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Physicians' Education Resource®, LLC, designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Acknowledgment of Commercial Support
This activity is supported by an educational grant from Amgen.
Advances In™: Metastatic Melanoma: Current Role and Future Potential of Oncolytic Viral Therapy
Release Date: June 30, 2019
Expiration Date: June 30, 2020
Media: Internet - based
Oncolytic viral therapy is an exciting area of development for the treatment of metastatic or advanced-stage melanoma. Therapeutic efficacy of oncolytic viruses is achieved through selective entry into cancer cells and aggressive replicative activity causing tumor lysis and promoting immune stimulation through release of cell debris and viral antigens in the tumor microenvironment. The first FDA approval for an oncolytic viral therapeutic for melanoma occurred in 2015 for talimogene laherparepvec (T-VEC) as monotherapy for unresectable or recurrent melanoma. Other viruses in early clinical trials for melanoma include the natural oncolytic herpes simplex virus, HF10; the bio-selected oncolytic and immunotherapeutic strain of coxsackievirus A21; and OBP-31, a novel, replication-competent, adenovirus serotype 5–based construct that incorporates a human telomerase reverse transcriptase gene promoter. Oncologists involved in the care of patients with melanoma may not be aware of current and emerging oncolytic viral therapies and may be uncertain how to integrate approved therapies into their clinical practice. By participating in this activity, clinicians will be better able to evaluate clinical data as they emerge regarding the efficacy and safety of novel oncolytic viral therapies.
In this activity, Advances in™ Metastatic Melanoma: Current Role and Future Potential of Oncolytic Viral Therapy, expert faculty will answer key questions regarding the evolution of oncolytic viral therapy and its growing potential in treating patients with mid to late-stage metastatic melanoma. Robert H.I. Andtbacka, MD, and Omid Hamid, MD, will discuss new data, present their perspectives on novel concepts that may affect the future, and guide participants on potential application to clinical practice.
Benefits of Participating
After participating in this activity, you should be better prepared to:
- Discuss the historical and current treatment landscape for advanced and metastatic melanoma
- Assess new viral therapeutics in melanoma and novel combination strategies with oncolytic viruses and existing immunotherapies
- Evaluate current and emerging data to select patients who may benefit from oncolytic viral therapy
- Monitor and mitigate adverse events of oncolytic viral therapy
- Describe the challenges of administering oncolytic viral therapy
CME Activity Table of Contents
- Module 1: Understanding Oncolytic Viral Therapy: Historical and Current Treatment Landscape
- Module 2: Clinical Trials of T-VEC as Monotherapy and as Combination With Immunotherapy
- Module 3: Oncolytic Viral Therapy in the Adjuvant and Neoadjuvant Setting
- Module 4: Novel Oncolytic Therapies in Clinical Trials
- Module 5: Final Remarks
- Posttest and Evaluation
Acknowledgement of Commercial Support
This activity is supported by an educational grant from Amgen.
Instructions for This Activity and Receiving Credit
This educational program is directed toward medical oncologists and surgical oncologists who treat patients with melanoma. Fellows, nurses, nurse practitioners, physician assistants, and other healthcare professionals (HCPs) involved in the treatment of melanoma are also invited to participate in this activity.
Upon successful completion of this activity, you should be better prepared to:
- Assess recently reported clinical trial data on the safety and efficacy of current and emerging oncolytic viral therapies for melanoma treatment
- Apply best practices to proactively identify and mitigate the impact of treatment-related toxicities in settings where patients with melanoma are managed
- Discuss emerging data on oncolytic viral therapy in combination therapy for the management of melanoma
- Integrate emerging data on oncolytic viral therapies into the treatment landscape for melanoma
Faculty, Staff, and Planners’ Disclosures
Chief, Translational Research and Immuno-oncology
Director, Cutaneous Malignancies
The Angeles Clinic and Research Institute
Director, Experimental Therapeutics
Cedars Sinai Medical Care Foundation
Los Angeles, CA
Disclosures: Grant research support: Amgen, Arcus, Astellas, AstraZeneca, Bristol-Myers Squibb, Celldex, CytomX, Genentech, GlaxoSmithKline, Immunocore, Incyte, Iovance, Merck, Merck-Serono, MedImmune, NextCure, Novartis, Parker Institute, Pfizer, Polynoma, Regeneron, Roche; consultant: Amgen, Bristol-Myers Squibb, Merck, Novartis, Roche; speakers bureau: Amgen, Array, Bristol-Myers Squibb, Genentech, Novartis, Sanofi/Regeneron.
