Il “valore” in Oncologia: verso una visione innovativa, comprensiva del paziente e della sua malattia

Sergio Bracarda MD Head, Medical Oncology Az. Ospedaliera S. Maria

Terni; Italy

Spoleto, 10 Settembre 2018

Chiudi gli occhi e pensa alla tua interpretazione di: “Valore” in Oncologia …

• Valore della Vita per il paziente oncologico, e importanza della qualità di questa vita

• Valore del “tempo” per il paziente,

.. e suo rispetto (tempi di attesa, n° di accessi in Ospedale) …

• Valore della (buona) Comunicazione Medico-Paziente,

.. Ma anche della necessaria formazione in merito …

• Valore dei nuovi Farmaci

.. Ma anche loro costo elevato e sostenibilità del Sistema …

• Valore del Volontariato,

.. e suo riconoscimento e valorizzazione …

Chiudi gli occhi e pensa alla tua interpretazione di: “Valore” in Oncologia …

Esiti complessivi della Cura (Efficacia e Tollerabilità)

• Valore* = ______________________________________________

Costi della Cura (Diretti e Indiretti

• E cioè, valore dei risultati complessivi ottenuti (o ottenibili) per il Paziente in termini di Appropriatezza e Qualità.

• Moving from EBM (Evidence Based Medicine) to VBM (Value Based Medicine) …

* da attribuire a tutto l’intervallo di tempo della malattia e non a fasi o farmaci specifici della stessa.

… I Classici End Points in Oncologia ….

• Efficacia

& ….

• QoL

… Spesso alternativi in passato

… I Classici End Points in Oncologia ….

• Efficacia:

now, frequently .. :

• QoL:

moving…:

→PFS % →OS %

Cure: +/- 20%

Chronic. 80%

→

QoL (a measure of..), usually discrepant in respect to Physician’

values %

→

status. More comparable to Physician perception?

%

End Points in Oncology: a new Model of Care ?

• Efficacia:

• QoL:

%

Divergence

% → To

Convergence

From alternative Efficacy End Points (one or the other..) in the past, to convergent End Points in –some-new Models of Care:

This is, really,The Patient in the Middle !!!

→ How & Which Ones ?

New Models of Care in Oncology

• Background:

New Biological Data

New Treatment Options

Less (frequently, but not always..) Toxic Profiles

…. but ... also shorter Follow Up Data in respect to previous Treatment Approaches !

New Models of Care in Oncology

• Some Examples:

Obviously MM & Breast Cancer

Obviously Lung Cancer (NSCLC Hystotipes) H &N (with some delusions…)

CRC (with some promises…) Kidney Cancer (Wow !!)

Prostate Cancer (quickly evolving...)

UBC (moving to a new model in only 3 years …?)

MM

Breast Cancer

AdenoC. EGFR, ALK, Ros-1 NSCLC: PD-L1

EGFR Resistant: T790m (Osimertinib)

Prostate Cancer: AR-Vx, PTEN Status, MMR Kidney Cancer: VEGF-I, I-O,

Urothelial Cancer: I-O, FGF GU Cancers

ER & PgR, Her-2,

Gastric Cancer: Her-2, I-O, Other ..

Colon Cancer: EGFR, K-Ras, bRAF, MSI BRAF V600E, CheckPoint Inh.

GI Cancers:

NSCLC

Moving from Traditional to Innovative Treatment Approaches in Oncology

Targeting AR: the Sequencing Dilemma:

New HT Drug-1 followed by new HT Drug-2

… the inverse Sequencing … or ... Chemoth. ? ... (…. this is the problem ...)

Prostate Cancer:

New Targets for the 3rd Millenium ?

mCRPC: Abiraterone Following Disease Progression on Enzalutamide and Vice Versa

• Abiraterone response after prior treatment with enzalutamide¹

• Enzalutamide versus docetaxel in men with CRPC progressing after abiraterone²

1. Loriot Y, et al. Ann Oncol 2013;24:1807-1812. 2. Suzman DL, et al. Prostate. 2014; 74:1278-1285.

Is there a ^{place for Treatment} Selection ?

AR-Vx: which Role, if any (at the ^{moment..) ?}

Moreover: It’s still valid the Antonarakis’s message (from 0% to 100% for ARS and CT),

or something change ?

