Head&Neck, and Thyroid Cancers: Incorporating New Therapies into Current Treatment Algorithms

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1 Head&Neck, and Thyroid Cancers: Incorporating New Therapies into Current Treatment Algorithms 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 Consultant: Merck,BMS, Eisai, Bayer, Pfizer, Astra Zeneca NCCN: Member: Head and Neck Committee NCCN: Chair: Thyroid Committee Pres

3 Head and Neck Cancer Introduction: Epidemiology, Clinical Features, Prevention, Treatment Modalities Concurrent Chemoradiotherapy Sequential Chemoradiotherapy Adjuvant Chemoradiotherapy Recurrent/Metastatic disease New drugs in Thyroid Cancer 3

4 Head and Neck Cancer Primary Disease Sites Oral Cavity Pharynx Larynx Nasal Cavity Paranasal Sinuses 4 Source: Maxwell V. Blum Cancer Resource Room

5 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 5

6 Human Papillomavirus (HPV) 6 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.

7 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 7 Fakhry C, et al. J Clin Oncol. 2006:24(17): Chaturvedi AK, et al. J Clin Oncol. 2008;26(4):

8 HPV testing in tumors In situ hybridization p16 immunohistochemistry PCR

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

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

11 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.

12 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

13 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

14 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

15 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

16 Endpoint: 2yr PFS and OS * 3 high-dose pts did not go on to receive RT

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 18 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).

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 Patient Characteristics: TPF vs PF Intent to Treat Population 30 Posner MR, et al. N Engl J Med. 2007;357(17): Posner. N Engl J Med. 2007;357:1705

31 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

32 TAX 324 Phase III Trial: Docetaxel/Cisplatin/5-FU vs Cisplatin/5-FU Sequential Therapy in Advanced SCCHN: Toxicity During ICT N = 251 TPF, 243 PF During CRT N = 203 TPF, 184 PF Grade 3/4 Toxicity TPF PF Stomatitis 21% 27% Nausea 14% 14% Lethargy 5% 10% Vomiting 8% 10% Diarrhea 7% 3% Anorexia 12% 12% Neutropenia 83% 56% Febrile neutropenia 12% 7% Neutropenic infection 12% 8% Stomatitis 37% 38% Dysphagia 23% 24% Mouth, nose dryness 5% 4% Nausea 6% 6% Rash/itch 5% 2% 32 Posner MR. N Engl J Med. 2007;357(17):

33 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):

34 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 34

35 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 35

36 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 36

37 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. 37 Pellitteri PK, et al. Head Neck. 2006;28(2): Ong SC, et al. J Nucl Med. 2008;49(4):

38 Adjuvant Chemoradiotherapy

39 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 39 Bernier J, et al. N Engl J Med. 2004;350(19): Cooper JS, et al. N Engl J Med. 2004;350(19):

40 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):

41 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):

42 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 42 Bernier J, et al. Head Neck. 2005;27(10):

43 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 43 NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers. V

44 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 44

45 Palliative Chemotherapy

46 Palliative Chemotherapy Treatment for recurrent disease without surgical or radiotherapy option 1st line therapy: historically platinum-based doublet overall RR 30-40% median survival 6-9 months regardless of treatment randomized controlled trials fail to demonstrate clear improvement in OS compared to RX with single agents Active agents: cisplatin, carboplatin, 5-FU, taxanes, methotrexate, cetuximab, ifosfamide, gemcitabine (for nasopharynx cancer) and others 46 DeVita VT, et al. Cancer: Principles & Practice of Oncology. 8th ed. Lippincott Williams & Wilkins; 2008.

47 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 47 Vermorken JB, et al. N Engl J Med. 2008;359(11):

48 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% 48 Vermorken JB, et al. N Engl J Med. 2008;359(11):

49 EXTREME: Overall Survival C225+Platinum+FU Platinum+5-FU HR P-value N = 222 N = months 7.4 months Conclusion: Addition of cetuximab to standard first-line platinum-based chemotherapy improves overall survival. 49 Vermorken JB, et al. N Engl J Med. 2008;359(11):

50 Keynote 012: Pembrolizumab in Recurrent and /or Metastatic Head and Neck Carcinoma 50 Chow et al: JCO 2016

51 KEYNOTE-012 Trial Initial Cohort Patients R/M HNSCC Measurable disease (RECIST v1.1) ECOG PS 0-1 PD-L1+ (initial cohort) PD-L1+ or PD-L1- (expansion cohort) Pembrolizumab 10 mg/kg Q2W N = 60 Expansion Cohort Pembrolizumab 200 mg Q3W N = 132 Continue until: 24 months of treatment PD Intolerable toxicity Combined analyses of Initial and Expansion cohorts Response assessment: Every 8 weeks Primary end points: ORR (RECIST v1.1, central imaging vendor), safety Secondary end points: ORR (investigator), PFS, OS, response duration, ORR in HPV+ patients Additional cohorts included bladder cancer, TN breast cancer, and gastric cancer. Treatment beyond progression was allowed. Initial cohort only.

