cancer medicine & hematology · 2019. 9. 18. · e. g. i. s. t. e. r. mandatory. p16. testing ....
TRANSCRIPT
Robert Haddad, MDChief, Head and Neck Oncology Program
Dana Farber Cancer InstituteProfessor of Medicine
Harvard Medical SchoolBoston, MA
Head and Neck Cancer Thyroid Cancer
Disclosures
• Research Funding: BMS, Merck, Pfizer, Genentech, Kura
• Consultant: Merck, BMS, Eisai, Pfizer , Astra Zeneca, Genentech, Loxo, Glenmark, Immunomic, GSK
• NCCN: Member: Head and Neck Committee• NCCN: Chair: Thyroid Committee
Presente
3
Head and Neck CancerThyroid Cancer
• Introduction:Epidemiology, Clinical Features, HPV, New Staging System, Treatment Modalities
• Concurrent/Sequential/Adjuvant Chemoradiotherapy
• Recurrent/Metastatic disease: Role of Immunotherapy
• Papillary Thyroid Cancer
• Medullary Thyroid Cancer
• Anaplastic Thyroid Cancer
4
Head and Neck Cancer Primary Disease Sites
Oral Cavity
Pharynx
Larynx
Nasal Cavity
Paranasal Sinuses
Source: Maxwell V. Blum Cancer Resource Room
5
Epidemiology
• 48000 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
Circular 8 kB dsDNA GenomesOnly One Coding Strand
Infect Epithelial Cells~ 200 HPV types
~ 30 Mucosal HPVsLow-Risk: Genital Warts
High-Risk: Lesions That Progress to Cancer
HPV E6/E7 OncoproteinsSmall, Non-Enzymatic Proteins
(~ 150aa E6; ~ 100aa E7)Associate With and Functionally Modify
Host Cellular Protein Complexes
HPV GENOME INTEGRATION
LCR E6 E7
Frequent Event During Malignant Progression Terminates Viral Life Cycle
Expression of E6 and E7 Is Retained
HPV-Associated Cancers
> 99% of Cervical Carcinoma~ 90% Anal Carcinomas
~ 40% Vulvar and Vaginal Carcinomas~ 60% of Oropharynx Cancers
Human Papillomavirus (HPV)
Münger et al, 2004.
6
7
Human Papillomavirus (HPV)-PositiveHead 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 high-
risk sexual practices • Favorable prognosis• In situ hybridization,p16 IHC, PCR
Fakhry C, et al. J Clin Oncol. 2006:24(17):2606-2617. Chaturvedi AK, et al. J Clin Oncol. 2008;26(4):612-619.
RTOG 0129 Phase III Trial: Concomitant CRT With Standard Vs. Accelerated Fractionation RT
Survival Outcomes by HPV Status
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
Cisplatin(IV on D1, 22, 43)Standard fractionation RT(5 d/wk for 7 wks)
CRT
RANDOMIZE
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. Ang et al NEJM 2010
RTOG 0129: OS and PFS by HPV Status
Ang. N Engl J Med. June 7, 2010
3-Year Outcomes HPV Positive (%) HPV Negative (%) P ValueOS 82.4 57.1 <0.001PFS 73.7 43.4 <0.001Locoregional failure 13.6 35.1 <0.001Distant metastases 8.7 14.6 0.23
PFSOverall Survival100
75
50
25
0
100
75
50
25
0
Ove
rall
Surv
ival
(%)
Prog
ress
ion-
Free
Sur
viva
l (%
)
HPV negativeHPV positive
HPV negativeHPV positive
HR=0.38 (95% CI:0.26-0.55); P<0.001
HR=0.40 (95% CI:0.29-0.557; P<0.001
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 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
should we treat them the same ?
