Head, Neck, and Thyroid Cancers: Evidence-Based Approaches to Multimodal Management

Transcription

1 Head, Neck, and Thyroid Cancers: Evidence-Based Approaches to Multimodal Management Robert Haddad, MD Disease Center Leader Head and Neck Oncology Program Dana Farber Cancer Institute Harvard Medical School Boston, MA

2 Disclosures Research Funding: BMS, Merck, Pfizer, Celgene, Astra Zeneca, Genentech Consultant: Merck,BMS, Eisai, Pfizer, Astra Zeneca, Genentech, Loxo NCCN: Member: Head and Neck Committee NCCN: Chair: Thyroid Committee Off Label/Investigational Discussion In accordance with Annenberg Center policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

3 Case 1 A 64 year old attorney has a biopsy proven squamous cell carcinoma of right lateral tongue. She is treated with a right partial glossectomy and ipsilateral neck dissection. Final pathology report c/w T1N2b disease (Stage 4): Primary tumor, 1.5 cm, margins clear. no LVI/PNI. 2/36 nodes with SCC measuring 1.5 and 2 cm. No ECE. You are seeing her to discuss adjuvant therapy. She is healthy and has a smoking history of 2 ppd for 15 years. You recommend: 1. No further therapy at this stage 2. Concurrent chemoradiotherapy with bolus cisplatin at 100 mg/m2 every 3 weeks 3. Radiotherapy alone 4. Contralateral neck dissection and radiation 5. Concurrent Cetuximab and Radiotherapy

4 Case 2 55 year old male, non smoker, with a history of HPV related squamous cell carcinoma(scc) of the left tonsil and ipsilateral neck metastasis. He was treated 7 years ago with concurrent bolus cisplatin and radiation. Recent Chest CT shows multiple lung nodules. Biopsy c/w p16+ SCC. He has a PS 0 and continues to work full time as an accountant. His only medication is Lipitor. You recommend: 1. PD1 inhibitor as a single agent 2. Cetuximab weekly 3. Cisplatin,5-fluorouracil and cetuximab 4. Carboplatin/Paclitaxel/Bevacizumab 5. Nivolumab+ Ipilumumab 4

5 Head and Neck Cancer Introduction: Epidemiology, Clinical Features, Prevention, Treatment Modalities Concurrent Chemoradiotherapy Sequential Chemoradiotherapy Adjuvant Chemoradiotherapy Recurrent/Metastatic disease Differentiated Thyroid Cancer 5

6 Head and Neck Cancer Primary Disease Sites Oral Cavity Pharynx Larynx Nasal Cavity Paranasal Sinuses 6 Source: Maxwell V. Blum Cancer Resource Room

7 Epidemiology new cases per year in US. Median age of diagnosis: ~60 years Male>Female Strongly associated with tobacco and alcohol Epstein-Barr virus risk factor for nasopharynx cancers Human papillomavirus increasingly appreciated as a risk factor 7

8 Human Papillomavirus (HPV) 8 HPV-Associated Cancers > 99% of Cervical Carcinoma ~ 90% Anal Carcinomas ~ 40% Vulvar and Vaginal Carcinomas ~ 60% of Oropharynx Cancers HPV GENOME INTEGRATION LCR E6 E7 Circular 8 kb dsdna Genomes Only One Coding Strand Infect Epithelial Cells ~ 200 HPV types ~ 30 Mucosal HPVs Low-Risk: Genital Warts High-Risk: Lesions That Progress to Cancer Frequent Event During Malignant Progression Terminates Viral Life Cycle Expression of E6 and E7 Is Retained HPV E6/E7 Oncoproteins Small, Non-Enzymatic Proteins (~ 150aa E6; ~ 100aa E7) Associate With and Functionally Modify Host Cellular Protein Complexes Münger et al, 2004.

9 Human Papillomavirus (HPV)-Positive Head and Neck Cancer HPV 16 is the viral subtype in the vast majority of patients. Half of oropharynx cancers will have HPV 16 DNA. Often occurs in nonsmokers, nondrinkers Median age younger than HPV-negative patients; incidence increasing Associated with number of sexual partners and highrisk sexual practices Favorable prognosis In situ hybridization,p16 IHC, PCR 9 Fakhry C, et al. J Clin Oncol. 2006:24(17): Chaturvedi AK, et al. J Clin Oncol. 2008;26(4):

10 Rising Incidence of HPV-Associated Cancers Smoking related HPV- related Chaturvedi et al, JCO 2008.

11 Survival Outcomes by HPV Status in Oropharyngeal Cancer in RTOG 0129 Ang et al NEJM 2010

12 RTOG 0129 Phase III Trial: Concomitant CRT With Standard Vs. Accelerated Fractionation RT CRT Stage III/IV (T2, N2 3, M0, or T3 4, any N, M0) SCCHN Oral cavity, oropharynx, hypopharynx, larynx No prior RT to head and neck except radioactive iodine therapy No prior surgery to primary tumor or nodes except for diagnostic biopsy Expected N = 720 R A N D O M I Z E Cisplatin (IV on D1, 22, 43) Standard fractionation RT (5 d/wk for 7 wks) Cisplatin (IV on D1, 22) Accelerated fractionation RT (5 d/wk for 3.5 wks; then twice daily, 5 d/wk for 2.5 wks) US NIH, 2010c.

