Appropriate e sostenibili
Alberto Sobrero
IRCCS San Martino IST
Genova
Clinical determinants of our choicesClinical 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
OSPFSRR
QOL
Prognosis of the
conditionToxicity
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 & 4
5
4
3
2
1
A
B
C
Curative Non-curative
Higher priorityfor 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
IF median OS with the standard treatment is ≤ 1 year
HR ≤ 0.65 AND Gain ≥ 3 monthsIncrease in 2 year survival alone ≥ 10%
Grade 3
Grade 2
HR ≤ 0.65 AND Gain 2.5-2.9 monthsIncrease in 2 year survival alone 5- <10%
HR > 0.65-0.70 OR Gain 1.5-2.4 monthsIncrease in 2 year survival alone 3- <5%
Grade 1HR > 0.70 OR Gain < 1.5 monthIncrease in 2 year survival alone < 3%
Grade 4
Evaluation form 2a: treatments with non-curative intent, primary endpoint OS
4 3 2 1
Preliminary magnitude of clinical benefit grade (highest grade scored)
Does secondary endpoint QoL show improvementAre there statistically significantly < grade 3-4 toxicities impacting daily well-being*
Assessment QoL & grade 3-4 toxicities
Final adjusted magnitude of clinical benefit grade5 4 3 2 1
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.
Studies with median PFS with standard treatment ≤ 6 months
HR ≤ 0.65 BUT Gain < 1.5 monthsGrade 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
Evaluation form 2b: treatments with non-curative intent, primary endpoint PFS or TTP
3 2 1
Preliminary magnitude of clinical benefit grade (highest grade scored)Step 1
Toxicity and QoL adjustment when only a PFS improvement
Field testing Breast CancerMedication Trial Setting Primary
outcomePFS
controlPFS gain
PFS HR OS control
OS gain
OS HR QoL ESM0-MCBS
Chemo +/- trastuzumab
HERA (Neo)Adjuvant HER-2 positive tumors
DFS 2 y DFS 77.4%
8.4% 0.54 (0.43-0.67)
A
T-DM1 vs capecitabine + lapatinib
EMILIA 2nd line metastatic after trastuzumab failure
PFS & OS 6.4 m 3.2 m
0.65 (0.55-0.77)
25 m 6.8 m
0.68 (0.55-0.85)
Later deterioration
5
Trastuzumab + chemo +/- pertuzumab
CLEOPATRA 1st line metastatic PFS 12.4 m 6 m 0.62 (0.52-0.84)
40.8 m 15.7 m
0.68 (0.56-0.84)
~ 4
Lapatinib +/-trastuzumab
EGF104900
3rd line metastatic PFS 2 m 1 m 0.73 (0.57-0.93)
9.5 m 4.5 m
0.74 (0.57-0.97)
4
Capecitabine +/- lapatinib
Geyer, 2006
2nd line metastatic after trastuzumab failure
PFS 4.4 m 4 m 0.49 (0.34-0.71)
NS 3
Eribulin vs other chemo
EMBRACE 3rd line metastatic after anthracycline & taxane
OS 10.6 m 2.5 m
0.81 (0.66-0.99)
2
Paclitaxel +/- bevacizumab
Miller, 2007
1st line metastatic PFS 5.9 m 5.8 m
0.6 (0.51-0.70)
NS ~ 2
Exemestane +/- everolimus
BOLERO-2 Metastatic after failure aromatase inhibitor+PFS >6 m
PFS 4.1 m 6.5 m
0.43 (0.36-0.54)
NS ~ 2
Medication Trial Setting Primary outcome
PFS control
PFS gain
PFS HR
OS control
OS HR
QoL Toxicity ESM0-MCBS
Erlotinib vs Pt-based chemo doublet
EURTAC 1st line stage 3b/4 non-squamous + EGFR mutation
PFS, crossover allowed
5.2 m 4.5 m 0.37 (0.25-0.54)
19.5 m NS 15% < severe adverse
reactions
4
Gefitinib vs carboplatin + paclitaxel
IPASS 1st line stage 3b/4 non-squamous + EGFR mutation
PFS, crossover allowed
6.3 m 3.3 m 0.48 (0.34-0.67)
< toxicity 4
Afatinib vs cisplatin + pemetrexed
LUXLung 3
1st line stage 3b/4 non-squamous + EGFR mutation
PFS,crossover allowed
6.9 m 4.2 m 0.58 (0.43-0.78)
4
Del19/L858R 6.9 m 6.7 m 0.47 (0.34-0.65)
4
Crizotinib vs chemo
Shaw 2013
1st line stage 3b/4 non-squamous + ALK mutation
PFS, crossover allowed
3.0 m 4.7 m 0.49 (0.37-0.64)
1% > toxic death
4
Field testing Lung Cancer (1)
Medication Trial Setting ESM0-MCBS
Pemetrexed vs placebo Ciuleanu 2009 Stage 3b/4 maintenanceafter response on 4 Pt doublets
4
Cisplatin pemetrexed vs cisplatin gemcitabine
Scagliotti 2008
1st line 3b/4 (non-squamous) 4
Chemo +/- palliative care Temel 2010
Stage 4 NSCLC ECOG<2 4
Paclitaxel/carboplatin +/- bevacizumab
Sandler 2006
1st line stage 3b or 4, non-squamous
2
Erlotinib vs placebo SATURN Stage 3b/4 diseasemaintenance after response to 4-6 cycles Pt doublet
