Nuove prospettive in immuno-oncologia: come valutare l’efficacia del trattamento

Nuove prospettive in

immuno‐oncologia: come valutare l’efficacia del trattamento

Paolo Bruzzi

Policlinico San Martino –IRCCS Genova

Milano, 16 Novembre 2017

2

DISCLOSURES

Fees for

- Courses on Clinical Reasearch Methodology/

Seminars/Lectures: Bristol Meier Squibb, Astra

Zeneca, Roche, Novartis, Merck Serono, Lilly, Glaxo, Ipsen, Sanofi, Takeda

- Advisory Boards & Consultations: Amgen, Cellgene, Lilly

No Stock

TRIAL METHODS IN IMMUNO-ONCOLOGY

• What has changed?

• Implications?

• New Perspectives?

3

FDA Approves XXX (Immunotherapy) for Microsatellite Instability-High and

Mismatch Repair Deficient Cancers

The FDA has granted an accelerated approval to XXX for the treatment of adult and pediatric patients

with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair

deficient (dMMR) solid tumors that have

progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-H or dMMR colorectal cancer following progression on a fluoropyrimidine,

oxaliplatin, and irinotecan.

The approval was based on

• data from 149 patients with MSI-H or dMMR cancers

• enrolled across 5 single-arm clinical trials.

• Ninety patients had colorectal cancer (CRC) and the remaining 59 patients had 1 of 14 other tumor types.

The objective response rate (ORR) with XXX was 39.6% (95% CI, 31.7-47.9), including

11 (7.4%) complete responses (CRs) 48 (32.2%) partial responses (PRs).

Median duration of response not yet reached (range, 1.6+ months to 22.7+ months).

Among patients who responded, 78% had

responses that lasted for at least 6 months.

Responses observed in

• CRC

• endometrial cancer (n = 5)

• biliary cancer (n = 3)

• gastric or GE junction cancer (n = 5)

• pancreatic cancer (n = 5)

• small intestinal cancer (n = 3)

• breast cancer (n = 2)

• prostate, esophageal, retroperitoneal adk and SCLC (n = 1 each).

?

• Site agnostic: cancers from 15 different sites (Biomarker+)

• Trial agnostic: Data from 5 different trials

• Design agnostic: Uncontrolled

• Endpoint agnostic: Objective

Response and response duration

• 1^st time

• 1^st time

• Unusual

• Unusual

Metodology of cancer trials what has changed?

Everything!

• Phases

• Design

• Endpoints

• Statistical Analyses

• Interpretation

BACK TO THE

FUTURE?

Back to the future?

Necessita’ di adeguare le regole metodologiche

all’evoluzione delle

conoscenze biologiche e molecolari?

Revisionismo metodologico?

(Non sempre disinteressato)

Nuove metodologie di ricerca clinica

?

Cancer Trials- Traditional Methods

Phase I

Phase II

Phase III

11

MTD -> DLT:Dose increases in subsequent groups (triplets ) of heavily pretreated patients

Activity -> Response Rate: Uncontrolled Trial in selected patients (measurable disease)

Efficacy -> Overall Survival: RCT in large population s of unselected patients;

(ITT; All analyses planned in advance)

Cancer Trials- What has changed?

Phase I

Methodology?

12

MTD -> DLT:Dose increases in subsequent groups (triplets ) of heavily pretreated patients

Immunotherapy: Survival

Phase I trials in Immuno-oncology

• The efficacy and safety of nivolumab (NIVO;

anti-PD-1) monotherapy in advanced

malignancies was validated in study CA209- 003, a phase I, dose-escalation trial¹

0.1 mg/kg IV Q2W (n = 17)

0.3 mg/kg IV Q2W (n = 18)

1 mg/kg IV Q2W (n = 35)

3 mg/kg IV Q2W (n = 17)

10 mg/kg IV Q2W (n = 20)

Treatment for

≤96 weeks Eligible patients with

advanced melanoma (N = 107)

• 1 to 5 lines of prior systemic therapies

Overall Survival at 5 Years of Follow-up

14

Probability of Survival

Months 0.0

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

Database lock Oct 2015

107 86 64 51 49 43 41 36 29 17 15 12 3 1 0

Number of Patients at Risk All Patients

All Patients (events: 69/107), median and 95% CI: 17.3 (12.5–37.8)

