Talimogene laherparepvec (T-VEC) is an oncolytic viral therapy genetically modified to selectively replicate in tumor cells. It is indicated for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. A clinical trial evaluated T-VEC in 50 patients with stage IIIc-IV melanoma and found an overall response rate of 26%, with durable responses in some patients and a manageable safety profile. T-VEC provides a new treatment option for advanced melanoma, though it has not been shown to improve overall survival or affect visceral metastases.
Talimogene laherparepvec (T-VEC, OncoVEX GM-CSF) phase 3 data in melanoma pre...Virotherapist
Phase 3 data from the OPTiM study in melanoma with talimogene laherparepvec presented as part of a talk on oncolytic immunotherapy at The Eighth International Conference on Oncolytic Virus Therapeutics, Oxford, UK,9-13 April 2014.
Types of immunotherapy
Oncology
cancer vaccines
adoptive T cell transfer
oncolytic viruses
monoclonal antibodies
cytokine
treatment of cancer with immunotherapy
The OncoScan(TM) platform for analysis of copy number and somatic mutations i...Lawrence Greenfield
The OncoScan microarray offers high-quality copy number, genotype, and somatic mutation data with whole-genome coverage and high resolution in cancer genes for use with challenging FFPE samples.
Talimogene laherparepvec (T-VEC, OncoVEX GM-CSF) phase 3 data in melanoma pre...Virotherapist
Phase 3 data from the OPTiM study in melanoma with talimogene laherparepvec presented as part of a talk on oncolytic immunotherapy at The Eighth International Conference on Oncolytic Virus Therapeutics, Oxford, UK,9-13 April 2014.
Types of immunotherapy
Oncology
cancer vaccines
adoptive T cell transfer
oncolytic viruses
monoclonal antibodies
cytokine
treatment of cancer with immunotherapy
The OncoScan(TM) platform for analysis of copy number and somatic mutations i...Lawrence Greenfield
The OncoScan microarray offers high-quality copy number, genotype, and somatic mutation data with whole-genome coverage and high resolution in cancer genes for use with challenging FFPE samples.
Perrotti A.P. L'Ematologia nel III° Millennio: cosa è cambiato e cosa bisogna...Gianfranco Tammaro
DOTT. PERROTTI ALESSIO P. (Sessione del 26/11/2015) - Convegno "Lunch Meeting al Pasteur: What's New In..." - dal 01/10/2015 al 10/12/2015 - Studio Pasteur - Viale Pasteur, 66 - Roma
Sito: www.asmad.net
Canale Youtube: https://www.youtube.com/channel/UCIggSJlnC77uDHuX5TUoFHg
Professor Akseli Hemminki presents on gene therapy and oncolytic virusesOncos Therapeutics
Presentation held on October 28, 2010, at Institute for Molecular Medicine for Finland (FIMM). The presentation includes information on a newest theory on immune response against the cancer tumor, mediated by oncolytic viruses
Normalization of Tumor Microenvironment in Hepatocellular Carcinoma
Oral presentation made at the 2016 World Gastrointestinal Cancer Symposium in Barcelona by Eric Raymond MD, PhD at Saint-Joseph Hospital. This presentation comprehensively updates drugs targeting the microenvironment such as antiangiogenic agents such as VEGF/VEGFR inhibitors, stromal signaling inhibitors such as HGF/c-MET, FGF19/FGFR4, TGF-beta targeting agents and immunotherapy such as PD1/PDL1 and CTLA4 inhibitors in hepatocellular carcinoma. This presentation is aimed at targeting physicians, scientists, students, and experts in pharmas who are interested in drug development in this area of oncology.
This slidedeck presents an up-to-date disease overview of BCC, reviews current treatment options in BCC, explains the hedgehog signaling pathway and its role in BCC, review recent data of the first-in-class hedgehog inhibitor, vismodegib, and other novel agents in clinical trials. Faculty will also review recently approved novel agents in melanoma, to include treatment planning and managing adverse events. Case studies will demonstrate the practical application of current and emerging clinical evidence for the treatment of BCC and melanoma. During the panel discussion, faculty will discuss the importance of cross-communication in the treatment planning process and strategies to optimize the continuum of care for patients with BCC.
Naiyer Rizvi, MD, Omid Hamid, MD, Solange Peters, MD, PhD, Thomas Powles, MBBS, MRCP, MD, and Nadeem Riaz, MD, MSc, prepared useful Practice Aids pertaining to immuno-oncology for this CME activity titled "Emerging Biomarkers, New Targets, and Rational Combinations: Are We on the Verge of the Next Generation of Immuno-Oncology?" For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2H2s92Y. CME credit will be available until June 17, 2019.
Richard Carvajal, MD presents Targeted Therapy for Uveal Melanoma and the Uveal Melanoma Clinical Research Landscape at the 2017 CURE OM Patient & Caregiver Symposium.