Chief Medical Officer
Seven and Eight Biopharmaceuticals Inc
Disclosures: : Consultant: Aduro, Merck, Novartis, Pfizer; stock/shareholder: Merck, Seven and Eight Biopharmaceuticals. Dr Andtbacka reports that his spouse is a marketing lead for a pharmaceutical company.
Employee: Dr Andtbacka is an employee of Seven and Eight Biopharmaceuticals Inc. This company is an early-stage biotech start-up and does not currently produce, market, resell, or distribute healthcare goods or services consumed by patients.
The staff of Physicians' Education Resource®, LLC (PER®), have no relevant financial relationships with commercial interests to disclose.
Disclosure Policy and Resolution of Conflicts of Interest (COI)
As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME activity to disclose all relevant financial relationships with commercial interests. The ACCME defines relevant financial relationships as financial relationships in any amount occurring within the past 12 months that create a conflict of interest (COI).
Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.
Off-Label Disclosure and Disclaimer
This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition.
The opinions expressed in the content are solely those of the individual faculty members, and do not reflect those of PER® or any of the companies that provided commercial support for this program.
PER Pulse Recap™
1 of 3
This first of 3 PER Pulse™ Recaps focuses on a brief overview outlining the FDA approval of talimogene laherparepvec (T-VEC) as a first-in-class intralesional oncolytic viral therapy approved for stage IIIb-IVM1c melanoma and its ongoing exploration in advanced clinical trials as combination therapy with immune checkpoint inhibitors.
- T-VEC is a recombinant form of herpes simplex virus type 1 (HSV-1), and its approval is supported by data that emerged from the phase III OPTiM clinical trial comparing T-VEC with granulocyte macrophage-colony stimulating factor (GM-CSF) for the treatment of unresected stage IIIb/c and IV melanoma. This study showed a statistically significant improvement in durable response rate compared with GM-CSF in patients with unresectable stage IIIb-IV melanoma and a tolerable safety profile.1,2
- The specific mechanism of action of T-VEC is still under investigation but is believed to have both an oncolytic effect, targeting and killing local tumor cells at the injection site, and an immunotherapy effect by inducing a local systemic immune response.3
- The benefit of adjuvant therapy with oncolytic viruses in combination with checkpoint inhibitor therapy achieves 2 goals by increasing efficacy of checkpoint inhibitors and overcoming drug resistance.4 The upregulation of proinflammatory cytokines and antigen expression induced by viral therapy should enhance checkpoint blockade based on increased expression of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death-ligand 1 (PD-L1) in response to inflammation or tissue damage.5,6
- Adjunctive therapy with oncolytic virus plus CTLA-4 or programmed cell death 1 (PD-1) checkpoint inhibition has been shown to be superior to monotherapy with either ipilimumab (anti-CTLA-4) or nivolumab (anti-PD-1) checkpoint inhibitor therapies.7,8
- The KEYNOTE-034 study is evaluating pembrolizumab (anti-PD-1) with or without T-VEC in unresected melanoma. Patients will be treated with T-VEC plus pembrolizumab or placebo plus pembrolizumab until 2 years from the date of the first dose of pembrolizumab or at the end of treatment due to disappearance of injectable lesions, complete response, disease progression, or intolerance.9
- Andtbacka RH, Ross M, Puzanov I, et al. Patterns of clinical response with talimogene laherparepvec (T-VEC) in patients with melanoma treated in the OPTiM phase III clinical trial. Ann Surg Oncol. 2016;23(13):4169-4177. doi: 10.1245/s10434-016-5286-0.