52 Baseline Demographics

53 53 Antitumor Activity of Pembrolizumab

54 Efficacy of Pembrolizumab Max change in Target lesions Median PFS 2 months Treatment exposure and Response duration in responders Median OS 8 months 54

55 CheckMate 141 Study Design 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

56 Demographics (1) Nivolumab (n = 240) n (%) Investigator s Choice (n = 121) n (%) Total (N = 361) n (%) Median age (years) < (71.7) 76 (62.8) 248 (68.7) (28.3) 45 (37.2) 113 (31.3) Gender Male 197 (82.1) 103 (85.1) 300 (83.1) Race White 196 (81.7) 104 (86.0) 300 (83.1) Asian 29 (12.1) 14 (11.6) 43 (11.9) Other 15 (6.3) 3 (2.5) 18 (5.0) Smoking/tobacco use Current/former 191 (79.6) 85 (70.2) 276 (76.5) Never 39 (16.3) 31 (25.6) 70 (19.4)

57 Demographics (2) Nivolumab (n = 240) n (%) Investigator s Choice (n = 121) n (%) Total (N = 361) n (%) ECOG performance status 0 49 (20.4) 23 (19.0) 72 (19.9) (78.8) 94 (77.7) 283 (78.4) 2 1 (0.4) 3 (2.5) 4 (1.1) Not reported 1 (0.4) 1 (0.8) 2 (0.6) Number of prior lines of systemic cancer therapy (43.8) 58 (47.9) 163 (45.2) 2 81 (33.8) 45 (37.2) 126 (34.9) 3 54 (22.5) 18 (14.9) 72 (19.9) Site of primary tumor Oral cavity 108 (45.0) 67 (55.4) 175 (48.5) Pharynx 92 (38.3) 36 (29.8) 128 (35.5) Larynx 34 (14.2) 15 (12.4) 49 (13.6)

58 Treatment Administration Nivolumab (n = 240) Investigator s Choice (n = 121) Total (N = 361) Patients receiving 1 dose, n (%) 236 (98.3) 111 (91.7) 347 (96.1) Investigator s choice therapy, n (%) Methotrexate 46 (38.0) Docetaxel 52 (43.0) Cetuximab 13 (10.7) Median time on therapy, mo (95% CI) Median duration of follow-up, mo (range) 1.9 ( ) 1.9 ( ) 5.3 (0 16.8) 4.6 (0 15.2) Number of deaths, n (%) 133 (55.4) 85 (70.2) 218 (60.4) Ongoing treatment, n (%) 41 (17.4) 3 (2.7) 44 (12.7)

59 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

60 Conclusions : PD-1 inhibitors in SCCHN Nivolumab is the first agent to demonstrate a significant improvement in survival in patients with SCCHN who progress after platinum-based therapy in a randomized, phase 3 comparative trial Pembrolizumab has shown robust, durable antitumor activity in heavily pretreated patients with R/M HNSCC Nivolumab and Pembrolizumab demonstrated a benefit in the overall study population, regardless of PD-L1 expression or p16 status Safety profile for both agents is favorable and consistent with prior studies Nivolumab and Pembrolizumab represents a new standard of care option for patients with R/M SCCHN after platinum-based therapy

61 RAI-Refractory Thyroid Carcinoma

62 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

63 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.

64 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

65 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:

66 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:

67 DECISION Trial: Overall Survival 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 67 Brose M, et al. Lancet. 2014;384:

68 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 68 Brose M, et al. Lancet. 2014;384:

69 DECISION Trial: Most Common Treatment-Emergent AEs Adverse Event* Sorafenib, % (n=207) Placebo, % (n=209) Any Grade Grade 3/4 Any Grade Grade 3/4 Hand-foot skin reaction Diarrhea Alopecia Rash/desquamation Fatigue Weight loss Hypertension Metabolic lab (other) Anorexia Oral mucositis Pruritus Nausea Hypocalcemia *National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version Brose M, et al. Lancet. 2014;384:

70 Summary: DECISION Trial Approved by FDA 2013 Sorafenib significantly improved PFS and extended median PFS by 5 months vs. placebo 10.8 vs 5.8 months Safety results are consistent with the known safety profile of sorafenib

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

72 SELECT Trial (Study 303): 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) 72 IRR=independent radiologic review; ORR=objective response rate; RECIST=Response Evaluation Criteria in Solid Tumors.