Perrotti A.P. L'Ematologia nel III° Millennio: cosa è cambiato e cosa bisogna...Gianfranco Tammaro
DOTT. PERROTTI ALESSIO P. (Sessione del 26/11/2015) - Convegno "Lunch Meeting al Pasteur: What's New In..." - dal 01/10/2015 al 10/12/2015 - Studio Pasteur - Viale Pasteur, 66 - Roma
Sito: www.asmad.net
Canale Youtube: https://www.youtube.com/channel/UCIggSJlnC77uDHuX5TUoFHg
Professor Akseli Hemminki presents on gene therapy and oncolytic virusesOncos Therapeutics
Presentation held on October 28, 2010, at Institute for Molecular Medicine for Finland (FIMM). The presentation includes information on a newest theory on immune response against the cancer tumor, mediated by oncolytic viruses
Normalization of Tumor Microenvironment in Hepatocellular Carcinoma
Oral presentation made at the 2016 World Gastrointestinal Cancer Symposium in Barcelona by Eric Raymond MD, PhD at Saint-Joseph Hospital. This presentation comprehensively updates drugs targeting the microenvironment such as antiangiogenic agents such as VEGF/VEGFR inhibitors, stromal signaling inhibitors such as HGF/c-MET, FGF19/FGFR4, TGF-beta targeting agents and immunotherapy such as PD1/PDL1 and CTLA4 inhibitors in hepatocellular carcinoma. This presentation is aimed at targeting physicians, scientists, students, and experts in pharmas who are interested in drug development in this area of oncology.
This slidedeck presents an up-to-date disease overview of BCC, reviews current treatment options in BCC, explains the hedgehog signaling pathway and its role in BCC, review recent data of the first-in-class hedgehog inhibitor, vismodegib, and other novel agents in clinical trials. Faculty will also review recently approved novel agents in melanoma, to include treatment planning and managing adverse events. Case studies will demonstrate the practical application of current and emerging clinical evidence for the treatment of BCC and melanoma. During the panel discussion, faculty will discuss the importance of cross-communication in the treatment planning process and strategies to optimize the continuum of care for patients with BCC.
Naiyer Rizvi, MD, Omid Hamid, MD, Solange Peters, MD, PhD, Thomas Powles, MBBS, MRCP, MD, and Nadeem Riaz, MD, MSc, prepared useful Practice Aids pertaining to immuno-oncology for this CME activity titled "Emerging Biomarkers, New Targets, and Rational Combinations: Are We on the Verge of the Next Generation of Immuno-Oncology?" For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2H2s92Y. CME credit will be available until June 17, 2019.
Richard Carvajal, MD presents Targeted Therapy for Uveal Melanoma and the Uveal Melanoma Clinical Research Landscape at the 2017 CURE OM Patient & Caregiver Symposium.
Chemotherapy 'vastly underutilized' in bladder cancerYael Waknine
A major weapon in the armamentarium against bladder cancer — neoadjuvant chemotherapy (NACT) — is rarely used in clinical practice, according to a large population study published online April 14 in Cancer.
Researchers analyzed 2944 patient records from the Ontario Cancer Registry, and found that a mere 4% of patients, on average, received standard-of-care NACT prior to cystectomy for muscle-invasive bladder cancer from 1994 to 2008.
Surprisingly, the popularity of adjuvant chemotherapy (ACT) rose over the same period; it was 16% from 1994 to 1998, 18% from 1999 to 2003, and 22% from 2004 to 2008.
Moreover, the controversial ACT was linked to benefits deemed "probably on the same order of magnitude" as NACT (all-cause mortality hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.62 - 0.81; cancer-related HR, 0.73; 95% CI, 0.64 - 0.84), after relevant patient- and disease-related characteristics were controlled for.
Cancer is a leading cause of death in developed countries. In this webcast Dr. Andreas Scherer will explain how personalized medicine can transform our approach to fighting this disease. He will also discuss current roadblocks and diagnostic challenges, and the pivotal role of Next Gen Sequencing to overcome these challenges.
The webcast will inform about best practices to design and implement a cancer testing pipeline: from sample preparation, to sequencing, to secondary and tertiary analysis of sequencing data. The goal is to rapidly identify clinically actionable data that allows an oncologist to quickly determine the best available treatment options.
The webcast will include demonstrations of the Golden Helix VarSeq software in the context of analyzing cancer gene panels and somatic mutations.
Cancer is a leading cause of death in developed countries. In this webcast Dr. Andreas Scherer will explain how personalized medicine can transform our approach to fighting this disease. He will also discuss current roadblocks and diagnostic challenges, and the pivotal role of Next Gen Sequencing to overcome these challenges.
The webcast will inform about best practices to design and implement a cancer testing pipeline: from sample preparation, to sequencing, to secondary and tertiary analysis of sequencing data. The goal is to rapidly identify clinically actionable data that allows an oncologist to quickly determine the best available treatment options.
