Ghassan Abou-Alfa, MD, MBA, Anthony El-Khoueiry, MD, and Richard S. Finn, MD, prepared useful practice aids pertaining to HCC management for this CME activity titled "New Options, Emerging Combinations in Advanced Hepatocellular Carcinoma: Are Management Approaches Poised For Transformation?" For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2okTvdb. CME credit will be available until March 7, 2019.

1. Selected Current and Ongoing
Clinical Trials in HCC1,a
PRACTICE AID
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
Access the activity,“New Options, Emerging Combinations in Advanced
Hepatocellular Carcinoma: Are Management Approaches Poised for
Transformation?”at www.peerview.com/PVM40.
LocallyAdvancedor
PotentiallyResectableDisease
Phase 3 Phase 2 Phase 1
TACE vs SBRT in patients
with residual or recurrent
disease after TACE
(NCT02762266)
CA209-956: Nivolumab +/-
ipilimumab as neoadjuvant
therapy (NCT03222076)
Pembrolizumab + Y90 in
locally advanced HCC
(NCT03099564)
CA209-678: Y90 +
nivolumab in Asian
patients (NCT03033446)
AURORA: Neoadjuvant
pembrolizumab
(NCT03337841)
RFA with neoadjuvant
cabozantinib/nivolumab in
locally advanced HCC
(NCT03299946)
First-LineTherapy
HIMALAYA: Durvalumab +/-
tremelimumab vs sorafenib
(NCT03298451)
CheckMate-040:
Nivolumab vs sorafenib,
nivolumab + ipilimumab,
nivolumab +/- ipilimumab +
cabozantinib,
nivolumab in Child–Pugh B
(NCT01658878)
Lenvatinib +
pembrolizumab
(NCT03006926)
TACE + sorafenib
(NCT02908165)
CheckMate-459:
Nivolumab vs sorafenib
(NCT02576509)
PHOCUS: Pexa-Vec +
sorafenib vs sorafenib
(NCT02562755)
OPTIMA: Liposomal
doxorubicin + RFA
vs placebo + RFA
(NCT02112656)
STOP-HCC: Y90 glass
microspheres + sorafenib
vs sorafenib
(NCT01556490)
Sorafenib + SBRT vs
sorafenib (NCT01730937)
Sorafenib +
pembrolizumab
(NCT03211416)
Pexa-Vec + nivolumab
(NCT03071094)
Nivolumab + drug-eluting
bead–TACE (NCT03143270)
Sorafenib + napabucasin
or amcasertib vs sorafenib
(NCT02279719)
Regorafenib +
pembrolizumab
(NCT03347292)
Currently recruiting Not yet recruiting Active, but not recruiting

2. Access the activity,“New Options, Emerging Combinations in Advanced
Hepatocellular Carcinoma: Are Management Approaches Poised for
Transformation?”at www.peerview.com/PVM40.
Selected Current and Ongoing
Clinical Trials in HCC1,a
PRACTICE AID
AFP: alpha-fetoprotein; BSC: best supportive care; HCC: hepatocellular carcinoma; HSP90: heat-shock protein 90; IDO: indoleamine 2,3-dioxygenase; RFA: radiofrequency ablation;
SBRT: stereotactic body radiation therapy; TACE: transarterial chemoembolization; Y90: yttrium 90.
1. www.clinicaltrials.gov. Accessed December 21, 2017.
a
Recruitment status as of December 12, 2017.
Second-LineTherapyorBeyond
Phase 3 Phase 2 Phase 1
KEYNOTE-394:
Pembrolizumab vs placebo
in Asian patients
(NCT03062358)
TATE-PD-1: Transarterial
tirapazamine embolization
+ PD-1 inhibitor
(NCT03259867)
SBRT followed by
nivolumab +/- ipilimumab
in unresectable HCC
(NCT03203304)
Tumor infiltrating
lymphocytes + pembrolizumab
(NCT01174121)
Pembrolizumab monotherapy
(NCT02658019)
Durvalumab +
tremelimumab with TACE,
RFA, or cryotherapy
(NCT02821754)
Currently recruiting Not yet recruiting Active, but not recruiting
Durvalumab, tremelimumab,
or in combination
(NCT02519348)
Y90 glass microspheres +
nivolumab in patients
with no prior therapies
(NCT02837029)
KEYNOTE-037:
Pembrolizumab +
epacadostat [IDO inhibitor]
(NCT02178722)
Pembrolizumab +
XL888 [HSP90 inhibitor]
(NCT03095781)
REACH-2: Ramucirumab
vs placebo in patients with
elevated AFP
(NCT02435433)
KEYNOTE-240:
Pembrolizumab vs BSC
(NCT02702401)

