Research in India Bangalore Tech Expo 2018

Recent Advances in Treatment
of Head & Neck Cancer
Focusing on recent developments
Nimotuzumab
Dr. V. Lokesh M.D
Professor & Head of the Department
Principal Investigator : Clinical Trial hR3 SCCHN/IND
Department of Radiation Oncology
Kidwai Memorial Institute of Oncology1, Bangalore

Cancer burden
• Worldwide PA
– new cases 18.1 million
– cancer deaths 9.6 million
• In India
– new cases 11,40,000
– cancer deaths 7,80,000

Head & Neck Cancer
58% of the Global H&N Ca burden - Asia
India: H&N Ca
• 30% of all Cancer ~ 3,80,000 cases PA
• 60-80% present in advanced stages
– (Cure rates < 25-30 %)

Economic impact of cancer
• Significant
• Increasing
• The total annual economic cost of cancer in
2010 was estimated at ~ US$ 1.16 trillion

Developing a new prescription
medicine (R&D)
• The biopharmaceutical industry invested ~ $90 billion
• From drug discovery through FDA approval ~ $2.6 billion
• rate of success ~12 percent
• Development of Cancer Medicines : confounding factors
– long term followup & survival data (min 2yrs or >5yrs)
and toxicity (early /late) data
– Subset of beneficiary or non benefiter patients
– Obtaining reasonable combinations of oncotherapeutics
(fitting it in the right place in Multimodality combination
of drugs/RT/Surgery)

Research & Development of
Drugs
Time frame Budget $
USD
Contributions
1 Drug Discovery 3-20 yrs 5-10 billion PVT / Govt
2 Trials
•Preclinical (10% of all drugs) 12 yrs 100 million PVT
•Clinical Trials (Human) – few 5-15 years
oPhase I 17 million PVT
oPhase II 34 million PVT
oPhase III 27 million PVT
3 Failed Drugs Loss PVT

Cancer cells :
three basic characteristics
• They grow (avoiding immune destruction)
• They tend to be immortal
• They move around uninhibited (metastasize)

Surgical
Oncology
Principle &
Practice of
Oncology
Radiation therapy
&
Technology
Radiation
Physics
Radiation Safety
& Protection
Quality
assurance
Regulations
Radiation Biology
Clinical -Basic
Science / Cellular /
Genetic
Goal :
Cure
Multidisciplinary
R & D
Clinical research &
Basic Science

More need to be done
• To improve Cure rates

Cancer Treatment is a Double
Edge Sword

↑ Dose ↓ Dose
↑ T – Control ↓ T – Control (loco regional
failures)
↑ Normal Tissue Toxicitites
(unacceptable complications)
↓ Normal Tissue Toxicitites

Primary Modality of Treatment
• Surgery & Radiation Therapy
• Onco Surgical procedures:Surgery :
– Operable / Inoperable / borderline resectable
– Cosmesis / morbidity / mortality
Technical Innovations and Advances:
– Increase Target Dose delivery
– Decreased Side Effect and late complications
– Decreased Treatment related mortality

Management:
Patients tolerance to oncotherapeutics
• Radiation Therapy (Advanced Inoperable)
– RT alone: 5yr OS :: 25-30% & DFS 22-26%
– RT with Radiation Sensitizers
– 1980`s : Hypoxic cell sensitizers
– 1990 `s : CT drugs – CDDP / 5 FU 5-8% gain OS&DFS
– 2000 : Biologicals – C225/hR3 mAb 10 % gain OS&DFS
> 2010 : CT + Biological (hR3mAb) 20 % gain OS&DFS

EGFR
 EGFR is a cell membrane Tyrosine Kinases Receptor
protein.
 first receptor linked directly to cancer. (1970-80`s
and subsequent clinical correlation)

EGFr Activation Mediates Multiple
Processes
Proliferation Metastasis
Angiogenesis
Apoptosis
Resistance
Shc
PI3-K
Raf
MEKK-1
MEK
MKK-7
JNK
ERK
Ras
mTOR
Grb2
AKT
Sos-1
Extracellular
Domain
Intracellular
Domain

EGFR as a Target
 EGFR Overexpression
o Malignant transformation
o Poor response to RT
o Strong predictor of ↓ DFS (decrease tumor control)

EGFR overexpression
• is an early event in SCCHN carcinogenesis
– present in "healthy" mucosa (field
cancerization) from cancer patients, when
compared to healthy controls;
– Over expression increase steadily in parallel to
observed histological abnormalities, from
hyperplasia to invasive carcinoma, through
dysplasia and in situ carcinoma.