Major changes in clinical vs. pathologic N staging, for p16+ HNC
• N0 No node metastasis• N1 Ipsilateral nodes, ≤6
cm• N2 Contralateral/bilateral
nodes, ≤6 cm • N3 Node >6 cm
No more N2a, N2b, N2c
Clinical system
• pN0 No node metastasis
• pN1 ≤4 nodes
• pN2 >4 nodes
Pathologic systemvs
Clinical ENE is not staged for p16+ OPC
Oropharynx Clinical Stage Grouping, 8th ed.
cN0 cN1 cN2 cN3cT0 I I II IIIcT1 I I II IIIcT2 I I II IIIcT3 II II II IIIcT4 III III III III
P16+ NEW
cN0 cN1 cN2 cN3cT1 I III IVA IVBcT2 II III IVA IVBcT3 III III IVA IVB
cT4a IVA IVA IVA IVBcT4
b IVB IVB IVB IVB
P16- UNCHANGED
M1 = stage IV
M1 = stage IVC
AJCC 8—Highlights Summary
• Recognition of New Disease: HPV+ Oropharynx Cancer– Also Separate Clinical and Pathological Systems
• Modification of T Stage For Oral Cavity, Depth of Invasion(DOI)
• HPV- Neck: Include ENE; Clinical & Path • Unknown Primary
14
Treatment Approach
Disease Extent Treatment
T1N0-1 or T2N0 Surgery or RT
T2N1 or T3-4 or N2-3 Combined modality
Recurrent or M1 Surgery and/or RTCombined modalityChemotherapy
Concurrent Chemoradiotherapy
16
The Debate Over Therapeutic Sequence: MACH-NC Findings
MACH-NC: Meta-Analysis of Chemotherapy in Head and Neck Cancer; PF=cisplatin + fluorouracil1. Pignon JP, et al. Lancet. 2000;355(9208):949-955. 2. Monnerat C, et al. Ann Oncol. 2002;13(7):995-
1006..
Design(No. of Studies/No. of Subjects)
Hazard Ratio(95% CI)
ChemotherapyEffect
(P -value)
Absolute Benefit
2 Years 5 Years
Adjuvant1
(8/1854)0.98
(0.85-1.19) 0.74 1% 1%
Neoadjuvant1
(31/5269)0.95
(0.88-1.01) 0.10 2% 2%
Concurrent1
(26/3727)0.81
(0.76-0.88) < 0.0001 7% 8%
Total1(65/10,850)
0.90(0.85-0.94) < 0.0001 4% 4%
No. of Trials No. of Subjects Difference at 5 Years P -value
PF induction2 15 2487 5% 0.01
Concurrent Therapy: Standard of Care
• RT standard fractionation, 70 Gy over 7 weeks (2-Gy fractions)
• Alternative Chemotherapy regimens: 1- Weekly cisplatin 40mg/m22- Weekly Cetuximab3- Weekly carboplatin auc 1.5-2+Paclitaxel 30-45mg/m2
• Cisplatin 100 mg/m2 days 1, 22, and 43 of RT
18
RTOG 91-11 Induction Cisplatin/5-FU vs Concomitant Cisplatin vs RT Alone in
Resectable SCC
Forastiere AA, et al. N Engl J Med. 2003;349(22):2091-2098.
Resectable stage III/IV SCC
• Glottic or supraglottic cancer
• Previously untreated
N = 515
Cisplatin (100 mg/m2, d1)5-FU (1000 mg/m2/day, d1-5 C-I)
every 3 wks, 2 cycles
CRT (N = 171)
RANDOMIZE
ICTRT (N = 173)
Cisplatin (100 mg/m2, every 3 wks, 3 cycles)
RT (2 Gy/fr, 35 fr, total 70 Gy)
RT (2 Gy/fr, 35 fr, total 70 Gy)RT (N = 171)
RT(2 Gy/fr, 35 fr, total 70 Gy)
• Primary end point: larynx preservation • Secondary end point: LFS
LFS=laryngectomy-free survival
19
RTOG 91-11Larynx 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 3
.Forastiere AA, et al. N Engl J Med. 2003;349(22):2091-2098.
20 Bonner JA, et al. N Engl J Med. 2006;354(6):567-578.
Phase III Trial: Cetuximab + RT for SCC
Advanced SCC• Stage III/IV• N = 424
RT*+
Cetuximab (400 mg/m2, then 250 mg/m2/wk)
RANDOMIZE
RT* alone
*Choice of: • Once-daily RT: 70 Gy in 35 fractions• Twice-daily RT: 72.0-76.8 Gy in 60-64 fractions• Concomitant boost: 72 Gy in 42 fractions
Grade 3-5 ToxicityRT 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% .006
21Bonner JA, et al. N Engl J Med. 2006;354(6):567-578.