3. Immuno-Oncology in the Clinic:
General Guidelines for Recognizing
and Managing Immune-Mediated
Adverse Reactions1-4
PRACTICE AID
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
Access the activity,“New Options, Emerging Combinations in Advanced
Hepatocellular Carcinoma: Are Management Approaches Poised for
Transformation?”at www.peerview.com/PVM40.
How Do Checkpoint Inhibitors Work?
Blocking negative regulatory signals activates the immune system
Immune-Mediated Adverse Reactions
More Common
Pulmonary (pneumonitis)
Dermatologic (rash, pruritus, blisters, ulcers, vitiligo)
Gastrointestinal (diarrhea, enterocolitis, transaminitis, hepatitis, pancreatitis)
Endocrine (thyroiditis, hypophysitis, adrenal insufficiency)
Less Common
Hematologic, cardiovascular, ocular, renal
Lymphoid Tissue
Anti–CTLA-4
antibodies
Cytotoxic
T cell
Dendritic
cell CD28
B7
B7
CTLA-4
Tumor Microenvironment
Anti–PD-L1
antibodies
Anti–PD-1
antibodies
PD-L1
Tumor
PD-1

4. Access the activity,“New Options, Emerging Combinations in Advanced
Hepatocellular Carcinoma: Are Management Approaches Poised for
Transformation?”at www.peerview.com/PVM40.
Immuno-Oncology in the Clinic:
General Guidelines for Recognizing
and Managing Immune-Mediated
Adverse Reactions1-4
PRACTICE AID
CD: cluster of differentiation; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; IMARs: immune-mediated adverse reactions; PD-1: programmed cell-death protein 1;
PD-L1: programmed death-ligand 1.
1. Postow MA et al. http://www.uptodate.com/contents/toxicities-associated-with-checkpoint-inhibitor-immunotherapy. Accessed December 21, 2017.
2. Weber JS et al. J Clin Oncol. 2015;33:2092-2099.
3. Weber JS et al. Oncologist. 2016;21:1230-1240.
4. Puzanov I et al. J Immunother Cancer. 2017;5:95.
IMARs: General Guidance for Diagnosis and Treatment
IMARs: General Management Principles
IMARs often diagnosed by exclusion; other causes should be ruled out,
including AEs of other therapies used, but immunotherapy-related
toxicity should always be included in the differential
Management may require:
• Corticosteroid or other
immunosuppressive
treatment
• Interruption or
discontinuation of therapy
If appropriate, immunosuppressive
treatment is used, and patients
generally recover from IMARs
Use of immunosuppressive
therapy to manage IMARs
does not impact response
to immunotherapy
Keys to Success
Early recognition, evaluation, and
treatment of IMARs plus patient education
are essential for best outcomes
If no improvement or progression, additional immunosuppressant treatment
may be needed; if >4 wk of immunosuppressants needed, administer
antimicrobial/antifungal prophylaxis to prevent opportunistic infections
q Continue immunotherapy
(or consider temporary delay)
q Symptomatic therapy
q Withhold immunotherapy
q Corticosteroids, if symptoms
do not resolve in 1 week (prednisone
0.5-1 mg/kg/d or equivalent)
q Taper corticosteroids over ≥1 month
to reduce recurrence
q Re-dose if toxicity resolves to
grade ≤1
q Discontinue immunotherapy
q Hospitalization and multidisciplinary
evaluation
q High-dose corticosteroids (prednisone
1-2 mg/kg/d or equivalent)
q Taper high-dose corticosteroids
over ≥1 month until toxicity resolves
to grade ≤1
Grade 1
(Minimal or no symptoms;
diagnostic changes only)
Grade 2
(Mild to moderate symptoms)
Grade 3/4
(Severe or life-threatening
symptoms)