- Ledford H. Cancer-fighting viruses win approval. Nature. 2015;526(7575):622-623. doi: 10.1038/526622a.
- Bommareddy PK, Patel A, Hossain S, Kaufman HL. Talimogene laherparepvec (T-VEC) and other oncolytic viruses for treatment of melanoma. Am J Clin Dermatol. 2017;18(1):1-15. doi: 10.1007/s40257-016-0238-9.
- Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375(9):819-829. doi: 10.1056/NEJMoa1604958.
- Kaplan DH, Shankaran V, Dighe AS, et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci. 1998;95(13):7556-7561. doi: 10.1073/pnas.95.13.7556.
- Dunn GP, Sheehan KC, Old LJ, Schreiber RD. IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression. Cancer Res. 2005;65(8):3447-3453. doi: 10.1158/0008-5472.CAN-04-4316.
- Puzanov I, Milhem MM, Minor D, et al. Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIb-IV melanoma. J Clin Oncol. 2016;34(22):2619-2626. doi: 10.1200/JCO.2016.67.1529.
- Long GV, Dummer R, Ribas A, et al. Efficacy analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma. J Clin Oncol. 2016;34(suppl 15; abstr 9568). doi: 10.1200/JCO.2016.34.15_suppl.9568.
- Pembrolizumab With or Without Talimogene Laherparepvec or Talimogene Laherparepvec Placebo in Unresected Melanoma (KEYNOTE-034). clinicaltrials.gov/ct2/show/NCT02263508. Updated December 19, 2018. Accessed July 10, 2019.
2 of 3
The success of talimogene laherparepvec (T-VEC) for advanced melanoma motivated the development of other oncolytic viruses; namely, PV-10 and coxsackievirus 21 (CVA21). This second of 3 PER Pulse™ Recaps focuses on data from ongoing clinical trials in various stages for these agents.
- PV-10 is a small molecule oncolytic immunotherapy that accumulates in the lysosome of cancer cells, causing cell death through acute autophagy and exposing antigenic tumor fragments to antigen-presenting cells.
- A phase III study is investigating single-agent intralesional PV-10 versus systemic chemotherapy with either dacarbazine or temozolomide or T-VEC for locally advanced cutaneous melanoma in patients who are not candidates for either targeted therapy or immune checkpoint inhibitor therapy.1
- CVA21 is a human enterovirus C that targets cells that express specific virus receptors, such as intercellular adhesion molecule 1 (ICAM-1), and is being studied in combination with checkpoint inhibitor therapy.2
- VLA-007 CALM is assessing clinical efficacy of CVA21 in terms of immune-related progression-free survival at 6 months, and the extension study (VLA-008 CALM Ext) will determine benefit of further treatment up to 48 weeks after the initial 10 doses of CVA21.3,4
- VLA-013 MITCI is a single-arm study of intratumoral CVA21 plus checkpoint inhibitor therapy with ipilimumab in advanced melanoma patients.5
- VLA-011 CAPRA is using a phase Ib design with the established dose of CVA21 plus pembrolizumab in advanced melanoma, with the hypothesis that CVA21 will amplify the T-cell potentiating effects of pembrolizumab.6
- PV-10 vs Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma. clinicaltrials.gov/ct2/show/NCT02288897. Updated December 7, 2018. Accessed July 10, 2019.
- Babiker HM, Riaz IB, Husnain M, Borad MJ. Oncolytic virotherapy including Rigvir and standard therapies in malignant melanoma [erratum in Oncolytic Virother. 2019;8:1. doi: 10.2147/OV.S196145]. Oncolytic Virother. 2017;6:11-18. doi: 10.2147/OV.S100072.
- A Study of Intratumoral CAVATAK in Patients With Stage IIIc and Stage IV Malignant Melanoma (VLA-007 CALM) (CALM). clinicaltrials.gov/ct2/show/NCT01227551. Updated July 3, 2019. Accessed July 12, 2019.