Phase III: Cetuximab + RT for SCC: Results
47% vs 34% at 3 yearsP < .01 at 3 years
55% vs 45% at 3 yearsP = .05 at 3 years
Locoregional Control OS
NRG-RTOG 1016: Phase III Trial Comparing Radiation/Cetuximab to Radiation/Cisplatin in
HPV-Related Cancer of the Oropharynx
Gillison et al : Lancet . January 2019
R
E
G
I
S
T
E
R
Mandatory
p16
testing
S
T
R
A
T
I
F
Y
T Stage1. T1-22. T3-4
N Stage1. N0-2a2. N2b-3
ZubrodPerformance Status1. 02. 1
Smoking History1. ≤ 10 pack-years2. > 10 pack-years
R
A
N
D
O
M
I
Z
E
Arm 1 (Control):Accelerated IMRT, 70 Gy for 6 weeks+ high dose cisplatin (100 mg/m2) Days 1 and 22(Total: 200 mg/m2)
Arm 2:Accelerated IMRT, 70 Gy for 6 weeks+ cetuximab (400 mg/m2) loading dose pre-IMRT,then 250 mg/m2 weekly during IMRT,+ 1 week after IMRT for a total of 8 doses ofcetuximab
Phase III Trial of Radiotherapy plus Cetuximab versus Chemoradiotherapy in HPV-Related Oropharynx Cancer
RTOG 1016 HPV Trial
Patient and Tumor Characteristics
• 805 patients analyzed • Median age 58 • 90% male; 93% white• 74%/26% Zubrod 0/1• 38% >10 pack-years smoking• T4 disease 12%• 90% N2-3 (AJCC 7th edition)
RTOG 1016 HPV Trial
Overall Outcomes
Hazard ratio (cetuximab/cisplatin): 1.451-sided 95% upper confidence bound: 1.94
Cisplatin Cetuximab
Overall Survival (5 yr) 85 vs 78 % (p=0.02)Progression-free (5 yr) 78 vs 67 (p<0.001)LRF (5 yr) 10 vs 17 (p<0.001)
RTOG 1016 HPV Trial
Overall Survival
RTOG 1016 HPV Trial
Cisplatin
85 vs 78% 5-yr
p-value (non-inferiority) 0.51
p-value (1-sided log-rank test) 0.02
Conclusions
• Non-inferiority of cetuximab was NOT demonstrated
• Cisplatin had better OS, PFS, LRC
• “Classical” Overall Acute Toxicity: no difference
• Acute “Toxicity Burden”: 40% worse with cisplatin
• Late “Toxicity Burden”: 40% worse with cisplatin
RTOG 1016 HPV Trial
Sequential Chemoradiotherapy
29
TAX 324: Sequential Combined Modality TherapyTPF vs PF Followed by Chemoradiotherapy
RANDOMIZE
P
P
F
F
Carboplatinum - AUC 1.5 Weekly
Daily Radiotherapy
T
TPF: Docetaxel 75D1 + Cisplatin 100D1 + 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
Surgery as
Needed
Posner MR, et al. N Engl J Med. 2007;357(17):1705-1715.
TAX 324: Results
TPF significantly improves survival and PFS compared with PF in an ICT regimen followed by CRT
Posner et al, 2007.
TPF 62%PF 48%
TPF 67%PF 54%
Log-rank p = .0058HR = 0.70
TPF 53%PF 42% TPF 49%
PF 37%
Log-rank p = .004HR = 0.701
Survival PFS
Time (mos)
Surv
ival
Pro
babi
lity
(%)
0 6 12 18 24 30 36 42 48 54 60 66 72
0
10
20
30
40
50
60
70
80
90
100
TPF (N = 255)
PF (N = 246)
Time (mos)PF
S Pr
obab
ility
(%)
0 6 12 18 24 30 36 42 48 54 60 66 72
0
10
20
30
40
50
60
70
80
90
100
TPF (N = 255)
PF (N = 246)
TPF significantly improves survival and PFS compared with PF in an ICT regimen followed by CRT
Posner. N Engl J Med. 2007;357:1705
31
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 = 0.0058)
• 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
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
Clinical Scenarios to Consider Induction Therapy
1. Potential distant metastasis2. Delay in radiation simulation3. 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
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.