13 RTOG 0129: OS and PFS by HPV Status Overall Survival (%) Overall Survival HPV negative HPV positive HR=0.38 (95% CI: ); P<0.001 Progression-Free Survival (%) PFS HPV negative HPV positive HR=0.40 (95% CI: ; P< Year Outcomes HPV Positive (%) HPV Negative (%) P Value OS <0.001 PFS <0.001 Locoregional failure <0.001 Distant metastases Ang. N Engl J Med. June 7, 2010

14 Two distinct HNSCC entities HPV positive HPV negative Anatomic site Tonsil /Base of Tongue All sites Histology Basaloid Keratinized Age Younger Older Gender 3:1 men 3:1 men SE status High Low Risk factors Sexual behavior ETOH/tobacco Cofactors should we treat them the same? Marijuana/?immune suppression ETOH/tobacco Incidence Rising Declining Survival Improved Worse There is a major change in the etiology of head and neck cancer, the incidence of OPC rapidly increasing mostly North America and Europe

15 E1308: Phase II Trial of Induction Chemotherapy Followed by Reduced- Dose Radiation and Weekly Cetuximab in Patients With HPV-Associated Resectable Squamous Cell Carcinoma of the Oropharynx ECOG- ACRIN Cancer Research Group Marur et al : JCO 2016

16 ECOG 1308: Phase II Schema Eligibility Oropharynx SCC HPV ISH + and / or p16+ Stage III, IVA Induction Chemotherapy Cisplatin 75mg/m 2 d1 Paclitaxel 90mg/m 2 d1,8,15 Cetuximab 250mg/m 2 d1,8,15 Q 21 days for 3 cycles R E S P O N S E E V A L U A T I O N Concurrent Chemoradiation CLINICAL CR Low dose IMRT 54Gy/27fx* + Cetuximab qweek CLINICAL PR/SD Full dose IMRT 69.3Gy/33fx* + Cetuximab qweek Marur et al : JCO 2016

17 E 1308: OS and PFS PFS (A) and OS (B) in cohort with clinical complete response to induction chemotherapy treated with low-dose radiation of 54 Gy (n = 51). 17

18 E 1308: OS and PFS PFS (A) and OS (B) in favorable cohort (non-t4, non-n2c, 10 pack-year smokers) with clinical complete response to induction chemotherapy treated with low-dose radiation of 54 Gy (n = 27). 18

19 Summary E1308 Induction chemo followed by reduced-dose IMRT/Cetuximab was feasible in a Cooperative Group setting CCR to induction was noted in 70% (56/80), and was well tolerated. The 2yr PFS in 54Gy IMRT patients was 80% ( 95% CI 0.70, 0.88) and 2yr OS was 94%. Best results of 54Gy was in smokers <10pk-yrs, non T-4 and non-n2c: 2yr PFS and 2yr OS of 96% (n=27) At 12 months : fewer pts in low dose had difficulty with swallowing solids. This approach remains investigational. Further studies are planned

20 Treatment Approach Disease Extent T 1 N 0-1 or T 2 N 0 Treatment Surgery or RT T 2 N 1 or T 3-4 or N 2-3 Combined modality Recurrent or M 1 Surgery and/or RT Combined modality Chemotherapy 20

21 Concurrent Chemoradiotherapy

22 The Debate Over Therapeutic Sequence: MACH-NC Findings Design (No. of Studies/ No. of Subjects) Hazard Ratio (95% CI) Chemotherapy Effect (P -value) Absolute Benefit 2 Years 5 Years Adjuvant 1 (8/1854) 0.98 ( ) % 1% Neoadjuvant 1 (31/5269) Concurrent 1 (26/3727) Total 1 (65/10,850) 0.95 ( ) 0.81 ( ) 0.90 ( ) % 2% < % 8% < % 4% No. of Trials No. of Subjects Difference at 5 Years P -value PF induction % MACH-NC: Meta-Analysis of Chemotherapy in Head and Neck Cancer; PF=cisplatin + fluorouracil 1. Pignon JP, et al. Lancet. 2000;355(9208): Monnerat C, et al. Ann Oncol. 2002;13(7):

