Neoplasie della testa e del collo e trattamenti combinati

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Neoplasie della testa e del collo e trattamenti combinati

“2

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

Messina 12-13 Ottobre 2017 NERINA DENARO

[email protected]

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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 2

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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

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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.

HPV

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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

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%.

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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

Neoplasie della testa e del collo e trattamenti combinati

Lo Nigro C 2017

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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

Nerina Denaro - A.S.O. Santa Croce e Carle 9

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FUTURE DIRECTIONS

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IMMUNOTHERAPIES IN HNC

1. Monoclonal Antibodies 2. Checkpoint Inhibitors 3. Vaccination

4. Adoptive therapy/CAR/TILs

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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 ( % )

months 7.4

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

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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

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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 141

¹

KEYNOTE-055

^2,3

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-012

⁴

N=132

Immunocheckpoint inhibitors (ICI)

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27

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

16

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

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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)

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Ferris RL AACR 2017

CHECKMATE 141

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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

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171 pts 82% PDL1 pos 22% HPV pos

KEYNOTE 055

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Keynote 040

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Keynote 040

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TOXICITY

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Checkmate 358

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

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

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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

28 Nerina Denaro - A.S.O. Santa Croce e Carle

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The future: combination

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Economopulou P. 2017

•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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The future: combination

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Economopoulou P 2017

ICI

RT

CT TT

IT

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The future: combination

31 Nerina Denaro - A.S.O. Santa Croce e Carle

Economopoulou P 2017

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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

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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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Nerina Denaro - A.S.O. Santa Croce e Carle Neoplasie della

testa e del collo e trattamenti combinati 35