Criteri di valutazione degli endpoint negli studi clinici: cosa cambia?

Immunoterapia in Oncologia

Criteri di valutazione degli endpoint negli studi clinici: cosa cambia?

Paolo Bruzzi

Policlinico San Martino –IRCCS Genova

Torino, 5 Settembre 2018

2

DISCLOSURES

Fees for

- Courses on Statistics-Methodology of Clinical

Research / Seminars / Lectures: Bristol Meier Squibb, Astra Zeneca, Roche, Novartis, Merck Serono, Lilly, Glaxo, Ipsen, Sanofi, Takeda

- Advisory Boards & Consultations: Amgen, Cellgene, Lilly

No Stock

Metodologia dei trials in immuno-oncologia

E’ cambiato qualcosa?

3

FDA Approves Pembrolizumab for Microsatellite Instability-High and Mismatch Repair Deficient Cancers

The FDA has granted an accelerated approval to Pembrolizumab 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.

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).

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.

?

• 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

Metodologia dei trials in immuno-oncologia

E’ cambiato qualcosa?

TUTTO!

9

Metodologia dei trials in immuno-oncologia

E’ cambiato qualcosa?

TUTTO!

Fasi

Disegno Endpoint

Analisi Statistiche

Indicatori riassuntivi Interpretazione

10

Endpoint nei Trials di

immunoterapia antitumorale?

E’ possibile/conveniente utilizzare la Risposta Obiettiva o il PFS…

1. Come endpoint primario nei trials di immunoterapia?

2. Per modulare i trattamenti

immunoterapici nel singolo paziente?

(= RR o PFS sono 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

17

Months

Nivolumab240 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

18

Months

Nivolumab240 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

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

Not significant 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

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%

26

CheckMate 227: Nivo + Ipiin 1L NSCLC With High TMB (≥10 mut/Mb)

Co-primary Endpoint: PFS With Nivolumab + Ipilimumab vs Chemotherapy in Patients With High TMB (≥10 mut/Mb)^a

26

Nivo + ipi 139 85 66 55 36 24 11 3 0

Chemo 160 103 51 17 7 6 4 0 0

Nivo + ipi (n = 139)

Chemo (n = 160) Median PFS,^b mo 7.2 5.4 HR^c

97.5% CI

0.58 0.41, 0.81 P = 0.0002

Months 0

20 40 60 80 100

0 3 6 9 12 15 18 21 24

PFS (%)

Chemotherapy Nivolumab + ipilimumab 1-y PFS = 43%

1-y PFS = 13%

aPer blinded independent central review (BICR); median (range) of follow-up in the co-primary analysis population was 13.6 mo (0.4, 25.1) for nivo + ipi and 13.2 mo (0.2, 26.0) for chemo;

b95% CI: nivo + ipi (5.5, 13.2 mo), chemo (4.4, 5.8 mo); ^c95% CI: 0.43, 0.77 mo; ^dThe P-value for the treatment interaction was 0.0018 No. at risk

• In patients with TMB <10 mut/Mb treated with nivo + ipi vs chemo, the HR was 1.07 (95% CI: 0.84, 1.35)^d

CheckMate 227: Nivo + Ipiin 1L NSCLC With High TMB (≥10 mut/Mb)

−80%

Best Change in Target Lesion Tumor Burden From Baseline in Patients With High TMB (≥10 mut/Mb)

17

Nivolumab + Ipilimumab^a Chemotherapy^a

Change in tumor size (%)b

75

50

25

0

−25

−50

−75

−100

75

50

25

0

−25

−50

−75

−100

*** ***

* ** ******

*******

******

***********

***********

*******

*

*****

* * ** *

***** ***** ** ***** * *** **** **

****

*****

Horizontal line indicates 30% reduction consistent with a RECIST 1.1 response; Asterisk (*): Responder per RECIST1.1 criteria, confirmation of response required

aWaterfall plots show patients with baseline and at least one on-treatment tumor assessment per BICR treated with nivolumab + ipilimumab (n = 119) or chemotherapy (n = 146). Percentages of deep response were calculated based on all randomized patients with baseline TMB ≥10 mut/Mb; ^bNegative/positive value means maximum tumor reduction/minimum tumor increase

−50%

−80%

−50%

35%

9%

12%

<1%

CheckMate 227: Nivo + Ipiin 1L NSCLC With High TMB (≥10 mut/Mb)

ORR and DOR in Patients With High TMB (≥10 mut/Mb)^a

28

0 10 20 30 40 50

Nivo + Ipi Chemo

ORR (TMB ≥10 mut/Mb)^b

ORR (%)

DOR (TMB ≥10 mut/Mb)

63/139 n/N:

Months 100

Chemotherapy Nivolumab + ipilimumab

Patients in response (%)

