neoplasie della testa e del collo e trattamenti...

Neoplasie della testa e del collo e trattamenti combinati

“2nd Young Sicilian Oncologists Day: Linee Guida AIOM, Appropriatezza e Medicina di precisione“

Messina 12-13 Ottobre 2017

NERINA DENARO [email protected]

http://tstgpi1srv.scroce.loc:8080/Portale/

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EPIDEMIOLOGY

• 6° malignancy worldwide

(6% of all cases /1%–2% of all deaths)

• Oral cavity 44%; larynx 31%; pharynx 25%

• European annual incidence of 43/100 000

• Italian annual incidence 20/100000

• Survival in HNSCC is predicted primarily by

- anatomical site

- stage

- HPV status

- other pathological and clinical factors influencing prognosis to a lesser degree Nerina Denaro - A.S.O. Santa Croce e Carle Neoplasie della testa e del collo e trattamenti combinati

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2HNC

• Tobacco-related HNSCC mutation of the p53 gene and downregulation of the p16 protein

• HPV-associated OPC wt p53 and Rb genes and upregulation of p53 protein levels

Nerina Denaro - A.S.O. Santa Croce e Carle Neoplasie della testa e del collo e trattamenti combinati

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HPV IMMUNOESCAPE

1. Weak T cell response to HPV early Ag in blood (downregulation HLA I/inhibition STAT1)

2. TILs that often lack cytotoxicity (Tregs)

3. TILs that express co-inhibitory molecules such as PD1, TGFβ at their surface and have a downregulation of CD3 complex and OX40 and IL2 response

4. Incresed number of IL 10 producing Treg

5. Loss of IFNƔ

6. E5 interacts with HLA-I heavy chain, resulting in reduced cell surface HLA-I

7. E6 inhibits the STAT-1 pathway. Destruction of p53

8. E7 down-regulates cell expression both of HLA class I, and transporter associated with antigen processing (TAP) [Li W, 2010]. E7 interacts with IRF-1 and disrupts its control [Um SJ 2002]. Inactivation rb


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• Distinct subset of HNSCC

• Primarily oropharynx.

• HPV16 90% of HPV+ OPCs.

• The time from first oral HPV infection to the development of cancer is estimated to be more than a decade.

• Measures of sexual behaviour (number of vaginal and oral partners, history of genital warts) have been associated with HPV+ OPC.


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HPV

HNSCC Treatment • STAGE I S or RT • STAGE II S eventually followed by RT or in selected pts only RT • Stage III S RT±CT (resectable) • Stage IVa-b CTRT(unresectable) • Stage IV c CT • Postop RT (pathological minor risk factors): Poor differentiation grade

(G3) /Perineural and/or vascular invasion/ Number of pathologically positive lymph nodes (≥2)/ pT3, pT4, close margins

• In selected non-radical excision, re-excision can be considered. • Concurrent CTRT ( major risk factors): R1 resection (resection with

microscopic residual disease)/ Lymph node extranodular extension (ENE)

• Multidisciplinary team is MANDATORY for adeguate management Lo Nigro C 2017


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HNSCC Treatment


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5-y OS St I-II = 70%–80%.

5-y OS St III-IV = ~ 30%.

5-y OS St I-II = 70%–85%.


5-y OS St I-II = 80%–95%.


5-y OS St I-II = 80%–95%.


5-y OS St I-II = 80%–95%.


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ADEGUATE SUPPORTIVE CARE

• Accurate patient selection and an individualised supportive care approach are mandatory BEFORE treatment initiation, DURING and AFTER tretment because allow program completion.

• CTRT is associated with severe acute toxicities, which can result in a mortality rate ranging from 2% to 9.3%.

• > acute toxicity > late adverse events <patients’ QoL and possibly cause late death


Lo Nigro C 2017

ADEGUATE SUPPORTIVE CARE

• Adequate oral care

• Dysphagia assessment before and during treatment

• It is recommended to minimise the dose to the main DARS

• A 3-drug regimen with a 5-HT3 receptor antagonist,Dexamethasone and an NK1 receptor antagonist for the prevention of cisplatin-induced nausea and vomiting.

• ESAs are NOT recommended in patients treated with curative intent with radiotherapy (DETRIMENTAL)

• Dietary counselling and/or supplements .

• Febrile neutropaenic HNC patients should be hospitalised.

• In case of Grade 3 skin and haematologic toxicity, do not stop radiotherapy

9 Nerina Denaro - A.S.O. Santa Croce e Carle Neoplasie della testa e del collo e trattamenti combinati

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FUTURE DIRECTIONS

IMMUNOTHERAPIES IN HNC

1. Monoclonal Antibodies

2. Checkpoint Inhibitors

3. Vaccination

4. Adoptive therapy/CAR/TILs


Bonner et al Lancet Oncol 2010

5 y OS 46% vs 36% 81% DCR in the cet arm 27% reduction in death risk (HR=0.73) Rash intensity correlates with > OS >OS in all primary sites

BioRT R/M HNSCC

Months

3 6 9 12 15 18 21 24

10.1 months

OS

(%

)

7.4 months

0 0

10

20

30

40

50

60

70

80

90

100

HR=0.80, p=0.04

-CT* alone (n=220) -PF Cetuximab(n=222)

Vermorken JB, et al. N Engl J Med 2008;359:1116–1127.

CETUXIMAB


CETUXIMAB

Cetuximab

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1. Trivedi S, et al. Ann Oncol 2015;26:40–47; 2. Belluci R, et al. OncoImmunol 2015;4:6,e1008824; 3. Lo Nigro C, et al. Cancer Res 2015;75:1327.