Emergingclinical evidence

14 Antona rakis ES, et al. N Engl J Med 2 014; 3 71:102 8-1038

Scher et al. JAMA Oncol. 2016 Jun 4.

Emergingclinical evidence

14 Antonarakis ES, et al. N Engl J Med 2014; 371:1028-1038

Take Home Message:

Similar Efficacy than DCT-CT Better Safety Profile.

Query: not completely overlapping Indications?

B) ^{PTEN LOSS} & PROGNOSIS ^{IN MCRPC}

Newly diagnosed, or surgically

resectedpatients with PTEN ^{loss or} low expression demonstrated an increased ^{risk for recurrence and}

death^1-6

In abiraterone-treated ^mCRPC patients, PTEN ^{loss by IHC was} associatedwith a shorter mOS¹ Paired intra-patient tumor samples from either ^{archival hormone-} sensitive ^{prostate tissues or}

castration-resistant ^{fresh biopsies} demonstrated a high concordance in PTEN status by IHC (86%)¹

15

Courtesy De Bono et al, Ipatasertib, ESMO 2016

0 12 24 36 48 60 72 84 96 0

50 100

k Time to death (months)

Overall Survival (%)

Overall Survival (95% CI) PTEN negative 13.9 (9.5 -18.2) PTEN positive 20.7 (13.8-26.6)

HR 1.75 (95% CI 1.19-2.55) P=0.004

IHC, immunohistochemistry; mOS, median overall survival.

1. Ferraldeschi et al. Eur Urol.2015. 4. Kim et al. PLOS. 2015.

2. Cuzick et al. BJC. 2013. 5. Chaux et al. Mod Pathol. 2012.

3. Reid et al. BJC. 2010. 6. Ahearn et al. J Natl Cancer Inst.2015.

PTEN loss

HR,^a0.39 (0.22-0.70)

CO-PRIMARY ENDPOINT: RPFS WITH IPATASERTIB OR PLACEBO + ABIRATERONE BY ICR IHC

15

aUnstratified HR; 90% CI.

400 mg Ipatasertib200 mg Ipatasertib

PTEN non-loss

HR,^a0.84 (0.51-1.37)

400 mg Ipat + Abi Median 7.5 mo

Pbo + Abi Median 5.6 mo

Courtesy de Bono et al, Ipatasertib, ESMO 2016

HR,^a1.13 (0.69-1.85)

200 mg Ipat + Abi Median 4.6 mo

Pbo + Abi Median 5.6 mo Pbo + Abi

Median 4.6 mo 400 mg Ipat + Abi Median 11.5 mo

HR,^a0.46 (0.25-0.83)

200 mg Ipat + Abi Median 11.1 mo

Pbo + Abi

Median 4.6 mo Take Home Message:

Increased Efficacy than Abi alone (in Target expressing cases)

Similar Safety Profile.

Query: Randomized Phase III ongoing

B) ^{PTEN LOSS} & PROGNOSIS ^{IN MCRPC}

Newly diagnosed, or surgically

resectedpatients with PTEN ^{loss or} low expression demonstrated an increased ^{risk for recurrence and}

death^1-6

In abiraterone-treated ^mCRPC patients, PTEN ^{loss by IHC was} associatedwith a shorter mOS¹ Paired intra-patient tumor samples from either ^{archival hormone-} sensitive ^{prostate tissues or}

castration-resistant ^{fresh biopsies} demonstrated a high concordance in PTEN status by IHC (86%)¹

15

Courtesy De Bono et al, Ipatasertib, ESMO 2016

0 12 24 36 48 60 72 84 96 0

50 100

k Time to death (months)

Overall Survival (%)

Overall Survival (95% CI) PTEN negative 13.9 (9.5 -18.2) PTEN positive 20.7 (13.8-26.6)

HR 1.75 (95% CI 1.19-2.55) P=0.004

IHC, immunohistochemistry; mOS, median overall survival.

1. Ferraldeschi et al. Eur Urol.2015. 4. Kim et al. PLOS. 2015.

2. Cuzick et al. BJC. 2013. 5. Chaux et al. Mod Pathol. 2012.

3. Reid et al. BJC. 2010. 6. Ahearn et al. J Natl Cancer Inst.2015.

• 50 pts with mCRPC in the Study

• Prior DCT in 50; Prior Abi or Enza in 49; Prior Caba in 29

• 16 of 49 evaluable cases responded (33%: as PSA response, RECIST 1.1 or CTC fall count).