- CAVATAK in Patients With Stage IIIc or Stage IV Malignant Melanoma to Extend Dosing to 48 weeks (VLA-008 CALM Ext) (CALMext). clinicaltrials.gov/ct2/show/NCT01636882. Updated July 9, 2019. Accessed July 12, 2019.
- Intratumoral CAVATAK (CVA21) and Ipilimumab in Patients With Advanced Melanoma (VLA-013 MITCI) (MITCI). clinicaltrials.gov/ct2/show/NCT02307149. Updated May 27, 2019. Accessed July 12, 2019.
- Intratumoral CAVATAK (CVA21) and Pembrolizumab in Patients With Advanced Melanoma (VLA-011 CAPRA) (CAPRA). clinicaltrials.gov/ct2/show/NCT02565992. Updated June 21, 2019. Accessed July 12, 2019.
3 of 3
This third of 3 PER Pulse™ Recaps focuses on recent phase II clinical trial activity involving the potential of oncolytic viral therapy with talimogene laherparepvec (T-VEC) and HF10 in the neoadjuvant setting of melanoma treatment.
- The goal of neoadjuvant treatment in the melanoma setting is to shrink tumors prior to surgery to improve both surgical and survival outcomes. Various therapies can be used in the neoadjuvant setting, including biochemotherapy consisting of a chemotherapy agent and interferon-alfa or interleukin 2; checkpoint inhibitor therapy (ie, CTLA-4 and PD-1 inhibitors); and targeted therapy with BRAF/MEK inhibitors.1 Oncolytic viral therapy is being investigated in ongoing studies of melanoma.
- T-VEC is being studied as neoadjuvant therapy versus surgery alone in patients with completely resectable stage IIIb, IIIc, or IVM1a melanoma. In the T-VEC-plus-surgery cohort, patients will receive 6 doses followed by surgical resection. The cohort undergoing surgery alone will receive adjuvant systemic therapy and/or radiotherapy at some point following surgical resection.2
- A neoadjuvant trial of nivolumab in combination with HF10 oncolytic viral therapy in resectable stage IIIb/c and IVM1a melanoma is ongoing.3 HF10 is an attenuated herpes simplex virus type 1 from the same family as T-VEC, with a natural deletion of UL56 and the latency-associated transcript.4
- Neoadjuvant therapy with a combination of the programmed death receptor 1 (PD-1) checkpoint inhibitor, nivolumab, and HF10 oncolytic viral therapy is being examined in resectable advanced stage melanoma. All patients will receive nivolumab and HF10 prior to surgery and will continue nivolumab therapy every 28 days after surgery for up to 1 year. All eligible tumors will be treated with HF10, except one that will be used as an untreated control lesion.5
- McCullagh L, O’Donnell H, Barrett S, et al. Neoadjuvant treatment for malignant and metastatic cutaneous melanoma.Cochrane Database Syst Rev. 2018(3):CD012974. doi: 10.1002/14651858.CD012974.
- Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Melanoma. clinicaltrials.gov/ct2/show/NCT02211131. Updated May 14, 2019. Accessed July 10, 2019.
- Neoadjuvant Trial of Nivolumab in Combination With HF10 Oncolytic Viral Therapy in Resectable stage IIIB, IIIC, IVM1a melanoma. clinicaltrials.gov/ct2/show/NCT03259425. Updated July 3, 2019. Accessed July 10, 2019.
- Eissa IR, Naoe Y, Bustos-Villalobos I, et al. Genomic signature of the natural oncolytic herpes simplex virus HF10 and its therapeutic role in preclinical and clinical trials. Front Oncol. 2017;7:149. doi: 10.3389/fonc.2017.00149.
- Neoadjuvant Trial of Nivolumab in Combination With HF10 Oncolytic Viral Therapy in Resectable Stage IIIB, IIIC, IVM1a Melanoma. clinicaltrials.gov/ct2/show/record/NCT03259425. Updated July 3, 2019. Accessed July 10, 2019.
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