1996, 140 patients with primary laryngeal squamous-cell
carcinoma – Surgery : 5-year survival rate was 81% for
patients with EGFR non-expressing tumors, compared with
25% for patients with EGFR-expressing tumors (P < 0.0001)

Survival rate according to EGFR status in 140 primary laryngeal cancer patients:
overall survival (37 patients had died), relapse-free survival (50 patients had local
recurrence).

2000, Head & Neck Ca Treated with Radiation Thepay : Correlation
between EGFR expression and OS (A), DFS (B), LR relapse (C), and
distant metastasis (D

• intense research done in the past 3 decade, has
initiated a new era of cancer treatment, that of
molecular therapeutics.
• Today, EGFR is a prime target for new anticancer
therapy, with a broad range of inhibitors currently
under investigation
• Note:
– novel biologial drugs developed sofar are not curative
themselves.
– Compared to other oncotherapeutics
(Chemotherpay/Surgery), molecular targeting approaches
are appearing to be particularly promising when integrated
with Radiation Therapy / Radiotherapy

Recent Developments &
Clinical Outcomes in use of
Nimothuzumab for SCCHN
More than 20 anti-EGFR agents are in
development

h-R3 mAb/Nimotuzumab/Biomab
• humanized monoclonal Antibody (mAb)
against the EGF-R extracellular ligand binding
domain
• Ig G subtype 1, similar to C225 (Cetuximab)
• in order to decrease immuno-reactivity and
HAMA response the mAb is Genetically
engineered
– Human immunoglobulin framework
– cloning hyper variable region of m-R3 (murine Ab,
ior egf/r3), CDR grafting

Invitro Studies - Nimotuzumab
• Nimotuzumab
– A. Enhances the Radiosensitivity of Cancer
Cells In Vitro by Inhibiting Radiation-Induced
DNA Damage Repair.(SLD & PLD)
– B. Induce Apoptosis
– C. auguments the effect of Chemotherapy

A. Effect of varying doses of radiation on DNA damage repair
related proteins in A549 cells pretreated with nimotuzumab.

B. Apoptosis of A549 cells and MCF-7 cells
induced by radiation and nimotuzumab.

Dose-survival curves derived from clonogenic survival assay and
the comparisons of plating efficiency.

C. Yanhong Yang et al A549 human lung adenocarcinoma
epithelial cell line was inhibited cell growth was inhibited A549
cells pretreated with nimotuzumab for 24 h prior to cisplatin
treatment > exhibited a higher inhibitory rate compared with
cells treated with cisplatin alone (P<0.05).

Human Studies: Clinical
Appplication

Phase I & II: Cuba
• Dose of Nimotuzumab 200mg weekly
• Tolerance – no HAMA reaction, no anaphylaxis
• Isotope tag studies - Targeted delivery
• Can be used with Radiotherapy (RT) – safely and
beneficial effect seen - when combined

Early & mid 2000
• Advanced inoperable Head & neck Cancer
– SC, Stage III or IVA (T1-T4a/ N0-N2)
• Radical RT with Radiation Sensitizers
(CDDP) - ->> Standard of Care
• There was need for knowing if RT + CT +
Biological (mAb) – were safe and effective
and improved cure rates

A Phase IIb, 4 Arm, Open-label, Randomized
Trial, to assess the Safety and Efficacy of
Concurrent Nimotuzumab (h-R3 Monoclonal
Antibody) in combination with Chemo-
Radiation therapy or with Radiotherapy alone
in patients with advanced inoperable (stage III
or IVA) Head and Neck Cancer
Study initiation date: 17/09/2004 – July 2005