1
Field testing Lung Cancer (2) version light
Medication Trial Setting ESM0-MCBS
FOLFOX4 +/- panitumumab PRIME 1st line metastatic (post hoc KRAS, NRAS BRAF WT)
4
FOLFIRI +/- cetuximab CRYSTAL 1st line metastatic stratified for (post hoc KRAS, NRAS BRAF WT)
4
Cetuximab vs best supportive care Karapetis 2008 Refractory metastatic KRAS-WT 4
FOLFOX4 +/- panitumumab PRIME 1st line metastatic KRAS-WT 3
FOLFIRI +/- cetuximab CRYSTAL 1st line metastatic stratified for KWAS-WT
3
ILF +/- bevacizumab Hurwitz 2004 1st line metastatic 3
Field testing Colorectal Cancer (1) version light
Medication Trial Setting ESM0-MCBS
FOLFOX +/- bevacizumab vs bevacizumab alone
E3200 2nd line metastatic after FOLFIRI 2
Panitumumab vs best supportive care
Amado, 2008 3rd line metastatic stratified for KRAS 2
FOLFIRI bevacizumab vs FOLFOXIRI bevacizumab
Loupakis 2014 1st line metastatic 2
TAS-102 vs placebo CONCOURSE 3rd line or beyond metastatic 2
Regorafenib vs placebo CORRECT 3rd line metastatic 1
2nd line chemotherapy +/- bevacizumab
ML18147 2nd line beyond progression on bevacizumab
1
FOLFIRI +/- aflibercept VELOUR 2nd line after oxaliplatin based treatment
1
Field testing Colorectal Cancer (2) version light
Days since randomisation
CORRECTRegorafenib
n=505Placebon=255
Median OS, months 6.4 5.0
HR (95%CI) 0.77 (0.64, 0.94)
P-value 0.0052
CONCURRegorafenib
n=136Placebo
n=68
Median OS, months 8.8 6.3
HR (95%CI) 0.550 (0.395, 0.765)
P-value 0.0002 (1-sidded)
0.2
0.0
0.4
0.6
0.8
1.0
Ove
rall
surv
ival
pro
babi
lity
0 100 300 600500400200
CONCUR2: 45% reduction in the risk of death
(primary endpoint)
Regorafenib 160 mg + BSC Placebo + BSC
Time from randomisation (months)
00 6 10 14842 12
Regorafenib 160 mg + BSCPlacebo + BSC
100
75
50
25Ove
rall
surv
ival
%
CORRECT1: 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
E 1-5 OS x16 max 80PFS x11RR x8
T 1-5 +75%- +100% -20+50%- +74% -10+49%- -49% 0-50%- -74% +10 max 20-75%- -100% +20
BONUS sx palliation +10 Rx-free interval +20 max 30
TOTAL NET HEALTH BENEFIT SCORE max 130
NET HEALTH BENEFIT ( ASCO 2015)
• NSCLC Pemetrexed 0/130
• NSCLC Bevacizumab 16/130
• NSCLC Erlotinib 44/130
• Prostate Enzalutamide 32/130
• Prostate Abiraterone 42/130
• Colon TAS 102 26/130 90/130
• Colon FOLFOXIRI - 4/130
NHB ASCO MCBS ESMO
• NSCLC Pemetrexed 0/130 4
• NSCLC Bevacizumab 16/130 2
• NSCLC Erlotinib 44/130 4
• Prostate Enzalutamide 32/130 4
• Prostate Abiraterone 42/130 4
• Colon TAS 102 26/130 90/130 2
• 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 months14%
2. HR 0.50 and median gain 5 months20%
3. HR 0.66 and median gain 4 months66%
Mission impossible: correspondence among endpoints. Control has MST of 14 m and PFS of 6 m
Drug A gives an improvement in OS of HR 0.75 and MST gain of 2.5 monthsWhat would be the corresponding benefit in PFS?
4. There is no way to compare the extent of benefit
Medication Trial Setting ESM0-MCBS
Ipilimumab +/- glycoprotein 100 vaccine vs vaccine alone
Hodi 2010
Previously treated metastatic 4
Vemurafenib vs dacarbazine
BRIM-3 1st line or 2nd line after IL-2 metastatic + BRAF V600E mutation
4
Trametinib vs dacarbazine or paclitaxel
METRIC Unresectable or metastatic + BRAF V600E mutation
4*
Dabrafenib +/- trametinib
Flagerty 2012
1st line unresectable or metastatic+ BRAF V600E mutation
4
Dabrafenib vs dacarbazine
Hauschild 2012Grob 2014
1st line unresectable or metastatic + BRAF V600E mutation
4
Field testing Melanoma (1) version light
* immature survival data
Medication Trial Setting ESM0-MCBS
Dabrafenib + trametinib vs vemurafenib
Robert 2015 1st line unresectable or metastatic + BRAF V600E mutation
4*
Vemurafenib +/- cobimetinib
Larkin 2014 1st line unresectable or metastatic + BRAF V600E mutation
4*
Dacarbazine +/- nivolumab
Robert 2015 1st line unresectable or metastatic+ BRAF V600E mutation
4
Dacarbazine +/- ipilimimab
Robert 2011Maio 2015
1st line metastatic 3
Field testing Melanoma (2) version light
* immature survival data