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

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