• Median time to response was 2.7 months with nivolumab + ipilimumab and 1.5 months with chemotherapy

43/160

a Per BICR; ^bORR in patients with TMB <10 mut/Mb was 24.6% in nivo + ipi arm and 25.9% in chemo arm

45.3

26.9

CR PR

Nivo + ipi Chemo

≥1-y DOR = 68%

≥1-y DOR = 25%

Nivo + ipi (n = 63)

Chemo (n = 43) Median DOR,

mo (95% CI)

NR (12.2,

NR)

5.4 (4.2,

6.9)

Nivo + ipi 63 56 46 32 22 10 5 0

Chemo 43 32 15 5 2 2 1 0

No. at risk

0 20 40 60 80

0 3 6 9 12 15 18 21

3.6

41.7 0.6

26.3

CheckMate 227: Nivo + Ipiin 1L NSCLC With High TMB (≥10 mut/Mb)

Preliminary Overall Survival With Nivolumab + Ipilimumab vs Chemotherapy in Patients With High TMB (≥10 mut/Mb)

29

Nivo + ipi (n = 139)

Chemo (n = 160) Median OS,^b mo 23.0 16.4

HR 95% CI

0.79 0.56, 1.10

Months

OS (%)a

aIn the first 1.5 months, 8 deaths occurred in the nivo + ipi arm (4 due to disease progression; 1 patient never treated [respiratory sepsis]; 2 due to AEs unrelated to study drug per investigator [thromboembolism, septic shock]; 1 due to myocarditis related to study drug), and 2 deaths occurred in the chemo arm (1 due to disease progression; 1 due to multiple brain infarctions related to carboplatin);^b95% CI: nivo + ipi (16.5 mo, NR), chemo (12.6 mo, NR); ^cPer investigator

No. at risk

Nivo + ipi 139 120 112 98 90 71 44 16 5

Chemo 160 148 129 104 90 75 45 23 9

0 1

0 0

Chemotherapy Nivolumab + ipilimumab 1-y OS = 67%

1-y OS = 58%

0 20 40 60 80 100

0 3 6 9 12 15 18 21 24 27 30

• Database lock: March 15, 2018; minimum follow-up: 14.2 months; 53% of patients were censored

• In the chemotherapy arm, 31.3% received subsequent immunotherapy (38.3% among those with disease progression^c)

Of patients assigned to chemotherapy, 30%

received subsequent immunotherapy

30

effective crossover rate of 41.3% in the intention-to- treat population and 50.% in the 170 patients who had discontinued all trial drugs

0.49

0.522

Progression-free Survival, According to PD-L1 Tumor Proportion Score.

Gandhi L et al. N Engl J Med 2018;378:2078-2092

Quadro Complessivo

• Molto confuso

• Il rapporto tra effetto su OS ed effetto su ORR e PFS appare molto variabile e non sempre effetto su OS >> effetto su PFS

• Cross-over inevitabile

• Espressione PDL1-> effetto su PFS (su OS?)

• Motivazioni per usare il PFS come unico endpoint primario?

• Cosa fare nei trials?

Regole Fondamentali nella statistica dei RCT

• Statistica:

Statistical Plan

• Metodologica:

Intention to treat

Regole Fondamentali nell’analisi di una S.C.C.

• Statistica: Tutte le analisi statistiche devono essere esplicitamente predeterminate

(endpoint, trasformazione, test, tempi, sottogruppi)

Piano Statistico

Contenuti:

- Endpoint primario e secondari

- Piano di analisi statistica (contrasti, test, analisi per sottogruppi)

- Interim analyses

- Livelli di significativita’

- Potenza- Sample Size - Indicatori riassuntivi

MOLTEPLICITA ’

All’aumentare del numero di analisi (molteplici) cresce la probabilita’ di

trovare, PER PURO CASO, qualcosa di

«interessante»

-> 5 rossi di fila alla roulette (p=0.03)

-> Mut. Germin. BRCA in Lung c (p=0.002)

-> Advanced NSCLC vivo a 10 aa (p = 0.01)

Esempio

• Trial A vs B - 3 fattori (es. sesso, </>50yrs, stadio I/II)

La probabilita’ di osservare per puro caso una differenza ‘significativa’ se A=B e’:

– 5% con la sola analisi principale

– 30% con 7 analisi (principale+ 6 sottogruppi) – 75%% con se faccio tutte le 27 analisi possibili

combinando i 3 fattori

(M, M<50aa, M<50aa I stadio, M>50aa, M>50aa I stadio, ….)

