Neoplasie della testa e del collo e trattamenti combinati

Transcription

1 Neoplasie della testa e del collo e trattamenti combinati 2 nd Young Sicilian Oncologists Day: Linee Guida AIOM, Appropriatezza e Medicina di precisione Messina Ottobre 2017 NERINA DENARO denaro.n@ospedale.cuneo.it

2 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/ Italian annual incidence 20/ Survival in HNSCC is predicted primarily by - anatomical site - stage - HPV status - other pathological and clinical factors influencing prognosis to a lesser degree 2

3 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 3

4 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 4

5 HPV 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. 5

6 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

7 HNSCC Treatment 5-y OS St I-II = 70% 85%. 5-y OS St III-IV = ~ 50%. 5-y OS St I-II = 80% 95%. 5-y OS St III-IV = ~ 40%. 5-y OS St I-II = 70% 80%. 5-y OS St III-IV = ~ 30%. 5-y OS St I-II = 80% 95%. 5-y OS St III-IV = ~ 40%. 7

8 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

9 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

10 FUTURE DIRECTIONS

11 IMMUNOTHERAPIES IN HNC 1. Monoclonal Antibodies 2. Checkpoint Inhibitors 3. Vaccination 4. Adoptive therapy/car/tils 11

12 OS (%) CETUXIMAB BioRT R/M HNSCC CT* alone (n=220) -PF Cetuximab(n=222) 7.4 months HR=0.80, p= months Months 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 Bonner et al Lancet Oncol 2010 Vermorken JB, et al. N Engl J Med 2008;359:

13 CETUXIMAB Cetuximab NK cell activation 1 Tumor cell EGFR Lysis 1 Cetuximab NK cell FC Receptor Dendritic cell activation and T cell recruitment 2 Tumor cell FC region of antibody Cetuximab also attenuates the decrease in T and NKT cells seen with platinum + 5-FU 3 1. Trivedi S, et al. Ann Oncol 2015;26:40 47; 2. Belluci R, et al. OncoImmunol 2015;4:6,e ; 3. Lo Nigro C, et al. Cancer Res 2015;75:

14 Biomarker for immune activity of Cetuximab? Lattanzio L

15 Immunocheckpoint inhibitors (ICI) CheckMate KEYNOTE-055 2,3 N=361 KEYNOTE N=132 *ITT population (Note: 13 patients actually received cetuximab); ASCO 2016 data cover analysis of the first 50 patients 1. Ferris RL, et al. ASCO 2016 (Abstract No. 6009); 2. Bauml J, et al. ASCO 2016 (Abstract No. 6011); 3. (Accessed NOv, 2016); 4. Chow LQ, et al. ASCO 2016 (Abstract No. 6010) 15

16 OS (%) Overall Survival, Minimum Follow-up: 11.4 Months Nivo IC Months No. of patients at risk CheckMate 141: Nivolumab in R/M SCCHN After Platinum Therapy 12-mo OS = 34.0% 19.7% 18-mo OS = 21.5% % Median OS, mo (95% CI) Nivolumab (n = 240) 7.7 (5.7, 8.8) 0.71 Investigator s choice (n = 121) 5.1 (4.0, 6.2) HR (95% CI) P value (0.55, 0.90) Nivolumab Investigator s choice Adapted by Haddad CM-141 IC = investigator s choice Gillison ML, et al. J Clin Oncol 2017;35(suppl): abstract

17 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) 17

18 CHECKMATE 141 Ferris RL AACR

19 KEYNOTE pts Median PFS 2 m 6 m PFS: HPV+ = 37% HPV - = 20% Median OS 8 m 6 m OS: HPV+ = 70 % HPV - = 56 % 19

20 KEYNOTE pts 82% PDL1 pos 22% HPV pos 20

21 Keynote

22 Keynote

23 TOXICITY 23

24 Checkmate 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 24

25 Tumor Reduction in PTS Treated beyond pd Courtesy R. Haddad 25

26 2 line Comparison 26

27 2 line Comparison 27

28 ACTIVITY ORR Checkmate 141 Keynote 040 Nivo SOC Pembro SOC CR PR No Resp % ( ) 5.8% ( ) 14.6% 10.1% LUX Head & Neck 1 ORR AFATINIB METHOTREXATE CR 0 0 PR 33 (10%) 9 (6%) No Resp

29 The future: combination Economopulou P 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 29

30 The future: combination RT IT ICI CT TT Economopoulou P

31 The future: combination Economopoulou P

32 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 32

33 BIOMARKERS 33

34 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? 34

35 GRAZIE per l attenzione Neoplasie della testa e del collo e trattamenti combinati 35