NIVO 3 mg/kg (events: 11/17), median and 95% CI: 20.3 (7.2–NR)

17 15 11 9 8 7 7 6 6 6 6 6 1 0

NIVO 3 mg/kg

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Response in Patients Who Discontinued for Reasons Other Than Progression*

• Among responders who discontinued for reasons other

than PD, 21 remained in response for

≥ 16 weeks

– Completed 96 weeks (n=9) – Discontinued due to AE (n=5) – Complete response (n=2) – Other reasons (n=5)^†

• Responses ongoing in 14 of 21

On treatment Off treatment Time to response

Ongoing response

Discontinued study drug due to toxicity

Discontinued study drug due to investigator-assessed CR

Time Since Treatment Initiation (months) 0.1 mg/kg

0.3 mg/kg

3.0 mg/kg 1.0 mg/kg

10.0 mg/kg

*And continued to respond for ≥ 16 weeks; ^†Withdrew consent or not available for scan.

September 2014 data analysis

Patients

Cancer Trials- Traditional Methods

Phase II Activity -> Response Rate:

Uncontrolled Trial in selected patients (measurable disease)

Many Targeted and immunologic agents are not expected to induce an “acute” tumor

shrinkage

No Objective Response? Uncontrolled trials?

16

Cancer Trials- What has changed?

Phase II

METHODOLOGY? Small RCT’s with PFS/OS as primary endpoint (sometimes leading to registration)

17

Activity -> Response Rate: Uncontrolled Trial in selected patients (measurable disease)

Cancer Trials- What has changed?

Phase III

Randomised CT’s?

Overall Survival?

Unselected patients?

Large populations?

Statistical Plan?

ITT?

18

RCT’s, Overall Survival, in large pop.tions of unselected patients;

Trials di efficacia in Immuno-oncologia

• Disegno di studio

• Endpoint

• Statistica/Indicatori riassuntivi

Trials di efficacia in Immuno-oncologia

• Disegno di studio

– Controllato randomizzato o non controllato?

On July 31, 2017, the U.S. Food and Drug Administration granted

accelerated approval to nivolumab for the treatment mismatch repair deficient (dMMR) and microsatellite instability high (MSI-H) metastatic colorectal cancer that has progressed following

treatment …

The approval was based on data from Study CA209142 a

multicenter, open-label, single arm study conducted in 53 patients with locally determined dMMR or MSI-H CRC, ..

This was a subset of the 74 patients who received at least one prior regimen for treatment of metastatic disease containing a

fluoropyrimidine with oxaliplatin or irinotecan for treatment of metastatic disease.

The objective response rate (ORR) as assessed by independent

radiographic review committee using RECIST 1.1 was 28% (n=15) (95%

CI: 17, 42) in the 53 patients who received prior fluoropyrimidine, oxaliplatin, and irinotecan. Responses lasted 6 or more months for 67% (95% CI: 38, 88) of patients.

On September 22, 2017, the Food and Drug Administration granted accelerated approval to pembrolizumab for patients with recurrent locally advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 as determined by an FDA-approved test. Patients must have had disease progression on or after two or more prior systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu- targeted therapy.

Approval is based on the results of KEYNOTE 059 (NCT02335411), an open-label, multicenter, non-comparative, multi-

cohort trial that enrolled 259 patients with gastric or

gastroesophageal junction adenocarcinoma. Among the 259 patients, 55% (n=143) had tumors expressing PD-L1 and either microsatellite stable (MSS), or undetermined microsatellite instability (MSI) or mismatch repair (MMR) status.

August 30, 2017 - The U.S. Food and Drug Administration issued a historic

action today making the first gene therapy available in the United States, … The FDA approved tisagenlecleucel for certain pediatric and young adult

patients with a form of acute lymphoblastic leukemia (ALL).

XXX is a genetically-modified autologous T-cell immunotherapy. Each dose of XXX is a customized treatment created using an individual patient’s own T-cells, a type of white blood cell known as a lymphocyte. The patient’s T-cells are

collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric

antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.