23 Concurrent Therapy: Standard of Care Cisplatin 100 mg/m 2 days 1, 22, and 43 of RT RT standard fractionation, 70 Gy over 7 weeks (2-Gy fractions) Alternative Chemotherapy regimens: 1- Weekly cisplatin 40mg/m2 2- Weekly Cetuximab 3- Weekly carboplatin auc Paclitaxel 30-45mg/m2

24 RTOG Induction Cisplatin/5-FU vs Concomitant Cisplatin vs RT Alone in Resectable SCC ICT RT (N = 173) Resectable stage III/IV SCC Glottic or supraglottic cancer Previously untreated N = 515 R A N D O M I Z E Cisplatin (100 mg/m 2, d1) 5-FU (1000 mg/m 2 /day, d1-5 C-I) every 3 wks, 2 cycles CRT (N = 171) Cisplatin (100 mg/m 2, every 3 wks, 3 cycles) RT (2 Gy/fr, 35 fr, total 70 Gy) RT (N = 171) RT (2 Gy/fr, 35 fr, total 70 Gy) RT (2 Gy/fr, 35 fr, total 70 Gy) Primary end point: larynx preservation Secondary end point: LFS LFS=laryngectomy-free survival Forastiere AA, et al. N Engl J Med. 2003;349(22):

25 RTOG Larynx Preservation (LP) Trial Arm Stomatitis* LP rate (5yrs) DFS (5yrs) OS (5yrs) RT 24% 65.7% 27.3% 53.5% Chemo RT 24% 70.5% 38.6% 59.2% ChemoRT 43% 83.6% 39.0% 54.6% * > or = Grade Forastiere AA, et al. N Engl J Med. 2003;349(22):

26 Phase III Trial: Cetuximab + RT for SCC Advanced SCC Stage III/IV N = 424 R A N D O M I Z E RT* + Cetuximab (400 mg/m 2, then 250 mg/m 2 /wk) RT* alone *Choice of: Once-daily RT: 70 Gy in 35 fractions Twice-daily RT: Gy in fractions Concomitant boost: 72 Gy in 42 fractions Grade 3-5 Toxicity RT Alone (N = 212) RT + Cetuximab (N = 208) P-value Mucositis 52% 56%.44 Acneiform Rash 1% 17% <.001 Infusion Reaction 0% 3%.01 Anemia 6% 1% Bonner JA, et al. N Engl J Med. 2006;354(6):

27 Phase III: Cetuximab + RT for SCC: Results Locoregional Control OS 47% vs 34% at 3 years P <.01 at 3 years 55% vs 45% at 3 years P =.05 at 3 years 27 Bonner JA, et al. N Engl J Med. 2006;354(6):

28 Sequential Chemoradiotherapy

29 TAX 324: Sequential Combined Modality Therapy TPF vs PF Followed by Chemoradiotherapy R A N D O M I Z E T P F P F Carboplatinum - AUC 1.5 Weekly Daily Radiotherapy Surgery as Needed TPF: Docetaxel 75 D1 + Cisplatin 100 D1 + 5-FU 1000 CI- D1-4 Q 3 weeks x3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3 29 Posner MR, et al. N Engl J Med. 2007;357(17):

30 TAX 324: Results 100 Survival 100 PFS Survival Probability (%) TPF 67% PF 54% TPF (N = 255) PF (N = 246) Log-rank p =.0058 HR = 0.70 TPF 62% PF 48% PFS Probability (%) TPF 53% PF 42% TPF (N = 255) PF (N = 246) Log-rank p =.004 HR = TPF 49% PF 37% Time (mos) Time (mos) TPF significantly improves survival and PFS compared with PF in an ICT regimen TPF significantly followed by CRT improves survival and PFS compared with PF in an ICT regimen followed by CRT Posner et al, Posner. N Engl J Med. 2007;357:1705

31 Taxane + PF Phase III Trials Vermorken (2007) 1 Hitt (2005) 2 Chemo PF DPF PF PaPF Subjects Med PFS* 8.2 mo 11.0 mo 12 mo 20 mo Med OS* 14.5 mo 18.8 mo 37 mo 43 mo RR* 54% 68% 68% 80% P < 0.05 for all outcomes except P = 0.06 for OS in Hitt study Vermorken JB, et al. N Engl J Med. 2007;357(17): Hitt R, et al. J Clin Oncol. 2005;23(34):

