Carla van Herpen Medical Oncologist Immunotherapyin Head & NeckCancer

Transcription

1 Carla van Herpen Medical Oncologist Immunotherapyin Head & NeckCancer

2 Disclosures Astra-Zeneca/medimmune: clinical trial BMS: advisory board, clinical trial Merck: advisory board, clinical trial, research funding MSD: advisory board, clinical trial

3 Head andneckcanceris an immunogeneictumor

4 Actuallandscape of systemic treatment in HNSCC Curative in combination with radiotherapy Cisplatin (CRT) or cetuximab (cet-rt) in locally advanced disease (primary treatment) organpreservation unresectable disease after surgery: postoperative CRT Palliative Distant metastases or local recurrence Cisplatin/5-FU/Cetuximab ( Extreme schedule)

5 Risk factors Tobacco and alcohol consumption: in 75% of patients Human papillomavirus (HPV): newlyidentified causalfactor, especially in oropharyngeal cancer Favourable prognostic factor Better responsiveness to radiotherapy and chemotherapy

6 HPV is prognosticandpredictive factor for OS andpfs Anget al; NEJM, 2010

7 HPVA-OPC HPV-associated oropharyngeal cancer (OPC) Low-risk population with an excellent prognosis Ang NEJM 2010

8 Argiris et al. Lancet 2008; 371:1695

9 DifferencesbetweenHPV-negative andhpva OPC Leemans Nat gen 2011

10 Advances HPV-associated oropharyngeal cancer (OPC) Low-risk population with an excellent prognosis De-escalation studies HPV-negative pharyngeal cancer Improving outcomes: intensifying treatment New drugs in recurrent or metastatic HNSCC Targeting the PI3K/AKT/mTOR pathway Immunotherapy Anti-programmed death (ligand)-1 (anti-pd(l)-1) studies in HPV- Positive and negative patients HPVA OPC: high PDL-1 expression HPV negative HNSCC: high mutational load

11 Immunotherapy: finalizedstudies Pembrolizumab: anti-pd1 Ab Keynote-012 Phase Ib Keynote-055 Phase II after platinum/cetuximab Nivolumab: anti-pd1 Ab Checkmate 141 Phase III after platinum/cetuximab Chow JCO 2016; Ferris ASCO 2016

12 PembrolizumabKeynote-012 n=132 Median age 60 57% 2 prior lines ORR 18% Mediandurationof response not reached 6 monthspfs 23% 6 monthsos 59% Chow JCO 2016

13 PDL1 is predictivefor PFS andos RR: p16+ 32% p16-15%

14 NivolumabCheckmate141 Ferris ASCO2016

15

16

17

18

19

20

21

22

23 Toxicities

24 Biomarker for response PD-L1 is used Non consensus in detection methods Lacking definition of positivity Lackingitsuseas prognosticor predictive marker Urgent need for better biomarkers Chow ASCO 216

25 Immunotherapy: running studies Anti-PDL1 (Durvalumab) Anti-CTLA4: ipilimumab or tremelimumab Combination: Anti-PD1 and anti-ctla4 Anti-PDL1 andanti-ctla4 Anti-PD1 and anti-pdl1 Cetuximab and anti-pd(l)1 Positive co-stimulation TLR8 agonist Targeting HPV-specific antigens in HPVA-OPC HPV vaccins

26 Checkpoint inhibitors in combination withcetuximab Cetuximab treatment in HNSCC Frequencyof Tregsuppressorcells expressing CTLA4 andpd-1 are enriched in the tumor microenvironment Increaseof CD4 + CD25 hi CD39 + FOXP3 + Treg: expansionof Treg EGFR pathway may contribute to regulation of PD-L1 expression (activation of the PD1 pathway contributes to immune escape in EGFR driven tumors) Ferris JCO 2015

27 Nivolumab Ph Trial Design III Nivolumab vs MTXor DTXor cetuximabin R/M SCCHN after failure of Pt-tx* II Nivolumab in 2L+ R/M nasopharyngeal cancer I/II I/II 1b Ib I/II Nivolumab + epacadostatin advanced cancers(including SCCHN with known HPV status) Nivolumab+ varlilumabin advanced/metastatic solid tumors(including SCCHN after failure of Pt-tx) Nivolumab + BMS (anti-lag-3)in 2L+advanced solid tumors Nivolumab+ cetuximab + motolimod as neoadjuvant therapy following surgical resection Nivolumabin virus-positive and virus-negativesolid tumors IDO-1 inhibitor Anti-CD27 Anti-LAG-3 TLR-8 agonist Abbreviations and reference can be found in the speaker notes.

