Immunotherapyin Head & NeckCancer Disclosures Astra-Zeneca/medimmune: clinical trial BMS: advisory board, clinical trial Merck: advisory board, clinical trial, research funding Carla van Herpen Medical Oncologist 27-05-2017 MSD: advisory board, clinical trial Head andneckcanceris an immunogeneic tumor Actual landscape 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) 1
Risk factors Tobacco and alcohol consumption: in 75% of patients HPV is prognostic and predictive factor for OS andpfs Human papillomavirus (HPV): newly identified causal factor, especially in oropharyngeal cancer Favourable prognostic factor Better responsiveness to radiotherapy and chemotherapy Ang et al; NEJM, 2010 HPVA-OPC HPV-associated oropharyngeal cancer (OPC) Low-risk population with an excellent prognosis Ang NEJM 2010 Argiris et al. Lancet 2008; 371:1695 2
Differences between HPV-negative andhpva OPC Advances HPV-associated oropharyngeal cancer (OPC) Low-risk population with an excellent prognosis De-escalation studies HPV-negative oropharyngeal 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 Leemans Nat gen 2011 Immunotherapy: finalized studies 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 Pembrolizumab Keynote-012 Multicohort phase Ib study, including R/M HNSCC Initial only PDL-1 + 1 Expansion regardless PDL-1 status 2 Primary endpoint ORR Secondary endpoints: PFS, OS, DOR Seiwert Lancet Oncol 2016;Chow JCO 2016; Bauml JCO 2017 Ferris NEJM 2016 1 Seiwert Lancet Oncology 2016; 2 Chow JCO 2016 3
Keynote-012 in R/M HNSCC n = 60 n=132 Median age 63 years 60 years Male 82% 83% WHO PS 1 68% 71% 2 prior lines 70% 57% PDL-1+ 100% tumor/immune cells ORR 18% 18% 25% in HPV+ vs 14% in HPV- 32% in HPV+ vs 14% in HPV- CR n=1; PR n=7 CR n=4; PR n=20 ORR in PDL-1+ 22% vs PDL-1-4% DOR 53 weeks Efficacy ORR 32% Reduction in target lesion size: 61% Median PFS/OS 2 / 8 months 6 months PFS/OS rate: 23% / 59% HPV+: 37% /70% HPV-: 20% / 56% 1 Seiwert Lancet Oncology 2016; 2 Chow JCO 2016 PDL1 is predictive for PFS and OS Keynote-055 Single-arm phase II study in platinum and cetuximab refractory HNSCC Disease progression within 6 months N=171 75% 2 prior lines PDL-1 +: 82% AEs 64% AE treatment related; 15% grade 3 ORR 16%; median DOR 8 months RR similar in all HPV and PDL-1 subgroups Median PFS 2.1 months; median OS 8 months Bauml JCO 2017 4
Efficacy Nivolumab CheckMate 141 Ferris NEJM 2016 5
Qualityof life 1-year OS 36% with nivolumab vs 16.6% standard therapy Immunotherapy: running studies Anti-PDL1 (Durvalumab) (EAGLE;KESTREL) Anti-CTLA4: ipilimumab or tremelimumab Combination: Anti-PD1 and anti-ctla4 Anti-PDL1 and anti-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 Checkpoint inhibitors in combination with cetuximab EGFR pathway may contribute to regulation of PD-L1 expression (activation of the PD1 pathway contributes to immune escape in EGFR driven tumors) Cetuximab treatment in HNSCC Increase of CD4 + CD25 hi CD39 + FOXP3 + Treg: expansion of Treg Frequency of Treg suppressor cells expressing CTLA4 and PD-1 are enriched in the tumor microenvironment Ferris JCO 2015 6
Running/upcoming studies In R/M: First line R/M In combination with docetaxel In LAHNC: In combination with RT and chemort In combination with cetuximab+ RT Adjuvant Intratumoral Neo-adjuvant -- Prior to surgery In nasopharyngeal cancer In salivary galnd cancers 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 Phase I results in 2016 Biologic vaccins ADXS11-001 phase II in HPVA OPC Semi-aloogenic human fibroblast vaccine phase I HNSCC, results in 2018 Pembrolizumab in PDL-1 + advanced salivary gland cancer(keynote-028) Of the 150 patients with salivary cancer screened, 34 (22.7%) had PD-L1 positive tumors As of February 17, 2016, median follow-up duration was 65 weeks (range, 9-98 weeks) 3 patients achieved a partial response (PR) for an ORR of 11.5% (95% confidence interval [CI], 2.4%-30.2%) Patients who achieved a PR had adenocarcinoma (n = 2) and high-grade serous carcinoma (n = 1) Cohen ASCO 2016 7
Supportive care/survivorship/ quality of life High number of patients: substantial coexisting disease as a consequence of age and tobacco and alcohol abuse; psychosocial problems Treatments are intensive Significant acute and late toxicities >60% of survivors have unmet needs Conclusions Nivolumab is effective in 2L after Extreme schedule: FDA and EMA approved Pembrolizumab is effective; phase III studies are running; FDA and EMA approved Better biomarkers are needed; effective in HPVA and HPV negative disease 1L and locally advanced HNSCC studies are running: less toxicity? Nasopharyngeal cancer and salivary gland cancer studies are running In HPVA OPC: HPV vaccins 8