Pellitteri PK, et al. Head Neck. 2006;28(2):166-175. Ong SC, et al. J Nucl Med. 2008;49(4):532-540.
Adjuvant Chemoradiotherapy
36
EORTC 22931 and RTOG 9501 Phase III Trials: Adjuvant RT ± Concomitant Cisplatin
Bernier J, et al. N Engl J Med. 2004;350(19):1945-1952. Cooper JS, et al. N Engl J Med. 2004;350(19):1937-1944.
Resectable SCC• Oral cavity, oropharynx, hypopharynx,
larynx• Stage III/IV (EORTC), high risk (RTOG)• Previously untreated
N = 334 (EORTC)N = 459 (RTOG)
Surgery
RANDOMIZE
RT+Cisplatin (100 mg/m2, d1,22,43)
EORTC: 66 Gy over 6.5 wksRTOG: 60-66 Gy over 6-6.6 wks
37
Poor Risk Criteria
RTOG 95011
≥ 2 nodesECE +Margins
EORTC 229312
Level IV/V (OC/OP)ECE+MarginsPerineural diseaseVascular emboli
ECE = extracapsular nodal extension; OC = oral cavity; OP = oropharynx
1. Cooper JS, et al. N Engl J Med. 2004;350(19):1937-1944.2. Bernier J, et al. N Engl J Med. 2004;350(19):1945-1952.
38
OS (EORTC)1 OS (RTOG)2
EORTC 22931 and RTOG 9501: Adjuvant RT ±Concomitant Cisplatin: Results
P=0.02P=0.19
Months After Randomization
1. Bernier J, et al. N Engl J Med. 2004;350(19):1945-1952. 2. Cooper JS, et al. N Engl J Med. 2004;350(19):1937-1944.
39
RTOG 9501/EORTC 22931Which 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
Bernier J, et al. Head Neck. 2005;27(10):843-850.
40
Survivorship /Follow-Up
• Assess for recurrence/2nd 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
NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers. V.2.2010. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
Palliative Chemotherapy
Management of Recurrent/Metastatic SCCHN
Salvage surgery or re-irradiation
Palliative systemic therapy
Supportive care
Chemotherapy +/-Targeted Therapy
Immunotherapy
Clinical Trials
Rec
urre
nt/ M
etas
tatic
HN
SCC
43
EXTREME: Study Design
5-FU 1000 mg/m2 d1-4withCisplatin 100 mg/m2 d1orCarboplatin AUC 5 d1plusCetuximab 250 mg/m2/week*q 3 weeks
*Loading dose of 400 mg/m2 on week 1
RANDOMIZE
N = 442
5-FU 1000 mg/m2 d1-4withCisplatin 100 mg/m2 d1orCarboplatin AUC 5 d1
Notreatment
6 cycles maximum
POD ortoxicity
POD ortoxicity
Cetuximab
Vermorken JB, et al. N Engl J Med. 2008;359(11):1116-1127.
44
EXTREME: First-Line Platinum/5-FU ± Cetuximab in Recurrent/Metastatic SCC: Survival
10.1 mos7.4 mos
Survival Time (months)Patients at Risk:Platinum/5-FU
Cetuximab + Platinum/5-FU220 173 127 83 65 47 19 8 1222 184 153 118 82 57 30 15 3
HR (95% CI)=0.797 (0.644-0.986)Strat. log-rank test: 0.0362
Platinum/5-FUCetuximab + Platinum/5-FU
Surv
ival
Pro
babi
lity
0.00.10.20.30.40.50.60.70.80.91.0
0 3 6 9 12 15 18 21 24
OS RR18%35%
Vermorken JB, et al. N Engl J Med. 2008;359(11):1116-1127.