32 Conclusions Overall survival advantage > 3 years with TPF sequential therapy 40.5 month improvement in median overall survival at 3 years 30% reduction in the risk of mortality (P = ) Consistent with prior phase III trial (TAX 323) Patients received a median of 3 cycles of induction chemotherapy in the TPF and PF arms. In the TPF arm, 81% of patients went on to receive CRT. Grade 3/4 treatment-emergent adverse events: Less stomatitis, thrombocytopenia, and lethargy in the TPF arm More neutropenia and febrile neutropenia (any grade) in the TPF arm 32

33 Impact of Induction Chemotherapy (CT): Opposing Views and Ongoing Controversy Pro: Allows time to optimize patient medical status; Possible customization of RT dosing based on response to treatment; provides early treatment of distant micrometastatic disease Con: Induction CT may affect adversely compliance to subsequent concurrent CT/RT or choice of CT/RT regimen; adds 2-4 months to treatment 33

34 Clinical Scenarios to Consider Induction Therapy 1. Potential distant metastasis 2. Delay in radiation simulation 3. Impending local issue (eg, airway) 4. Markedly advanced disease (eg, bulky, N2c, N2b, N3, low neck, dermal infiltration) 5. Organ preservation strategy in patients with markedly advanced disease 34

35 Neck Dissection (ND) After Chemoradiotherapy Indicated for gross residual disease Not indicated for pretreatment N1 disease that has achieved clinical complete response For pretreatment N2-3 disease, opinions vary: When pretreatment neck disease is N2-3, some centers recommend routine ND regardless of response to chemoradiotherapy. However, others will observe if a clinical complete response on PET scan 12 weeks post-therapy is achieved with chemoradiotherapy. 35 Pellitteri PK, et al. Head Neck. 2006;28(2): Ong SC, et al. J Nucl Med. 2008;49(4):

36 Adjuvant Chemoradiotherapy

37 EORTC and RTOG 9501 Phase III Trials: Adjuvant RT ± Concomitant Cisplatin Resectable SCC Oral cavity, oropharynx, hypopharynx, larynx Stage III/IV (EORTC), high risk (RTOG) Previously untreated N = 334 (EORTC) N = 459 (RTOG) Surgery R A N D O M I Z E RT+ Cisplatin (100 mg/m 2, d1,22,43) EORTC: 66 Gy over 6.5 wks RTOG: Gy over wks 37 Bernier J, et al. N Engl J Med. 2004;350(19): Cooper JS, et al. N Engl J Med. 2004;350(19):

38 Poor Risk Criteria RTOG EORTC nodes ECE +Margins Level IV/V (OC/OP) ECE +Margins Perineural disease Vascular emboli ECE = extracapsular nodal extension; OC = oral cavity; OP = oropharynx Cooper JS, et al. N Engl J Med. 2004;350(19): Bernier J, et al. N Engl J Med. 2004;350(19):

39 EORTC and RTOG 9501: Adjuvant RT ± Concomitant Cisplatin: Results OS (EORTC) 1 OS (RTOG) 2 P=0.02 P=0.19 Months After Randomization Bernier J, et al. N Engl J Med. 2004;350(19): Cooper JS, et al. N Engl J Med. 2004;350(19):

40 RTOG 9501/EORTC Which prognostic risk factors are most important? Extracapsular nodal extension and + margins: significant benefit from chemoradiotherapy Trend toward benefit for stage III-IV disease, perineural invasion, vascular embolisms, and/or clinically enlarged level IV/V lymph nodes secondary to tumors in oral cavity or oropharynx No benefit in patients with 2 or more nodes but no extracapsular extension 40 Bernier J, et al. Head Neck. 2005;27(10):

41 Survivorship /Follow-Up Assess for recurrence/2 nd primary/premalignant lesions 1st year: Q 1-3 mos 2nd year: Q 2-4 mos 3rd 5th year: Q 4-6 mos > 5 years: Q 6-12 mos TSH q 6-12 months if neck irradiated Chest imaging as indicated Speech/Swallowing evaluation/rehabilitation as indicated Counsel regarding tobacco and alcohol use Integrate general medical care Once felt disease free, imaging of primary and neck not routinely indicated unless suspicious signs or symptoms 41 NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers. V

42 Palliative Chemotherapy

43 Management of Recurrent/Metastatic SCCHN Recurrent/ Metastatic HNSCC Salvage surgery or re-irradiation Palliative systemic therapy Supportive care Chemotherapy +/- Targeted Therapy Immunotherapy Clinical Trials

44 EXTREME: Study Design R A N D O M I Z E N = FU 1000 mg/m 2 d1-4 with Cisplatin 100 mg/m 2 d1 or Carboplatin AUC 5 d1 6 cycles maximum 5-FU 1000 mg/m 2 d1-4 with Cisplatin 100 mg/m 2 d1 or Carboplatin AUC 5 d1 plus Cetuximab 250 mg/m 2 /week* q 3 weeks No treatment Cetuximab POD or toxicity POD or toxicity *Loading dose of 400 mg/m 2 on week 1 44 Vermorken JB, et al. N Engl J Med. 2008;359(11):