• 14/16 of the mCRPC responding Pts with genetic defects in DNA damage repair genes

(BRCA2, ATM, Fanconi’s Anemia genes, CHEK2) responded to the PARP inhibitor Olaparib.

• Of these 14 Pts: 7/7 of BRCA2 loss and 4/5 ATM aberrations

• Anemia (20%) and Fatigue (12%) most common gr. 3-4 AEs

• Specificity of the Biomarker Suite (DNA repair gene) for Response: 94%

Mateo J et al. N Engl J Med 2015;373:1697-1708 Original Article

DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer

Joaquin Mateo, M.D., Suzanne Carreira, Ph.D., Shahneen Sandhu, M.D., Susana Miranda, et Al.

N Engl J Med

Volume 373(18):1697-1708 October 29, 2015

Olaparib in mCRPC:

PFS & OS

Mateo J, et al. N Engl J Med. 2015;373:1697-1708.

Take Home Message:

New Target

Good Safety Profile Query: still unconfirmed data for Efficacy

Histology and setting

Risk group Standard

Clear-cell Post cytokines Axitinib [I, A]

Sorafenib [I, A]

Pazopanib [II, A]

Post TKIs Cabozantinib [I, A]

Nivolumab [I, A]

New Second line Setting, already old ?

Escudier, et al. Ann Oncol 2016

METEOR: OS*

Choueiri et al. NEJM 2015

*Interim analysis (49% information fraction)

Medians cannot yet be estimated due to frequent early censoring

METEOR: phase III study of cabozantinib vs everolimus in mRCC patients who received at least 1 prior VEGFR TKI^1,2

•Pri mary endpoint: PFS

•Secondary endpoints: OS, ORR

•Expl oratory endpoints: safety, tolerabil ity, tumour MET status, circulating tumour cells, serum bone m arkers and plasm a biomarkers, skeletal-related events, and HRQoL

•Stratification: MSKCC risk criteria; num ber of prior VEGFR TKIs Eligibility:

•mRCC with clear-cell component

•At least 1 prior VEGFR TKI

•Progression on pri or VEGFR TKI within 6 months of study enrolment

•Karnofsky PS ≥70

Cabozantinib 60 mg oral ly daily

Everolimus 10 mg oral ly daily R

A N D O M I S A T I O N

N=658 1:1

1. www.clinicaltrials.gov ( NCT01865747);

2. Choueir i et al. NEJ M 2015

ASCO 2016

CheckMate-025:

Phase III study of Nivolumab vs Everolimus in locally advanced/mRCC with prior anti-angiogenic

therapy^1,2

•Primary endpoint: OS

•Secondary endpoints: PFS, ORR, DOR, duration of OS in PD-L1-positive vs PD-L1-negative subgroups, safety, disease-related symptom progression rate

•Stratification: MSKCC risk criteria; number of prior anti-angiogenic therapies; region Eligibility:

• Advanced or mRCC with clear-cell component

• Received 1 or 2 prior anti-angiogenic therapies

• Progression on or after most recent therapy (within 6 months of study enrolment)

• Karnofsky PS ≥70

Nivolumab 3 mg/kg IV every 2 weeks

Everolimus 10 mg orally daily R

A N D O M I S A T I O N N=821

1:1

Treatment until disease progression or unacceptable toxicity

1. www.clinicaltrials.gov (NCT01668784);

et al. NEJM

RCC: 2016 ESMO Guidelines

Updated Results

4 Nivolumab

Overall Survival (Probability)

0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

6 12 18

Months

24 30 36 42

Everolimus Median OS, months (95% CI) Nivolumab 26.0 (22.2–29.6) Everolimus 19.7 (17.6–22.3) HR (95% CI) 0.73 (0.61–0.88) P = 0.0006

3 9 15 21 27 33 39

No. at risk Nivolumab Everolimus

410 359 305 251 204 129 38 0

411 325 268 214 162 103 32 0

390 337 276 225 171 80 5

367 289 247 183 130 61 5

52%

76%

67%

42%

•Minimum follow-up 26 months at the database lock on May 11, 2016 (Figure 2)

•Median OS benefit observed with nivolumab versus everolimus in pts with MSKCC intermediate risk (21.9 vs 18.4 months, respectively) and poor risk (15.3 vs 7.9 months)

Fig. 2. Overall Survival

Adapted from poster presented by Plimack ER et al at the 15th International Kidney Cancer Symposium; November 4–5, 2016; Miami, FL, USA.