Immunotherapy in Head and Neck Cancer
Protocol-Specified Final Results of the KEYNOTE-048 Trial of Pembrolizumab as First-Line Therapy for Recurrent/ Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC)
Presented By Danny Rischin at 2019 ASCO Annual Meeting
KEYNOTE-048 Study Design (NCT02358031)
Presented By Danny Rischin at 2019 ASCO Annual Meeting
Study End Points: Pembrolizumab vs EXTREME and Pembrolizumab + Chemotherapy vs EXTREME
Presented By Danny Rischin at 2019 ASCO Annual Meeting
Baseline Characteristics, ITT Population
Presented By Danny Rischin at 2019 ASCO Annual Meeting
KEYNOTE-048 Study Design (NCT02358031)
Presented By Danny Rischin at 2019 ASCO Annual Meeting
OS, P+C vs E, CPS ≥20 Population
Presented By Danny Rischin at 2019 ASCO Annual Meeting
OS, P+C vs E, CPS ≥1 Population
Presented By Danny Rischin at 2019 ASCO Annual Meeting
OS, P+C vs E, Total Population
Presented By Danny Rischin at 2019 ASCO Annual Meeting
KEYNOTE-048 Study Design (NCT02358031)
Presented By Danny Rischin at 2019 ASCO Annual Meeting
OS, P vs E, Total Population
Presented By Danny Rischin at 2019 ASCO Annual Meeting
OS, P vs E, CPS ≥20 Population
Presented By Danny Rischin at 2019 ASCO Annual Meeting
OS, P vs E, CPS ≥1 Population
Presented By Danny Rischin at 2019 ASCO Annual Meeting
Summary and Conclusions
Presented By Danny Rischin at 2019 ASCO Annual Meeting
CheckMate 141 Study DesignNivolumab VS. Chemotherapy
R2:1
Nivolumab3 mg/kg IV q2w
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)
Key Eligibility Criteria
• R/M SCCHN of the oral cavity, pharynx, or larynx
• 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
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. NCT02105636.
Primary endpoint• OS
Other endpoints• PFS• ORR• Safety• DOR• Biomarkers• Quality of life
Randomized, global, phase 3 trial of the efficacy and safety of nivolumab versus investigator’s choice in patients with R/M SCCHN
Ferris et al : NEJM 2016
0 3 6 9 12 15 18
Median OS, mo (95% CI)
HR(97.73% CI) p-value
Nivolumab (n = 240) 7.5 (5.5–9.1) 0.70 (0.51–0.96) 0.0101
Investigator’s Choice (n = 121) 5.1 (4.0–6.0)
Overall Survival
Months
Nivolumab 240 167 109 52 24 7 0
Investigator’sChoice
121 87 42 17 5 1
No. at Risk
0
0
10
20
30
40
50
60
70
80
90
100
Ove
rall
Surv
ival
(% o
f pat
ient
s)
1-year OS rate (95% CI)36.0% (28.5–43.4)
16.6% (8.6–26.8)
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 platinuma
• ECOG PS 0 or 1• Known p16 status (oropharynx)b
• Tissue samplec for PD-L1 assessmentd
Pembrolizumab 200 mg IV Q3W
for 2 y
Stratification Factors• ECOG PS (0 vs 1)• p16 statusb (positive vs negative)• PD-L1 TPSd (≥50% vs <50%)
Methotrexate 40 mg/m2 QWe
ORDocetaxel 75 mg/m2 Q3W
ORCetuximab 250 mg/m2 QWf
R 1:1
• Clinically stable patients with radiologic PD could continue treatment until imaging performed ≥4 wk later confirmed PD
• Crossover not permitted
aLimit of 2 prior therapies for R/M HNSCC. bAssessed using the CINtec p16 Histology assay (Ventana); cutpoint for positivity = 70%.cNewly collected preferred. dAssessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies). TPS = tumor proportion score = % of tumor cells with membranous PD-L1 expression. eCould be increased to 60 mg/m2 QW in the absence of toxicity. fFollowing a loading dose of 400 mg/m2.
0 5 1 0 1 5 2 0 2 5 3 00
1 02 03 04 05 06 07 08 09 0
1 0 0
T im e , m o n th s
OS
, %
N o . a t r is k2 4 7 1 5 9 1 0 3 48 14 2 02 4 8 1 4 8 82 34 10 1 0
1 2
Overall Survival in ITT Population
aCox proportional hazards model with treatment as a covariate stratified by the randomization stratification factors. Initially reported data: HR 0.82 (95% CI, 0.67-1.01), P = 0.0316. After the initial report, updated survival data were obtained for 4 patients. bOne-sided P value based on the log-rank test stratified by the randomization stratification factors. Data cutoff date: May 15, 2017.
