Pharmacogenetic, the Future of

Precision and Personalized Medicine:

Head & Neck Cancer as a focus
Dr. dr. Andhika Rachman, Sp.PD-KHOM
“You can’t cure what you don’t understand”

“Every person is unique, so is every cancer”

“Dealing with cancer is not just dealing with the cancer. It’s treating the whole person.”
Background
Helping clinicians:
Improved understanding of
• making correct diagnosis
molecular mechanism and
• predicting outcomes
cellular interaction
• optimally selecting patients
for therapies
New insights about disease-
Personalized and precision
initiating exogenous factors
medicine – rapidly growing
and endogenous elicitors of
new disciplines
disease development
Facilitating the development of:
- Therapeutic approaches
Better understanding of drug
- New drugs
actions and interactions that
- New prognostic scoring
underlie efficacy and adverse
models
events
Precision Medicine: In Drug Development
Critical Question for the Next Ten Years:
How to Use the Genome to Improve Human Health?
Sequencing Cost per Genome,
$100,000,000 2001-2020
$10,000,000 Current Progress
$1,000,000
$100,000
$10,000
$1000 Average Progress
$100
$10
$1 Rapid Progress
$.10
$.01
$0

$1,000 barrier for whole genome

broke in September 2015
by Veritas Genetics
Technology Advances:
Sequencing to Clinical Reports in 1-2 Weeks
Head and Neck Squamous cell carcinoma (HNSCC) is associated
with elevated mutational load but lacks specific genetic
mutations

Exposure to carcinogens including tobacco & alcohol are the

most dominant etiologic factors of HNSCC, while EBV& HPV are
associated with nasopharyngeal and oropharyngeal carcinoma
• The treatment of patients with head and neck cancer is complex and
has undergone considerable transformation in the last decade
• Surgery including open & minimally invasive procedures is considered
the soc for the majority of oral cavity & early larynx cancers
• Radiation therapy or concurrent chemoradiation are used for the
other head and neck cancers.
• These modalities include immunotherapy, targeted therapy (small
molecule inhibitors or antibodies), or combined modality treatments.
Emerging evidence supports a vital role of the immune system in
eradicating HNSCC
• The ultimate goals of treatment of patients with HNSCC are
1) to eradicate the tumor while minimizing adverse effects of
treatment,
2) to preserve quality of life and,
3) to prevent second primary cancers
• The determinants that influence the modality of treatment can be
divided into several factors:
1) tumor factors,
2) patient factors,
3) patient preference.
• Tumor factors can be divided into
histological and molecular features.
• Histological features include:
tumor type, stage, tumor cell differentiation, depth of invasion,
extracapsular spread, the presence of regional or distant metastases
and neural invasion
• Molecular features in head and neck cancer include
1. HPV status,
2. expression of programmed death ligands (i.e. PD-L1 and PD-L2),
3. mutational load & involvement of specific genetic mutations,
4. deletions or genomic amplifications
Nasopharyngeal Carcinoma: Screening and Diagnosis
• The term “precision medicine” & “personalized medicine” are often
used incorrectly and interchangeably.
• Other commonly used terms: “P4 medicine”, “stratified medicine”,
“genomic medicine”, “evidence-based medicine” – all referring to
disease-specific and patient-related approaches that are based on
improved knowledge of the clinical impact of large-scale genetic,
molecular, epigenetic, metabolic and functional profiles to determine
diagnosis, prognosis and outcome.
 Definition
Precision Medicine
Concept or approach in preclinical, translational or
applied medicine that takes 1 or more defined
molecules, cells and/or interactions between
(networks of) molecules and cells into account with
the aim to improve diagnostics, prognostication,
prevention and/or therapy
Personalized medicine
Concept or approach in preclinical, translational
or applied medicine that takes 1 or more defined
molecules, cells and/or interactions between
(networks of) molecules and cells as well as
several (or all) relevant patient-related factors
into account with the aim to apply optimal
diagnostic procedures, algorithms, and
prognostications tool and to select the optimal
preventive strategy and/or treatment approach
to the individual patient at the right time

