WAŻNE WYDARZENIA W CIĄGU OSTATNIEGO ROKU

NOWOTWORY NARZĄDÓW GŁOWY I SZYI

Prof. dr hab. n. med. ANDRZEJ KAWECKI

KLINIKA NOWOTWORÓW GŁOWY I SZYI

NOWOTWORY NARZĄDÓW GŁOWY I SZYI OSTATNI ROK

Leczenie radykalne (SHNC):

• trwające badania fazy 2R i 3 – CTRT / RT +/- immunoterapia: wyniki za kilka lat niestety…..

• poszukiwanie biomarkerów

• próby de-eskalacji intensywności leczenia w rakach HPV zależnych

Leczenie systemowe (SCHNC, NPC):

• badania fazy 2R i 3 – immunoterapia w I linii w fazie podsumowań: korekta „złotego standardu” (schematu EXTREME)

• poszukiwania biomarkerów

Polska:

• czekamy na program lekowy EXTREME (wkrótce 10 rocznica starań)

• czekamy na programy lekowe immunoterapia w II linii SCHNC

HPV – ZALEŻNY PŁASKONABŁONKOWY RAK NARZĄDÓW GŁOWY I SZYI

ODMIENNA OD KLASYCZNEJ POSTAĆ SCHNC

HPV(+) HPV(-)

Lokalizacja ustna część gardła różna

Stopień sprawności wysoki często gorszy

Wiek chorych młodszy starszy

Status socjalny często wysoki często niski

Czynniki ryzyka zachowania seksualne tytoń, alkohol

Zachorowalność wzrasta spada

HPV – ZALEŻNY PŁASKONABŁONKOWY RAK NARZĄDÓW GŁOWY I SZYI

ODMIENNA OD KLASYCZNEJ POSTAĆ SCHNC

HPV(+) HPV(-)

HPV(+) HPV(-)

Obraz molekularny p53WT, p16+ p53M, p16-

Zróżnicowanie HP niskie średnie / wysokie

Cecha T T1-2>60%* T1-2<50%

Cecha N N+>90%* niższy odsetek

Podatność na RT / CT +++ ++

Podatność na LUM +++ ++

Wtórne SCC rzadko często

Rokowanie dobre znamiennie gorsze

HPV-ZALEŻNY RAK USTNEJ CZĘŚCI GARDŁA WPŁYW NA EFEKT CTRT

Dane z badania

RTOG 0129

(AF-RT + cDDP vs

CF-RT + cDDP)

Ang KK et al.

N Eng J Med 2010,

363, 24 - 35

HPV+ RAK USTNEJ CZĘŚCI GARDŁA DE=ESKALACJA INTENSYWNOŚCI LECZENIA

BADANIE RTOG 1016

Gillison ML i wsp., published on line The Lancet, November 15, 2018

849 chorych

ustna część gardła aIMRT + cDDP 2x100mg/m2

HPV+ R

CS III-IV (AJCC w.7) aIMRT + cetuksymab co tydzień

Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer

(De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial

Mehana H. et al.

www.thelancet.com Published online November 15, 2018

IMMUNOTERAPIA RAKI NARZĄDÓW GŁOWY I SZYI (SCHNC)

STAN WIEDZY 2018

• Zakończone duże badania w II linii leczenia R/M SCHNC (niwolumab faza 3, pembrolizumab faza 2): podstawowe źródło wiedzy klinicznej.

• Wyniki badania KEYNOTE 048 = zmiana standardu I linii leczenia R/M SCHNC

Inne badania kliniczne fazy 2R i 3 w toku

• W toku badania kliniczne w leczeniu radykalnym (kojarzenie z RT i CTRT)

KEYNOTE-048: Phase 3 Study of First-Line Pembrolizumab for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC)

Barbara Burtness,1 Kevin Harrington,2 Richard Greil,3 Denis Soulières,4 Makoto Tahara,5 Gilberto de Castro,6 Amanda Psyrri,7 Neus Basté Rotllan,8 Prakash Neupane,9 Åse Bratland,10 Thorsten Fuereder,11 Brett GM Hughes,12 Ricard Mesia,13 Nuttapong Ngamphaiboon,14 Tamara Rordorf,15 Wan Zamaniah Wan Ishak,16 Ananya Roy,17 Jonathan Cheng,17 Fan Jin,17 Danny Rischin18

1Yale School of Medicine and Yale Cancer Center, New Haven, CT, USA; 2The Institute of Cancer Research/The Royal Marsden NHS Foundation Trust National Institute of Health Research Biomedical Research Centre, London, UK; 3Paracelsus Medical University, Salzburg Cancer Research Institute, and Cancer Cluster Salzburg, Salzburg, Austria; 4Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada; 5National Cancer Center Hospital East, Kashiwa, Japan; 6Instituto do Cancer do Estado de Sao Paulo, Sao Paulo, Brazil; 7National Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece; 8Vall d’Hebron University Hospital, Barcelona, Spain (currently at Institut Gustave Roussy, Paris, France); 9University of Kansas Medical Center, Kansas City, KS, USA; 10Oslo University Hospital, Oslo, Norway; 11Medical University of Vienna, Vienna, Austria; 12Royal Brisbane and Women’s Hospital and University of Queensland, Brisbane, QLD, Australia; 13Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain; 14Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 15University Hospital, Zurich, Switzerland; 16University Malaya, Kuala Lumpur, Malaysia; 17Merck & Co., Inc., Kenilworth, NJ, USA; 18Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

