Maria Grazia Ghi

Oncologia Medica 2 Istituto Oncologico Veneto – IRCCS, Padova

Milano, 17 novembre 2017

Tumori testa collo

Il ruolo dell’immunoterapia

Rationale for immunotherapy in HNSCC

1. Response to immunotherapy correlates with mutational burden

2. Tumors containing T-cell infiltrates (inflamed phenotype) might

be induced to respond to immunotherapy

3. High mutational burden in H&N cancer (tobacco use and HPV)

1. High expression of PD-L1 (50-78%) 1. Ferris RL, et al. J Clin Oncol. 2015;33:3293-3304 2. Badoual C, et al. Cancer Res. 2013;73:128-138 3. Concha-Benavente F, et al. Cancer Res. 2016;76:1031-1043

Anti PD-1 in HNSCC: finalized studies

- Pembrolizumab, humanized anti PD-1 moAb

- Nivolumab, fully human anti PD-1 moAb

- The majority of pts with R/M are no longer amenable to curative treatment - PF + cetuximab (Extreme regimen) recommended first line for fit patients with R/M disease (median OS 10 mo) - Median OS for pts progressed after platinum-based therapy is 6 months or less - New therapeutic options needed to prolong survival while optmizing QoL

Recurrent/metastatic HNSCC

CheckMate 141 phase III trial

361

54.5% > 2 lines treatment

CheckMate 141 : efficacy

Late separation of the survival curves with a subsequent plateau phase

Overall Survival Progression Free Survival

with ~1-Year Follow-up (ASCO 2017)

CheckMate 141 : response rate

CheckMate 141 : Adverse Events

CheckMate 141 trial OS according to PD-L1 expression (tumor cells)

The magnitude of OS benefit of nivo greater in PD-L1 positive

Increasing PD-L1 expression did not result in further OS benefit

Nivolumab effective regardless of PD-L1 expression

Dako, IHC 28-8

CheckMate 141 trial OS according to HPV status (25% HPV +)

Nivolumab effective regardless of HPV status

The magnitude of OS benefit of nivo greater in HPV positive

Harrington KJ et al, Lancet Oncol 2017

Checkmate 141 : explorative analysis

- Longer OS and higher RR for Nivo regardless prior cetuximab exposure (221 pts)

Ferris R et al, ASCO 2017

- Potential predictive biomarker: PBLs (36 pts)

Concha-Benavente F et al, ASCO 2017

- Treatment effect by Overall Response

Licitra L et al, ESMO 2017

Outcomes in 1st line R/M patients

(explorative analysis)

78 pts (52 Nivo + 26 IC) platinum-refr. in primary/adjuvant setting

Gillison M et al, ASCO 2017

Longer OS and higher ORR in 1st line R/M patients

Extreme - Vermorken et al, NEJM 2008

ORR: 19.2% vs 11.5% ORR: 36% vs 20%

Nivo beyond progression subgroups

(explorative analysis)

146 pts progressed -> 62 (42%) treated beyond progression 25.8% of the pts in tne Nivo arm

Haddad R et al, ESMO 2017

Tumor reduction in 24% of pts (15/62) median OS of 12.7 months

1. Seiwert T et al, Lancet Oncol 2016 2. Chow L et al, J Clin Oncol 2016

Pembrolizumab in R/M HNSCC

Bauml J et al, JCO 2017

PD-L1 expression: Dako, IHC 22C3

Keynote-012 and Keynote 055 trials

1. Seiwert T et al, Lancet Oncol 2016 2. Chow L et al, J Clin Oncol 2016 3. Bauml et al, J Clin Oncol 2017

Cohen E et al, ESMO 2017

KEYNOTE-040 phase III trial

495

28% > 2 lines treatment

24% HPV+

KEYNOTE-040: efficacy

Median FU 7.3 mo (range 0.03-28.4)

Cohen E et al, ESMO 2017

OS by PD-L1

expression

PFS by PD-L1

expression

Cohen E et al, ESMO 2017

KEYNOTE-040: ORR and AEs

Cohen E et al, ESMO 2017

Cohen E et al, ESMO 2017

KEYNOTE-040

cross over from SOC to Pembro= 12.5%

CheckMate 141 vs KEYNOTE 040

. Different drug effect?

* TPS vs CPS; different assays

ChecMate 141 Nivo n=240

ChecMate 141 IC n=121

Keynote-040 Pembro n=247

Keynote-040 IC n=248

ECOG PS > 1

79.2%

80.2% 71.3% 72.6%

> 2 previous treatment line

55.8% 52.1% 29.1% 27%

P 16 +ve 26.2% 24% 24.7% 23.4%

PDL-1* >1 36.7% 50.4% 79% 77%

Cross over - nr - 12.5%

Immune checkpoint inhibitor beyond PD

25.8% - 4.5% -

Anti PD-L1 in HNSCC

- Durvalumab, humanized anti PD-L1 moAb

- Atezolizumab, fully human anti PD-L1 moAb

Zandberg ZP et al, ESMO 2017

112 pts :TC > 25%, Ventana IHC SP263

Bahleda R et al, ESMO 2017

32 pts ; 53% > 2 lines treatment

PD-L1 expression of ≥ 5% on IC =78% (IC2/3)

ORR median duration: 7.4 mo (26.2 mo in IC2/3) PFS: median 2.6 mo; 31% at 6 mo OS: median 6 mo; 36% at 1 y

Future directions

Integration of immunotherapy

in earlier lines of treatment

- Combination with concomitant CRT

- Combination with surgery

- Combination with targeted therapy

- Combination with other immunotherapies

Powell et al, ASCO 2017

Interim analysis on the first 27 pts (96% stage IV) - safety cohort

Primary EP: Safety

Safety data ORR - day 150

- RT delivered without significant delays

- 85% of the pts received CDDP > 200 mg/mq

Primary EP: LRR and DM rate reduce from 35% to 15% in high risk pts

High risk

Low risk

Preliminary data on the first 25 patients (monocenter)

96% stage IV; 58% PD-L1 >1%

Planned sample size: 46 pts, HPV - ve

Uppaluri et al, ASCO 2017

Pathologic treatment effect : tumor necrosis and/or giant cell/histiocytic reaction to keratinous debris in > 10% of tumor area

Preliminary data on 29 patients evaluable for safety (PD-L1 > 1% =65%)

Primary EP: safety and tolerability

Ferris R et al, ESMO 2017

Immunotherapy in HNSCC

- Similar activity/efficacy data for Pembro and Nivo

- Well tolerated, with manageable toxicity profile

- RR and median PFS are not good surrogates for clinical benefit

- Evidence of benefit regardless of PD-L1 expression and HPV

status but benefit of different size

- Preliminary data for combination treatment strategies in earlier

line of treatment

Unanswered questions

- Criteria for response evaluation: Recist vs Immunological

- Optimal timing of immunoth and treatment duration

-PD-L1 expression as a predictive marker is still controversial

standardized definition of PD-L1 positivity

ICH cut off

tumor cells vs tumor infiltrating inflammatory cells

-Timing biopsy (archival or fresh), primary vs metastatic

-A single biomarker may not be enough

Patient selection and biomarker crucial for further development

Cost : 120-150,000 $/year/patient

Thank you for your attention

mariagrazia.ghi@iov.veneto.it