Objective of the Study
• This study was designed to investigate the
safety and efficacy of concurrent h-R3mAb
(Nimotuzumab) along with Radiation therapy
or with Chemo-radiation therapy of advanced
inoperable Head & Neck Cancer

Random Allocation to:
• Group A : planned for Radical Radiation
therapy (n=46)
• Group B: planned for Chemo-Radiation
therapy (n=46)

• Computer Randomization within the
Group:
[RT alone arm] (n=23)
– Group A : v/s
[RT + h-R3 mAb] (n=23)
[RT + CT] (n=23)
– Group B : v/s
[RT+CT+ h-R3 mAb] (n=23)
 [BRM + Any RT] v/s [Any RT]
(n=46) (n=46)

Results
• Number of subjects:
– Screened: 113
– Enrolled & Randomized : 92
– Safety analysis : 92
– Efficacy analysis : 76

Efficacy – Response assessment
6mths after end of RT
RT arm Chemo radiation arm
RT + CT + Nimotuzumab
RT alone
(n=19)
RT +
Nimotuzumab
(n=17)
CT +RT
(n=20)
CT + RT +
Nimotuzumab
(n=20)
CR 31.5% (6) 70.59% (12) 70% (14) 90% (18)
ITT (n=23 in
each arm)
CR rate
26% 52% 60.8% 78%
CR + PR 37% (7) 76% (13) 70% (14) 100% (20)

5 year Overall Survival rate (ITT):
• Median follow-up time - 65.7 months
– Study subjects observed for a minimum of 60 months
• CRT+Nimotuzumab - 57% (95% CI, 34.49, 76.81)
• CRT arm - 26% (95% CI, 10.23, 48.41) (p = 0.03)
• RT+Nimotuzumab - 39% (95% CI, 19.71, 61.46)
• RT arm - 26% (95% CI, 10.23, 48.41) (NS).

CRT v/s CRT+Nimo OS ITT - 60mo

Any RT with Nimotuzumab v/s
non Nimotuzuamb Group
• .n=46 in each arm
• Median 5yr overall survival
– Any RT + h-R3 arms - 49.38 months
– Any RT non h-R3 arms - 16.36 months
• (p=0.012, HR= 0.52 (95% CI, 0.30 to 0.89)
• 48% reduction in the risk of death in the subjects
in h-R3 compared to non h-R3 arms

Progression Free Survival at 60 Months
h-R3mAb v/s non h-R3mAb
Group ITT Population
Statistics h-R3 Group Non h-R3 Group p-Value
N 46 46
0.0286
Mean (SE) (in months) 33.71 (3.68) 20.86 (3.04)
Median (in months) 44.97 12.78
95% CI for Median (11.99 , NA) (6.90 , 25.00)
Hazard Ratio (Relative to
Non – nimotuzumab
Group)
0.566
Note: p-Value calculated using log-rank test to compare survival distributions of two groups.

5 yrs
Any RT+hR3
Group
Any RT
ITT: 5yr OS

Discussion : Chemo Radiation +
BRM
• H.Quon Univ
Pennsylvania ASRTO
2009
• Phase II Data : n=60
– RT – 70Gy, 35# + C
225 (Load-400mg/m2
+ weekly 250mg/m2)
– CT – CDDP –
75mg/m2
– Dec 2004-Jul 2006 ,
– 33.8 mo,
– 2yr
• OS – 66%
Median OS –
34.2 mo
• PFS – 44%
 Our Study
ASTRO 2009
 Phase IIb, n=23
 CRT+Nimotuzumab
 RT – 66Gy, 333# +
weekly 200mg)
 CT – CDDP – 50mg
 Sept 2004-Ju2005 ,
n=23
 30 mo
 2 ½ yr
 OS – 69.5%%
Median OS – not
reached
 PFS – 56.5%
 5yrs
 OS - 57%
 PFS- 47.83%
 Pfister et al (2006)
 Phase II, n = 20
 RT – 70Gy CB
 C225 400 mg m-
2 LD +
250 mg m-2
weekly
 Cisplatin
100 mg m-2
w1+4
 3yrs
 OS (3y)
76%
 PFS (3y)
56%