Evidence-based medicine
Concept or approach in in hematology that is based on generally accepted, published evidence with
recognition of the evidence-source, evidence level, applicability, and the consequences and risk profiles in
individual patients.
Definition (cont.)
• Precision medicine needs to be complemented by a personalized approach in order to manage all
subgroups of patients in an optimal manner.
• Precision medicine is more closely related to disease-specific feature and molecular or cellular
interactions and explores how these feature impact the patient’s diagnosis, prognosis and
outcome in general.
• In drug development, precision medicine focuses more on drug-target interactions and
drug efficacy in cells and patients.
• Personalized medicine relates to multiple aspects of the individual patient in a comprehensive
way, including age, gender, genetic features, epigenetic variables and comorbidities, also mental,
social and psychological aspects.
• In drug development, personalized medicine has to consider multiple patient-related
aspects (mentioned above), drug-drug interactions → in order to develop risk scores,
disease-preventing strategies, or early intervention
 “Personalised cancer management – which means giving patients the
optimum treatment according to their individual circumstances (including
their genetics) and the molecular characteristics of their tumors – was a key
theme of ESMO in 2013”

“personalized medicine is operating beyond the scope of precision medicine, as

it also takes into account multiple patient-related variables, with the aim of
selecting patient subsets and individual patients for “optimal” personalized
(individualized) intervention by balancing between efficacy, side effects
(potential), quality of life, and the patient’s expectations”
Goals and Endpoints
Precision medicine Personalized medicine
1. Early recognition of premalignant states 1. Early recognition of individual’s risk
2. Age/sex/comorbidity-based selection of optimal
2. Prevention of cancer development prophylactic approaches to prevent cancer
(prophylactic approaches)
3. Defining individual’s risk of malignant transformation
3. Establishing correct diagnosis in all subsets using prognostic scores
of patients 4. Define optimal monitoring strategies
4. Establishing prognostic profile (prognostic 5. Establish correct diagnosis in individual patients
scores) (considering disease-related and patient-related
variables)
5. Establishing treatment plans based on 6. Establish prognosis of individual’s survival, DFS,
molecular and cell-based information and expected QoL, treatment-related death and
biomarker (Including genetic, somatic, epigenetic, morbidities.
pathway-related, metabolic, and/or proteome-related
patterns and interactions, including pre-interventional 7. Select optimal therapeutic approaches and timing of
in vitro drug testing) individual patients based on disease-related and
patient-related aspects
6. Defining optimal tools and parameters to 8. Defining optimal ways to measure treatment response
monitor long-term outcomes and monitor long-term outcomes in individual patients
Advances of precision and personalized
medicine (PPM) in solid tumors

• Next-generation sequencing (NGS)

• Whole-exome sequencing (WES) / whole
transcriptome sequencing (WTS)
• Tumor microenvironment (TME)
researches
• Mutation-guided treatment – immune
checkpoint inhibitor (ICI) therapy
Immunotherapy for head and neck cancer patients: shifting the balance

Turksma et al, Immunotherapy. 2013

Jan;5(1):49-61. Immunotherapy for head and
neck cancer patients: shifting the balance.

CTLA-4
PD-1
PD-L1
…others
Ongoing clinical trials of PD-1 inhibitors for NPC
 Selected Ongoing Phase II/III Immunotherapy Trials in HNSCC
Trial Treatment Population N Intervention
Locally advanced HNSCC (HPV+ for select 780
KEYNOTE-412[1] Pembrolizumab + cis + RT vs placebo + cis + RT
stages/primary sites)
Avelumab + cis + RT vs cis + RT
REACH[2] Stage III/IVb HNSCC 707
Avelumab + cetuximab + RT vs cis + RT
Neoadjuvant nivolumab, surgery, and adj CRT +
IMSTAR-HN[3] Stage III/IV p16- OPC, L, HP, OC 276
adj nivolumab ± ipi vs SoC surgery + CRT
Resectable stage III/IVa L, HP, OC, p16-OPC
KEYNOTE-689[4] 704* Pembrolizumab before surgery/with adj CRT vs surgery
Stage III p16+ OPC
Locally advanced HNSCC treated with
IMvoke010[5] 400* Atezolizumab vs placebo after CRT
curative-intent therapy
Durvalumab + RT vs cetuximab + RT in cis-ineligible
HN004[6] Cisplatin-unfit locally advanced HNSCC 474*
patients
KEYCHAIN[7] Locally advanced p16+ OPC, L, OC 114* Cis + RT vs pembrolizumab + RT
EA3161[8] High-risk HPV-associated disease 744* Maint. nivolumab or observation after 1 yr of cis + RT
*Recruiting patients as of April 2021.