The safety and efficacy of XXX were demonstrated in one multicenter clinical trial of 63 pediatric and young adult patients with

relapsed or refractory B-cell precursor ALL. The overall remission rate within three months of treatment was 83 percent^.

September 28, 2017; FDA granted accelerated approval to nivolumab for patients with

hepatocellular carcinoma (HCC) following prior treatment with sorafenib (Nexavar). The approval was granted for patients regardless of their PD-L1 status.

The approval is based on 154 patients enrolled in the phase I/II CheckMate-040 trial, in which the overall response rate (ORR) by blinded

independent central review (BICR) was 18.2% per mRECIST criteria for patients who had previously

been treated with sorafenib. Additionally, 3.2% of patients experienced a complete response.

Trials

in Very Rare Cancers/Subgroups

• Single arm trials

– Preferred by patients and oncologists – Difficult to interpret

– Often poorly designed

• No reference, Response rate, Disguised as Phase II

– If dramatic effects, practice changing

“…phase 2, single group, Simon’s two-stage…”

Response Rate: 14/25 (56%) (Historical RR: 50-60%)

Median PFS: 9 months (Historical: 3 months)

Kaufmann HL Lancet Oncology 2016

Response Rate: 28/88 (32%)

Target 20%

Historical : 50-60% in 1^st line

Median PFS: 2.7 months (Historical ?)

The accelerated approval is contingent on the results of a confirmatory trial.

“

conversion to regular approval. These were based on 18 RCTs.”

Borrel PR, ESMO 2017)

Reck M et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1606774

Overall Survival in the Intention-to-Treat Population.

mNSCLC

Reck M et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1606774

Overall Survival in the Intention-to-Treat Population.

mNSCLC

Reck M et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1606774

Overall Survival in the Intention-to-Treat Population.

Challenge for methodologists

• To develop a reliable trial methodology when a randomised control group is not ethically

acceptable

– Historical Controls (Registries)

– Concurrent controls from administrative databases – Cluster trials

– Geographical comparisons – …?

Trials di efficacia in Immuno-oncologia

• Disegno di studio

• Endpoint

Immunoterapia?

E’ plausibile che RR o PFS siano surrogati validi di OS per

l’immunoterapia?

0 3 6 9 12 15 18

Primary Endpoint: Overall Survival

Patients who died, n/N

Median OS mo (95% CI)

Nivolumab 50/210 NR

Dacarbazine 96/208 10.8 (9.3–12.1)

NR = not reached.

Based on 5 August 2014 database lock.

100 90 80 70 60

0 50 40 30 20 10

HR 0.42 (99.79% CI, 0.25–0.73; P < 0.0001)

(Boundary for statistical significance 0.0021)

210 208

185 177

150 123

105 82

45 22

8 3

0 0

Nivolumab (N = 210)

Dacarbazine (N = 208)

Months

Patients Surviving (%) 1-yr OS 73%

1-yr OS 42%

Patients at Risk Nivolumab Dacarbazine

Follow-up since randomization: 5.2–16.7 months.

Secondary Endpoint: PFS

Death or disease progression, n/N

Median PFS mo (95% CI) Nivolumab 108/210 5.1 (3.5–10.8) Dacarbazine 163/208 2.2 (2.1–2.4)

HR 0.43 (95% CI, 0.34–0.56; P < 0.0001)

Patients Without Progression (%)

Dacarbazine (N = 208)

Nivolumab (N = 210)

6-mo PFS 48%

6-mo PFS 19%

100 90 80 70 60

0 50 40 30 20 10

0 3 6 9 12 15 18

Months

Patients at Risk Nivolumab Dacarbazine

210 208

116 74

82 28

57 12

12 0

1 0

0 0

Based on 5 August 2014 database lock.

