A practical guide to the handling and administration of talimogene laherparepvec in Europe

Figures & data

Figure 1 Proposed mechanism of action of talimogene laherparepvec. Copyright of Amgen Inc., reproduced with permission.

Abbreviations: GM-CSF, granulocyte–macrophage colony-stimulating factor; HSV-1, herpes simplex virus-1; MHC, major histocompatibility complex; TCR, T cell receptor; TDAs, tumor-derived antigens; T-VEC, talimogene laherparepvec.

Table 1 Characteristics/modifications of talimogene laherparepvec and their impact on safety and antitumor response

Characteristic/modification	Rationale
Deletion of ICP34.5 (neurovirulence factor)	Mediates tumor-selective replication
Deletion of ICP47	Restores antigen presentation (enhances the antitumor immune response)
Early/increased US11 expression	Increases replication of ICP34.5-deleted HSV
Insertion of human GM-CSF gene	Enhances the antitumor immune response
Use of a new HSV-1 strain (JS1)	Improves tumor cell lysis
Intact thymidine kinase gene	Fully susceptible to acyclovir and ganciclovir

Note: Data from Liu et al.²³

Abbreviations: GM-CSF, granulocyte–macrophage colony-stimulating factor; HSV-1, herpes simplex virus-1; ICP, infected cell protein.

Table 2 Summary of key efficacy data from OPTiM

	ITT (stage IIIB–IVM1c)		Stage IIIB–IVM1a subseta
	T-VEC (n=295)	GM-CSF (n=141)	T-VEC (n=163)	GM-CSF (n=86)
Durable response rate, n (%)	48 (16.3)	3 (2.1)	41 (25.2)	1 (1.2)
Treatment difference, % (95% CI)	14.1 (9.3–19.0)		24.0 (17.0–31.0)
P-value	<0.0001		<0.0001b
Best response, n (%)
Complete response	32 (10.8)	1 (0.7)	27 (16.6)	0 (0.0)
Partial response	46 (15.6)	7 (5.0)	39 (23.9)	2 (2.3)
Objective response rate, % (95% CI)	26.4 (21.4–31.5)	5.7 (1.9–9.5)	40.5 (32.9–48.4)	2.3 (0.3–8.1)
P-value	<0.0001b		<0.0001b
Overall survival, median – months (95% CI)	23.3 (19.5–29.6)	18.9 (16.0–23.7)	41.1 (30.6–NR)	21.5 (17.4–29.6)
HR (95% CI)	0.79 (0.62–1.00)		0.57 (0.40–0.80)
P-value	0.051		<0.001b

Notes:

a Analyses are exploratory for this subpopulation.

b Descriptive P-value. Data from Andtbacka et al¹⁹ and Harrington et al.²⁸

Abbreviations: CI, confidence interval; GM-CSF, granulocyte–macrophage colony-stimulating factor; HR, hazard ratio; ITT, intent-to-treat; NR, not reached; OPTiM, Oncovex (GM-CSF) Pivotal Trial in Melanoma; T-VEC, talimogene laherparepvec.

Figure 2 Overview of the talimogene laherparepvec handling and administration process.

Abbreviations: PFU, plaque-forming units; Q2W, once every 2 weeks.

Table 3 Talimogene laherparepvec dosing schedule, including injection volumes based on lesion size²²

Treatment visit	Treatment interval	Dose concentration (PFU/mL)	Prioritization of lesions to be injected	Injection volume based on lesion size
				Lesion sizea	Injection volume
Initial	–	10^6 (1 million)	Inject largest lesion(s) first Prioritize injection of remaining lesions based on lesion size until maximum injection volume is reached
Second	3 weeks after initial treatment	10^8 (100 million)	Inject any new lesions (lesions may have developed since initial treatment) Prioritize injection of remaining lesions based on lesion size until maximum injection volume is reached	>5 cm >2.5–5 cm >1.5–2.5 cm >0.5–1.5 cm	Up to 4 mL Up to 2 mL Up to 1 mL Up to 0.5 mL
All subsequent visitsb	2 weeks after previous treatment	10^8 (100 million)	Inject any new lesions (lesions may have developed since initial treatment) Prioritize injection of remaining lesions based on lesion size until maximum injection volume is reached	≤0.5 cm	Up to 0.1 mL

Notes:

a Longest diameter.

b Including reinitiation of treatment.