The webcast will include demonstrations of the Golden Helix VarSeq software in the context of analyzing cancer gene panels and somatic mutations.
Cancer Immunotherapies (Focus on Melanoma & Lung Cancers)Zeena Nackerdien
Effective immunotherapy i.e. enlisting the patient’s own immune system to fight disease may mark a milestone in the fight against certain cancers. Three lymphocytes – T cells, B cells and NK-cells – involved in specific immune responses against cancers and other diseases. T cells recognize specific antigens via a T-cell antigen-receptor. The two main types of T cells, CD4- and CD8 T-cells, are categorized according to their respective CD4 and CD8 surface markers. The latter group includes cytotoxic T cells, also known as killer T lymphocytes. These cells kill invading pathogens or other disease-causing agents. Scientists discovered that a type of protein receptor, cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), prevented T cells from launching immune attacks [1]. In the early 1990s, another “brake” was discovered in dying T cells namely programmed death 1 or PD-1. The rationale underlying cancer immunotherapy is that exposing CTLA-4, PD-1 or using other appropriate immune-system-based therapies may enable the activation of the immune system to destroy cancer.
Genetically engineering a patient’s T cells to target tumor cells marked one of the promising turning points in cancer immunotherapy, particularly for certain blood cancers and solid tumors. Melanoma and lung cancer, two often-fatal diseases, are treatable in the early stages with surgery or other standards of care. However, some patients are diagnosed during the later stages of the disease or relapse with refractory/unresectable tumors. For these subgroups, the latest National Comprehensive Cancer Network (NCCN) tailored algorithms coupled with systemic treatment options, including immunotherapies, could potentially improve outcomes. Here, I summarize the latest approved immunotherapies mentioned in the NCCN guidelines, along with other examples of investigational agents such as monoclonal antibodies, cancer vaccines, and natural killer cells. Additional examples of targeted therapies, novel “druggable” and other immunotargets are presented in the section, ”Future Directions.”
Reference
1. Couzin-Frankel, J., Breakthrough of the year 2013. Cancer immunotherapy. Science, 2013. 342(6165): p. 1432-3.
Dr. Michael Morse from Duke University and Fight CRC’s Andi Dwyer discuss the state of the science and clinical care of Immunotherapy (IO); giving a glimpse of the contributions of the Fight CRC IO Workgroup.
2. Objectives
List the etiology, risk factors/epidemiology, pathophysiology, staging,
prognostic factors, and clinical presentation of melanoma.
Name the usual treatment options for Stage III to Stage IV melanoma.
Describe the mechanism of action, dosing/administration, adverse
effects, and monitoring parameters of T-VEC.
Discuss the methods, results, and strengths/weaknesses of T-VEC in
clinical trials.
Summarize the author’s conclusions, relevance to pharmacy practice,
and student’s conclusions to these studies.
3. Melanoma
Etiology:
Unknown, though there may be contributing factors from
the environment and patient
UVB>UVA
Epidemiology:
Number of new cases: “21.6 per 100,000 men and women
per year (2008-2012)”~SEER Stat Facts Sheet
Deaths: “2.7 per 100,000 men and women per year”~SEER
Stat Facts Sheet
(Cancer.gov. [Internet]. Rockville, Marlyand. National Cancer Institute. c2012. SEER Stat Facts Sheet: Melanoma of the Skin National Cancer Institute; 2012. [cited 28 Feb
2016]; [about 2 screens]. Available from: http://seer.cancer.gov/statfacts/html/melan.html).
(O’Bryant CL et. al. Pharmacotherapy: A Pathophysiologic Approach [Internet]. 9ed. New York (NY): McGraw-Hill; c2015. Chapter 116. Melanoma; 2014 [cited 2016 Feb 28];
[Etiology and Epidemiology]; AccessPharmacy. Available from: http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Sectionid=48811511).
4. Pathophysiology
Melanocytes (epidermal & non-cutaneous)
Epidermal-dermal junctions of the skin,
choroid of the eye, meninges, digestive
tract, respiratory tract
Skin (most common)
Stages; can skip steps
No growth factors needed
PI3K-AKT pathway
(O’Bryant CL, et. al. Pharmacotherapy: A Pathophysiologic Approach [Internet]. 9ed. New York (NY): McGraw-Hill; c2015. Chapter 116. Melanoma; 2014 [cited 2016 Feb 28];
[Pathogenesis]; AccessPharmacy. Available from: http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Sectionid=48811511) .
5. Mutations
BRAF Mutation (MAPK) (higher
survival)
NRAS (lower survival)
c-KIT
CDKN2A
(O’Bryant CL, et. al. Pharmacotherapy: A Pathophysiologic Approach [Internet]. 9ed. New York (NY): McGraw-Hill; c2015. Chapter 116. Melanoma; 2014 [cited 2016 Feb 28];
[Etiology and Epidemiology]; AccessPharmacy. Available from: http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Sectionid=48811511).