28 Pembrolizumab Ph Trial Design* Ib Pembrolizumab in advanced solid tumors (including SCCHN) III III II I II II II I Pembrolizumab vs MTXor DTXor cetuximabin R/M SCCHN after failure of Pt-tx Pembrolizumab vs pembrolizumab + Pt + 5-FU vs cetuximab + Pt + 5-FU in 1L R/M SCCHN Pembrolizumabin R/M SCCHN after failure of cetuximab + Pt-tx Pembrolizumab inadvanced solid tumors (including SCCHN) Pembrolizumab + RT in locoregional inoperable recurrence or second primary SCCHN Pembrolizumab vs standard chemotherapy in platinum pretreated recurrent/metastatic nasopharyngeal cancer Neoadjuvantpembrolizumab andadjuvant pembrolizumab + RT+ cisplatin in1l LA-SCCHN Pembrolizumab + RT in advanced solid tumors (including R/M SCCHN) With RT With CRT With RT

29 Ipilimumab and Tremelimumab Ph Trial Design Ib Ipilimumab + cetuximab + IMRTin 1L LA-SCCHN I Ipilimumab + MGA271 in SCCHN Anti-B7-H3 I I Mogamulizumab + tremelimumabor durvalumab in 2L+ locally advanced/metastatic solid tumors Durvalumab ± tremelimumab in advanced solid tumors Anti-CCR4 I Durvalumab + tremelimumabin R/M SCCHN III II I III Durvalumab ±tremelimumabin R/M SCCHN who have not received prior systemic therapy in R/M setting Tremelimumab + durvalumab vs tremelimumabvs durvalumab in PD-L1 R/M SCCHN after failure of Pt-tx Tremelimumab+ durvalumab + first-line chemotherapy in patients with advanced solid tumors Durvalumab + tremelimumaband durvalumab monotherapyvs SOC in R/M SCCHN after Pt-tx Abbreviations and references can be found in the speaker notes.

30 Vaccine therapy DNA vaccins INO-3112: DNA vaccin HPV E6,E7 phase I-II, competion in 2017 Peptide vaccins Mucin-1 phase I-II in HNSCC is running; completion in 2021 Allovax: tumorlysate own tumor phase I-II: completion in 2016/2018 HESPECTA (ISA101 and ISA201): 13 peptides derived from HPV16 E6 and E7 PhaseI results in 2016 Biologic vaccins ADXS phase II in HPVA OPC Semi-aloogenic human fibroblast vaccine phase I HNSCC, results in 2018

31 Pembrolizumabin PDL-1 + advanced salivaryglandcancer(keynote-028) Of the 150 patients with salivary cancer screened, 34 (22.7%) had PD-L1 positive tumors As of February17, 2016, medianfollow-up durationwas 65 weeks (range, 9-98 weeks) 3 patients achieved a partial response (PR) for anorr of 11.5% (95% confidenceinterval [CI], 2.4%-30.2%) Patients who achieved a PR had adenocarcinoma (n = 2) and high-grade serous carcinoma (n = 1)

32 Cohen ASCO 2016

33 Supportivecare/survivorship/ qualityof life High number of patients: substantial coexisting disease as a consequenceof ageandtobaccoandalcohol abuse; psychosocial problems Treatments are intensive Significant acute and late toxicities >60% of survivors have unmet needs

34 Conclusions Nivolumab is effective in 2L after Extreme schedule: registration is coming soon Pembrolizumab is effective; phase III studies are running Betterbiomarkersare needed; effective in HPVA andhpv negative disease 1L and locally advanced HNSCC studies are running: less toxicity? Nasopharyngealcancerandsalivaryglandcancerstudies are running In HPVA OPC: HPV vaccins