45 EXTREME: First-Line Platinum/5-FU ± Cetuximab in Recurrent/Metastatic SCC: Survival OS Survival Probability Patients at Risk: Platinum/5-FU Cetuximab + Platinum/5-FU 7.4 mos Platinum/5-FU Cetuximab + Platinum/5-FU 10.1 mos HR (95% CI)=0.797 ( ) Strat. log-rank test: Survival Time (months) RR 18% 35% 45 Vermorken JB, et al. N Engl J Med. 2008;359(11):

46 Phase III randomized trial of chemotherapy with or without bevacizumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: survival analysis of E1305, an ECOG-ACRIN Cancer Research Group trial Athanassios Argiris,, 1 Shuli Li,, 2 Panayiotis Savvides, 3 James Ohr, 4 Jill Gilbert, 5 Marshall A. Levine, 6 Missak Haigentz Jr., 7 Nabil F. Saba, 8 Arnab Chakravarti, 9 Chukwuemeka Ikpeazu, 10 Charles Schneider, 11 Harlan Pinto, 12 Arlene A. Forastiere, 13 Barbara Burtness 14 A. Argiris et al; Abstract 6000 ASCO 2017

47 Phase III Randomized Trial of Platinum-based Chemotherapy With or Without Bevacizumab in Recurrent or Metastatic SCCHN (E1305) STUDY SCHEMA Recurrent or metastatic SCCHN Performance status 0-1 No prior therapy for recurrent or metastatic SCCHN R A N D O M I Z E Stratify by a. Performance status b. Weight loss c. Prior radiotherapy d. Chemo regimen Arm A Platinum doublet* Every 21 days until progression Arm B Platinum doublet* + Bevacizumab 15 mg/kg Every 21 days until progression Option to discontinue chemotherapy after 6 cycles if maximum response Option to discontinue chemotherapy after 6 cycles if maximum response. Bevacizumab continued until progression * Choice of one of 4 chemotherapy regimens: 1. cisplatin 100 mg/m 2 day 1, 5-FU continuous infusion 1000 mg/m 2 /day x 4 days 2. carboplatin AUC 6, day 1, 5-FU continuous infusion 1000 mg/m 2 /day x 4 days 3. cisplatin 75 mg/m 2 day 1, docetaxel 75 mg/m 2, day 1, 4. carboplatin AUC 6, day 1, docetaxel 75 mg/m 2, day 1, (in regimens 1 and 3, carbopatin substitution was allowed for specific severe cisplatin-related toxicities) All patients received prophylactic ciprofloxacin on days 5-14 Presented by: A. Argiris Abstract 6000

48 E1305 Patient Characteristics (I) Arm A: Chemo (N=200) Arm B: Chemo +Bev (N=203) Sex, N (%) Male 168 (84) 176 (87) Female 32 (16) 27 (13) Age Median (range) 58 (32-86) 58 (29-82) Chemo doublet, N (%) Cisplatin/Docetaxel 95 (48) 99 (49) Cisplatin/5-FU 14 (7) 17 (8) Carboplatin/Docetaxel 79 (40) 78 (38) Carboplatin/5-FU 11 (6) 9 (4) ECOG Performance Status, N (%) 0 86 (43) 85 (42) (57) 118 (58) Weight loss previous 6 months, N (%) <5% 135 (68) 127 (63) >=5% 62 (31) 75 (37)

49 E1305 Overall Survival Median OS, months Arm A: Chemo only 11.0 Arm B: Chemo + Bevacizumab 12.6 P value HR (95% CI) ( ) 2-year 26% 3-year 16% 4-year 13% 18% 8% 6%

50 E1305 Progression-Free Survival Median PFS, months Arm A: Chemo 4.4 Arm B: Chemo + Bevacizumab 6.1 P value HR (95% CI) ( )