6. Melanoma: Risk Factors
(The Skin Cancer Foundation. [Internet]. New York (NY). The Skin Cancer Foundation; c2016. Skin Cancer Facts; 2016 [updated 2016 Feb 5]. [about 5 screens]. Available from: http://www.skincancer.org/skin-cancer-
information/skin-cancer-facts#men/women/ ).
(O’Bryant CL, et. al. Pharmacotherapy: A Pathophysiologic Approach [Internet]. 9ed. New York (NY): McGraw-Hill; c2015. Chapter 116. Melanoma; 2014 [cited 2016 Feb 28]; [Etiology and Epidemiology]; AccessPharmacy.
Available from: http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Sectionid=48811511).
Genetic Risk Factors Environmental Risk Factors
Caucasian Melanocytic moles (number)
Light Hair Color Severe sunburns (blistering)
Family history High Intensity Sun Exposure
(Isolated)
Younger Men (Deaths) UV light <age 18 (UVB)
Immunocompromised Immunocompromised
Individual History of Cancer
7. Staging
T- Thickness of tumor
N- Number of Metastatic Nodes
M- Site of Tumor
Stage III: lymph node involvement
Stage IV: metastasis
(Urba WJ, et. al.Harrison's Principles of Internal Medicine [Internet]. 19 e New York (NY): McGraw-Hill; c2015. Chapter 105, Table 105-3, Staging Criteria for Melanoma. [cited 2016
Feb 28]. [Prognostic Factors]. Available from: http://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=98709335 ).
(O’Bryant CL, Poust JC, DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach [Internet]. 9ed. New York (NY): McGraw-Hill; c2015. Chapter 116. Table 116-3, Melanoma Tumor,
Node, Metastasis Classification; 2014 [cited 2016 Feb 28]. [Staging and Prognostic Factors]; AccessPharmacy. Available from:
http://accesspharmacy.mhmedical.com/ViewLarge.aspx?figid=48830564 ).
8. Clinical Presentation
Benign mole-------Dysplastic nevi --------
Melanoma lesion
Mid-region in men
Feet and legs in women
Warning Signs: Itchy, red, bleeding, swelling
Asymmetry, Border, Color, Diameter,
Enlargement/Evolution
Palpable lymph nodes
Diagnostic: SLNB, CMP, LDH
(O’Bryant CL, et. al. Pharmacotherapy: A Pathophysiologic Approach [Internet]. 9ed. New York (NY): McGraw-Hill; c2015. Chapter 116. Melanoma; 2014 [cited 2016 Feb 28]; [Clinical Presentation, Side Bar: Clinical
Presentation: General, Local Signs and Symptoms, Systemic Signs and Symptoms, Laboratory Tests, Other Diagnostic Tests]; AccessPharmacy. Available from:
http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Sectionid=48811511).
9. Patient case
JM is a 25 yo blonde Caucasian male. He reports to his friend who is a
pharmacist that he has had a mole on his back since he was a kid, but recently
that it has been changing color and bleeding. What should the pharmacist do?
A. Tell JM to ignore it, “it will go away.”
B. Tell JM that if he is worried about melanoma, there is a good prognosis for
people who have melanoma, and catch it in the early stages, so it a good idea
for him to go see his PCP for a definitive diagnosis.
C. Tell JM to use an emollient moisturizer, because it’s just dry skin.
D. Tell JM that he has a low prognosis of survival.
10. Standard of Treatment
(Stages III and IV)
Stage III after surgery
Interferon (IFN-Alpha2b)
Stage IV:
dacarbazine
temozolomide
ipilumumab
vemurafenib
T-VEC(O’Bryant CL, et. al. Pharmacotherapy: A Pathophysiologic Approach [Internet]. 9ed. New York (NY): McGraw-Hill; c2015. Chapter 116. Melanoma; 2014 [cited 2016 Feb 28]; [Treatment]; AccessPharmacy. Available from:
http://accesspharmacy.mhmedical.com/ViewLarge.aspx?figid=48830564 ).
(Shead DA, et. al. NCCN Guidelines for Patients: Melanoma Version 1 [Internet]. Fort Washington, PA: National Comprehensive Cancer Network Foundation; c2014 [cited 2016 Feb 29]. Chart 6, Systemic Therapy for advanced or metastatic melanoma [p. 83].
Available from: http://www.nccn.org/patients/guidelines/melanoma/#83/z ).
(Shead DA, Hanisch LJ, Marlow L, Ho M, McMillian N, Kidney S, Clarke R. NCCN Guidelines for Patients: Melanoma Version 1 [Internet]. Fort Washington, PA: National Comprehensive Cancer Network Foundation; c2014 [cited 2016 Feb 29]. Chart 5.3.2.,
Primary and Adjuvant Treatment [p. 64]. Available from: http://www.nccn.org/patients/guidelines/melanoma/#64/z ).
