < grade 3-4 toxicities impacting daily well-being* Assessment QoL & grade 3-4 toxicities Final adjusted magnitude of clinical benefit grade Adjustment: Upgrade 1 level if improved QoL or less toxicity or is shown Step 1 Step 2 Step 3 *not including alopecia, myelosuppression, but rather chronic nausea, diarrhea, fatigue, etc.

6 months Studies with median PFS with standard treatment ≤ 6 months HR ≤ 0.65 BUT Gain < 1.5 months Grade 2 Grade 1 Grade 3 HR ≤ 0.65 AND Gain ≥ 1.5 months HR > 0.65 Mark with X if relevant Evaluation form 2b: treatments with non-curative intent, primary endpoint PFS or TTP

321 Preliminary magnitude of clinical benefit grade (highest grade scored) Step 1 Toxicity and QoL adjustment when only a PFS improvement

Field testing Breast Cancer MedicationTrialSettingPrimary outcome PFS control PFS gain PFS HROS control OS gain OS HRQoLESM0 - MCBS Chemo +/- trastuzumab HERA(Neo)Adjuvant HER-2 positive tumors DFS2 y DFS 77.4% 8.4%0.54 ( ) A T-DM1 vs capecitabine + lapatinib EMILIA2 nd line metastatic after trastuzumab failure PFS & OS6.4 m3.2 m 0.65 ( ) 25 m6.8 m 0.68 ( ) Later deterio ration 5 Trastuzumab + chemo +/- pertuzumab CLEOPATRA1 st line metastaticPFS12.4 m6 m0.62 ( ) 40.8 m15.7 m 0.68 ( ) ~ 4 Lapatinib +/- trastuzumab EGF rd line metastaticPFS2 m1 m0.73 ( ) 9.5 m4.5 m 0.74 ( ) 4 Capecitabine +/- lapatinib Geyer, nd line metastatic after trastuzumab failure PFS4.4 m4 m0.49 ( ) NS 3 Eribulin vs other chemo EMBRACE3 rd line metastatic after anthracycline & taxane OS10.6 m2.5 m 0.81 ( ) 2 Paclitaxel +/- bevacizumab Miller, st line metastaticPFS5.9 m5.8 m 0.6 ( ) NS~ 2 Exemestane +/- everolimus BOLERO-2Metastatic after failure aromatase inhibitor+PFS >6 m PFS4.1 m6.5 m 0.43 ( ) NS~ 2

MedicationTrial SettingPrimary outcome PFS control PFS gain PFS HR OS control OS HR QoLToxicityESM0- MCBS Erlotinib vs Pt-based chemo doublet EURTAC1 st line stage 3b/4 non-squamous + EGFR mutation PFS, crossover allowed 5.2 m4.5 m0.37 ( ) 19.5 mNS15% < severe adverse reactions 4 Gefitinib vs carboplatin + paclitaxel IPASS1 st line stage 3b/4 non-squamous + EGFR mutation PFS, crossover allowed 6.3 m3.3 m0.48 ( ) < toxicity 4 Afatinib vs cisplatin + pemetrexed LUX Lung 3 1 st line stage 3b/4 non-squamous + EGFR mutation PFS, crossover allowed 6.9 m4.2 m0.58 ( ) 4 Del19/L858R6.9 m6.7 m0.47 ( ) 4 Crizotinib vs chemo Shaw st line stage 3b/4 non-squamous + ALK mutation PFS, crossover allowed 3.0 m4.7 m0.49 ( ) 1% > toxic death 4 Field testing Lung Cancer (1)

MedicationTrialSettingESM0-MCBS Pemetrexed vs placeboCiuleanu 2009Stage 3b/4 maintenance after response on 4 Pt doublets 4 Cisplatin pemetrexed vs cisplatin gemcitabine Scagliotti st line 3b/4 (non-squamous)4 Chemo +/- palliative careTemel 2010 Stage 4 NSCLC ECOG<24 Paclitaxel/ carboplatin +/- bevacizumab Sandler st line stage 3b or 4, non-squamous 2 Erlotinib vs placeboSATURNStage 3b/4 disease maintenance after response to 4-6 cycles Pt doublet 1 Field testing Lung Cancer (2) version light

MedicationTrialSettingESM0-MCBS FOLFOX4 +/- panitumumabPRIME1 st line metastatic (post hoc KRAS, NRAS BRAF WT) 4 FOLFIRI +/- cetuximabCRYSTAL1 st line metastatic stratified for (post hoc KRAS, NRAS BRAF WT) 4 Cetuximab vs best supportive careKarapetis 2008Refractory metastatic KRAS-WT 4 FOLFOX4 +/- panitumumabPRIME1 st line metastatic KRAS-WT 3 FOLFIRI +/- cetuximabCRYSTAL1 st line metastatic stratified for KWAS-WT 3 ILF +/- bevacizumabHurwitz st line metastatic 3 Field testing Colorectal Cancer (1) version light

