Teaming Up to Improve Outcomes in Advanced Hepatocellular Carcinoma: A Tumor Board Evaluating the Potential of Immunotherapy and Novel Targeted Approaches
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Ghassan Abou-Alfa, MD, MBA, Anthony El-Khoueiry, MD, and R. Kate Kelley, MD, prepared useful Practice Aids pertaining to liver cancer for this CME/CE activity titled "Teaming Up to Improve Outcomes in Advanced Hepatocellular Carcinoma: A Tumor Board Evaluating the Potential of Immunotherapy and Novel Targeted Approaches." For the full presentation, monograph, complete CME/CE information, and to apply for credit, please visit us at http://bit.ly/2FG0J75. CME/CE credit will be available until March 25, 2019.
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Teaming Up to Improve Outcomes in Advanced Hepatocellular Carcinoma: A Tumor Board Evaluating the Potential of Immunotherapy and Novel Targeted Approaches
- 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. Phase 3 Phase 2 Phase 1/2 Currently recruiting Not yet recruiting Active, but not recruiting Systemic Therapies and Combinations NCT03298451, HIMALAYA Durvalumab +/- tremelimumab vs sorafenib First line NCT01761266, REFLECT Lenvatinib vs sorafenib First line NCT02435433, REACH-2 Ramucirumab vs placebo Previously treated, elevated AFP NCT03062358, KEYNOTE-394 Pembrolizumab vs placebo Previously treated Asian population NCT02702401, KEYNOTE-240 Pembrolizumab vs placebo Previously treated patients NCT02576509, CheckMate-459 Nivolumab vs sorafenib First line NCT01658878, CheckMate-040 Nivolumab vs sorafenib, Nivolumab + ipilimumab, Nivolumab +/- ipilimumab + cabozantinib, Nivolumab in Child–Pugh B First line NCT03222076, CA209-956 Nivolumab +/- ipilimumab Neoadjuvant NCT02658019 Pembrolizumab Prior systemic therapy NCT01174121 Tumor infiltrating lymphocytes (TIL) + pembrolizumab Prior sorafenib NCT03337841, AURORA Pembrolizumab Neoadjuvant NCT02519348 Durvalumab, tremelimumab, or in combination Previously treated patients NCT03006926 Lenvatinib + pembrolizumab First line (expansion phase) NCT03211416 Sorafenib + pembrolizumab First line NCT03071094 Pexa-Vec + nivolumab First line NCT02178722, KEYNOTE-037 Pembrolizumab + epacadostat (IDO inhibitor) Previously treated patients NCT03095781 Pembrolizumab + XL888 (HSP90 inhibitor) Previously treated patients NCT02279719 Sorafenib + napabucasin or amcasetrib vs sorafenib First line NCT01761266, REFLECT Lenvatinib vs sorafenib First line NCT01761266, REFLECT Lenvatinib vs sorafenib First line NCT03434379, IMbrave150 Atezolizumab + bevacizumab vs sorafenib First line NCT01908426, CELESTIAL Cabozantinib vs placebo Prior sorafenib NCT01761266, REFLECT Lenvatinib vs sorafenib First line NCT01774344, RESORCE Regorafenib vs placebo Prior sorafenib NCT03439891 Sorafenib + nivolumab First line Access the activity,“Teaming Up to Improve Outcomes in Advanced Hepatocellular Carcinoma: A Tumor Board Evaluating the Potential of Immunotherapy and Novel Targeted Approaches”at www.peerview.com/EMA40.
- 2. Access the activity,“Teaming Up to Improve Outcomes in Advanced Hepatocellular Carcinoma: A Tumor Board Evaluating the Potential of Immunotherapy and Novel Targeted Approaches”at www.peerview.com/EMA40. Selected Current and Ongoing Clinical Trials in HCC1,a PRACTICE AID AFP: alpha-fetoprotein; deb-TACE: drug-eluting bead transarterial chemoembolization; HCC: hepatocellular carcinoma; HSP90: heat-shock protein 90; IDO: indoleamine 2,3-dioxygenase; PD-1: programmed cell death protein 1; RFA: radiofrequency ablation; SBRT: stereotactic body radiation therapy; TACE: transarterial chemoembolization; Y90: yttrium 90. 1. www.clinicaltrials.gov. Accessed March 16, 2018. a Recruitment status as of March 16, 2018. Please note that the status of a trial may have changed after March 16, 2018. Please refer to www.clinicaltrials.gov for the most recent information. Phase 3 Phase 2 Phase 1/2 Currently recruiting Not yet recruiting Active, but not recruiting NCT02112656, OPTIMA Liposomal doxorubicin + RFA vs placebo + RFA First line NCT01556490, STOP-HCC Y90 glass microspheres + sorafenib vs sorafenib First line NCT02762266 TACE vs SBRT Prior TACE, residual or recurrent disease NCT01730937 Sorafenib + SBRT vs sorafenib First line NCT03259867, TATE-PD1 Transarterial tirapazamine embolization + PD-1 inhibitor Previously treated patients NCT03033446, CA209-678 Y90 + nivolumab, Asian population Eligible for Y90 radioembolization NCT03203304 SBRT followed by nivolumab +/- ipilimumab First-line or prior therapy NCT02821754 Durvalumab + tremelimumab with TACE, RFA, or cryotherapy Prior therapy NCT02837029 Y90 glass microspheres + nivolumab First-line or prior therapy NCT03299946 RFA with neoadjuvant cabozantinib/nivolumab Locally advanced HCC NCT03099564 Pembrolizumab + Y90 Locally advanced HCC NCT03143270 Nivolumab + deb-TACE First line Combinations of Systemic Therapy With Locoregional Therapy NCT02562755, PHOCUS Pexa-Vec + sorafenib vs sorafenib First line
- 3. AGuidetoManagementofAdverse 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. 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%1 in the SHARP trial; incidence of HFSR with regorafenib was 12.6% in the RESORCE trial2 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 Hand–Foot Skin Reaction Grade 1a Grade 2 Grade 3 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 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 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 Access the activity,“Teaming Up to Improve Outcomes in Advanced Hepatocellular Carcinoma: A Tumor Board Evaluating the Potential of Immunotherapy and Novel Targeted Approaches”at www.peerview.com/EMA40.