Lexicomp [Internet]. Hudson, Ohio: Wolters Kluwer. 2016. Lexi-Drugs: dacarbazine; [cited 2016 Feb 28]; [about 2 screens]. Available from: https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6685
(Amgen.com. [Internet]. Thousand Oaks (CA). c2016. Imylgic Package Insert. 2016. [updated 2015 Oct] [cited 28 Feb 2016]; [page 1] Available from: http://pi.amgen.com/united_states/imlygic/imlygic_pi.pdf ).
11. Indication of T-VEC
T-VEC: Package Insert, “genetically modified
oncolytic viral therapy that is indicated for local
treatment of unresectable cutaneous, subcutaneous,
and nodal lesion patients with melanoma recurrent
after initial surgery.”
Package Insert, “Limitations of Use: Imylgic has not
been shown to improve overall survival or have an
effect on visceral metastases.”
https://media.licdn.com/mpr/mpr/AAEAAQAAAAAAAAaPAAAAJGExZ
TdlNmQzLTAzNGYtNDFkZi04NGIwLTU2ODBiODM5NDFiMg.jpg
(Amgen.com. [Internet]. Thousand Oaks (CA). c2016. Imylgic Package Insert. 2016. [updated 2015 Oct] [cited 28 Feb 2016]; [page 1] Available from:
http://pi.amgen.com/united_states/imlygic/imlygic_pi.pdf) .
12. (Lexicomp [Internet]. Hudson, Ohio: Wolters Kluwer. 2016. Lexi-Drugs: talimogene laherparepvec; [cited 2016 Feb 28]; [about 3 screens]. Available from: https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/5909571) .
Pharmacology of T-
VEC
Modified Herpes Simplex
Virus-1 (HSV-1) with two
proposed mechanisms of
action.
Selectivity Tumor cells
Site of Action Locally (Indication)
Strengths 1 million PFU/mL
100 million PFU/mL
Adverse effects Flu-like symptoms
Pain at injection site
T-VEC Summary
http://classroomclipart.com/images/gal
lery/Animations/Cartoons/virus_animati
on.gif
13. T-VEC Summary (Con’t)
Contraindications
Pregnancy or Immunocompromised
Who Should Use T-
VEC
Post-Surgery
(Labeled)
Mortality Overall Survival Not
Improved
Drug-Drug
Interactions
acyclovir
Company Amgen
(Lexicomp [Internet]. Hudson, Ohio: Wolters Kluwer. 2016. Lexi-Drugs: talimogene laherparepvec; [cited 2016 Feb 28]; [about 3 screens]. Available from: https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/5909571).
(Amgen.com. [Internet]. Thousand Oaks (CA). c2016. Imylgic Package Insert. 2016. [updated 2015 Oct] [cited 28 Feb 2016]; [page 1] Available from: http://pi.amgen.com/united_states/imlygic/imlygic_pi.pdf).
http://img.medscape.com/
news/2015/is_150430_mela
noma_needle_800x600.jpg
14. Follow-Up
JM saw his healthcare provider and Stage IV melanoma was confirmed. He has
recently had surgery, but the melanoma has come back, and this time it’s
inoperable. JM’s physician has suggested T-VEC. Which answer best describes the
role of T-VEC in the treatment of melanoma?
A. An injection administered in the earlier stages of melanoma
B. An injection administered by a healthcare provider that is indicated for use in
unresectable melanoma that is recurrent after surgery, that is generally used
in Stage III and IV melanoma, but is not the standard of treatment.
C. An injection that is first line therapy
D. An agent that is taken by the patient orally
(Lexicomp [Internet]. Hudson, Ohio: Wolters Kluwer. 2016. Lexi-Drugs: talimogene laherparepvec; [cited 2016 Feb 28]; [about 3 screens]. Available from:
https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/5909571).
(Amgen.com. [Internet]. Thousand Oaks (CA). c2016. Imylgic Package Insert. 2016. [updated 2015 Oct] [cited 28 Feb 2016]; [page 1] Available from:
http://pi.amgen.com/united_states/imlygic/imlygic_pi.pdf ).
15. Dosing
>5 cm < 4mL
>2.5 to 5 cm <2 mL
>1.5 to 2.5 cm <1 mL
> 0.5 to 1.5 cm <0.5 mL
<0.5 cm <0.1mL
Hepatic Impairment No adjustment
Renal Impairment No adjustment
(Lexicomp [Internet]. Hudson, Ohio: Wolters Kluwer. 2016. Lexi-Drugs: talimogene laherparepvec; [cited 2016 Feb 28]; [about 1 screens].
Available from: https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/5909571).
16. Administration
Route of
Administration
Injection
Site Tumor
Administered by Healthcare Providers
(Lexicomp [Internet]. Hudson, Ohio: Wolters Kluwer. 2016. Lexi-Drugs: talimogene laherparepvec; [cited 2016 Feb 28]; [about 2 screens]. Available from:
https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/5909571).