Abbreviation: PFU, plaque-forming units.

Table 4 Maximum storage times for talimogene laherparepvec²²

Storage temperature	Maximum storage time for thawed talimogene laherparepvec in syringe
	10^6 (1 million) PFU/mL	10^8 (100 million) PFU/mL
2°C to 8°C	8 hours	16 hours
Up to 25°C	2.5 hours	4 hours
Storage temperature	Maximum cumulative storage timea for thawed talimogene laherparepvec
	10^6 (1 million) PFU/mL	10^8 (100 million) PFU/mL
2°C to 8°C	31 hours	6 weeks (42 days)
Up to 25°C	17 hours	85 hours

Note:

a In vial plus storage time in syringe.

Abbreviation: PFU, plaque-forming units.

Figure 3 Diagram showing intralesional injection of talimogene laherparepvec into (A) cutaneous, (B) subcutaneous, and (C) nodal lesions. Copyright of Amgen Inc., reproduced with permission.²²

Notes: Using a single injection point, talimogene laherparepvec should be injected and redirected along multiple tracks as far as the radial reach of the needle allows to achieve complete and even dispersion within the lesion. The needle should be withdrawn slowly to avoid leakage.

Figure 4 Key points for avoiding spreading talimogene laherparepvec – advice for patients.

Table 5 Evaluation of response by immune-related response criteria (irRC), World Health Organization (WHO) criteria, and Response Evaluation Criteria In Solid Tumors (RECIST)

	irRC^Citation40	WHO^Citation42	RECIST^Citation43
Method	Sum of products of the two longest diameters in perpendicular dimensions (bidimensional)	Sum of products of the two longest diameters in perpendicular dimensions (bidimensional)	Sum of longest diameters (unidimensional)
Number of measured lesions	Index lesions (maximum 5 per organ; 10 visceral lesions and 5 cutaneous lesions) plus new, measurable lesions (≥5×5 mm; up to 5 new lesions per organ; 5 new cutaneous lesions and 10 visceral lesions)	All lesions	Target lesions (maximum 2 per organ; 5 in total)
New, measurable lesions	≥5×5 mm; incorporated into tumor burden	≥5×5 mm; always represent PD	≥10 mm; always represent PD
New non-measurable lesions	<5×5 mm; do not define PD (but precludes CR)	<5×5 mm; always represent PD	<10 mm; always represent PD
Non-index lesions	Contribute to defining CR	Changes contribute to defining best overall response of CR, PR, SD, and PD	Changes contribute to defining best overall response of CR, PR, SD, and PD
Response
CR	Disappearance of all lesions in two consecutive observations not less than 4 weeks apart	Disappearance of all known disease, confirmed at 4 weeks	Disappearance of all known disease, confirmed at 4 weeks
PR	≥50% decrease in tumor burden compared with baseline in two consecutive observations not less than 4 weeks apart	≥50% decrease, confirmed at 4 weeks	≥30% decrease, confirmed at 4 weeks
SD	Neither PR nor PD criteria met	Neither PR nor PD criteria met	Neither PR nor PD criteria met
PD	≥25% increase in tumor burden compared with nadir (at any single time point) in two consecutive observations at least 4 weeks apart	≥25% increase, no CR, PR, or SD documented before increased disease, new lesion(s), ≥25% increase in 1 lesion	≥20% increase, no CR, PR, or SD documented before increased disease, new lesion(s)

Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 5 Case studies demonstrating standard and ultrasound-guided administration of talimogene laherparepvec. The yellow oval indicates the injected lesion under ultrasound guidance. The patients provided written informed consent for the publication of the case details and any accompanying images.

Abbreviation: CR, complete response.

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