37.3%27.2%
8.4 mo (6.5-9.4)7.1 mo (5.9-8.1)
Median (95% CI)
Events, n HR (95% CI) PPembrolizumab 179 0.81a (0.66-0.99) 0.0204b
SOC 201
RAI-Refractory Thyroid Carcinoma
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
Radioactive-Iodine (RAI)-Refractory Differentiated Thyroid Cancer (DTC)
• It is estimated that in the USA in 2013 there will be: – >60 000 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 2.5–3.5 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; http://seer.cancer.gov/statfacts/html/thyro.html; 2. Xing M et al. Lancet 2013; 381:1058–69; 3. Pacini F et al. Expert Rev Endocrinol Metab 2012;7:541–54; 4. Durante C et al. J Clin Endocrinol Metab 2006;91:2892–99. 5. Robbins RJ et al. J Clin Endocrinol Metab 2006;91:498–505. 5. Brose et al Lancet. 2014 Apr 23.
Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine-refractory
Differentiated Thyroid Cancer
The Phase 3 DECISION Trial
Brose et al : Lancet. 2014 Apr 23
• 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
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
Primary endpoint• PFS
Secondary endpoints• OS• Response rate• Safety• Time to progression • Disease control rate • Duration of response
Sorafenib400 mg orally
twice daily
RANDOMIZATION
1:1
Placebo orally twice
daily
Brose M, et al. Lancet. 2014;384:319-328.
DECISION Trial: Progression-Free Survival
nMedian PFS,
Days (Months)Sorafenib 207 329 (10.8)
Placebo 210 175 (5.8)
PFS
Prob
abili
ty, %
Days From Randomization0 100 200 300 400 500 600 700 800
HR=0.587; 95% CI: 0.454-0.758; P<0.0001
01020
40
60
80
100
30
50
70
90
Brose M, et al. Lancet. 2014;384:319-328.
At progression:• 150 patients on placebo (71%) received open-label sorafenib• 55 patients on sorafenib (27%) received open-label sorafenib
69
DECISION Trial: Overall Survival
01020
40
60
80
100
30
50
70
90
0 100 200 300 400 500 600 700 800 900 1000
Median OS
Sorafenib Not reached
Placebo Not reached
HR=0.802 (95% CI: 0.539-1.194)P=0.138, one-sidedSu
rviv
al P
roba
bilit
y, %
Days From Randomization
Brose M, et al. Lancet. 2014;384:319-328.
70
DECISION Trial: Response Rates
Endpoints Sorafenib Placebo P ValueTotal evaluable patients, n (%) 196 201Response rate, n (%) 24 (12.2) 1 (0.5) <0.0001
Complete response 0 0 –Partial response 24 (12.2) 1 (0.5) –
Stable disease for ≥6 months, n (%) 82 (41.8) 67 (33.2) –
Disease control rate (CR + PR + SD ≥6 months), n (%) 106 (54.1) 68 (33.8) <0.0001
Median duration of response (PRs) (range), months 10.2 (7.4-16.6) NA –
Brose M, et al. Lancet. 2014;384:319-328.
SELECT TrialStudy of (E7080) LEnvatinib in
Differentiated Cancer of the Thyroid (SELECT)
Schlumberger M et al : NEJM 2015
• Stratified by– Geographic region (Europe, North America, other)– Prior VEGF-/VEGFR-targeted therapy (0, 1)– Age (≤65, >65 years)
72
SELECT Trial : Study Design
Global, randomized, double-blind, phase III trial
Patients with DTC (N=392)
• IRR evidence of progression within previous 13 months
• 131I-refractory disease• Measurable disease• Up to 1 prior VEGF- or
VEGFR-targeted therapyLenvatinib
(optional, open-label)
Primary endpoint• PFS
Secondary endpoints• ORR• OS• Safety
Lenvatinib (n=261)24 mg daily po
RANDOMIZATION
Placebo (n=131)24 mg daily po
Treatment until disease progression
confirmed by IRR(RECIST v1.1)
IRR=independent radiologic review; ORR=objective response rate; RECIST=Response Evaluation Criteria in Solid Tumors.