KEYNOTE-048 Study Design (NCT02358031)

Pembrolizumab 200 mg Q3W

for up to 35 cycles

Cetuximab 250 mg/m2 Q1Wc + Carboplatin AUC 5 OR Cisplatin 100 mg/m2 +

5-FU 1000 mg/m2/d for 4 days

for 6 cycles (each 3 wk)

R

1:1:1

Cetuximab 250 mg/m2 Q1W

Stratification Factors

• PD-L1 expressiona (TPS ≥50% vs <50%)

• p16 status in oropharynx (positive vs negative)

• ECOG performance status (0 vs 1)

aAssessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent). TPS = tumor proportion score = % of tumor cells with membranous PD -L1 expression. bAssessed using the CINtec p16 Histology assay (Ventana); cutpoint for positivity = 70%. cFollowing a loading dose of 400 mg/m2.

Pembrolizumab 200 mg + Carboplatin AUC 5 OR Cisplatin 100 mg/m2 +

5-FU 1000 mg/m2/d for 4 days

for 6 cycles (each 3 wk)

Pembrolizumab 200 mg Q3W

for up to 35 cycles total

Key Eligibility Criteria

• SCC of the oropharynx, oral cavity, hypopharynx, or larynx

• R/M disease incurable by local therapies

• ECOG PS 0 or 1

• Tissue sample for PD-L1 assessmenta

• Known p16 status in the oropharynxb

Pembrolizumab

Monotherapy

Pembrolizumab

+ Chemotherapy

EXTREME

Disposition of All Randomized Patients

aThere was an enrollment hold for the pembrolizumab + chemotherapy arm from Aug 13, 2015 to Oct 2, 2015. bDefined as the time from randomization to the date of death or database cutoff date of Jun 13, 2018, if the patient was alive.

882 patients randomly allocated from April 1, 2015, to January 17, 2017a

Pembrolizumab (P)

• 301 allocated • 300 treated

EXTREME (E)

• 300 allocated • 287 treated

• 16 ongoing • 16 completed • 268 discontinued

– 213 radiographic or clinical PD – 33 AEs – 9 consent withdrawal – 6 complete response – 3 death – 3 physician decision – 1 lost to follow-up – 0 use of excluded medication

• 10 ongoing

• 277 discontinued – 202 radiographic or clinical PD – 44 AEs – 18 consent withdrawal – 3 complete response – 2 death – 7 physician decision – 1 lost to follow-up – 0 use of excluded medication

Pembro + Chemo (P+C)

• 281 allocated • 276 treated

• 13 ongoing • 14 completed • 249 discontinued

– 178 radiographic or clinical PD – 44 AEs – 13 consent withdrawal – 9 complete response – 2 death – 2 physician decision – 0 lost to follow-up – 1 use of excluded medication

Median follow-upb:

11.7 mo Median follow-upb:

13.0 mo

Median follow-upb:

10.7 mo

KEYNOTE-048 Study Design (NCT02358031)

Key Eligibility Criteria

• SCC of the oropharynx, oral cavity, hypopharynx, or larynx

• R/M disease incurable by local therapies

• ECOG PS 0 or 1

• Tissue sample for PD-L1 assessmenta

• Known p16 status in the oropharynxb

Pembrolizumab 200 mg Q3W

for up to 35 cycles

Cetuximab 250 mg/m2 Q1Wc + Carboplatin AUC 5 OR Cisplatin 100 mg/m2 +

5-FU 1000 mg/m2/d for 4 days

for 6 cycles (each 3 wk)

R

(1:1:1)

Cetuximab 250 mg/m2 Q1W

Stratification Factors

• PD-L1 expressiona (TPS ≥50% vs <50%)

• p16 status in oropharynx (positive vs negative)

• ECOG performance status (0 vs 1)

aAssessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent). TPS = tumor proportion score = % of tumor cells with membranous PD -L1 expression. bAssessed using the CINtec p16 Histology assay (Ventana); cutpoint for positivity = 70%. cFollowing a loading dose of 400 mg/m2.

Pembrolizumab 200 mg + Carboplatin AUC 5 OR Cisplatin 100 mg/m2 +

5-FU 1000 mg/m2/d for 4 days

for 6 cycles (each 3 wk)

Pembrolizumab 200 mg Q3W

for up to 29 cycles

Overall Survival: P vs E, CPS ≥20 Population

Data cutoff date: Jun 13, 2018.