CheckMate-025 Study. Two-Year Efficacy & Safety Update.

Renal Cell Carcinoma(s)

CheckMate 214: Efficacy and Safety of Nivolumab Plus Ipilimumab vs Sunitinib for Treatment-Naïve

Advanced or Metastatic RCC, Including IMDC Risk and PD-L1 Expression Subgroups.

Bernard Escudier, et al LBA5

Overall Survival (IMDC intermediate/poor risk)

Hazard ratio (99.8% CI), 0.63 (0.44–0.89) P < 0.0001

Median OS, months (95% CI) NIVO + IPI NR (28.2–NE)

SUN 26.0 (22.1–NE)

Overall Survival (Probability)

425 399 372 348 332 318 300 241 119 44 2 0

422 387 352 315 288 253 225 179 89 34 3 0

No. at Risk NIVO + IPI

SUN

Months 1.0

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

18 21 24 27 30 33

15 12

9 6

3 0

Co-primary endpoint

CheckMate 214: Study design

Treatment until progression or unacceptable

toxicity

• Treatment-naïve advanced or metastatic clear-cell RCC

• Measurable disease

• KPS ≥70%

• Tumor tissue available for PD-L1 testing

Treatment Patients

Randomize 1:1 3 mg/kg nivolumab IV + ^{Arm A} 1 mg/kg ipilimumab IV Q3W

for four doses, then 3 mg/kg nivolumab IV Q2W

Arm B 50 mg sunitinib orally once

daily for 4 weeks (6-week cycles)

Stratified by

•IMDC prognostic score (0 vs 1–2 vs 3–6)

•Region (US vs Canada/Europe vs Rest of World)

284 202 155 119 102 90 70 23 9 1 0

278 200 138 105 83 67 43 25 11 1 0

IMDC (intermediate/poor risk) PFS by PD-L1 expression:

PD-L1 <1% (n = 562) PD-L1 ≥1% (n = 214)

HR (95% CI) 0.48 (0.28–0.82) P = 0.0003

Median PFS, months (95% CI) NIVO + IPI 22.8 (9.4–NE)

SUN 5.9 (4.4–7.1)

HR (95% CI) 1.00 (0.74–1.36) P = 0.9670

Median PFS, months (95% CI) NIVO + IPI 11.0 (8.1–14.9)

SUN 10.4 (7.5–13.8)

NIVO SUN No. at

Risk

100 77 61 54 50 48 41 21 8 2 0

114 63 40 24 17 13 9 4 0 0 3

0.8 0.9 1.0

0.4 0.5 0.6 0.7

0 3 6 9 12 15 18 21 24 27 30

0.1 0.0 0.2 0.3 0.8

0.9 1.0

0.4 0.5 0.6 0.7

0 3 6 9 12 15 18 21 24 27 30

0.1 0.0 0.2 0.3

Progression-Free Survival (Probability)

Months Months

Exploratory endpoint

0 3 6 9 12 15 18 21 24 27 30

PFS per IRRC: IMDC intermediate/poor risk

Hazard ratio (99.1% CI), 0.82 (0.64–1.05) P = 0.0331 Median PFS, months (95% CI) NIVO + IPI 11.6 (8.7–15.5)

SUN 8.4 (7.0–10.8)

Progression-Free Survival (Probability)

425 304 233 187 163 149 118 46 17 3 0

422 282 191 139 107 86 57 33 11 1 0

No. at Risk NIVO + IPI SUN

Months 1.0

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Co-primary endpoint

CheckMate-025:

median OS benefit irrespective of PD-L1 status

PD-L1 ≥1% (n = 24%) PD-L1 <1% (n = 76%)

# of patients at risk

Nivolumab94 86 79 73 66 58 45 31 1841 0 Everolimus 87 77 68 59 52 47 40 19 9 41 0