17. Storage
-90 to -70 degrees Celsius
Keep out of Light
Thaw vials as soon as
possible before
administration
Refrigerate
Do not refreeze
(Lexicomp [Internet]. Hudson, Ohio: Wolters Kluwer. 2016. Lexi-Drugs: talimogene laherparepvec; [cited 2016 Feb 28]; [about 2 screens]. Available from:
https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/5909571).
18. Clinical Trial 1: “Phase II Clinical Trial
of a Granulocyte-Macrophage Colony-
Stimulating Factor-Encoding, Second-
Generation Oncolytic Herpesvirus in
Patients with Unresectable Metastatic
Melanoma”
(Senzer NN, Kaufman HL, Amatruda T, Nemunaitis M, Reid T, Daniels G, Gonzalez R, Glaspy J, Whitman E, Harrington K, Goldsweig H, Marshall T, Love C, Coffin R, and Nemunaitis JJ. Phase II clinical trial of a granulocyte-macrophage colony-
stimulating factor-encoding, second generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol. 2009 Dec 1; 27(34): 5763-5771).
19. Methods
Phase II Clinical Trial
No control group
Intent to Treat
50 patients:
10 patients Stage IIIC
40 patients Stage IV
January 2006- February 2008
74% non-surgical therapy
Funding: Gregory Daniels, Biovex
(Senzer NN, et. al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol. 2009 Dec 1; 27(34):
5763-5771, Author’s Disclosures of Potential Conflicts of Interest (5771)).
20. Outcomes Measured
Primary Outcome:
Overall Response Rate
Complete Response + Partial Response
CT Scan
Secondary Outcomes:
Overall Survival
Safety
(Senzer NN, et. al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol. 2009 Dec 1;
27(34): 5763-5771 (5764)).
21. Methods
(Senzer NN, et. al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol. 2009
Dec 1; 27(34): 5763-5771 (5764)).
Inclusion Criteria Exclusion Criteria
Stage IIIc or IV melanoma Pregnant or lactating
Tumor apparent, but not operable Antivirals <14 days
Able to Inject Tumor Major Surgery < 14 days
Age >18 years old Participation in Clinical Trial < 1
month before entry
ECOG < 1 Bone Metastases
Life Expectancy > 4 months Tumor Swelling in areas that could
cause death
Recovery from prior therapy with > 4
weeks since chemotherapy or
radiotherapy
Autoimmune disease
Immunosuppressed
Adequate liver and renal function
22. Treatment Regimen
JS1/34.5-/47/granulocyte-macrophage colony stimulating factor:
HSV-1 (herpes simplex virus type 1)
Deleted ICP34.5- and ICP47
Treatment plan:
Initial: <4 mL of 106 pfu/mL
3 weeks later: 1 treatment of < 4 mL of 108 pfu/mL every 2
weeks for max of 24 treatments
(Non)-Compliant Patients: 1
(Senzer NN, et. al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol. 2009 Dec
1; 27(34): 5763-5771 (5764, 5767)).
23. Methods: Statistical Analysis and
Other Analyses
Overall Response Rate: RECIST (Response
Evaluation Criteria of Solid Tumors)
Response Rate of the Patients: Two-Stage Simon
Design
Overall Survival Rates: Kaplan Meier Curve
Median Survival Rates: Kaplan Meier Curve
Safety Profile: National Cancer Institute Common
Technology Criteria of Adverse Events
(Senzer NN, et. al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second generation oncolytic herpesvirus in patients with unresectable
metastatic melanoma. J Clin Oncol. 2009 Dec 1; 27(34): 5763-5771 (5764)).
24. Results: Baseline Characteristics
(Senzer NN, et. al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second generation oncolytic herpesvirus in patients
with unresectable metastatic melanoma. J Clin Oncol. 2009 Dec 1; 27(34): 5763-5771, Table 1, Baseline Demographic and Clinical Characteristics, (5765)).
Baseline Characteristics
Number Percent
Male 22 44%
Female 28 56%
White 48 96%
Asian 1 2%
Hispanic 1 2%
IIIc 10 20%
IV 40 80%
IVM1a 16 32%
IVM1b 4 8%
IVM1c 20 40%
ECOG PS 1 31 62%
ECOG PS 0 19 38%
25. Results: Primary Endpoint & Follow-up
Overall Number of Patients 50
Partial Response: Number
of Patients
5
Complete Response:
Number of Patients
8
Overall Response Rate:
Number of Patients
13
Overall Response Percent
of Patients
26%
Median Follow-up 18 months
(Senzer NN, et. al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin
Oncol. 2009 Dec 1; 27(34): 5763-5771, Table 2, Response Correlations, (5765)).