1. NCT03040999. 2. NCT02999087. 3. NCT03700905. 4. NCT03765918.

5. NCT03452137. 6. NCT03258554. 7. NCT03383094. 8. NCT03811015. Slide credit: clinicaloptions.com
Clinical trials of molecular-targeted therapies for NPC
 Biomarkers and Targeted Drugs in Head and Neck
Cancer
Biomarker Drug Head and Neck Cancer
PD-L1 Pembrolizumab First line in R/M HNSCC as monotherapy (CPS ≥ 1) and
in combination with chemotherapy
PD-L1 Nivolumab, pembrolizumab Monotherapy in R/M HNSCC with progression on/after
platinum-based chemotherapy
MSI-H Pembrolizumab Monotherapy in R/M HNSCC with progression on/after
prior treatment
TMB-H Pembrolizumab Monotherapy in head and neck cancers with
progression on/after prior treatment
AR + Leuprolide*, bicalutamide* Salivary gland tumors
NTRK gene fusion Larotrectinib, entrectinib Salivary gland tumors
HER2+ Trastuzumab ± pertuzumab or Salivary gland tumors
docetaxel*, TDM-1*
*Guideline-recommended off-label use under certain circumstances.
Pembrolizumab PI. Nivolumab PI. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Head and Neck Cancers. Version 1.2021.
11/08/2020. Available at: www.NCCN.org. Accessed March 8, 2021. Slide credit: clinicaloptions.com
 Immune Checkpoint Inhibitors in Head and Neck Cancer

Drug Approved Indication Target

Nivolumab[1] Second line in R/M HNSCC with progression PD-1
on/after platinum-based chemotherapy
Pembrolizumab[2] Second line in R/M HNSCC with progression PD-1
on/after platinum-containing chemotherapy
First line in R/M HNSCC as a single agent in patients with
PD-L1–expressing tumors (CPS ≥ 1) and in combination
with platinum + 5-FU for all patients
Atezolizumab[3] Not approved in HNSCC PD-L1
Durvalumab[4] Not approved in HNSCC PD-L1
Avelumab[5] Not approved in HNSCC PD-L1

1.. Nivolumab PI. 2. Pembrolizumab PI. 3. Atezolizumab PI. 4. Durvalumab PI. 5. Avelumab PI. Slide credit: clinicaloptions.com
 Phase III CheckMate 141: Nivolumab in
Recurrent/Metastatic HNSCC After Platinum Therapy
Stratified by prior
cetuximab
Patients with recurrent or metastatic
Nivolumab 3 mg/kg IV Q2W
HNSCC (oral cavity, pharynx, or larynx),
(n = 240)
progression or recurrence in ≤ 6 mos
after last dose of platinum-based
chemotherapy, p16 documented for Randomized 2:1
determining HPV status (oropharyngeal
cancer only), any prior tx experience, Investigator’s Choice of methotrexate 40 mg/m2/wk IV,
any PD-L1 status docetaxel 30 mg/m2/wk IV, or
(N = 361) cetuximab 400 mg/m2 IV once followed by 250 mg/m2/wk
(n = 121)

▪ Primary endpoint: OS
▪ Other endpoints: PFS, ORR, DoR, safety, biomarkers, QoL
Ferris. NEJM. 2016;375:1856. Slide credit: clinicaloptions.com
Questions and limitations
• Is it applicable?
• Will it be affordable? – for example CAR-T cell technology
• Are new diagnostic tools, interpretations and emerging drugs
validated rigorously?

• Not all clinical trials are designed and resourced to evaluate all
precision medicine aspects.
Strategies
• Global data exchange – global validation of new tools
• Employ large pre-existing database
• Establish global competence networks (focus groups)
• Establish reference centers
• Establish centralized first-class diagnostic labs
• Implement uniform evidence based precision and personalized
medicine in local comprehensive cancer centers and tumor boards
• Global data registries, global database
• Establish robust biobanking systems and a molecular tumour board
• Telemedicine