ASCO 2016

All patients

(>1% cells)

ASCO 2016

All patients

(>1% cells)

ASCO 2016

Median OS, mo (95%

CI)

HR (97.73%

CI)

P- value Nivolumab (n = 240) 7.5 (5.5,

9.1) 0.70

(0.51, 0.96)

0.0101 Investigator’s Choice

(n = 121)

5.1 (4.0, 6.0)

Overall Survival

Nivolumab in R/M SCCHN After Platinum Therapy

41

Months

Nivolumab 240 167 109 52 24 7 0

Investigato r’s Choice

121 87 42 17 5 1

No. at Risk

0

Overall Survival (% of patients)

0 3 6 9 12 15 18

0 10 20 30 40 50 60 70 80 90 100

1-year OS rate (95% CI) 36.0% (28.5, 43.4)

16.6% (8.6, 26.8)

ASCO 2016

Progression-Free Survival

Nivolumab in R/M SCCHN After Platinum Therapy

42

Months

Nivolumab 240 79 32 12 4 1 0

Investigato r’s Choice

121 43 9 2 0 0

No. at Risk

0 Progression-Free Survival (% of patients)

0 3 6 9 12 15 18

0 10 20 30 40 50 60 70 80 90 100

6-month PFS rate (95% CI) 19.7% (14.6, 25.4)

9.9% (5.0, 16.9)

Median OS, mo (95%

CI)

HR (97.73%

CI)

P- value Nivolumab (n = 240) 2.0 (1.9,

2.1) 0.89

(0.70, 1.1) 0.3236 Investigator’s Choice

(n = 121)

2.3 (1.9, 3.1)

Attenzione (2016)

L’utilizzo di RR e soprattutto di PFS come endpoint primario nei trials

delle nuove terapie antineoplastiche, targeted e immunoterapiche e’ poco prudente,

(FALSI NEGATIVI?)

anche per la peculiarita’ degli effetti

sulla SOPRAVVIVENZA

Bernard Escudier,¹ Nizar M. Tannir,² David F. McDermott,³ Osvaldo Arén Frontera,⁴ Bohuslav Melichar,⁵ Elizabeth R. Plimack,⁶ Philippe Barthelemy,⁷ Saby George,⁸ Victoria Neiman,⁹ Camillo Porta,¹⁰ Toni K. Choueiri,¹¹ Thomas Powles,¹² Frede Donskov,¹³ Pamela Salman,¹⁴ Christian K. Kollmannsberger,¹⁵

Brian Rini,¹⁶ Sabeen Mekan,¹⁷ M. Brent McHenry,¹⁷ Hans J. Hammers,¹⁸ Robert J. Motzer¹⁹

1Gustave Roussy, Villejuif, France; ²University of Texas, MD Anderson Cancer Center Hospital, Houston, TX, USA; ³Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA, USA; ⁴Centro Internacional de Estudios Clinicos, Santiago, Chile; ⁵Palacky

University, and University Hospital Olomouc, Olomouc, Czech Republic; ⁶Fox Chase Cancer Center, Philadelphia, PA, USA; ⁷Hôpitaux Universitaires de Strasbourg, Strasbourg, France; ⁸Roswell Park Cancer Institute, Buffalo, NY, USA; ⁹Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel, and Tel Aviv University, Tel Aviv, Israel; ¹⁰IRCCS San Matteo University Hospital Foundation, Pavia, Italy; ¹¹Dana- Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA; ¹²Barts Cancer Institute, Cancer

Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free NHS Trust, London, UK; ¹³Aarhus University Hospital, Aarhus, Denmark; ¹⁴Fundación Arturo López Pérez, Santiago, Chile; ¹⁵British Columbia Cancer Agency, Vancouver, BC,

Canada; ¹⁶Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; ¹⁷Bristol-Myers Squibb, Princeton, NJ, USA; ¹⁸Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD, USA; ¹⁹Memorial Sloan Kettering Cancer Center, New York, NY, USA

CheckMate 214: Efficacy and Safety of Nivolumab Plus Ipilimumab vs Sunitinib for Treatment-Naïve Advanced or Metastatic Renal Cell Carcinoma, Including IMDC Risk and PD-L1

Expression Subgroups

LBA5

ORR and DOR: IMDC intermediate/poor risk

N = 847 Outcome

NIVO + IPI N = 425

SUN N = 422 Confirmed ORR,^a % (95%

CI)

42 (37–

47)