26. Results: Secondary Endpoint
(Senzer NN, et. al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol. 2009 Dec 1; 27(34):
5763-5771, Figure 5, Kaplan Meier Curves (A) Survival Curves for all patients enrolled and those who achieved complete response (CR), partial response (PR), or surgical CR (sCR), (B) Survival Curves by Disease State, (5770)).
27. Adverse Effects (Safety)
Most common (3 or more patients):
Fever (52%)
Chills (48%)
Fatigue (32%)
Nausea (30%)
Vomiting (20%)
Headache (20%)
(Senzer NN, et. al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin
Oncol. 2009 Dec 1; 27(34): 5763-5771 , Table 3, Safety Data (5767, 5770)).
28. Author’s Conclusions:
Overall Responses and safety
were shown in patients
Randomized, controlled
phase III study should be
performed
(Senzer NN, et. al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol. 2009 Dec 1;
27(34): 5763-5771).
29. Strengths/Limitations
Strengths:
Intent to Treat
Variety of sub-stages
Limitations:
• Talked about Overall Survival Rate in
Conclusion
• Did not report p-values
• No discussion of how compliance measured
• Lack of racial diversity
• Overall Survival took into account Surgical
Response
• Unclear on modified RECIST criteria
(Senzer NN, et. al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second generation oncolytic herpesvirus in patients with unresectable metastatic
melanoma. J Clin Oncol. 2009 Dec 1; 27(34): 5763-5771).
30. Clinical Trial 2: “Talimogene
Laherparevec Improves Durable
Response Rate in Patients with
Advanced Melanoma”
(Andtbacka R H.I., Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller Jr. WH, Zager JS, Ye Y, Yao
B, Li Ai, Doleman S, VanderWalde A, Gansert J, and Coffin RS. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1; 33(25): 2780-2788).
31. Methods
Phase III Randomized Clinical Trial
Open-Label Study
May 2009- June 2011
Multi-national trial: U.S., Canada, South Africa
64 centers
Independent Monitoring Committee
Funding: Amgen, Takeda Pharmaceuticals, Viralytics
(Andtbacka R H.I. et. al.. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1; 33(25): 2780-2788, Authors’ Disclosures of Potential Conflict of
Interest (Authors’ Disclosures of Potential Conflict of Interests).
32. Methods
682 total patients screened
436 patients randomized
Treatment Regimen: T-VEC vs. GM-CSF
T-VEC: Initial: 106 pfu/mL; 3 weeks later: 108 pfu/mL; 2 weeks
later: 108 pfu/mL
GM-CSF: 125 micrograms/m2 once daily for 14 days in 28 day cycles
Primary Outcome: Durable Response Rate (DRR)
Secondary Outcomes: Overall Survival (OS), Overall Response Rate (ORR)
Median follow up: 44.4 months
(Andtbacka R H.I. et. al.. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1; 33(25): 2780-2788).
33. Methods: Patient Population
Screened: N= 682
(Andtbacka R H.I. et. al.. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1; 33(25): 2780-2788, Figure 1
Deposition of Patients, (2781)).
Did not undergo
random assignment:
n= 245
Randomly Assigned:
n= 436
Assigned to T-
VEC: n= 295
Assigned to
GM-CSF: n= 141
Discontinued:
Adverse Events: n= 3
Included in Efficacy Analysis: n=
295
Included in Safety Analysis: n= 292
Included in Efficacy Analysis: n=
141
Included in Safety Analysis: n= 127
Discontinued:
Adverse Events: n= 11
34. Methods: Statistical Analysis
95% power, 90% power for planned 430
patients in groups randomized at a 2:1 ratio
respectively
Two-sided alpha of 0.05
Intent to Treat: Fisher’s Exact Test
Per-Protocol Population: Fisher’s Exact Test
Overall Survival: unadjusted log-rank test
(Andtbacka R H.I. et. al.. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1; 33(25): 2780-2788 (2782)).
35. Inclusion/Exclusion Criteria Criteria
(Andtbacka R H.I. et. al.. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1; 33(25): 2780-2788, (2781)).
Inclusion Criteria Exclusion Criteria
Age > 18 Antiviral agents; intermittent or
chronic treatment
Confirmed tumor, not surgically
removable
High dose steroids
Stage IIIB-Stage IV melanoma Primary ocular melanoma
Injectable lesions Primary mucosal melanoma
LDH <1.5x the ULN Bone or Cerebral metastases
ECOG <1
39. Secondary Endpoint: Overall
Response Rate
Overall Response Rate over
95% CI
T-VEC: 21.4- 31.5 vs. GM-CSF:
1.9-9.5
P-Value<0.001
No Alpha Calculated
(Andtbacka R H.I. et. al.. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1; 33(25): 2780-2788, Table 2, Efficacy, (2783)).
40. Results: Overall Survival Rate
(Andtbacka R H.I., et. al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1; 33(25): 2780-2788, Figure 4
Outcomes in Patient Subgroups, (2786)).