51 Immunotherapy in Head and Neck Cancer

52 CheckMate 141 Study Design Nivolumab VS. Chemotherapy Randomized, global, phase 3 trial of the efficacy and safety of nivolumab versus investigator s choice in patients with R/M SCCHN Key Eligibility Criteria R/M SCCHN of the oral cavity, pharynx, or larynx Nivolumab 3 mg/kg IV q2w Not amenable to curative therapy Progression on or within 6 months of last dose of platinum-based therapy ECOG PS 0 1 Documentation of p16 to determine HPV status No active CNS metastases Stratification factor Prior cetuximab treatment R 2:1 Investigator s Choice Methotrexate 40 mg/m² IV weekly Docetaxel 30 mg/m² IV weekly Cetuximab 400 mg/m² IV once, then 250 mg/m² weekly) Primary endpoint OS Other endpoints PFS ORR Safety DOR Biomarkers Quality of life Ferris et al : NEJM 2016 CNS, central nervous system; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; HPV, human papillomavirus; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; R, randomized; R/M, recurrent/metastatic; SCCHN, squamous cell carcinoma of the head and neck; Clinicaltrials.gov. NCT

53 Overall Survival Median OS, mo (95% CI) HR (97.73% CI) p-value Overall Survival (% of patients) Nivolumab (n = 240) 7.5 ( ) Investigator s Choice (n = 121) 5.1 ( ) 0.70 ( ) 1-year OS rate (95% CI) 36.0% ( ) 16.6% ( ) Months No. at Risk Nivolumab Investigator s Choice

54 Phase 3 KEYNOTE-040 Study Pembrolizumab vs Chemotherapy Key Eligibility Criteria SCC of the oral cavity, oropharynx, hypopharynx, or larynx PD after platinum-containing regimen for R/M HNSCC or recurrence or PD within 3-6 mo of multimodal therapy using platinum a ECOG PS 0 or 1 Known p16 status (oropharynx) b Tissue sample c for PD-L1 assessment d Stratification Factors ECOG PS (0 vs 1) p16 status b (positive vs negative) PD-L1 TPS d ( 50% vs <50%) R 1:1 Pembrolizumab 200 mg IV Q3W for 2 y Methotrexate 40 mg/m 2 QW e OR Docetaxel 75 mg/m 2 Q3W OR Cetuximab 250 mg/m 2 QW f Clinically stable patients with radiologic PD could continue treatment until imaging performed 4 wk later confirmed PD Crossover not permitted a Limit of 2 prior therapies for R/M HNSCC. b Assessed using the CINtec p16 Histology assay (Ventana); cutpoint for positivity = 70%. c Newly collected preferred. d Assessed using the PD-L1 IHC 22C3 pharmdx assay (Agilent Technologies). TPS = tumor proportion score = % of tumor cells with membranous PD-L1 expression. e Could be increased to 60 mg/m 2 QW in the absence of toxicity. f Following a loading dose of 400 mg/m 2.

55 Overall Survival in ITT Population O S, % % 27.2% Events, n HR (95% CI) P Pembrolizumab a ( ) b SOC N o. at risk Time, months Median (95% CI) 8.4 mo ( ) 7.1 mo ( ) a Cox proportional hazards model with treatment as a covariate stratified by the randomization stratification factors. Initially reported data: HR 0.82 (95% CI, ), P = After the initial report, updated survival data were obtained for 4 patients. b One-sided P value based on the log-rank test stratified by the randomization stratification factors. Data cutoff date: May 15, 2017.

56 CHECKMATE-651: Phase III randomized, open-label study of nivolumab + ipilimumab compared to the EXTREME regimen as 1L treatment in patients with R/M SCCHN Platinum Sensitive CTLA-4 PD-1 PD-L1 Key Eligibility Criteria No prior systemic therapy for R/M disease except if chemotherapy was part of multimodal treatment 6 months prior to enrollment Tumor tissue required for HPV p16 (for OPC) and PD-L1 testing prior to randomization Adapted from Mellman I et al Randomized Start Date: August 2016 Primary Endpoints: OS, PFS Other Endpoints: ORR, time to deterioration, PD-L1 expression as biomarker Nivolumab + Ipilimumab EXTREME Cetuximab + cisplatin/carboplatin + 5- FU

57 KEYNOTE-048: Phase III, randomized, open-label, clinical trial of pembrolizumab in first line treatment versus active comparator in patients with R/M SCCHN without prior systemic chemotherapy Platinum Sensitive PD-1 PD-L1 Key Eligibility Criteria No prior systemic therapy in R/M setting, except if completed >6 months prior to locally advanced disease Available tumor biopsy for PD-L1 analysis Have results for HPV status for oropharyngeal cancer Adapted from Mellman I et al Randomized Start Date: March 2015 Primary Endpoint: PFS Other Endpoints: OS, PFS (by Immune-Related Response), ORR Pembrolizumab Pembrolizumab + Platinum + 5FU Active Comparator (cetuximab+ platinum+5- FU)