MedicationTrialSettingESM0-MCBS FOLFOX +/- bevacizumab vs bevacizumab alone E32002 nd line metastatic after FOLFIRI 2 Panitumumab vs best supportive care Amado, rd line metastatic stratified for KRAS 2 FOLFIRI bevacizumab vs FOLFOXIRI bevacizumab Loupakis st line metastatic 2 TAS-102 vs placeboCONCOURSE3 rd line or beyond metastatic 2 Regorafenib vs placeboCORRECT3 rd line metastatic 1 2 nd line chemotherapy +/- bevacizumab ML nd line beyond progression on bevacizumab 1 FOLFIRI +/- afliberceptVELOUR2 nd line after oxaliplatin based treatment 1 Field testing Colorectal Cancer (2) version light

Days since randomisation CORRECT Regorafenib n=505 Placebo n=255 Median OS, months HR (95%CI)0.77 (0.64, 0.94) P-value CONCUR Regorafenib n=136 Placebo n=68 Median OS, months HR (95%CI)0.550 (0.395, 0.765) P-value (1-sidded) Overall survival probability CONCUR 2 : 45% reduction in the risk of death (primary endpoint) Regorafenib 160 mg + BSC Placebo + BSC Time from randomisation (months) Regorafenib 160 mg + BSC Placebo + BSC Overall survival % CORRECT 1 : 23% reduction in the risk of death (primary endpoint) BSC, best supportive care; CI, confidence interval; HR, hazard ratio; OS, overall survival 1. Grothey A, et al. Lancet 2013;381:303–12; 2. Li J, et al. Lancet Oncol 2015;16:619–29. Significant improvements in OS with regorafenib vs. placebo in CORRECT and CONCUR trials

ASCO VALUE FRAMEWORK E1-5OS x16max 80 PFSx11 RRx8 T1-5+75%- +100% %- +74% %- -49% 0 -50%- -74%+10max %- -100% +20 BONUS sx palliation +10 Rx-free interval+20max 30 TOTAL NET HEALTH BENEFIT SCORE max 130

NET HEALTH BENEFIT ( ASCO 2015) NSCLC Pemetrexed 0/130 NSCLC Bevacizumab16/130 NSCLC Erlotinib44/130 ProstateEnzalutamide 32/130 Prostate Abiraterone42/130 Colon TAS /130 90/130 Colon FOLFOXIRI- 4/130 NSCLC Pemetrexed 0/130 NSCLC Bevacizumab16/130 NSCLC Erlotinib44/130 ProstateEnzalutamide 32/130 Prostate Abiraterone42/130 Colon TAS /130 90/130 Colon FOLFOXIRI- 4/130

NHB ASCO MCBS ESMO NSCLC Pemetrexed 0/1304 NSCLC Bevacizumab16/1302 NSCLC Erlotinib44/1304 ProstateEnzalutamide 32/1304 Prostate Abiraterone42/1304 Colon TAS /130 90/1302 Colon FOLFOXIRI- 4/130 1 NSCLC Pemetrexed 0/1304 NSCLC Bevacizumab16/1302 NSCLC Erlotinib44/1304 ProstateEnzalutamide 32/1304 Prostate Abiraterone42/1304 Colon TAS /130 90/1302 Colon FOLFOXIRI- 4/130 1

PROBLEMS: How about 1.‘Curative’ 2.PFS 3.Other efficacy endpoints 4.Pt reported outcomes 5.The impact of toxicity

1.HR 0.33 and median gain 6 months 14% 2.HR 0.50 and median gain 5 months 20% 3.HR 0.66 and median gain 4 months 66% Mission impossible: correspondence among endpoints. Control has MST of 14 m and PFS of 6 m Vote Trigger Drug A gives an improvement in OS of HR 0.75 and MST gain of 2.5 months What would be the corresponding benefit in PFS? 4.There is no way to compare the extent of benefit

MedicationTrialSettingESM0-MCBS Ipilimumab +/- glycoprotein 100 vaccine vs vaccine alone Hodi 2010 Previously treated metastatic4 Vemurafenib vs dacarbazine BRIM-31 st line or 2 nd line after IL-2 metastatic + BRAF V600E mutation 4 Trametinib vs dacarbazine or paclitaxel METRICUnresectable or metastatic + BRAF V600E mutation 4* Dabrafenib +/- trametinib Flagerty st line unresectable or metastatic + BRAF V600E mutation 4 Dabrafenib vs dacarbazine Hauschild 2012 Grob st line unresectable or metastatic + BRAF V600E mutation 4 Field testing Melanoma (1) version light * immature survival data

MedicationTrialSettingESM0- MCBS Dabrafenib + trametinib vs vemurafenib Robert st line unresectable or metastatic + BRAF V600E mutation 4* Vemurafenib +/- cobimetinib Larkin st line unresectable or metastatic + BRAF V600E mutation 4* Dacarbazine +/- nivolumab Robert st line unresectable or metastatic + BRAF V600E mutation 4 Dacarbazine +/- ipilimimab Robert 2011 Maio st line metastatic3 Field testing Melanoma (2) version light * immature survival data