New Paradigms for Treatment of. Erminia Massarelli, MD, PHD, MS Clinical Associate Professor

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1 New Paradigms for Treatment of Head and Neck cancers Erminia Massarelli, MD, PHD, MS Clinical Associate Professor City of Hope

2 Disclosure Statement Grant/Research Support frommerck Bristol Grant/Research Support from Merck, Bristol Myers Squibb and Astra Zeneca.

3 Head and Neck Squamous Cell Carcinoma Epidemiology i 48,000 new cases per year in US Median age at diagnosis: 60 years Male>Female l Strong association with tobacco and alcohol Human papillomavirus p (HPV) increasingly gy appreciate as risk factor for oropharyngeal carcinomas

4 Incidence and survival Chaturvedi AK. Et al J Clin Oncology 2011

5 Human Papillomavirus (HPV) 60% oropharyngeal cancer HPV+ Expression of E6 and E7 is retained after integration The most common oncogenic type is HPV-16 Often in non-smokers, non-drinkers Younger median age Associated with sexual transmission Favorable prognosis HPV-testing by: In situ hybridization P16 IHC PCR

6 HPV HPV+ Site HPV+ Tonsil base of tongue HPV All sites Histology Basalioid Keratinized Age Younger Older Risk factors Sexual behavior Tobacco alcohol Cofactors Marijuana Tobacco immune alcohol suppression Incidence Rising Declining Survival Improved Worse Lawrence MS et al. Nature 2015 The Cancer Genome Atlas Network. Nature 2015

7 Treatment approach to curable HNSCC Disease extent T1N0-1 or T2N0 T2N1 or T3-4 or N2-3 Recurrent or M1 Treatment Surgery or XRT Combined modality Surgery and/or XRT Combined modality Chemotherapy

8 Radiation therapy standard fractionation i dosage Treatment t setting Dose Definitive Radiation therapy Primary and gross lymph nodes 70 Gy Neck: low-risk nodal stations 50 Gy Adjuvant Radiation therapy (4-6 weeks after surgery) Primary 60 Gy Neck: high-risk nodal stations 60 Gy Neck: low-risk nodal stations 50 Gy

9 Phase III trial: Cetuximab+XRT R Bonner JA et al. N Engl J Med 2006

10 Phase III Cetuximab+XRT: Results Bonner JA et al. N Engl J Med 2006

11 Bonner trial by HPV-status Rosenthal DI et al. JCO 2016

12 Cetuximab versus Cisplatin Concomitant to radiotherapy in Locally advanced HNSCC Magrini SM et al. J Clin Oncol 2016

13 Cetuximab versus Cisplatin Concomitant to radiotherapy in Locally advanced HNSCC: toxicity Magrini SM et al. J Clin Oncol 2016

14 Do we treat t them differently according to HPV-status? NO Standard treatment Cisplatin 100 mg/m2 days 1, 22, 43 or XRT XRT standard fractionation 70Gy over 7 weeks (2Gy fractions)

15 Induction chemotherapy (IC) in HNSCC National Cancer Data Base study of 8,003 records of patients diagnosed with T(any)N2b- 3M0 oropharyngeal, laryngeal, hypopharyngeal cancers between IC group were less likely to receive a full course of XRT following IC. Shorter median survival following IC compared to concurrent chemoxrt. Stokes WA et al. Multidisciplinary head and Neck symposium 2016 (abstract 109)

16 Induction Therapy pros and cons Pros Optimization of RT dosing based on response to induction regimen Early treatment for distant metastatic disease Cons May affect compliant to subsequent concurrent chemoxrt Adds to 2-4 months to treatment

17 Ongoing trials efforts In HPV positive oropharyngeal cancer: are In HPV positive oropharyngeal cancer: are Cetuximab XRT and Platinum XRT equivalent? (RTOG 1016) Addition of checkpoint inhibitors to standard chemoradiation therapy (Ipilimumab+Cetuximab, anti PD1+CDDP+XRT) De intensification regimens Adjuvant checkpoint inhibitor (PATHWAY Study)

18 Development of effective therapies for metastatic t ti HNSCC HD MTX Bleomycin Pembrolizumab drug combo: CIS/5FU EXTREME: Cetuximab/Ca rbo/5fu

19 Mutational load in carcinogen associated HNSCC is highh LB Alexandrov et al. Nature 000, 1-7 (2013)

20 Response to anti-pd1 antibody correlates with mutation burden in non small cell lung cancer patients Naiyer A. Rizvi et al. Science 2015;science.aaa1348

21 High expression of PDL-1 in HPV-positive HNSCC Lyford Pike S. et al. Cancer Res 2013

22 HNSCC Cohorts of Nonrandomized, Phase 1b, Multi-cohort KEYNOTE-012 Trial Response assessment every 8 weeks Primary end point: ORR, safety Secondary end points: ORR, PFS, OS, duration of response, ORR in HPV+ patients