41. Results: Overall Survival Rate
(Andtbacka R H.I. et. al.. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1; 33(25): 2780-2788, Figure 4 Outcomes in Patient Subgroups,
(2786).)
42. Adverse Effects of T-VEC
Adverse Events Percentage of Events in
the T-VEC group
Percentage of Events in
the GM-CSF Group
Fatigue 50.3% 36.2%
Chills 48.6% 8.7%
Pyrexia 42.9% 8.7%
Nausea 35.6% 19.7%
Influenza-Like Illness 30.5% 15.0%
Injection Site Pain 27.7% 6.3%
Vomiting 21.2% 9.4%
Diarrhea 19.9% 10.2%
(Andtbacka R H.I. et. al.. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1; 33(25): 2780-2788, Table 3, Patient Incidence of AEs, (2787))
43. Author’s Conclusions
T-VEC improved DRR
T-VEC may help prevent
relapse or progression
New treatment option
(Andtbacka R H.I. et. al.. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1; 33(25): 2780-2788 (2787))
44. Strengths/Limitations
Strengths:
Randomized
Met Power
Multicenter
International Trial
Independent Monitoring
Committee
Intent to Treat
Variety of sub-stages
Limitations:
• ~67% of the patients
were in the T-VEC
treatment group
• Included some
patients with an
unknown ECOG and
LDH status
• Open-Label
(Andtbacka R H.I. et. al.. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1; 33(25): 2780-2788).
45. Student Conclusions
Phase II
Phase III: Efficacy and
Safety
Long-term effects
(Senzer NN, et. al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol. 2009 Dec 1;
27(34): 5763-5771).
(Andtbacka R H.I. et. al.. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1; 33(25): 2780-2788).
47. References
O’Bryant CL, Poust JC, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach [Internet]. 9ed. New York (NY): McGraw-Hill; c2015.
Chapter 116. Melanoma; 2014 [cited 2016 Feb 28]; [Chapter 116]; AccessPharmacy. Available from: <http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Sectionid=48811511>.
Cancer.gov. [Internet]. Rockville, Maryland. National Cancer Institute. c2012. SEER Stat Facts Sheet: Melanoma of the Skin National Cancer Institute; 2012. [cited 28 Feb 2016]; [about 2
screens]. Available from: http://seer.cancer.gov/statfacts/html/melan.html
The Skin Cancer Foundation. [Internet]. New York (NY). The Skin Cancer Foundation; c2016. Skin Cancer Facts; 2016 [updated 2016 Feb 5]. [about 5 screens]. Available from:
http://www.skincancer.org/skin-cancer-information/skin-cancer-facts#men/women/
Urba WJ, Curti BD, Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. Harrison's Principles of Internal Medicine [Internet]. 19 e New York (NY): McGraw-Hill; c2015. Chapter 105,
Table 105-3, Cancer of the Skin. [cited 2016 Feb 28]. [Prognostic Factors]. Available from: http://accessmedicine.mhmedical.com/content.aspx?bookid=1130&Sectionid=79729820.
48. References (Con’t)
Shead DA, Hanisch LJ, Marlow L, Ho M, McMillian N, Kidney S, Clarke R. NCCN Guidelines for Patients: Melanoma Version 1 [Internet]. Fort Washington, PA:
National Comprehensive Cancer Network Foundation; 2014 [cited 2016 Feb 29]. Available from: http://www.nccn.org/patients/guidelines/melanoma/#1/z
Lexicomp [Internet]. Hudson, Ohio: Wolters Kluwer. 2016. Lexi-Drugs: dacarbazine; [cited 2016 Feb 28]; [about 3 screens]. Available from:
https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/5909571
Amgen.com. [Internet]. Thousand Oaks (CA). c2016. Imylgic Package Insert. 2016. [updated 2015 Oct] [cited 28 Feb 2016]; [page 1] Available from:
http://pi.amgen.com/united_states/imlygic/imlygic_pi.pdf .
Lexicomp [Internet]. Hudson, Ohio: Wolters Kluwer. 2016. Lexi-Drugs: talimogene laherparepvec; [cited 2016 Feb 28]; [about 3 screens]. Available from:
https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/5909571
49. References (Con’t)
Senzer NN, Kaufman HL, Amatruda T, Nemunaitis M, Reid T, Daniels G, Gonzalez R, Glaspy J, Whitman E, Harrington K, Goldsweig H, Marshall T, Love C,
Coffin R, and Nemunaitis JJ. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second generation oncolytic herpesvirus
in patients with unresectable metastatic melanoma. J Clin Oncol. 2009 Dec 1; 27(34): 5763-5771.
Andtbacka R H.I., Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B,
Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller Jr. WH, Zager JS, Ye Y, Yao B, Li Ai, Doleman S, VanderWalde A,
Gansert J, and Coffin RS. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1; 33(25):
2780-2788
Fisher D, Geller A. Disproportionate burden of melanoma mortality in young US men. JAMA Dermatol 2013; 1-2.