5. A Guide to Management
of Adverse Events Associated
With Tyrosine Kinase Inhibitors
PRACTICE AID
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
Access the activity,“New Options, Emerging Combinations in Advanced
Hepatocellular Carcinoma: Are Management Approaches Poised for
Transformation?”at www.peerview.com/PVM40.
Diarrhea1,2
HFSR (alternative names: hand–foot syndrome, palmar–plantar erythrodysesthesia,
acral erythema) is an acute-onset symptom complex
Incidence of HFSR (all grades) with sorafenib in patients with hepatocellular carcinoma was
21% in the SHARP trial3
; incidence of HFSR with regorafenib was 12.6% in the RESORCE trial4
Appropriate methods of prophylaxis and management of HFSR are necessary to ensure proper
administration of the drugs and to improve the health-related QOL of patients
Symptoms
• Frequent, watery, bloody, or
nocturnal stools
General management
• Monitor bowel habits and report any
increase in activity above normal
• Avoid spicy or fatty foods; plain, simple
foods are best
• Avoid fruit and caffeine
• Maintain adequate fluid intake to
avoid dehydration
• Monitor/manage electrolytes
Medical interventions
• Loperamide is usually effective
• If loperamide is ineffective, consider
diphenoxylate/atropine
Patient education
• Direct patient to notify medical team of
diarrhea or abdominal distress
Maintain activity
• Stay as active as possible, because that
will help regulate sleep
Establish routine
• Maintain normal work and social schedule
Take breaks
• Take breaks as needed
Always communicate
• Tell your medical team if activity is
intolerable or fatigue worsens
Hand–Foot Skin Reaction
Fatigue1,2

6. Access the activity,“New Options, Emerging Combinations in Advanced
Hepatocellular Carcinoma: Are Management Approaches Poised for
Transformation?”at www.peerview.com/PVM40.
A Guide to Management
of Adverse Events Associated
With Tyrosine Kinase Inhibitors
PRACTICE AID
HFSR: hand–foot skin reaction; QOL: quality of life.
Photos provided courtesy of Elizabeth Manchen, RN, MS, OCN.
1. Brose MS et al. Semin Oncol. 2014;41:S1-S16. 2. Walko CM et al. Semin Oncol. 2014;41:S17-S28. 3. Llovet JM et al. N Engl J Med. 2008;24:359-390. 4. Bruix J et al. Lancet. 2017;389:56-66.
5. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_v40. Accessed December 21, 2017. 6. Lacouture ME et al. Oncologist. 2008;13:1001-1011.
7. McLellannB et al. Ann Oncol. 2015;26:2017-2026.
Grade 1
General tips:
• Educate patients about HFSR, engage them in the monitoring and treatment plan
• Encourage patients to report possible symptoms early, to take digital photos of
their hands and feet, and to email them to the treatment team regularly to
monitor for development and progression of HFSR
Hand–Foot Skin Reaction (Cont'd)4-7
Grade 2
Grade 3
Symptoms
Tingling, numbness, accompanied
by minimal skin changes or
dermatitis, such as erythema,
edema, or hyperkeratosis of the
hands and/or feet without pain;
does not disrupt normal activities
Symptoms
Skin changes of the hands and/or
feet may include peeling, blisters,
bleeding, edema, or hyperkeratosis
with pain; discomfort affecting the
patient's normal activities
Symptoms
Severe skin changes of the hands
and/or feet may include peeling,
blisters, bleeding, edema, or
hyperkeratosis with pain and/or
severe discomfort that causes
the patient to be unable to work
or perform activities of daily living
Management
Avoid hot water
Wear thick socks
Wear cotton gloves/socks at night
Use moisturizing creams
Use keratolytics (urea 20% to 40%;
salicylic acid 5% to 10%)
No dose reduction needed
Follow up within 2 weeks
Management
Employ grade 1 strategies
Consider clobetasol 0.05% ointment
twice daily for erythematous areas
Use topical analgesic
Use systemic analgesics if no
contraindications (bleeding or
kidney dysfunction)
Consider 50% dose reduction for
7-28 days until HFSR is grade 1/0
→ full dose
Management
Employ grade 1/2 strategies
Treatment interruption for ≥7 days until
HFSR is grade 1/0 → 50% of full dose
→ escalation if possible
Resume treatment at lower dose as
recommended in package insert
Dose may be escalated if reaction
does not reoccur