58 JAVELIN Head and Neck 100: Study Design A randomized double-blind phase III study of avelumab in combination with standard of care (SOC) chemoradiotherapy versus SOC chemoradiotherapy in the front-line treatment of SCCHN Lead in Phase CRT Phase Maintenance Phase N=640 Avelumab 10 mg/kg IV Avelumab 10 mg/kg IV + SOC Chemoradiation Avelumab 10 mg/kg IV Q2W Up to 12 months LA SCCHN R 1:1 Randomization Inclusion criteria: LA SCC oral cavity, oropharynx, larynx, hypopharynx HPV-; stage II, Iva, Ivb HPV+: T4 or N2c (AJCC 7) or N3 ECOG PS = 0 or 1 No prior therapy Placebo IV Placebo IV + SOC Chemoradiation Primary Endpoint: PFS by investigator per modified RECIST v1.1 Stratification Factors T stage (<T4 vs T4) N stage (N0/N1/2b vs N2c/N3) HPV (+ vs -) as measured by p16 IHC Placebo IV Q2W Up to 12 months National Institutes of Health. Available at: Accessed: April 19, 2017

59 RAI-Refractory Thyroid Carcinoma

60 Advanced Thyroid Cancer Patients with advanced, progressive thyroid carcinoma that is refractory to radioactive iodine (RaI) have few treatment options. All types of thyroid carcinoma (papillary, follicular, medullary, and anaplastic) are poorly responsive to traditional systemic chemotherapy. A number of targeted agents are now approved or under investigation in this patient population

61 Radioactive-Iodine (RAI)-Refractory Differentiated Thyroid Cancer (DTC) It is estimated that in the USA in 2013 there will be: > new cases of thyroid cancer, and 1850 deaths due to thyroid cancer In approximately 5 15% of patients with thyroid cancer, the disease becomes refractory to RAI Median survival for patients with RAI-refractory DTC and distant metastases is estimated to be years Patients often suffer multiple complications associated with disease progression Sorafenib approved in USA in 2013 based on DECISION trial Lenvatinib approved in USA in 2015 based on SELECT trial 1. Howlader N et al. SEER Cancer Statistics Review; 2. Xing M et al. Lancet 2013; 381: ; 3. Pacini F et al. Expert Rev Endocrinol Metab 2012;7:541 54; 4. Durante C et al. J Clin Endocrinol Metab 2006;91: Robbins RJ et al. J Clin Endocrinol Metab 2006;91: Brose et al Lancet Apr 23.

62 Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine-refractory Differentiated Thyroid Cancer The Phase 3 DECISION Trial Brose et al : Lancet Apr 23

63 DECISION Trial: Study Design N=417 randomized from Nov 2009 to Aug 2011 Locally advanced or metastatic, RAI-refractory DTC Progression (RECIST) within the previous 14 months No prior chemotherapy, targeted therapy, or thalidomide R A N D O M I Z A T I O N 1:1 Sorafenib 400 mg orally twice daily Placebo orally twice daily Primary endpoint PFS Secondary endpoints OS Response rate Safety Time to progression Disease control rate Duration of response Stratified by Geographical region (North America, Europe, Asia) Age (<60, 60 years) Progression assessed by independent central review every 8 weeks At progression: Patients on placebo allowed to cross over at the investigator s discretion Patients on sorafenib allowed to continue on open-label sorafenib at the investigator s discretion Brose M, et al. Lancet. 2014;384:

64 DECISION Trial: Progression-Free Survival PFS Probability, % Days From Randomization n Median PFS, Days (Months) Sorafenib (10.8) Placebo (5.8) HR=0.587; 95% CI: ; P< Brose M, et al. Lancet. 2014;384:

65 DECISION Trial: Overall Survival 65 Survival Probability, % Sorafenib Placebo Median OS Not reached Not reached HR=0.802 (95% CI: ) P=0.138, one-sided Days From Randomization At progression: 150 patients on placebo (71%) received open-label sorafenib 55 patients on sorafenib (27%) received open-label sorafenib Brose M, et al. Lancet. 2014;384:

66 DECISION Trial: Response Rates Endpoints Sorafenib Placebo P Value Total evaluable patients, n (%) Response rate, n (%) 24 (12.2) 1 (0.5) < Complete response 0 0 Partial response 24 (12.2) 1 (0.5) Stable disease for 6 months, n (%) Disease control rate (CR + PR + SD 6 months), n (%) Median duration of response (PRs) (range), months 82 (41.8) 67 (33.2) 106 (54.1) 68 (33.8) < ( ) NA 66 Brose M, et al. Lancet. 2014;384:

67 SELECT Trial Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid (SELECT) Schlumberger M et al : NEJM 2015

68 SELECT Trial : Study Design Global, randomized, double-blind, phase III trial Patients with DTC (N=392) IRR evidence of progression within previous 13 months 131 I-refractory disease Measurable disease Up to 1 prior VEGF- or VEGFR-targeted therapy R A N D O M I Z A T I O N Lenvatinib (n=261) 24 mg daily po Treatment until disease progression confirmed by IRR (RECIST v1.1) Placebo (n=131) 24 mg daily po Primary endpoint PFS Secondary endpoints ORR OS Safety Lenvatinib (optional, open-label) Stratified by Geographic region (Europe, North America, other) Prior VEGF-/VEGFR-targeted therapy (0, 1) Age ( 65, >65 years) 68 IRR=independent radiologic review; ORR=objective response rate; RECIST=Response Evaluation Criteria in Solid Tumors.