• Per quasi tutte le malattie i potenziali fattori

‘di modificazione’ dell’effetto sono >10

Test multipli vs Analisi post hoc

• Test multipli :

• Predeterminati (Protocollo di studio)

• Numero finito

• Possibile correzione statistica

• Analisi Post hoc

• Analisi derivate dai dati: L’osservazione di un fenomeno induce a fare il test di significatività

• Analisi intensive (analizzo tutto x tutto)

• Numero potenzialmente illimitato

• Prive di alcuna validità statistica

Possibili fonti di molteplicita’

in un clinical trial

• Endpoints multipli

• Trasformazione degli endpoints (es. curva di sopravvivenza vs % di pz vivi a 3 anni)

• Test statistico

• Misura di effetto

• Dati mancanti

• Analisi nel corso dello studio (interim analysis)

• Analisi per sottogruppi

MOLTEPLICITA’ : Regole generali

• Viene stabilito, prima dell’inizio dello studio, il numero e tipo (tempo) delle analisi (ES. 2 analisi per soggetti < 50 e >50 anni, oppure 3 analisi, dopo 100, 200 e 300 eventi (finale)

• Viene stabilito un insieme di regole STATISTICHE per decidere che lo studio ha dato un risultato significativo (o per interrompere lo studio)

• TUTTO E’ SCRITTO NEL PIANO STATISTICO!

Metodi per gestire la molteplicita’

1. Modificazione dei livelli di significativita’

2. Procedure Gerarchiche 3. Closed test procedures

1. Modificazione dei livelli di significativita’

1. Livelli di significativita’ (tutti < α) calcolati in modo che la probabilita’ di errore α complessiva sia quella desiderata

Esempio: Se

– livello di significativita’ desiderato = 0.05 (5%) – Previste 4 analisi

– Studio positivo se in almeno 1 analisi p<0.0125

1. Modificazione dei livelli di significativita’

Tutti i metodi comportano una perdita di potenza (risultati falsamente negativi)

• Bonferroni = Il piu’ facile – Notevole perdita di potenza

• Bonferroni-Holm (molto usato – ancora forte perdita di potenza)

• Procedure di Hochberg - Hommel > Potenza

• Altre procedure piu’ complesse

Metodi per gestire la molteplicita’

1. Modificazione dei livelli di significativita’

2. Procedure Gerarchiche 3. Closed test procedures

2. Procedure gerarchiche

• Si mettono i test in ordine (di importanza rilevanza, potenza, plausibilita’,etc.)

• Si esegue il primo test

– Se negativo stop (studio negativo)

– Se positivo si procede con il secondo test

• NON RICHIEDONO CORREZIONE DEL LIVELLO DI SIGNFICATIVITA’

Non richiedono correzione del livello di signficativita

’: Perche’?

Assunzione: ipotesi nulla e’vera; si vogliono testare (α= 0.05) 3 endpoint (OS, PFS, QoL) in sequenza

OS

95%

Studio negativo 5%-> PFS?

Effetto su OS

ma non su PFS OS +PFS - 5%*5%

=0.0025->QoL?

Effetto su su OS e PFS ma non su

QoL

1/20+1/20*1/20

= 1/8000

2. Procedure gerarchiche

• Non comportano perdita di potenza sull’analisi primaria

• Molto usate per endpoint multipli

• Rischiose se si sbaglia l’endpoint primario

Metodi per gestire la molteplicita’

1. Modificazione dei livelli di significativita’

2. Procedure Gerarchiche 3. Closed test procedures

3. Closed test procedure

• “Closed test procedure” e’ un principio generale per costruire procedure per test multipli

• Serve a proteggere dal rischio di un risultato falsamente positivo mantenendo efficienza

• Molte procedure ( Holm, Gerarchiche) si basano su questo principio

Endpoints Multipli

2 strategie

a) Endpoint co-primari

- Lo studio e’ positivo se anche uno solo degli endpoints e’ significativo

- Correzione per molteplicita’ Es. se 2 analisi, p significativa se ≈ < 0.05 /2 = 0.025

(In realta’ se p<(1-√(1 - 0.05)) = 0.0.253) Perdita di potenza

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

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

3 Co-primary endpoints: RR, PFS & OS

The overall alpha level was 0.05, split among three coprimary end points.

• The objective response rate was analyzed at an alpha level of 0.001

• Progression-free survival was evaluated at an alpha level of 0.009, with a power of 80% or more.

• We evaluated overall survival at an alpha level of 0.04 with 90%

power (independent of coprimary end points) on the basis of a hazard ratio of 0.77, accounting for two formal interim analyses after 51% (reported herein) and 75% of deaths had occurred, using a stratified log-rank test.

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

Not significant 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

• the study was designed to show a difference in overall survival or progression-free survival in patients with a PD-L1 CPS of 1 or higher

• The familywise type I error rate was strictly controlled at a one-sided α of 2·50%,

– with 0·35% allocated to the hypothesis of PFS – and 2·15% allocated to the hypothesis of OS

• superiority of pembrolizumab was only

required for one of the primary endpoints to conclude a significant treatment effect for

pembrolizumab.