0.0

03 691215

Months 18 21 24 27 30 33 0.3

0.1 0.2 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Overall Survival (Probability)

Nivoluma b Everolimus

276 265 245 233 210 189 145 94 48 2220 299 267 238 214 200 182 137 92 51 1610 Nivolumab

0 36 91215

Months18 21 24 27 30 33 0.3

0.1 0.2 0.4 0.5 0.6 0.7 0.8 0.9 1.0

0.0

Everolimus Median OS, months (95% CI)

Nivolumab 21.8 (16.5–28.1) Everolimus 18.8 (11.9–19.9)

Median OS, months (95% CI) Nivolumab 27.4 (21.4–NE) Everolimus 21.2 (17.7–26.2)

Adapted from Motzer et al, 2015, N Engl J Med.

UBC (Urothelial Bladder Carcinoma): Overview

Ta/T1/Tis: Non- muscle invasive TURBT/ intravesical BCG

T2-T4: Muscle Invasive:

radical cystectomy; <25%

get adjuvant/neoadjuvant (Gem/Cis)

1L Metastatic:

•Gem/Cis or MVAC are SOC in US;

•Gem/Carbo for Cis ineligible (50%);

2L Metastatic:No SOC in US Taxanes, Gemcitabine,

Pemetrexed, Vinfluinine (EU)

ORR: 10%; mOS: 7–9 mo Normal urothelium

10-15%

10 - 15%

70-80%

In 2013, new 72,570 cases estimated and 15,210 deaths in US (ACS, 2013)

Urothelial Cancer

• No Expectancy for a Cure

• Significant Complexity of UBC Cases: mainly Elderly, frequent Comorbidities (impaired renal function, cardiovascular problems, polypharmacy) or frail cases.

Slide 11

Presented By Seth Lerner at 2017 ASCO Annual Meeting

A new Paradigm in UBC ?

Molecular Subtypes and Outcome

Presented By Seth Lerner at 2017 ASCO Annual Meeting

1. Bellmunt. Ann Oncol. 2013; 2. TCGA. Nature. 2014; 3. Lawrence. Nature. 2013; 4. Kandoth. Nature. 2013; 5. Galsky. Clin Adv Hematol Oncol. 2013.

Somatic mutation frequencies observed in exomes from 3083 tumor-normal pairs

Reprinted pending permission from Macmillan Publishers Ltd: Nature, Lawrence MS, et al. Jul 11;499(7457):214-8, 2013.

•Patients with UBC have a high rate of somatic mutations

• High mutational complexity rates similar to tobacco/environmental carcinogen exposure^2-4

• Potential for many neo-antigens to be seen as foreign by host immune system^2-4

But also…: High rate of Somatic Mutations in UBC

Overall Survival: Total

Dean Bajorin, 2017 ASCO Annual Meeting

But, NON Solo Immuno…:

FGFR Gene Alterations in Multiple Tumor Types

Parker BC, Zhang W. Chin J Cancer. 2013;32:594-603.

M eta st at ic Bladder Cancer:

an FGF- R ( not a n I - O) I nhibit or Partial Response

A 52-year female with metastatic bladder cancer with multiple lung metastasis who failed 4 prior lines of chemotherapy Hematuria and cough improved in 1^stweek of therapy

PR (-38% tumor reduction) in week 6, confirmed in week 12, on treatment for

~9 month

Visceral & bone lesion shrinkage

Scree ning W eek 6

Figure included with permission from Bahleda R, et al. Presented at the 50th Annual Meeting of the American Society for Clinical Oncology;

30 May – 3 June 2014; Chicago, Illinois. Abstract 2501.

NEW VALUES IN ONCOLOGY:

Moving to I-O & Targeted Approaches, but combined with a

“Real-Life, Patient’ based QoL”

• Treatment Options in Oncology quickly moving from “general approaches (eg. Chemo for NSCLC) to Taylored Approaches (I-O & Target Agents, but also Chemo in some cases).

• Adapting Treatment Selection also by Line of Treatment (by Checking clonal selection: DNA, mRNA Blood Biopsy)

• Considering the “Modified Natural History of the Disease” as the new Target (End Point?) of the modern Tumoral’ Approaches.