SELECT Trial: Primary Endpoint,Kaplan-Meier Estimate of PFS
Median PFS (95% CI), Months
Lenvatinib 18.3 (15.1-NR)
Placebo 3.6 (2.2-3.7)
HR (99% CI): 0.21 (0.14-0.31)Log-rank test: P<0.0001
Progression events, 41%
Progression events, 86%
Prog
ress
ion-
Free
Sur
viva
l, Pr
opor
tion
Time, MonthsNumber of patients at risk:LenvatinibPlacebo
261131
22571
19848
17629
15919
14818
13611
925
664
442
242
112
30
00
NR=not reached.Schlumberger M, et al. NEJM 2015
SELECT Trial: PFS by Previous VEGF-Targeted Therapy
Time, Months
Time, Months
Prog
ress
ion-
Free
Su
rviv
al, P
ropo
rtio
n 1.00.90.80.70.60.50.40.30.20.10.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
No Previous VEGF-Targeted Therapy (n=299)
1.00.90.80.70.60.50.40.30.20.10.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Previous VEGF-Targeted Therapy: 1 Line (n=93)
Lenvatinib 195 167 148 135 123 116 108 72 52 34 20 11 3 0Placebo 104 56 36 25 17 12 10 4 3 1 1 1 0 0
Number of patients at risk:
Lenvatinib 66 58 50 41 36 32 28 20 14 10 4 0 0 0Placebo 27 15 7 4 2 1 1 1 1 1 1 1 0 0
Number of patients at risk:
Prog
ress
ion-
Free
Su
rviv
al, P
ropo
rtio
nMedian PFS
(95% CI), Months
Lenvatinib 18.7 (16.4-NR)
Placebo 3.6 (2.1-5.3)
HR (95% CI): 0.20 (0.14-0.27)Log-rank test: P<0.0001
Median PFS (95% CI), Months
Lenvatinib 15.1 (8.8-NR)
Placebo 3.6 (1.9-3.7)
HR (95% CI): 0.22 (0.12-0.41)Log-rank test: P<0.0001
SELECT Trial: OS, ITT Population
Number of subjects at risk:
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 261 248 239 230 219 211 203 169 114 78 55 22 10 3 0Placebo 131 126 126 118 108 103 96 78 53 39 23 8 2 1 0
Time, Months
Ove
rall
Surv
ival
, Pro
port
ion
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 2 4 6 8 10 12 14 16 18 20 22 24 2826
Median OS (95% CI), Months
Lenvatinib NR (22.0-NR)Placebo NR (20.3-NR)
ITT=intent-to-treat; IRR=independent radiologic review; RPSFT=rank-preserving structural failure time.Schlumberger M, et al. NEJM 2015
• 109 (95.6%) of 114 eligible placebo patients received open-label lenvatinib post progression
SELECT Trial: Response Rates
Lenvatinib(n=261)
Placebo(n=131)
ORR, n (%) 169 (65) 2 (2)[95% CI] [59.0-70.5] [0.0-3.6]P value <0.0001
Complete response, n (%) 4 (2) 0Partial 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* 2.0 (1.9-3.5) –
Duration of response (95% CI), months* NR (16.8-NR) –
*Nonresponders were not included in the median time to response assessment.Schlumberger M, et al. NEJM 2015
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)
Medullary Thyroid Cancer
Derived from parafollicular C-cells
Markers : CEA, CTN
Metastatic disease frequently affecting mediastinum, lung, bone and liver.