23 KEYNOTE-055: Single Arm, Phase 2 Trial in R/M HNSCC After Progression on Platinum/Cetuximab Response assessment every 6 9 weeks Primary end points: ORR in all patients and PDL1+ patients, safety Secondary end points: ORR in HPV+ patients, PFS, OS, duration of response

24 Anti PD1 Pembrolizumab in HNSCC: Demographics Characteristics Keynote 055 N=171 Keynote 012 N=192 Age 61 (33-90) 60 (20-84) Male 138 (81) 159 (83) ECOG PS 0 48 (28) 57 (30) ECOG PS (70) 135 (70) HPV status Positive 71 (41) 45 (23) Negative 100 (59) 147 (77) Median no. prior 2 (1-6) 2 (0-7) chemotherapy 1 28 (16) 47 (24) 2 71 (42) 56 (29) 3 72 (42) 86 (45)

25 Anti PD1 Pembrolizumab in HNSCC: Overall Response Rate Keynote 055 Keynote 012 Best Overall Response Patients with 6 months follow-up Total N=192 N=92 ORR 16 (17%) 34 (18%) CR - 8 (4%) PR 16 (17%) 25 (13%) SD 17 (18%) 33 (17%) PD 51 (55%) 93 (48%) NA 8 (9%) 33 (17%) HPV (total HPV+ n=18) (total HPV+ n=45) HPV+ 4 (22%) 11 (20%) HPV- 12 (16%) 23 (16%) PDL1 (PDL1+ n=76) (PDL1+ n=123) PDL1+ 13 (17%) 22 (18%) PDL1-1 (7%) 12 (18%)

26 Nivolumab CheckMate 141 N=361, 2:1 randomized to Nivolumab (n=240) ORR 13% Median OS 7.5 vs. 5.1 months with cetuximab, docetaxel or MTX (HR 0.7) Presented By Anthony Chan at 2016 ASCO Annual Meeting

27 CheckMate 141 Overall Survival PDL1 positive PDL1 negative Overall Response 17% 12% Hazard Ratio HPV positive (n=92) HPV negative (n=86) Hazard Ratio

28 Immune-related side effects a Adapted from Eigentler T.K et al. Can Treat Rev 2016

29 Are anti PD-1 agents the new standard for recurrent/ metastatic HNSCC? Results reveal improved response rate in HNSCC for both Pembrolizumab and Nivolumab: ORR 17-18% compared to 5-6% (MTX) and 12% (cetuximab) Responses are durable Well tolerated with distinct toxicity profile Nivolumab is the first of the two agents to show a survival benefit in metastatic HNSCC Pembrolizumab accelerated FDA approval in August 2016 for patients previously treated with platinumbased chemotherapy in metastatic/incurable HNSCC

30 The PI3K/mTOR pathway is frequently activated in HNSCC Key PI3K/mTOR Pathway alterations in HNSCC include: -reduced PTEN activity (30-50%) -PIK3CA amplification (20-40%)or mutations (15%) Buparlisib (BKM120) is an oral pan PI3K inhibitor that targets all four isoforms of class I PI3K (α, β, γ, δ) ) Soulieres D. et al ASCO 2016 abstract #6008

31 BERIL-1 Soulieres D. et al ASCO 2016 abstract #6008

32 BERIL 1-Primary endpoint Progression free survival Soulieres D. et al ASCO 2016 abstract #6008

33 BERIL 1-Primary endpoint Progression free survival Soulieres D. et al ASCO 2016 abstract #6008

34 The immunity cycle Cancer-Immunity Cycle 1

35 Future Directions: combination with other immunotherapies i Combination o Target aget Durvalumab+Tremelimumab Nivolumab+Ipilimumab Urelumab+Nivolumab OX40 agonist+ Pembrolizumab Epacadostat+ Nivolumab Epacadostat+ Pembrolizumab Urelumab+Cetuximab Anti PD1 or PDL1 Anti CTLA4 CD137 agonist Anti PD1 OX40 agonist Anti PD1 IDO-inhibitor Anti PD1 IDO-inhibitor Anti PD1 CD137 agonist EGFR antibody

36 HPV immunosuppressive mechanisms to escape host immune system Adapted from Duray A. et al. Adv Cell Mol Otolaryngology 2014

37 Future Directions: HPV associated HNSCC HPV specific therapeutic vaccines alone or in combination Adoptive T cell therapy

38 Combination of vaccination and checkpoint inhibition Cécile Badoual et al. Cancer Res 2013;73:

39 Study Schema ISA101 vaccine Dose #1 Dose #2 Dose #3 Day1 Day8 Day 22 Day 36 Day 50 Dose #1 Dose #2 Dose #3 Dose #4 and then q. 2 w until PD* Nivolumab W=week; PD=disease progression *Subjects may be allowed to continue taking nivolumab beyond PD ISA101 administered s.q. at 100 mcg for 3 doses. Nivolumab administered i.v. 3 mg/kg every 2 weeks beginning on day 8 after first vaccine dose until PD or toxicity. First radiographic tumor assessment at week 10 and then every 6 weeks. Treatment beyond PD allowed.

40 THANK YOU