FC Receptor

NK cell

Tumor cell

FC region of antibody

NK cell activation1

Lysis1

Tumor cell

EGFR

Cetuximab

Dendritic cell activation and T cell recruitment2

Cetuximab also attenuates the decrease in T and NKT cells seen with platinum + 5-FU3


Biomarker for immune activity of Cetuximab?

Lattanzio L 2017


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N=361

*ITT population (Note: 13 patients actually received cetuximab); †ASCO 2016 data cover analysis of the first 50 patients

CheckMate 1411

KEYNOTE-0552,3

1. Ferris RL, et al. ASCO 2016 (Abstract No. 6009); 2. Bauml J, et al. ASCO 2016 (Abstract No. 6011); 3. https://clinicaltrials.gov/ct2/show/NCT02255097 (Accessed NOv, 2016); 4. Chow LQ, et al. ASCO 2016 (Abstract No. 6010)

KEYNOTE-0124

N=132

Immunocheckpoint inhibitors (ICI)


https://clinicaltrials.gov/ct2/show/NCT02255097

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240 169 132 98 76 45 27 12 3

121 88 51 32 22 9 4 3 0

Months

0 3 6 9 12 15 18 21 24

OS

(%)

0

10

20

30

40

50

60

70

80

100

90

Nivo

IC

No. of patients at risk

19.7%

34.0%

21.5%

8.3%

Nivolumab

Investigator’s choice

0

0

12-mo OS =

18-mo OS =

Median OS, mo (95% CI)

HR (95% CI)

P value

Nivolumab (n = 240) 7.7 (5.7, 8.8) 0.71

(0.55, 0.90) 0.0048

Investigator’s choice (n = 121) 5.1 (4.0, 6.2)

Overall Survival, Minimum Follow-up: 11.4 Months

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IC = investigator’s choice Gillison ML, et al. J Clin Oncol 2017;35(suppl): abstract 6019. Adapted by Haddad CM-141

CheckMate 141: Nivolumab in R/M SCCHN After Platinum Therapy


CHECKMATE 141 • Among patients achieving CR/PR, nivo improved OS

compared with IC

• Median OS was not reached vs 13.6 months (HR = 0.08; 95% CI: 0.01, 0.47)

• 18-month survival rates were 86.1% vs 38.1%

• Patients with SD are not considered responders per RECIST 1.1, but treatment with nivolumab resulted in survival benefits compared with IC

• Median OS was 10.4 vs 7.1 months (HR = 0.53; 95% CI: 0.33, 0.85)

• 18-month survival rates were 32.6% vs 11.7%

• Nivolumab’s safety profile was favorable vs IC, including for patients with CR/PR who were on therapy longer (median duration, >12 months vs <5 months)


Ferris RL AACR 2017

CHECKMATE 141


132 pts

Median PFS 2 m 6 m PFS: HPV+ = 37% HPV - = 20%

Median OS 8 m 6 m OS: HPV+ = 70 % HPV - = 56 %

KEYNOTE 012


171 pts 82% PDL1 pos 22% HPV pos

KEYNOTE 055


Keynote 040


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22

Keynote 040

TOXICITY


Checkmate 358

23 pts pre surgery response in 11/23 (48% ) RECIST Criteria


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Reductions were seen in both HPV+ and

HPV− tumors

3 pts had tumor reduction ≥40%

The largest reduction was 75% in 1 pt HPV+

Grade 3–4 TRAEs occurred in 2 (16.7%) pts

HPV+ and 2 (11.8%) pts HPV−

Serious TRAEs occurred in 1 (8.3%) patient

with an HPV+ tumor and 3

(17.6%) patients with HPV− tumors

Courtesy R. Haddad

Tumor Reduction in PTS Treated beyond pd


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2° line Comparison


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2° line Comparison


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ORR Checkmate 141 Keynote 040

Nivo SOC Pembro SOC

CR 6 1 4 1

PR 26 6 32 24

No Resp 208 114 211 223

13.3% (9.3 - 18.3) 5.8% (2.4 - 11.6) 14.6% 10.1%

LUX Head & Neck 1

ORR AFATINIB METHOTREXATE

CR 0 0

PR 33 (10%) 9 (6%)

No Resp 289 152

ACTIVITY


The future: combination

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Econ

om

op

ulo

u P

. 20

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•PD1/PDL1+CTLA4

•PD1+CD137 (urelumab)

•PD1+anti KIR (lirilumab

•PD1+IDO

•Oncolytic virus/GM-CSF+PD1 (TVec)

•PD1+RT±CT

•PD1+EGFR

Blanck CU 2016 Science



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Economopoulou P 2017


ICI

RT

CT

TT

IT



Economopoulou P 2017

Immunotherapy for HNC : conclusions…

Few responders but long survivors

Unclear treatment duration and position of IC in the therapeutic algoritm

1. Need for selection

Biomarkers

gene signatures

TAIC, NLR

2. Need of «useful»trials


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BIOMARKERS


Conclusions

• In LAHNSCC outcome depends on both clinical /pathological prognostic factor and on multidisciplinary team expertise /protocol adherence

• Acute and late treatment sequalae impact on quality of life and overall survival

• ICI therapy, specifically PD1 pathway blockade, improves survival in R/M HNC independently from the number of prior treatment lines

• Achievement of an OR during ICI therapy predicts a good outcome (considering the # line of treatment)

• The ideal biomarker to select ICI responders is unknown

• What immuno-oncology (IO) combinations make sense for HNC? Which position in our treatment flow chart?

• What are the optimal dose,fractionation and field size in IO-RT for LAHNC?


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