• the significance threshold for overall survival was p=0·0135 (one-sided).

• the coprimary end points were overall survival and progression-free survival

• The overall family-wise type I error rate was strictly controlled at a 1-sided α level of 2.5%.

Studio Positivo

Endpoints Multipli

2 strategie

b) Procedura gerarchica

- Lo studio e’ positivo solo se la differenza nell’endpoint primario e’ significativa

- Gli altri endpoints si testano in sequenza e ci si ferma quando uno non risulta significativo - Non e’ necessaria correzione per

molteplicita’

Outcomes

• The primary endpoint was overall survival.

• Secondary efficacy endpoints were

– progression-free survival,

– objective response (proportion of patients with confirmed complete response or partial response)

– disease control (proportion of patients with confirmed complete response, partial response, or stable

disease)

– duration of response, time to response, best overall response, and the maximum percentage change from baseline in the sum of diameters of target lesions

Riassumendo: Si deve scegliere tra

• Procedura gerarchica : Si procede solo se p significativa (studio positivo)

Non si corregge la p, ma rischioso se endpoint primario scelto male

• Analisi multiple con correzione p: Si procede anche se I analisi negativa Perdita di potenza

Endpoints Multipli

Nota bene: Alcuni recenti trials usano:

a) >1 Co-primary endpoint senza correzione

E’ necessario che tutti gli endpoint raggiungano la significativita’

Perdita di potenza senza alcun beneficio

LUX-LUNG 7 STUDY DESIGN

Co-primary endpoints:

• PFS (independent review)

• TTF

• OS

Secondary endpoints:

• ORR

• Time to response

• Duration of response

• Tumour shrinkage

• HRQoL 1:1

Patients (N=319)

• Stage IIIB/IV

adenocarcinoma of the lung

• EGFR mutation

(Del19 and/or L858R) in the tumour tissue*

• No prior treatment for advanced/metastatic disease

• ECOG PS 0/1

Stratified by

• Mutation type (Del19/L858R)

• Brain metastases (present/absent)

Afatinib 40 mg QD^†

Gefitinib 250 mg QD

◆ Treatment beyond progression allowed if deemed beneficial by investigator

◆ RECIST assessment performed at Weeks 4, 8 and every 8 weeks thereafter until Week 64, and every 12 weeks thereafter

◆ Primary PFS analysis conducted after ~250 events; primary OS analysis conducted after ~213 events and ≥32-mo follow-up

◆ All statistical testing at two-sided 5% alpha level with no adjustment for multiplicity

*Central or local test; ^†Dose modification to 50, 30, or 20 mg was permitted in line with prescribing information ECOG PS, Eastern Cooperative Oncology Group performance status; HRQoL, health-related quality of life;

QD, once daily; RECIST, Response Evaluation Criteria In Solid Tumors;

Pf PFS

TTF

3 co-primary endpoints

a) Correzione x molteplicita’ (e’ sufficiente 1 significativo): non specificata nel protocollo b) Tutti e 3 devono risultare significativi

- La potenza e’ quella nei confronti

dell’endpoint meno sensibile (OS) – Gli altri due sono superflui

os

LL7 – Risultati

PFS: HR = 0·73 (95% CI 0·57–0·95); p=0·017 TTF: HR = 0·73 (95% CI 0·58–0·92); p=0·0073 OS: HR = 0.86 (95% CI 0·66 – 1.12); p=0.2580

STUDIO FORMALMENTE NEGATIVO!

Endpoints Multipli

Nota bene: Alcuni recenti trials usano:

a) >1 Co-primary endpoint senza correzione b) Procedura gerarchica + correzione per

molteplicita’

- Concettualmente sbagliato - Autolesionistico

Perdita di potenza senza alcun vantaggio in cambio

Correzione della P x

analisi multiple

Procedura gerarchica: p

invariata?

8

EVENTI IN PIU’

2 VS 6

Nota Bene

• Formalmente, la seconda analisi (non prevista) non potrebbe cambiare le conclusioni

(negative) della prima

• Ma il buon senso...

Conclusioni personali

La ricerca ossessiva di formalismi statistici ‘anti-

bias’ per dimostrare l’efficacia dell’immunoterapia in varie situazioni cliniche

– ha raggiunto livelli di complessita’ RIDICOLI – Ci ha fatto ritornare alla p dimenticando

l’importanza del tipo e delle dimensioni dell’effetto – Ha trascurato un quesito altrettanto importante

In un paziente che non risponde o progredisce all’immunoterapia, cosa/quando si deve fare?

OS nei nonresponders? PostProgression OS? Etc POCHISSIME ANALISI/TRIALS