69 SELECT Trial: Primary Endpoint, Kaplan-Meier Estimate of PFS Lenvatinib Median PFS (95% CI), Months 18.3 (15.1-NR) Progression-Free Survival, Proportion Placebo 3.6 ( ) HR (99% CI): 0.21 ( ) Log-rank test: P< Progression events, 86% Progression events, 41% Time, Months Number of patients at risk: Lenvatinib Placebo NR=not reached. Schlumberger M, et al. NEJM 2015

70 SELECT Trial: PFS by Previous VEGF-Targeted Therapy Progression-Free Survival, Proportion Number of patients at risk: No Previous VEGF-Targeted Therapy (n=299) Time, Months Lenvatinib Placebo Lenvatinib Median PFS (95% CI), Months 18.7 (16.4-NR) Placebo 3.6 ( ) HR (95% CI): 0.20 ( ) Log-rank test: P< Progression-Free Survival, Proportion Previous VEGF-Targeted Therapy: 1 Line (n=93) Time, Months Number of patients at risk: Lenvatinib Placebo Lenvatinib Median PFS (95% CI), Months 15.1 (8.8-NR) Placebo 3.6 ( ) HR (95% CI): 0.22 ( ) Log-rank test: P<0.0001

71 SELECT Trial: OS, ITT Population Overall Survival, Proportion No significant difference was observed in the RPSFT adjusted OS (secondary endpoint; P=0.051), which was used to correct for a potential crossover effect in the placebo arm Lenvatinib Placebo Median OS (95% CI), Months NR (22.0-NR) NR (20.3-NR) Number of subjects at risk: Time, Months Lenvatinib Placebo (95.6%) of 114 eligible placebo patients received open-label lenvatinib post progression ITT=intent-to-treat; IRR=independent radiologic review; RPSFT=rank-preserving structural failure time. Schlumberger M, et al. NEJM 2015

72 SELECT Trial: Response Rates Lenvatinib (n=261) Placebo (n=131) ORR, n (%) 169 (65) 2 (2) [95% CI] [ ] [ ] P value < Complete response, n (%) 4 (2) 0 Partial response, n (%) 165 (63) 2 (2) Stable disease 23 weeks, n (%) 40 (15) 39 (30) Progressive disease, n (%) 18 (7) 52 (40) Median time to objective response (95% CI), months* Duration of response (95% CI), months* 2.0 ( ) NR (16.8-NR) *Nonresponders were not included in the median time to response assessment. Schlumberger M, et al. NEJM 2015

73 Ho et al : N Engl J Med 2013; 368:

74 Protocol Schema Definitions of RAI-Refractory Disease 1. Index lesion that did not take up RAI on a diagnostic RAI scan (up to 2 years prior to enrolment) 2. RAI-avid index lesion that did not respond to therapeutic RAI treatment 6 months or more prior to entry in the study F-fluoro-deoxy glucose (FDG) avid PET lesions

75 124 I PET: Selumetinib induces iodine incorporation in a BRAF MUT patient Baseline Post-selumetinib

76 124 I PET/CT: Fused axial images (BRAF MUT patient) Baseline Post-selumetinib

77 NCCN Guidelines 2017 Principles of TKI Therapy Oral kinase inhibitors showed significant activity in recurrent/metastatic DTC and MTC Benefit seen in PFS not OS Toxicity can be significant and may impact QOL Pace of progression should be factored in treatment decisions Side effects management is essential for optimal outcomes

78 NCCN Guidelines: Recurrent/Metastatic disease not amenable to RAI Papillary, Follicular. Hurtle cell Carcinomas First Line: Consider Lenvatinib (preferred) or Sorafenib for progressive and/or symptomatic disease Subsequent therapy: Consider other TKI s on further progression (everolimus, vandetanib, cabozantinib, vemurafenib, axitinib, sunitinib, pazopanib) Consider local therapies: Surgery, cryotherapy, Ethanol ablation, radiation therapy Active surveillance when appropriate Biphosphonate or Denosumab (If Bone metastasis) Radiation, Surgery (Brain metastatsis)