Events HR (95% CI) P

Pembro alone 62% 0.61 (0.45-0.83) 0.0007

EXTREME 78%

Median (95% CI)

14.9 mo (11.6-21.5)

10.7 mo (8.8-12.8)

0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

M o n th s

OS

, %

N o . a t R is k

133 106 85 65 24

122 100 64 42 12

47

22

0

0

11

5

2

0

12-mo rate

56.9%

44.9% 24-mo rate

38.3%

22.1%

0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

M o n th s

OS

, %

N o . a t R is k

257 196 152 110 34

255 207 131 89 21

74

47

0

0

17

9

2

1

Overall Survival: P vs E, CPS ≥1 Population

Data cutoff date: Jun 13, 2018.

Events HR (95% CI) P

Pembro alone 69% 0.78 (0.64-0.96) 0.0086

EXTREME 81%

Median (95% CI)

12.3 mo (10.8-14.9)

10.3 mo (9.0-11.5)

12-mo rate

51.0%

43.6% 24-mo rate

30.2%

18.6%

KEYNOTE-048 Study Design (NCT02358031)

Key Eligibility Criteria

• SCC of the oropharynx, oral cavity, hypopharynx, or larynx

• R/M disease incurable by local therapies

• ECOG PS 0 or 1

• Tissue sample for PD-L1 assessmenta

• Known p16 status in the oropharynxb

Pembrolizumab 200 mg Q3W

for up to 35 cycles

Cetuximab 250 mg/m2 Q1Wc + Carboplatin AUC 5 OR Cisplatin 100 mg/m2 +

5-FU 1000 mg/m2/d for 4 days

for 6 cycles (each 3 wk)

R

(1:1:1)

Cetuximab 250 mg/m2 Q1W

Stratification Factors

• PD-L1 expressiona (TPS ≥50% vs <50%)

• p16 status in oropharynx (positive vs negative)

• ECOG performance status (0 vs 1)

aAssessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent). TPS = tumor proportion score = % of tumor cells with membranous PD -L1 expression. bAssessed using the CINtec p16 Histology assay (Ventana); cutpoint for positivity = 70%. cFollowing a loading dose of 400 mg/m2.

Pembrolizumab 200 mg + Carboplatin AUC 5 OR Cisplatin 100 mg/m2 +

5-FU 1000 mg/m2/d for 4 days

for 6 cycles (each 3 wk)

Pembrolizumab 200 mg Q3W

for up to 29 cycles

0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

M o n th s

OS

, %

N o . a t R is k

281 227 169 122 40

278 227 147 100 20

75

51

0

0

10

5

1

1

Overall Survival: P+C vs E, Total Population

Data cutoff date: Jun 13, 2018.

Events HR (95% CI) P

Pembro + Chemo 70% 0.77 (0.63-0.93)

0.0034

EXTREME 80%

Median (95% CI)

13.0 mo (10.9-14.7)

10.7 mo (9.3-11.7)

12-mo rate

53.0%

43.9% 24-mo rate

29.0%

18.7%

0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

M o n th sO

ng

oin

g R

es

po

ns

e,

%

N o . a t R is k

1 0 0 6 2 2 9 1 3 1

1 0 1 3 8 1 4 6 0

3

1

0

0

2 0

1 1

0

0

Response Summary, P+C vs E, Total Population

aPatients without measurable disease per central review at baseline who did not have CR or PD. bPatients who did not have a post-baseline imaging assessment evaluable for response or who did not have post-baseline imaging. Response assessed per RECIST v1.1 by blinded, independent central radiologic review. Data cutoff date: Jun 13, 2018.

Confirmed

Response,

n (%)

Pembro +

Chemo

N = 281

EXTREME

N = 278

ORR 100 (35.6) 101 (36.3)

CR 17 (6.0) 8 (2.9)

PR 83 (29.5) 93 (33.5)

SD 78 (27.8) 94 (33.8)

PD 48 (17.1) 34 (12.2)

Non-CR/non-PDa 13 (4.6) 9 (3.2)

Not evaluable or

assessedb 42 (14.9) 40 (14.4)

Duration of Response

Median (range)

P+C: 6.7 mo (1.6+ to 30.4+)

E: 4.3 mo (1.2+ to 27.9+)

NOWOTWORY NARZĄDÓW GŁOWY I SZYI OSTATNI ROK – NAJWAŻNIEJSZE WYDARZENIA

PODSUMOWANIE

• Zdefiniowanie raków HPV – zależnych jako nowotworu o lepszym rokowaniu nie przekłada się na zmianę standardów postepowania, jednoczesna CTRT pozostaje optymalnym leczeniem przypadków zaawansowanych

• Schematy leczenia systemowego z udziałem immunoterapii wydają się optymalnym postępowaniem w I linii leczenia z powocu nawrotów lub przerzutów odległych raka płaskonabłonkowego narządów głowy i szyi