SCCHN – Comparison of Overall Survival
69.5% (hR3mAb)
2 ½ yrs
57% (hR3mAb)
39%
(74% Stg-IV)
26%
(100% Stg-IV)
26%
(87% Stg-IV)
OUR STUDY (hR3mAb Trial)
60mths
37-68%
23-34%
Kyle E
46%
36%
60mths
76% (C225)
(86% Stg-IV)
55% (74% Stage- IV)
45%
Bonners, C225 Phase III 25mths
37%
RTOG 99-14 n=84(76 eval) III/IV
C-Boost
31%
Univ Vienna : VCHART
41%
24%
Univ Vienna :
40%
25%
GORTEC 94-01
38%
20%
FNLCC-GORTEC
49%
24%
Wendt et al
* Biological
Response Modifiers
Chemoradiation
20%
Gleich L L (n=86)
RT+CT+BRM
RT+BRM*
RT+CT
RT alone
Advanced Inoperable SCCHN
(87% Stg-IV)
Pfister D (n=22)

ITT - 60mo n=23
Pfister et al
N=23
RT+CT+BRM
RT+CT+BRM
CRT+BRM

Grade - 3 Toxicity
TOXICITY
RTOG (%)
RT ALONE RT+hR3 RT+CT RT+CT
+hR3
Mucositis 59.26 55.56 29.41 55
RT Skin Reaction 6.67 - 5 -
Grade 1 -2
RT Skin reaction 65.22 73.91 86.96 86.96

Conclusion
• This study demonstrates that hR3
mAb/Nimotuzumab is safe and efficaious for
administration along with radiation therapy or with
chemo-radiation therapy
• Concurrent use of hR3 mAb as a 2nd Radiation
Sensitizer along with Chemoradiation has
enhanced long term loco-regional control &
survival.
• Even low dose CDDP seems to augment the
efficacy of Nimotuzumab

• The data generated adds to the currently available
proof to the principle that adding biological agents
(BRM) to physically targeted modality improves
long-term therapeutic outcome in advanced
inoperable SCCHN.
• hR3 mAb is a newer humanized BRM, with lower
skin and hypersensitivity toxicity and is found safe
for usage along with Chemoradiation.
• Further studies with more aggressive Radiotherapy
& Chemotherapy schedules are indicated.

Phase III
Investigator Initiated Study

A randomized phase III study of
Nimotuzumab in combination with
concurrent radiotherapy and Cisplatin
versus radiotherapy and Cisplatin alone,
in locally advanced squamous cell
carcinoma of the head and neck
7
1
Dr.Kumar Prabash, Dr Sachin Hingmire, , Vijay Patil
On behalf of Department of Medical Oncology
Head and Neck- Disease Management Group
Tata Memorial Hospital, Mumbai, India
Presented at ASCO on 3rd June 2018

Advanced Inoperable
Head & Neck Cancer
n=754
RT + CT
n=268
RT - 70 Gy/35 #/-7 weeks
CT – Weekly CDDP 30mg/m2
RT + CT +
Nimotuzumab
n=268
RT - 70 Gy/35 #/-7 weeks
CT – Weekly CDDP 30mg/m2
Nimotuzumab: 200mg/wk
Randomization

