t-vec seminar 2

Talimogene Laherparepvec: “T-VEC”:

Imlygic for Advanced MelanomaWilliam Joseph Helms

Doctoral Seminar Doctor of Pharmacy Candidate 2017

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.

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).

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 stepsNo growth factors neededPI3K-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) .

MutationsBRAF Mutation (MAPK)

(higher survival)NRAS (lower survival)

c-KITCDKN2A

(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).

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

StagingT- Thickness of tumorN- Number of Metastatic NodesM- Site of Tumor

Stage III: lymph node involvementStage 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 ).

Clinical PresentationBenign mole-------Dysplastic nevi

--------Melanoma lesionMid-region in menFeet and legs in womenWarning Signs: Itchy, red, bleeding,

swellingAsymmetry, Border, Color, Diameter,

Enlargement/EvolutionPalpable lymph nodesDiagnostic: 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).

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.

Standard of Treatment(Stages III and IV)

Stage III after surgery Interferon (IFN-Alpha2b)

Stage IV: dacarbazine temozolomideipilumumab 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 ).

Indication of T-VECT-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/AAEAAQAAAAAAAAaPAAAAJGExZTdlNmQzLTAzNGYtNDFkZi04NGIwLTU2ODBiODM5NDFiMg.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) .

(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/mLAdverse effects Flu-like symptoms

Pain at injection site

T-VEC Summary http://classroomclipart.com/images/gallery/Animations/Cartoons/virus_animation.gif

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_melanoma_needle_800x600.jpg

Follow-UpJM 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 melanomaB. 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 therapyD. 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 ).

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 <0.1mLHepatic Impairment No adjustmentRenal 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).

Administration

Route of Administration

Injection

Site TumorAdministered 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).

Storage-90 to -70 degrees

CelsiusKeep out of Light

Thaw vials as soon as possible before administration

RefrigerateDo 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).

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).

Methods Phase II Clinical Trial No control group Intent to Treat 50 patients:

10 patients Stage IIIC 40 patients Stage IV January 2006- February 200874% 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)).

Outcomes MeasuredPrimary Outcome:

Overall Response RateComplete Response + Partial ResponseCT 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)).

Methods


Inclusion Criteria Exclusion CriteriaStage IIIc or IV melanoma Pregnant or lactating

Tumor apparent, but not operable Antivirals <14 daysAble to Inject Tumor Major Surgery < 14 daysAge >18 years old Participation in Clinical Trial < 1

month before entryECOG < 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

Treatment RegimenJS1/34.5-/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)).

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


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 PercentMale 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%

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)).

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)).

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)).

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).

Strengths/LimitationsStrengths: 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).

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).

MethodsPhase III Randomized Clinical TrialOpen-Label StudyMay 2009- June 2011Multi-national trial: U.S., Canada, South Africa64 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).

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).

Methods: Patient PopulationScreened: 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= 245Randomly

Assigned: n= 436

Assigned to T-VEC: n=

295

Assigned to GM-CSF: n= 141Discontinued:

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

Methods: Statistical Analysis95% 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 TestPer-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)).

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 melanomaLDH <1.5x the ULN Bone or Cerebral metastases

ECOG <1

Results: Baseline Characteristics

(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 1, Baseline Demographics and Clinical Characteristics, (2782)).

Characteristics Percent (T-VEC) Percent (GM-CSF)Male 59% 55%

Female 41% 45%IIIB 8% 9%IIIC 22% 22%

IVM1a 25% 30%IVM1b 22% 18%IVM1c 23% 21%

Unknown <1% 0%ECOG 0 71% 69%ECOG1 28% 23%

Unknown ECOG 1% 9%LDH < ULN 90% 88%LDH> ULN 5% 4%

Unknown LDH 5% 9%

Results: Primary Endpoint and Overall Survival

(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)).

Primary Endpoint: Durable Response Rate

Durable Response Rate (DRR)

T-VEC: 16.3% vs. GM-CSF: 2.1%

P-Value <0.001

(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)).

Secondary Endpoint: Overall Response RateOverall Response Rate

over 95% CIT-VEC: 21.4- 31.5 vs. GM-

CSF: 1.9-9.5P-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)).

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)).

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).)

Adverse Effects of T-VECAdverse Events Percentage of Events in

the T-VEC groupPercentage 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))

Author’s Conclusions

T-VEC improved DRRT-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))

Strengths/LimitationsStrengths: 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).

Student ConclusionsPhase IIPhase 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).

Relevance to Pharmacy PracticeNew option/Combination

Implications of improved DRR

Revolutionary

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.

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

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.

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