73 SELECT Trial: Primary Endpoint, Kaplan-Meier Estimate of PFS Median PFS (95% CI), Months Lenvatinib 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

74 SELECT Trial: PFS by Previous VEGF-Targeted Therapy Progression-Free Survival, Proportion No Previous VEGF-Targeted Therapy (n=299) Time, Months Number of patients at risk: 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

75 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

76 SELECT Trial: PFS Subgroup Analyses Baseline Tumor Events/N Median, Months HR (95% CI) Lenvatinib Placebo Lenvatinib Placebo Burden, mm 35 14/65 21/ ( ) NR /72 31/ ( ) /63 31/ ( ) >92 31/61 30/ ( ) Histology Papillary 61/141 60/ ( ) Poorly differentiated 14/28 18/ ( ) Follicular 32/92 35/ ( ) NR 3.7 Bone metastasis No 60/157 74/ ( ) Yes 47/104 39/ ( ) Lung metastasis No 17/35 7/ ( ) Yes 90/ / ( ) NR=not reached. Schlumberger M, et al. NEJM Favors Lenvatinib Favors Placebo HR and 95% CI

77 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

78 SELECT Trial: Treatment-Emergent Adverse Events (TEAEs) Lenvatinib, n (%) (n=261) Placebo, n (%) (n=131) TEAE 260 (>99) 118 (90) TEAE reported as treatment related 254 (97) 78 (60) Serious TEAEs 133 (51) 31 (24) TEAE resulting in Dose reduction 177 (68) 6 (5) Dose interruption 215 (82) 24 (18) Discontinuation of treatment 37 (14) 3 (2.3) Fatal TEAE 20 (8) 6 (5) Fatal TEAE reported by investigator as treatment related 6 (2) 0 6/20 lenvatinib treatment-emergent deaths were considered by investigator as treatment related: Pulmonary embolism (n=1); hemorrhagic stroke (n=1); general health deterioration (n=4)

79 Most Frequent Treatment-Related AEs (>20%) Adverse Event Lenvatinib, % (n=261) Placebo, % (n=131) Any Grade Grade 3 Any Grade Grade 3 Hypertension Diarrhea Fatigue/asthenia Decreased appetite Nausea/vomiting Decreased weight Stomatitis Palmar-plantar erythrodysesthesia syndrome Proteinuria Headache Dysphonia Schlumberger M, et al. NEJM 2015

80 SELECT Trial: Conclusions In patients with RR-DTC, lenvatinib significantly prolonged median PFS by 14.7 months compared with placebo: Lenvatinib, median PFS: 18.3 months (95% CI, 15.1-NR months) Placebo, median PFS: 3.6 months (95% CI, months) HR=0.21 (99% CI, ) Response rates for lenvatinib vs placebo, respectively, were: ORR: 65% vs 2% (with CR: 2% vs 0%) The median time to objective response for lenvatinib was 2.0 months (95% CI, months) The median duration of response for lenvatinib has not been reached 75% of responders had an objective response >9.4 months Main toxicities: hypertension, proteinuria, diarrhea, fatigue, and weight loss 80

81 Summary of Advanced Thyroid Cancer Trials Targeted Therapy Compound Targets Clinical Trials Vandetanib Cabozantinib RET, VEGFR, EGFR RET, MET, VEGFR2, c-kit Approved MTC Approved MTC Sunitinib VEGFR-2, PDGFR, c-kit, RET Phase II Gefitinib EGFR Phase II Sorafenib VEGFR-2/3, BRAF, PDGFR, RET Approved DTC Lenvatinib VEGFR-1/2, PDGFR, FGFR-1 Approved DTC Motesanib VEGFR, PDGFR, c-kit, RET Phase II Pazopanib VEGFR, PDGFR, c-kit Phase II Depsipeptide HDAC inhibitor Phase II Everolimus mtor Phase II Vemurafenib BRAF Phase II Dabrafenib BRAF Phase II

82 Conclusions - 1 RAIR-DTC is a therapeutic challenge New agents are available VEGF, mtor inhibitors are active agents Lenvatinib and Sorafenib are now FDA approved. Many other agents currently in phase III

83 DTC can be an indolent disease Conclusions - 2 Many patients do not require therapy immediately Great deal of judgment should be exercised on when to initiate therapy 1- Rapidly growing disease 2- Symptomatic disease Drug-related toxicity can be significant and close monitoring is required