Assessed for eligibility
(n=754) Excluded (n= 218 )
¨ Not meeting inclusion criteria (n=
143 )
¨ Participating in another trial (n=
57)
¨ Declined to participate (n= 18)
¨ Other reasons (n= 0 )
Analysed for outcome measures (n=268)
Analysed for safety measures (n=267)
• Completed chemoradiation: (n=252)
• Did not complete chemoradiation (n=16)
• Did not start chemoradiation (n=1)
• Defaulted during chemoradiation (n=9)
• Disease progression during
chemoradiation (n=2)
• Therapy stopped because of toxicity
(n=2)
• Others (n=2)
Allocated to chemoradiation arm (n=268)
¨ Received cisplatin based chemoradiation (n=
266)
¨ Did not receive cisplatin based chemoradiation
(n=2 )
•Patient defaulted (n=1)
•Received carboplatin instead of cisplatin (n=1)
• Completed nimotuzumab- chemoradiation: (n=250)
• Did not complete nimotuzumab-chemoradiation
(n=18)
• Did not start nimotuzumab-chemoradiation
(n=1)
• Defaulted during nimotuzumab-chemoradiation
(n=7)
• Disease progression during chemoradiation
(n=2)
• Therapy stopped because of toxicity (n=6)
• Others (n=1)
• Neurosis-Mania (n=1)
Allocated to nimotuzumab-chemoradiation arm (n=268)
¨ Received nimotuzumab- chemoradiation (n=266 )
¨ Did not receive nimotuzumab chemoradiation (n=2 )
•Patient defaulted (n=1)
•Patient received NACT followed by cisplatin –radiation
alone (n=1)
Analysed for outcome measures (n=268)
Analysed for safety measures (n=267)
Allocation
Analysis
Therapy
Randomized (n= 536)
Enrollment
Consort Diagram

Results- Baseline
characteristics
7
6

Baseline characteristics
7
7
Variable Cisplatin -
Radiotherapy arm
Nimotuzumab-cisplatin -
Radiotherapy arm
P value
Median age 54.00 (26-77 years) 55.00 (20-73 years) 0.636
ECOG PS 0-1
ECOG PS 2
267 (99.6%)
1 (0.4%)
267 (99.6%)
1 (0.4%)
1
Oropharynx
Hypopharynx
Larynx
Oral cavity
135 (50.4)
47 (17.5)
83 (31)
3 (1.1)
134 (50)
62 (23.1)
72 (26.9)
0 (0)
0.119
T0-T2
T3-T4
56 (20.9%)
212 (79.1%)
41 (15.3%)
227 (84.7%)
0.113
N0-N1
N2-N3
131 (48.9%)
137 (51.1%)
122 (45.5%)
146 (54.5%)
0.488
Stage III
Stage IVA
Stage IV B
87 (32.5%)
172 (64.2%)
9 (3.4%)
80 (29.9%)
177 (66.0%)
11 (4.1%)
0.753
HPV analysis is ongoing; less than 6% of the 340 patients analyzed have HPV-positive
tumors.

Results- Treatment
Compliance
7
8

Chemotherapy compliance
1
8
Radiotherapy arm
Nimotuzumab-
cisplatin -
Radiotherapy arm
P value
Median number of
cisplatin cycles
7 (IQR 7-7) 7 (IQR 7-7) 0.389
Proportion of patients
receiving >7 cycles
cisplatin
219 (81.7%) 226 (84.3%) 0.421
requiring cisplatin dose
reduction
21 (7.8) 26 (9.7) 0.445
with
> 200 mg/m2 of cisplatin
211 (78.7%) 208 (77.6%) 0.754
Median number of
Nimotuzumab cycles
Not applicable 7 (IQR 7-7) -
receiving >7 cycles
Nimotuzumab
Not applicable 226 (84.3%) -

Radiation compliance
1
9
Radiotherapy arm
Nimotuzumab-
cisplatin -
Radiotherapy arm
P value
Median radiotherapy
dose
70 Gy (IQR 70-70Gy) 70 Gy (IQR 70-70
Gy)
0.713
100 % of planned
radiotherapy dose
completed
252 (94.0%) 250 (93.3%) 0.723
Conventional
IMRT
Not received
229 (85.4%)
38 (14.2%)
1 (0.4%)
238 (88.8%)
29 (10.8%)
1 (0.4%)
0.240
Time for completion of
radiation
51 (IQR 49-54) 51 (IQR 49-54) 0.630
Radiation completion
time > 63 days
7 (2.6%) 5 (1.9%) 0.559
with gaps greater than 2
days
72 (26.9%) 80 (29.9%) 0.443
Median cumulative
duration of gap
5 (IQR 3-9) 5 (IQR 3-8) 0.824

OS
2
4
• The median overall survival:
NCRT 43.4 months v/s
CRT 31.3 months (P
=0.220).
• The hazard ratio in favor of
NCRT arm was 0.851,
suggesting a 15% reduction
in the risk of death ( 95% CI
0.65-1.10) but was not
statistically significant.