27 (22–

31) P < 0.0001 Confirmed BOR,^a %

Complete response Partial response Stable disease

Progressive disease Unable to determine/not reported

9^b 32 31 20 8

1^b 25 45 17 12

aIRRC-assessed ORR and BOR by RECIST v1.1; ^bP < 0.0001

SUN NIVO + IPI No. at Risk

177 146 120 55 3

112 75 52 17 0

0 .0 0 .1 0 .2 0 .3 0 .4 0 .5 0 .6 0 .7 0 .8 0 .9 1 .0

0 6 12 18 24

Months

Duration of Response (Probability)

Co-primary endpoint: ORR

Median duration of response, months (95%

CI)

Patients with ongoing response,

% NIVO +

IPI NR (21.8–NE) 72

SUN 18.2 (14.8–NE) 63

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

Nivolumab Plus Ipilimumab vs Sunitinib for Treatment- Naïve Advanced/ Metastatic Renal Cell Carcinoma

OS: 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

284 202 155 119 102 90 70 23 9 1 0 278 200 138 105 83 67 43 25 11 1 0

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

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)

NIV O 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 1 2 1 5 1 8 2 1 2 4 2 7 3 0

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 1 2 1 5 1 8 2 1 2 4 2 7 3 0

0 . 1 0 . 0 0 . 2 0 . 3

Progression-Free Survival (Probability)

Months Months

Exploratory endpoint

Wolchok JD et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1709684

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

+22%

+18%

Quadro Complessivo

• Molto confuso

• Il rapporto tra effetto su OS ed effetto su ORR e PFS appare molto variabile e spesso (non

sempre), effetto su OS piu’ forte di quello su PFS

• Scarse motivazioni per usare il PFS come unico endpoint primario (2/3 coprimary endpoints?)

• ORR piu’ efficiente di PFS?

BMJ 2017

 What this study adds

 Most new oncology drugs authorised by the EMA in 2009-13 came onto the market without clear

evidence that they improved the quality or quantity of patients’ lives

 After market entry, cancer drugs rarely show benefits on overall survival or quality of life in randomised

trials

 When survival gains over available treatment

alternatives are shown, they are not always clinically meaningful

Nota bibliografica

Solo titolo

Trials di efficacia in Immuno-oncologia

• Disegno di studio

• Endpoint

• Statistica/Indicatori riassuntivi

Pianificazione statistica di uno studio =

come descrivere gli effetti di un trattamento

• Come rilevarli?

= Endpoint

• Come valutarli e presentarli?

= Indicatore Riassuntivo

Indicatori riassuntivi piu’

utilizzati

1. Differenza nella sopravvivenza mediana

2. Hazard Ratio (Modello di Cox)

3. Differenza nella % vivi al tempo x (es. 3 aa)

Small for many

Large (for few?)

Nota Bene

Piccolo beneficioper la

maggior parte dei pazienti (“small”)

Descrzione

Incremento OS Mediana

RESTRICTED MEANS (+ informativa)

Incremento MEDIO OS Restricted Means

Descrizione meno appropriata

Hazard Ratio (MEDIO)

Large benefit (for few)

In molte situazioni cliniche, e’ necessario

descrivere il beneficio di un trattamento in termini di PROBABILITA’

• di un beneficio importante

• nei soggetti suscettibili/sensibili

• o nei soggetti che rispondono al trattamento

• (e.g. 2-yrs PFS, P.Ascierto?)

= LARGE benefit (years, decades) For few?

PDL1?

(Sobrero …& Bruzzi, Clin. Cancer

Res. Sett. 2014)

Neuroblastoma

0 10 20 30 40 50 60 70 80 90 100

Time

OS

Standard CT High Dose CT

HR= 0.9 (N.S.)