- 4. Access the activity,“Teaming Up to Improve Outcomes in Advanced Hepatocellular Carcinoma: A Tumor Board Evaluating the Potential of Immunotherapy and Novel Targeted Approaches”at www.peerview.com/EMA40. AGuidetoManagementofAdverse Events Associated With Tyrosine Kinase Inhibitors PRACTICE AID a Photos provided courtesy of Elizabeth Manchen, RN, MS, OCN. 1. Llovet JM et al. N Engl J Med. 2008;24:359-390. 2. Bruix J et al. Lancet. 2017;389:56-66. 3. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_v40. Accessed January 24, 2018. 4. Lacouture ME et al. Oncologist. 2008;13:1001-1011. 5. McLellan B et al. Ann Oncol. 2015;26:2017-2026. 6. Brose MS et al. Semin Oncol. 2014;41:S1-S16. 7. Walko CM et al. Semin Oncol. 2014;41:S17-S28. Management General tips: • Educate patients about HFSR, and 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 Grade 1 Grade 2 Grade 3 • Employ grade 1 strategies • Consider clobetasol 0.05% ointment BID 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 • 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 • 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 Frequent, watery, bloody, or nocturnal stoolsSymptoms Stay as active as possible, because that will help regulate sleep Maintain activity Maintain normal work and social schedule Establish routine Take breaks as needed Take breaks Tell your medical team if activity is intolerable or fatigue worsens Always communicate Direct patient to notify medical team of diarrhea or abdominal distressPatient education ü Monitor bowel habits and report any increase in activity above normal ü Avoid spicy or fatty foods; plain, simple foods are best ü Avoid fruit and caffeine ü Maintain adequate fluid intake to avoid dehydration ü Monitor/manage electrolytes General management ü Loperamide is usually effective ü If loperamide is ineffective, consider diphenoxylate/atropine Medical interventions Diarrhea6 Hand–Foot Skin Reaction (Cont'd)3-5 Fatigue: Clinician Guidance for Patient Education7
- 5. Immuno-OncologyintheClinic:General GuidelinesforRecognizingandManaging Immune-MediatedAdverseReactions1-4 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. Blocking negative regulatory signals activates the immune system 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 How Do Checkpoint Inhibitors Work? What Are the Potential IMARs? Immune checkpoint inhibitors are associated with important clinical benefits, but can also lead to a unique spectrum of immune-mediated adverse reactions (IMARs) • Fatigue • Dermatologic (rash, pruritus, blisters, vitiligo, ulcers) • Gastrointestinal (diarrhea, enterocolitis, transaminitis, hepatitis, pancreatitis) • Endocrine (thyroiditis, hypophysitis, adrenal insufficiency) • Pulmonary (pneumonitis) • Hematologic • Cardiovascular • Ocular • Renal • Neurologic More common Any organ system can be affected at any time throughout the treatment course Less common Access the activity,“Teaming Up to Improve Outcomes in Advanced Hepatocellular Carcinoma: A Tumor Board Evaluating the Potential of Immunotherapy and Novel Targeted Approaches”at www.peerview.com/EMA40.
- 6. Access the activity,“Teaming Up to Improve Outcomes in Advanced Hepatocellular Carcinoma: A Tumor Board Evaluating the Potential of Immunotherapy and Novel Targeted Approaches”at www.peerview.com/EMA40. Immuno-OncologyintheClinic:General GuidelinesforRecognizingandManaging Immune-MediatedAdverseReactions1-4 PRACTICE AID CD: cluster of differentiation; CTLA-4: cytotoxic T-lymphocyte–associated protein 4; 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 January 12, 2018. 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 Management Principles 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 Resume immunotherapy if toxicity resolves to grade ≤1 q Discontinue immunotherapy q Hospitalization & multidisciplinary evaluation q High-dose corticosteroids (prednisone 1-2 mg/kg/d or equivalent) q Taper high-dose corticosteroids over ≥1 mo until toxicity resolves to grade ≤1 • If no improvement or progression, additional immunosuppressant treatment may be needed • If >4 weeks of immunosuppressants needed → administer antimicrobial/antifungal prophylaxis to prevent opportunistic infections Grade 1 (Minimal or no symptoms; diagnostic changes only) Grade 2 (Mild-to-moderate symptoms) Grade 3/4 (Severe or life-threatening symptoms)