DFS
2
2
• Addition of Nimotuzumab
decreased the hazard of
disease recurrence by
25% (Hazard ratio 0.75;
95%CI 0.57-0.97).
• The 2 year DFS :
NCRT 59.2% v/s CRT
49.0%

PFS
2
1
• PFS was significantly
longer in the patients
treated in the NCRT arm
(Hazard ratio, 0.74; 95%
CI 0.56-0.95)
• The 2 year PFS : NCRT
58.9% v/s CRT 49.5%

LRC
2
3
• The increment in PFS
seen with addition of
Nimotuzumab, is
contributed largely due to
a decrease in
locoregional failures .
• The 2 year locoregional
control was significantly
better in the NCRT arm
• NCRT 65.1% v/s
CRT56.5% .

Adverse events
8
7
Radiotherapy arm
Nimotuzumab-cisplatin -
Radiotherapy arm
P value
All Grades Grade 3-5 All Grades Grade 3-5 Grade 3-5
Mucositis 252 (96.9%) 145 (55.8%) 256 (97.0%) 176 (66.7%) 0.010
Radiation dermatitis 238 (91.5%) 76 (29.2%) 234 (88.6%) 73 (27.7%) 0.689
Odynophagia 252 (96.9%) 98 (37.7%) 257 (97.3%) 109 (41.3%) 0.400
Dysphagia 226 (86.9%) 75 (28.8%) 229 (86.7%) 80 (30.3%) 0.715
Nausea 124 (47.7%) 2(0.8%) 127 (48.1%) 4 (1.5%) 0.422
Vomiting 78 (30.0%) 4(1.5%) 77 (29.2%) 3(1.1%) 0.689
Weight loss 133 (51.2%) 2 (0.8%) 160 (60.6%) 3 (1.1%) 0.666
Maculopapular rash 6 (2.3%) - 19 (17.2%) - -
Increased serum
creatinine
26 (9.9%) - 24 (9.0%) 2 (0.8%) 0.160
Increased SGOT 48 (18.3%) 3(1.1%) 41(15.4%) 2 (0.8%) 0.641
Increased SGPT 75 (28.6%) 3(1.1%) 85 (32.0%) 4 (1.5%) 0.719
Hyponatremia 236 (90.1%) 82 (31.3%) 237 (89.1%) 89 (33.5%) 0.596
Hypokalemia 10 (3.8%) 3 (1.1%) 16 (6.0%) 2 (0.8%) 0.641
Hypomagnesemia 79 (30.2%) - 89 (33.5%) - -
Hospitalization because of toxicities was higher in NCRT arm [58 patients (21.6%) versus 41
patients (15.3%); P=0.058]

Cetuximab + CRT could not improve
the outcomes over CRT: RTOG 0522
Locally
advanced head
and neck cancer
patients
Stage III, IV ; M0
N = 940
Cetuximab +
Cisplatin +
Radiotherapy
Cisplatin +
Radiotherapy

Difference with previous
study
2
9
Factors RTOG 0522-
Cetuximab
arm
Our study-
Nimotuzumab
arm
Patient characteristics
HPV positivity 73.2% <10 % HPV
positive
Hypo pharynx 6.4% 23.1%
T3-T4 60% 84.7%
Treatment
Radiation
interruptions (any
cause)
51.8% 34.3%
Cisplatin 160 or
above*
88.5% 92.9%
Ang et al. J Clin Oncol. 2014 Sep
20;32(27):2940-50.
*-As data in RTOG 0522 available for 160mg/m2

• Addition of Nimotuzumab to CDDP + RT
improves PFS, time to local control and
disease free survival
9
2

Acknowledgements
• To all our patients and relatives who
participated in the clinical studies.
• Biocon

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