Two agents approved in US : Vandetanib Cabozantinib
Courtesy Drs Justine Barletta/Cheryl Adackapara
Vandetanib in Medullary Thyroid Cancer:ZETA Trial
• Phase III, double-blind, placebo-controlled study•
• 331 patients with advanced MTC
• Measurable disease (no progression required), Calcitonin level >500pg/ml
• Vandetanib 300mg (n=231) or placebo (100)
• Cross-over allowed
• Primary endpoint: Progression free survival
Wells S A et al. JCO 2012;30:134-141
•54% reduction in the rate of progression (HR=0.46, p=0.0001)
Wells S A et al. JCO 2012;30:134-141
Vandetanib in Medullary Thyroid Cancer:ZETA Trial
•54% reduction in the rate of progression (HR=0.46, p=0.0001)
•PFS NR in Vandetanib arm, 19.3m for placebo
Wells S A et al. JCO 2012;30:134-141
•54% reduction in the rate of progression (HR=0.46, p=0.0001)
•PFS NR in Vandetanib arm, 19.3m for placebo
Wells S A et al. JCO 2012;30:134-141
P=0.0001
Vandetanib in Medullary Thyroid Cancer:ZETA Trial
•54% reduction in the rate of progression (HR=0.46, p=0.0001)
•PFS NR in Vandetanib arm, 19.3m for placebo
•Objective response rate (ORR) 45% versus 13% (p<0.0001)
Wells S A et al. JCO 2012;30:134-141
P=0.0001
Vandetanib in Medullary Thyroid Cancer:ZETA Trial
Cabozantinib in Medullary Thyroid Cancer :EXAM Trial
Treatment until progression or unacceptable toxicity
Locally advanced or metastatic
MTC with documented
RECIST progression
Cabozantinib 140 mg
Placebo
2:1 Randomization
PRO
GR
ESSI
ON
Survival follow-up
No Cross-OverNo Unblinding
Elisai et al : JCO 2014
• Randomized, placebo-controlled study• 330 patients with locally advanced or metastatic MTC • Documented RECIST progressive disease within 14 months of
screening• No limit on prior therapy• Primary endpoint PFS
PFS: 11.2 versus 4.0 months (HR 0.28 95%CI 0.19-0.4 p<0.0001)
Cabozantinib in Medullary Thyroid Cancer :EXAM Trial
Elisai et al : JCO 2014
NCCN Guidelines MTC: Recurrent/Metastatic disease
• First Line: Consider Vandetanib or Cabozantinib for progressive and/or symptomatic disease.
• Subsequent therapy: Consider other TKI’s on further progression (Sorafenib, Lenvatinib, sunitinib, pazopanib)
• Dacarbazine based chemotherapy. • Do NOT treat based on CEA /CTN levels alone. • Consider local therapies.• Active surveillance when appropriate. • Biphosphonate or Denosumab (If Bone metastasis) • Radiation , Surgery (Brain metastatsis)
Typically a tumor of older adults
Presence of pre-existing or co-existing well differentiated carcinoma in 23-78% of cases, usually papillary TC
History of long-standing goiter frequent.
Clinical presentation: Rapidly growing neck mass, hoarseness, vocal cord paralysis,dysphagia
Early hematogenous metastasis
Spindle cell patternPleomorphic giant cell patternSquamoid pattern
Anaplastic Thyroid Cancer
Courtesy Drs Justine Barletta/Cheryl Adackapara
Dabrafenib Plus Trametinib in BRAF V600E-Positive ATC
.Subbiah et al, 2017.
Design
• Multicenter, open-label, phas e 2 in rare B R AF V6 0 0 E -pos cancers (AT C, biliary tract cancer, Gr 1 / 2 and 3 / 4 glioma, adeno CA s mall intes tine, hairy cell leukemia, and multiple myeloma)
• 1 6 AT C patients included• Dabrafenib 1 5 0 mg bid plus trametinib 2 mg daily P O• P rimary end point: res pons e rate
R es ults
• All patients had received prior R T , 6 w/ prior line of s ys temic therapy• Median follow up of 4 7 weeks• R es pons e rate 6 9 % (1 1 / 1 6 )• Median s urvival, P FS , OS not reached• 1 -year s urvival 8 0 %
Adver s eE vents
• Grade 3 and 4 events acros s all cohorts (n=1 0 0 )• Fatigue 5 %• P yrexia 4 %• Anemia 5 %• Hyperglycemia 3 %
Subbiah et al JCO 2018
Conclusions: Thyroid Cancer
• A number of TKI are available for patients with DTC and MTC • For PTC: Lenvatinib and Sorafenib are the two agents of choice • For MTC: Cabozantinib and Vandetanib are the two agents of
choice • Observation is often a reasonable options for many patients • Treatment has side effects and patient selection is very
important • Management of side effects is essential to good outcome • Consider local therapies when appropriate