Effetto della terapia: +10%

guarigioni

1 2 3 4

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Proportion alive

Years

lpi + Gp100 (A) lpi Alone (B) Gp100 Alone (C)

Survival

Rate Ipi + gp100 N=403 Ipi + pbo N=137 gp100 + pbo N=136

1 year 44% 46% 25%

2 year 22% 24% 14%

Comparison HR p-value Arms A vs. C 0.68 0.0004 Arms B vs. C 0.66 0.0026

Hodi S et al. NEJM 2010;363(8):711-23

MDX010-20: Kaplan-Meier Analysis of Survival (patients included regardless BRAF status)

Pooled OS Data From Melanoma Patients

• In a pooled analysis of 12 studies, an OS plateau starts at approximately 3 years with follow-up of up to 10 years in some patients

Patients at risk

Ipilimumab 1861 839 370 254 192 170 120 26 15 5 0

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

N=1861

0 12 24 36 48 60 72 84 96 108 120

Proportion alive

Months

Median OS, months (95% CI): 11.4 (10.7–12.1)^a 3-year OS rate, % (95% CI): 22 (20–24)^a

Ipilimumab CENSORED

aIpilimumab was given at different doses and lines of therapy, and using different schedules across the 12 studies Schadendorf D, et al. ECC Congress. 2013 Abs 124LBA

S. Hodi, ASCO 2014

Grande Beneficio per pochi pazienti

0 10 20 30 40 50 60 70 80 90 100

Time

OS

Anni, mesi o settimane?

No!

N. di lungo-sopravviventi

Malattia Avanzata

Obiettivi del trattamento

(Palliare i sintomi, se presenti)

Arrestare la progressione della malattia

Prolungare la sopravvivenza a breve termine

Incrementare la probabilita’ di

sopravvivere a lungo termine

0 1 2 3 4 5 6 7 8 9 10 100

90 80 70 60

0 50 40 30 20 10

Overall Survival (%)

Years

IPI (Pooled analysis)¹

NIVO Monotherapy (Phase 3 Checkmate 066)³

N=210

NIVO Monotherapy (Phase 1 CA209-003)²

N=107

N=1,861

75

Immune Checkpoint Inhibitors Provide Durable Long- term Survival for Patients with Advanced Melanoma

1. Schadendorf et al. J Clin Oncol 2015;33:1889-1894; 2. Current analysis; 3. Poster presentation by Dr. Victoria Atkinson at SMR 2015 International Congress.

FOR FEW?

+22%

+18%

3 yrs PFS= 39%

3 yrs OS= 58%

Cancer Trials- What has changed?

Phase III

Randomised CT’s?

Overall Survival?

Unselected patients?

Large populations?

Statistical Plan?

77

Overall Survival: RCT’s

in large pop.tions of unselected patients;

What about Intention To Treat (ITT)?

New Concept: Estimand

• Definition:

The estimand is the quantity of interest whose true value you want to know

Example:

- Estimand: Treatment Effect on Overall Survival - Estimator: Difference in Median OS ?

- Estimate: Difference in median OS in a given study?

1 Estimand,

Several Estimators

Estimand: Treatment effect on OS

•Estimators:

–Difference in median OS –Hazard Ratio

–Probability of 5yrs Os

– Probability of 5 yrs OS in Compliers – Probability of 5 yrs OS in Responders – etc

The result of an intention-to-treat analysis … may not be directly relevant for guiding decisions in clinical

settings.

Health care professionals and patients would like to have an effect measure that, unlike the intention-to- treat effect, is not influenced by the degree of

adherence.

Conclusions

“…the protocols of pragmatic trials would benefit from explicit definition of the per protocol effect, ….

… to prioritize the patient-centeredness of

the research.”

Conclusions

Response/PFS?

Uncontrolled trials?

Small trials?

Selected Patients?

No statistical plan?

Per protocol?

NEW?

“New”(?) methods in clinical research

Objective Response?

Uncontrolled trials?

Small trials?

Selected Patients?

No statistical plan!

Objective Response?

Uncontrolled trials?

Small trials?

Selected Patients?

No statistical plan?

Randomization of patients: Patients were classified in one of 12 categories, according to the number of years after spontaneous or induced menopause and dominant site of metastases…For each of the 12 categories sequentially numbered sealed cards randomly distributed the 2 compounds which were selected and administered in a double-blind fashion. The code was not broken until the study had been completed and each case had been evaluated finally.

Back to the future?

Need to adapt methods to the dramatic scientific growth in genetics, molecular biology, phamacologic

engineering, etc.?

Methodologic Revisionism ? (Not always selfless)

“New”(?) methods in clinical research

or forward to the

past?